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Sample records for ace inhibitors improve

  1. ACE inhibition can improve orthostatic proteinuria associated with nutcracker syndrome.

    PubMed

    Ha, Tae-Sun; Lee, Eun-Ju

    2006-11-01

    Left renal vein entrapment syndrome (nutcracker syndrome) was documented by magnetic resonance angiography (MRA) as a cause of orthostatic proteinuria in a 14-year-old girl female adolescent. Because of continuous proteinuria we performed a left renal biopsy which showed moderate mesangial hypercellularity. Her overt orthostatic proteinuria disappeared after a treatment of angiotensin-converting enzyme (ACE) inhibition. Nutcracker syndrome remains a rare but important cause of elevated protein excretion, which can induce mesangial changes and be improved by ACE inhibitor treatment.

  2. Unraveling the Pivotal Role of Bradykinin in ACE Inhibitor Activity.

    PubMed

    Taddei, Stefano; Bortolotto, L

    2016-10-01

    Historically, the first described effect of an angiotensin converting enzyme (ACE) inhibitor was an increased activity of bradykinin, one of the substrates of ACE. However, in the subsequent years, molecular models describing the mechanism of action of ACE inhibitors in decreasing blood pressure and cardiovascular risk have focused mostly on the renin-angiotensin system. Nonetheless, over the last 20 years, the importance of bradykinin in regulating vasodilation, natriuresis, oxidative stress, fibrinolysis, inflammation, and apoptosis has become clearer. The affinity of ACE appears to be higher for bradykinin than for angiotensin I, thereby suggesting that ACE inhibitors may be more effective inhibitors of bradykinin degradation than of angiotensin II production. Data describing the effect of ACE inhibition on bradykinin signaling support the hypothesis that the most cardioprotective benefits attributed to ACE inhibition may be due to increased bradykinin signaling rather than to decreased angiotensin II signaling, especially when high dosages of ACE inhibitors are considered. In particular, modulation of bradykinin in the endothelium appears to be a major target of ACE inhibition. These new mechanistic concepts may lead to further development of strategies enhancing the bradykinin signaling. PMID:27260014

  3. ACE Inhibitor in the treatment of cutaneous and lymphatic sarcoidosis.

    PubMed

    Kaura, Vinod; Kaura, Samantha H; Kaura, Claire S

    2007-01-01

    Angiotensin-converting enzyme is used as a marker for sarcoid activity. We describe a case of remission of cutaneous and lymphatic sarcoidosis in a patient treated with an ACE inhibitor for congestive heart failure and hypertension; the remission has continued over 4 years of follow-up. Because this is a report of only one case, there is a possibility of sampling error. Whether the patient's remission in this case was a serendipitous spontaneous remission that happened to occur during ACE inhibitor therapy or whether ACE inhibitor therapy can play a role in the treatment of sarcoidosis needs to be determined in a large clinical trial.

  4. Antihypertensive treatment in renal transplant patients--is there a role for ACE inhibitors?

    PubMed

    Hausberg, M; Kosch, M; Hohage, H; Suwelack, B; Barenbrock, M; Kisters, K; Rahn, K H

    2001-01-01

    During the past two decades great progress was achieved with regards to short-term kidney graft survival. However, long-term graft survival did not improve similarly. Many factors contribute to chronic graft nephropathy eventually resulting in late graft loss, among these arterial hypertension is of major importance. In patients with chronic renal disease of diabetic and non-diabetic origin, angiotensin converting enzyme inhibitors have been convincingly shown to slow the progression of renal failure. The achieved nephroprotection correlates with the reduction of proteinuria by ACE inhibitor treatment. Also in renal transplant patients, ACE inhibitors have been shown unequivocally to reduce urinary protein excretion. The prevention of hyperfiltration, particular in the context of a reduced number of functional nephrons in patients with chronic graft nephropathy, could be important to prolong graft survival after renal transplantation. Moreover, ACE inhibitors may exert beneficial effects on immunologic processes contributing to chronic graft nephropathy. Many studies published in the last decade show convincingly that ACE inhibitors are safe and effective for the treatment of hypertension in renal allograft recipients. However, no data exist so far showing that ACE inhibitors are superior to other antihypertensive drugs in renal transplant patients and that they prolong graft survival. Studies investigating this issue are warranted. Apart from effects on the graft, ACE inhibitors may improve alterations of the cardiovascular system generally observed in renal transplant patients, such as structural alterations of large arteries, left ventricular hypertrophy, disturbed mechanical vessel wall properties and endothelial dysfunction. Therefore, angiotensin converting enzyme inhibitors could reduce cardiovascular morbidity and mortality in kidney transplant patients.

  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. Cutaneous allergy to insulin: could statins and ACE inhibitors play a role? A case report.

    PubMed

    Pitrola, D; MacIver, C; Mallipedhi, A; Udiawar, M; Price, D E; Stephens, J W

    2014-04-01

    Insulin allergy is rare. Both statins and angiotensin converting enzyme (ACE) inhibitors may cause local urticarial skin reactions and have been implicated to precipitate local reactions to insulin. We describe a case of a localised urticarial allergic reaction related to insulin use in a patient co-prescribed an ACE inhibitor and statin. PMID:24534533

  8. Effect of ace inhibitors and TMOF on growth, development, and trypsin activity of larval Spodoptera littoralis.

    PubMed

    Lemeire, Els; Borovsky, Dov; Van Camp, John; Smagghe, Guy

    2008-12-01

    Angiotensin converting enzyme (ACE) is a zinc metallopeptidase capable of cleaving dipeptide or dipeptideamide moieties at the C-terminal end of peptides. ACE is present in the hemolymph and reproductive tissues of insects. The presence of ACE in the hemolymph and its broad substrate specificity suggests an important role in processing of bioactive peptides. This study reports the effects of ACE inhibitors on larval growth in the cotton leafworm Spodoptera littoralis. Feeding ACE inhibitors ad lib decreased the growth rate, inhibited ACE activity in the larval hemolymph, and down-regulated trypsin activity in the larval gut. These results indicate that S. littoralis ACE may influence trypsin biosynthesis in the larval gut by interacting with a trypsin-modulating oostatic factor (TMOF). Injecting third instar larvae with a combination of Aea-TMOF and the ACE inhibitor captopril, down-regulated trypsin biosynthesis in the larval gut indicating that an Aea-TMOF gut receptor analogue could be present. Injecting captopril and enalapril into newly molted fifth instar larvae stopped larval feeding and decreased weight gain. Together, these results indicate that ACE inhibitors are efficacious in stunting larval growth and ACE plays an important role in larval growth and development. PMID:18949805

  9. Statins, ACE inhibitors and ARBs in cardiovascular disease.

    PubMed

    Montecucco, Fabrizio; Mach, François

    2009-06-01

    Atherosclerotic cardiovascular disease (CVD) is the main cause of death in developed and developing countries. It is well accepted that several diseases - including hypertension, dyslipidemia and diabetes mellitus - increase CVD. More recently also chronic inflammatory diseases, such as rheumatoid arthritis, have been shown to accelerate CVD. This association further supports a responsible role for inflammatory processes in all stages of CVD pathophysiology. Clinically, CVD ranges through different acute and chronic syndromes with ischemic symptoms in distal tissues, including heart, cerebral region or peripheral arteries. Several treatments for reducing CVD are under investigation. In this review we focus on statins, angiotensin-converting-enzyme (ACE) inhibitors, and angiotensin-II receptor blockers (ARBs), updating therapeutic evidence from the last clinical trials with particular relevance to diabetic patients. PMID:19520311

  10. Risk-benefit ratio of angiotensin antagonists versus ACE inhibitors in end-stage renal disease.

    PubMed

    Sica, D A; Gehr, T W; Fernandez, A

    2000-05-01

    The effective treatment of hypertension is an extremely important consideration in patients with end-stage renal disease (ESRD). Virtually any drug class--with the possible exception of diuretics--can be used to treat hypertension in the patient with ESRD. Despite there being such a wide range of treatment options, drugs which interrupt the renin-angiotensin axis are generally suggested as agents of choice in this population, even though the evidence in support of their preferential use is quite scanty. ACE inhibitors, and more recently angiotensin antagonists, are the 2 drug classes most commonly employed to alter renin-angiotensin axis activity and therefore produce blood pressure control. ACE inhibitor use in patients with ESRD can sometimes prove an exacting proposition. ACE inhibitors are variably dialysed, with compounds such as catopril, enalapril, lisinopril and perindopril undergoing substantial cross-dialyser clearance during a standard dialysis session. This phenomenon makes the selection of a dose and the timing of administration for an ACE inhibitor a complex issue in patients with ESRD. Furthermore, ACE inhibitors are recognised as having a range of nonpressor effects that are pertinent to patients with ESRD. Such effects include their ability to decrease thirst drive and to decrease erythropoiesis. In addition, ACE inhibitors have a unique adverse effect profile. As is the case with their use in patients without renal failure, use of ACE inhibitors in patients with ESRD can be accompanied by cough and less frequently by angioneurotic oedema. In the ESRD population, ACE inhibitor use is also accompanied by so-called anaphylactoid dialyser reactions. Angiotensin antagonists are similar to ACE inhibitors in their mechanism of blood pressure lowering. Angiotensin antagonists are not dialysable and therefore can be distinguished from a number of the ACE inhibitors. In addition, the adverse effect profile for angiotensin antagonists is remarkably bland

  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. Tissue ACE inhibition improves microcirculation in remote myocardium after coronary stenosis: MR imaging study in rats.

    PubMed

    Hiller, Karl-Heinz; Ruile, Philipp; Kraus, Günter; Bauer, Wolfgang R; Waller, Christiane

    2010-12-01

    ACE inhibition has been shown to improve left ventricular (LV) and myocardial blood flow. Previous data regarding changes in capillary density and angiogenesis during ACE inhibition are controversial. The aim of the following study was to determine myocardial microcirculation and heart function in the rat after coronary stenosis using non invasive MR imaging techniques. MR spin labeling and cine techniques have been performed in female Wistar rats 2weeks after coronary artery stenosis. In one group, animals were treated with quinapril in a dose of 6mg/kg/day. Perfusion, relative blood volume (RBV), LV mass and function were determined non-invasively 2weeks after treatment. Finally, fibrosis and capillary density were analyzed histologically. Additionally, hemodynamic measurements were realized in a further group in order to calculate systemic vascular resistance (SVR). Quinapril resulted in a significant increase in perfusion at rest in the remote and the poststenotic myocardium with improved systolic function and a decrease in SVR compared to the non treated control group. Additionally, maximum perfusion and RBV were slightly elevated whereas capillary density was unchanged among the groups. MRI allows for non-invasive quantification of functional microcirculation and heart function. In addition to the well known effect of ACE inhibition on systolic function, treatment with the tissue specific ACE inhibitor quinapril revealed an important microvascular improvement, especially at arteriolar level. These findings may support the use of tissue ACE inhibitors to improve cardiac microcirculation after ischemia.

  13. Evaluation of renal function in elderly heart failure patients on ACE inhibitors

    PubMed Central

    Jolobe, O

    1999-01-01

    A total of 187 heart failure patients aged 65-92 years, with pretreatment serum creatinine levels below 200 µmol/l, were monitored for more than 12 months on angiotensin-converting enzyme (ACE) inhibitor therapy. Optimal ACE inhibitor dosage was found in 27% of patients, while a significant deterioration in renal function, characterised by >20% increase in serum creatinine to >200 µmol/l, occurred in 25 patients. This was most closely attributable to ACE inhibitor treatment per se (implying co-existence of bilateral renal artery stenosis) in only four cases, including one in whom renal deterioration was reproducible on inadvertent rechallenge. In the other 21, renal deterioration was attributable to diuretic-related blood volume depletion (two cases), nonsteroidal anti-inflammatory drugs (two cases), obstructive uropathy (two cases), preterminal renal shutdown (two cases), and the interaction between diuretic and ACE inhibitor dosage (including long-acting vs short-acting drugs) (13 cases). This study could serve as the basis for future comparisons of ACE-inhibitor-related renal deterioration when the entry requirement is optimal ACE inhibitor dosage.


Keywords: heart failure; elderly patients; angiotensin-converting enzyme inhibitors; renal deterioration PMID:10533630

  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. Tissue and plasma angiotensin converting enzyme and the response to ACE inhibitor drugs.

    PubMed Central

    MacFadyen, R J; Lees, K R; Reid, J L

    1991-01-01

    1. There is a body of circumstantial and direct evidence supporting the existence and functional importance of a tissue based RAS at a variety of sites. 2. The relation between circulatory and tissue based systems is complex. The relative importance of the two in determining haemodynamic effects is unknown. 3. Despite the wide range of ACE inhibitors already available, it remains unclear whether there are genuine differences related to tissue specificity. 4. Pathological states such as chronic cardiac failure need to be explored with regard to the contribution of tissue based ACE activities in generating acute and chronic haemodynamic responses to ACE inhibitors. 5. The role of tissue vs plasma ACE activity may be clarified by study of the relation between drug concentration and haemodynamic effect, provided that the temporal dissociation is examined and linked to circulating and tissue based changes in ACE activity, angiotensin peptides and sympathetic hormones. PMID:1849731

  16. 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.

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

    PubMed Central

    Kumar, Sandeep; Dietrich, Nicholas; Kornfeld, Kerry

    2016-01-01

    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 Caenorhabdtitis 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

  18. 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

  19. Does the addition of losartan improve the beneficial effects of ACE inhibitors in patients with anterior myocardial infarction? A pilot study

    PubMed Central

    Di, P; Bucca, V; Scalzo, S; Cannizzaro, S; Giubilato, A; Paterna, S

    1999-01-01

    (141) pg/ml; AII 12.77 (4.79) v 12.65 (4.71) pg/ml) or 10 days after admission (NA 283 (93) v 277 (98) pg/ml; AII 5.31 (2.25) v 6.09 (3.31) pg/ml). However, patients in group C had higher plasma concentrations of AII (14.79 (5.7) pg/ml on the third day and 7.98 (4.92) pg/ml on the 10th day) than patients in either group A or B (p = 0.006). After 90 days following treatment, group B (captopril plus losartan) patients had a smaller ESV than patients in group A (captopril) and group C (losartan).
CONCLUSION—The data suggest that the combination of captopril plus losartan is feasible in the early treatment of acute myocardial infarction patients, and it appears that this combination has more effect on ESV than captopril alone in the short term.


Keywords: acute myocardial infarction; angiotensin converting enzyme inhibitors; captopril; losartan PMID:10336919

  20. 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.

  1. Tailored therapy of ACE inhibitors in stable coronary artery disease: pharmacogenetic profiling of treatment benefit.

    PubMed

    Brugts, Jasper J; Boersma, Eric; Simoons, Maarten L

    2010-08-01

    Angiotensin-converting enzyme (ACE) inhibitors are among the most commonly used drugs in stable coronary artery disease as these agents have been proven to be effective for reducing the risk of cardiovascular morbidity and mortality. As with other drugs, individual variation in treatment benefit is likely. Such heterogeneity could be used to target ACE-inhibitor therapy to those patients most likely to benefit from treatment. However, prior attempts to target ACE-inhibitor therapy to those patients who are most likely to benefit of such prophylactic treatment in secondary prevention using clinical characteristics or the level of baseline risk appeared not to be useful. A new approach of 'tailored therapy' could be to integrate more patient-specific characteristics, such as the genetic information of patients. Pharmacogenetic research of ACE inhibitors in coronary artery disease patients is at a formative stage, and studies are limited. The Perindopril Genetic association (PERGENE) study is a large pharmacogenetic substudy of the randomized placebo-controlled European trial On Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery disease (EUROPA) trial, aimed to assess the feasibility of pharmacogenetic profiling of ACE-inhibitor therapy by perindopril. This article summarizes the recent findings of the PERGENE study and pharmacogenetic research of the treatment benefit of perindopril in stable coronary artery disease. PMID:20712529

  2. Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors, or both? Expectations from the ONTARGET Trial Programme.

    PubMed

    Ruilope, Luis Miguel; Redón, Josep; Schmieder, Roland

    2007-01-01

    Endothelial dysfunction is the initial pathophysiological step in a progression of vascular damage that leads to overt cardiovascular and chronic kidney disease. Angiotensin II, the primary agent of the renin-angiotensin system (RAS), has a central role in endothelial dysfunction. Therefore, RAS blockade with an angiotensin receptor blocker (ARB) and/or angiotensin-converting enzyme (ACE) inhibitor provides a rational approach to reverse endothelial dysfunction, reduce microalbuminuria, and, thus, improves cardiovascular and renal prognosis. ARBs and ACE inhibitors act at different points in the RAS pathway and recent evidence suggests that there are differences regarding their effects on endothelial dysfunction. In addition to blood pressure lowering, studies have shown that ARBs reduce target-organ damage, including improvements in endothelial dysfunction, arterial stiffness, the progression of renal dysfunction in patients with type 2 diabetes, proteinuria, and left ventricular hypertrophy. The ONgoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial (ONTARGET) Programme is expected to provide the ultimate evidence of whether improved endothelial function translates into reduced cardiovascular and renal events in high-risk patients, and to assess possible differential outcomes with telmisartan, the ACE inhibitor ramipril, or a combination of both (dual RAS blockade). Completion of ONTARGET is expected in 2008.

  3. Does the use of ACE inhibitors or angiotensin receptor blockers affect bone loss in older men?

    PubMed Central

    Leung, J.; Zhang, Y. F.; Bauer, D.; Ensrud, K. E.; Barrett-Connor, E.; Leung, P. C.

    2013-01-01

    Summary In a prospective cohort study of 5,995 older American men (MrOS), users of angiotensin-converting enzyme (ACE) inhibitors had a small but significant increase in bone loss at the hip over 4 years after adjustment for confounders. Use of angiotensin II AT1 receptor blockers (ARB) was not significantly associated with bone loss. Introduction Experimental evidence suggests that angiotensin II promotes bone loss by its effects on osteoblasts. It is therefore plausible that ACE inhibitor and ARB may reduce rates of bone loss. The objective of this study is to examine the independent effects of ACE inhibitor and ARB on bone loss in older men. Methods Out of 5,995 American men (87.2%) aged ≥65 years, 5,229 were followed up for an average of 4.6 years in a prospective six-center cohort study—The Osteoporotic Fractures in Men Study (MrOS). Bone mineral densities (BMD) at total hip, femoral neck, and trochanter were measured by Hologic densitometer (QDR 4500) at baseline and year 4. Results Out of 3,494 eligible subjects with complete data, 1,166 and 433 subjects reported use of ACE inhibitors and ARBs, respectively. When compared with nonusers, continuous use of ACE inhibitors was associated with a small (0.004 g/cm2) but significant increase in the average rate of BMD loss at total hip and trochanter over 4 years after adjustment for confounders. Use of ARB was not significantly associated with bone loss. Conclusion Use of ACE inhibitors but not ARB may marginally increase bone loss in older men. PMID:22080379

  4. SY 12-2 ACE INHIBITORS AND ARBS: SIMILARITIES AND DIFFERENCES IN CV RISK REDUCTION.

    PubMed

    Danser, Alexander

    2016-09-01

    Blockade of the renin-angiotensin-aldosterone system (RAAS) can be accomplished at the level of the angiotensin-generating enzymes renin and angiotensin-converting enzyme (ACE; using renin inhibitors or ACE inhibitors), the type 1 angiotensin II (AT1) receptor or mineralocorticoid receptor (MR; using angiotensin receptor blockers [ARBs] or MR blockers) and/or renin release (using beta-blockers). Several of these drugs are often combined-for example in heart failure-but such approaches may ultimately lead to RAAS annihilation with adverse consequences such as hypotension, renal dysfunction and hyperkalaemia. The biochemical consequences of each type of blockade are different. For instance, ACE inhibitors will lower angiotensin II, thus no longer allowing stimulation of both AT1 and type 2 angiotensin II (AT2) receptors, while ARBs raise angiotensin II, allowing selective stimulation of the unoccupied AT2 receptor. This might be of particular importance in women, in whom the protective AT2 receptor pathway is believed to be upregulated. Multiple clinical trials have compared the various types of RAAS blockers and/or their combination. This talk will summarize the current evidence with regard to similarities and differences between ACE inhibitors and ARBs, also considering their side-effect profile, dose and combination with other RAAS blockers. PMID:27643121

  5. ACE Inhibitor Delapril Prevents Ca(2+)-Dependent Blunting of IK1 and Ventricular Arrhythmia in Ischemic Heart Disease.

    PubMed

    Thireau, J; Zalvidea, S; Meschin, P; Pasquie, J-L; Aimond, F; Richard, S

    2015-01-01

    Angiotensin-converting enzyme inhibitors (ACE-I) improve clinical outcome in patients with myocardial infarction (MI) and chronic heart failure. We investigated potential anti-arrhythmic (AA) benefits in a mouse model of ischemic HF. We hypothesized that normalization of diastolic calcium (Ca(2+)) by ACE-I may prevent Ca(2+)-dependent reduction of inward rectifying K(+) current (IK1) and occurrence of arrhythmias after MI. Mice were randomly assigned to three groups: Sham, MI, and MI-D (6 weeks of treatment with ACE-I delapril started 24h after MI). Electrophysiological analyses showed that delapril attenuates MI-induced prolongations of electrocardiogram parameters (QRS complex, QT, QTc intervals) and conduction time from His bundle to ventricular activation. Delapril improved the sympatho-vagal balance (LF/HF) and reduced atrio-ventricular blocks and ventricular arrhythmia. Investigations in cardiomyocytes showed that delapril prevented the decrease of IK1 measured by patch-clamp technique. IK1 reduction was related to intracellular Ca(2+) overload. This reduction was not observed when intracellular free-Ca(2+) was maintained low. Conversely, increasing intracellular free-Ca(2+) in Sham following application of SERCA2a inhibitor thapsigargin reduced IK1. Thapsigargin had no effect in MI animals and abolished the benefits of delapril on IK1 in MI-D mice. Delapril prevented both the prolongation of action potential late repolarization and the depolarization of resting membrane potential, two phenomena known to trigger abnormal electrical activities, promoted by MI. In conclusion, early chronic therapy with delapril after MI prevented Ca(2+)-dependent reduction of IK1. This mechanism may significantly contribute to the antiarrhythmic benefits of ACE-I in patients at risk for sudden cardiac death. PMID:26321755

  6. Taking ACE inhibitors during pregnancy. Is it safe?

    PubMed Central

    Ratnapalan, Savithiri; Koren, Gideon

    2002-01-01

    QUESTION: A pregnant patient is taking enalapril for primary hypertension. How safe are angiotension-converting enzyme inhibitors (ACEI) during pregnancy? ANSWER: Evidence of whether ACEIs cause problems during the first trimester of pregnancy is reassuring. There is evidence that they cause severe renal and other problems during the second and third trimesters, however. These drugs should be avoided during pregnancy. PMID:12113190

  7. Potentially lethal ACE-inhibitor-induced angioedema in a child.

    PubMed

    Bukhari, Esraa; Safdar, Osama Y; Shalaby, Mohammed; AlSharif, Shafiqa Mj; Alsufiany, Khoulod; Kari, Jameela A

    2015-06-01

    We report a case of a 9-year-old female with known end-stage kidney disease who presented with sudden onset tongue swelling. A diagnosis of angiotensin-converting enzyme inhibitor-induced angioedema related to bradykinin accumulation was made. Her symptoms resolved shortly after discontinuation of captopril. Early diagnosis can save patients from severe upper airway obstruction.

  8. Potentially lethal ACE-inhibitor-induced angioedema in a child

    PubMed Central

    Bukhari, Esraa; Safdar, Osama Y; Shalaby, Mohammed; AlSharif, Shafiqa MJ; Alsufiany, Khoulod; Kari, Jameela A

    2015-01-01

    Key Clinical Message We report a case of a 9-year-old female with known end-stage kidney disease who presented with sudden onset tongue swelling. A diagnosis of angiotensin-converting enzyme inhibitor-induced angioedema related to bradykinin accumulation was made. Her symptoms resolved shortly after discontinuation of captopril. Early diagnosis can save patients from severe upper airway obstruction. PMID:26185642

  9. 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.

  10. 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.

  11. Model Development and Use of ACE Inhibitors for Preclinical Mitigation of Radiation-Induced Injury to Multiple Organs

    PubMed Central

    Medhora, Meetha; Gao, Feng; Wu, Qingping; Molthen, Robert C.; Jacobs, Elizabeth R.; Moulder, John E.; Fish, Brian L.

    2014-01-01

    The NIH/NIAID initiated a countermeasure program to develop mitigators for radiation-induced injuries from a radiological attack or nuclear accident. We have previously characterized and demonstrated mitigation of single organ injuries, such as radiation pneumonitis, pulmonary fibrosis or nephropathy by angiotensin converting enzyme (ACE) inhibitors. Our current work extends this research to examine the potential for mitigating multiple organ dysfunctions occurring in the same irradiated rats. Using total body irradiation (TBI) followed by bone marrow transplant, we tested four doses of X radiation (11, 11.25, 11.5 and 12 Gy) to develop lethal late effects. We identified three of these doses (11, 11.25 and 11.5 Gy TBI) that were lethal to all irradiated rats by 160 days to test mitigation by ACE inhibitors of injury to the lungs and kidneys. In this study we tested three ACE inhibitors at doses: captopril (88 and 176 mg/m2/day), enalapril (18, 24 and 36 mg/m2/day) and fosinopril (60 mg/m2/day) for mitigation. Our primary end point was survival or criteria for euthanization of morbid animals. Secondary end points included breathing intervals, other assays for lung structure and function and blood urea nitrogen (BUN) to assess renal damage. We found that captopril at 176 mg/m2/day increased survival after 11 or 11.5 Gy TBI. Enalapril at 18–36 mg/m2/day improved survival at all three doses (TBI). Fosinopril at 60 mg/m2/day enhanced survival at a dose of 11 Gy, although no improvement was observed for pneumonitis. These results demonstrate the use of a single countermeasure to mitigate the lethal late effects in the same animal after TBI. PMID:25361399

  12. 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.

  13. ACE inhibitors

    MedlinePlus

    ... Clinical Cardiology; American Heart Association Council on Nutrition, Physical Activity, and Metabolism; American Heart Association Interdisciplinary Council on Quality of Care and Outcomes Research. State of the science: promoting self-care in persons with heart failure: ...

  14. The binding of metal ions and angiotensin converting enzyme (ACE) inhibitor by 13C NMR

    NASA Astrophysics Data System (ADS)

    Sakamoto, Yohko; Sakamoto, Yuko; Ishii, Tomoko; Ohmoto, Taichi

    1991-06-01

    Enalaprilat (MK-422, 1- [ N- [1 (S)-carboxy-3-phenylpropyl]- L-alanyl]- L-proline (1)) and Lisinopril (MK521, N- N- [ (s)-l-carboxy-3- phenylpropyl]- L-lysyl- L-proline, (2)) exhibit the capacity to act as a chelate, unidentate or bridge towards metal ions in aqueous solution, as determined by 13C NMR. By adding metal ions, in the series of Zn 2+, Ni 2+, Pb 2+, Pd 2+ and Cd 2+, the active site of the ACE inhibitor was well defined. MK-521 was more influenced by nuclei that were distant from the active site than MK-422.

  15. Secoisolariciresinol Diglucoside (SDG) Isolated from Flaxseed, an Alternative to ACE Inhibitors in the Treatment of Hypertension.

    PubMed

    Prasad, Kailash

    2013-12-01

    Secoisolariciresionol diglucoside (SDG) is a plant lignan isolated from flaxseed and is phytoestrogen. SDG is a potent and long-acting hypotensive agent. Plant phytoestrogens have inhibitory effects on angiotensin-converting enzyme (ACE). The hypotensive effects of SDG, a phytoestrogen, may be mediated through inhibition of ACE. The objective of this study was to investigate if SDG-induced hypotension is mediated through inhibition of ACE. The Sprague Dawley male rats were anesthetized and trachea was cannulated. The right jugular vein was cannulated to administer the drug and the carotid artery was cannulated to record arterial pressures using PIOEZ-1 miniature model transducer (Becton, Dickinson and Company, Franklin Lakes, NJ) and Beckman dynograph (Beckman Instruments, Inc., Schiller Park, IL). The effects of angiotensin I (0.2 µg/kg, intravenously [IV]) in the absence and presence of SDG (10 mg/kg, IV), and SDG alone on systolic, diastolic, and mean arterial pressures were measured before and after 15, 30, and 60 minutes of drug administration. SDG decreased the systolic, diastolic, and mean arterial pressure by 37, 47, and 43%, respectively, at 15 minutes and 18.8, 21.2, and 20.3%, respectively, at 60 minutes. Angiotensin I increased the arterial pressure. SDG decreased angiotensin I-induced rise in the systolic, diastolic, and mean arterial pressures by 60, 58, and 51%, respectively, at 15 minutes and 48, 46, and 30%, respectively, at 60 minutes. The data suggest that SDG reduced the angiotensin I-induced rise in the arterial pressures and hence SDG is a potent ACE inhibitor.

  16. What is the impact of the ACE gene insertion/deletion (I/D) polymorphism on the clinical effectiveness and adverse events of ACE inhibitors? – Protocol of a systematic review

    PubMed Central

    Scharplatz, M; Puhan, MA; Steurer, J; Bachmann, LM

    2004-01-01

    Background The Angiotensin Converting Enzyme (ACE) insertion/deletion (I/D) polymorphism has received much attention in pharmacogenetic research because observed variations in response to ACE inhibitors might be associated with this polymorphism. Pharmacogenetic testing raises the hope to individualise ACE inhibitor therapy in order to optimise its effectiveness and to reduce adverse effects for genetically different subgroups. However, the extent of its effect modification in patients treated with ACE inhibitors remains inconclusive. Therefore our objective is to quantify the effect modification of the insertion/deletion polymorphism of the angiotensin converting enzyme gene on any surrogate and clinically relevant parameters in patients with cardiovascular diseases, diabetes, renal transplantation and/or renal failure. Methods Systematic Review. We will perform literature searches in six electronic databases to identify randomised controlled trials comparing the effectiveness and occurrence of adverse events of ACE inhibitor therapy against placebo or any active treatment stratified by the I/D gene polymorphism. In addition, authors of trials, experts in pharmacogenetics and pharmaceutical companies will be contacted for further published or unpublished data. Hand searching will be accomplished by reviewing the reference lists of all included studies. The methodological quality of included papers will be assessed. Data analyses will be performed in clinically and methodologically cogent subgroups. The results of the quantitative assessment will be pooled statistically where appropriate to produce an estimate of the differences in the effect of ACE inhibitors observed between the three ACE genotypes. Discussion This protocol describes a strategy to quantify the effect modification of the ACE polymorphism on ACE inhibitors in relevant clinical domains using meta-epidemiological research methods. The results may provide evidence for the usefulness of pharmacogenetic

  17. 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

  18. Congenital renal tubular dysplasia and skull ossification defects similar to teratogenic effects of angiotensin converting enzyme (ACE) inhibitors.

    PubMed Central

    Kumar, D; Moss, G; Primhak, R; Coombs, R

    1997-01-01

    An apparently autosomal recessive syndrome of congenital renal tubular dysplasia and skull ossification defects is described in five infants from two separate, consanguineous, Pakistani Muslim kindreds. The clinical, pathological, and radiological features are similar to the phenotype associated with fetal exposure to angiotensin converting enzyme (ACE) inhibitors: intrauterine growth retardation, skull ossification defects, and fetal/ neonatal anuric renal failure associated with renal tubular dysplasia. There was no fetal exposure to ACE inhibitors in the affected infants. Phenotypic similarities between these familial cases and those associated with ACE inhibition suggest an abnormality of the "renin-angiotensin-aldosterone" system (RAS). It is postulated that the molecular pathology in this uncommon autosomal recessive proximal renal tubular dysgenesis could be related to mutations of the gene systems governing the RAS. Images PMID:9222960

  19. 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. PMID:25172679

  20. Possible Improvements of the ACE Diversity Interchange Methodology

    SciTech Connect

    Etingov, Pavel V.; Zhou, Ning; Makarov, Yuri V.; Ma, Jian; Guttromson, Ross T.; McManus, Bart; Loutan, Clyde

    2010-07-26

    North American Electric Reliability Corporation (NERC) grid is operated by about 131 balancing authorities (BA). Within each BA, operators are responsible for managing the unbalance (caused by both load and wind). As wind penetration levels increase, the challenges of managing power variation increases. Working independently, balancing area with limited regulating/load following generation and high wind power penetration faces significant challenges. The benefits of BA cooperation and consolidation increase when there is a significant wind energy penetration. To explore the benefits of BA cooperation, this paper investigates ACE sharing approach. A technology called ACE diversity interchange (ADI) is already in use in the western interconnection. A new methodology extending ADI is proposed in the paper. The proposed advanced ADI overcoming some limitations existing in conventional ADI. Simulations using real statistical data of CAISO and BPA have shown high performance of the proposed advanced ADI methodology.

  1. Therapeutic substitution post-patent expiry: the cases of ACE inhibitors and proton pump inhibitors.

    PubMed

    Vandoros, Sotiris

    2014-05-01

    This paper examines whether there is a switch in total (originator and generic) consumption after generic entry from molecules that face generic competition towards other molecules of the same class, which are still in-patent. Data from six European countries for the time period 1991 to 2006 are used to study the cases of angiotensin-converting enzyme inhibitors and proton pump inhibitors. Empirical evidence shows that patent expiry of captopril and enalapril led to a switch in total (off-patent originator and generic) consumption towards other in-patent angiotensin-converting enzyme inhibitors, whereas patent expiry of omeprazole led to a switch in consumption towards other proton pump inhibitors. This phenomenon makes generic policies ineffective and results in an increase in pharmaceutical expenditure due to the absence of generic alternatives in the market of in-patent molecules.

  2. Comparison of the Efficacy and Safety of Different ACE Inhibitors in Patients With Chronic Heart Failure

    PubMed Central

    Sun, WeiPing; Zhang, HaiBin; Guo, JinCheng; Zhang, XueKun; Zhang, LiXin; Li, ChunLei; Zhang, Ling

    2016-01-01

    Abstract Heart failure is a public health problem and a great economic burden for patients and healthcare systems. Suppression of the renin–angiotensin system (RAS) by angiotensin-converting enzyme (ACE)-inhibitors remains the mainstay of treatment for heart failure. However, the abundance of ACE inhibitors makes it difficult for doctors to choose. We performed this network meta-analysis of ACEIs in patients with heart failure in order to address this area of uncertainty. We searched PubMed, Embase, CENTRAL, and Medline. Any randomized controlled trial evaluating the efficacy and safety of captopril, enalapril, lisinopril, ramipril, or trandolapril or combined interventions of 2 or more of these drugs. Two reviewers extracted the data and made the quality assessment. At first, we used Stata software (version 12.0, StataCorp, College Station, TX) to make traditional pairwise meta-analyses for studies that directly compared different interventions. Then, network meta-analysis was performed using WinBUGS (version 1.4.3, MRC Biostatistics Unit, Cambridge, UK). A total of 29 studies were included. Lisinopril was associated with a higher rate of all-cause mortality compared with placebo (odds ratio 65.9, 95% credible interval 1.91 to 239.6) or ramipril (14.65, 1.23 to 49.5). Enalapril significantly reduced systolic blood pressure when compared with placebo (standardized mean differences −0.6, 95% credible interval −1.03 to −0.18). Both captopril (odds ratio 76.2, 95% credible interval 1.56 to 149.3) and enalapril (274.4, 2.4 to 512.9) were associated with a higher incidence of cough compared to placebo. Some important outcomes such as rehospitalization and cardiac death were not included. The sample size and the number of studies were limited, especially for ramipril. Our results suggest that enalapril might be the best option when considering factors such as increased ejection fraction, stroke volume, and decreased mean arterial pressure. However, enalapril was

  3. Renal hemodynamics in hypertensive renal allograft recipients: effects of calcium antagonists and ACE inhibitors.

    PubMed

    Grekas, D; Dioudis, C; Kalevrosoglou, I; Alivanis, P; Derveniotis, V; Tourkantonis, A

    1996-06-01

    Hypertension present in more than 50% of successfully renal transplanted patients and its prevalence has slightly increased since the introduction of cyclosporine A. Twenty patients, 9 women and 11 men aged from 30 to 58 years, with stable cadaveric renal allograft function and moderate to severe hypertension, were included in the study. Renal artery graft stenosis causing hypertension were excluded. All patients were given triple drug immunosuppressive treatment with methylprednisolone, azathioprine and cyclosporine A (CsA) and their hypertension was treated with a nifedipine dose of 20 mg twice daily. To evaluate the effect of ACE inhibitors on renal hemodynamics and hypertension, a 4 mg/daily dose of perindopril was added to the above regimen for two months. Effective renal plasma flow (ERPF) decreased from 208 +/- 54 to 168 +/- 61 ml/min and renal vascular resistance (RVR) increased from 75 +/- 12 to 88 +/- 17 mm Hg/ml/min (P < 0.05 and P < 0.01, respectively). Mean blood pressure was significantly (P < 0.001) reduced by the combination of both agents in comparison to the blood pressure control by monotherapy with nifedipine. It is suggested that the combination of both antihypertensive agents was more effective than monotherapy with nifedipine in controlling blood pressure, but less favorable on the renal hemodynamic response in hypertensive renal transplant patients who were maintained on CsA.

  4. Cardiorespiratory effects of continuous i.v. administration of the ACE inhibitor enalaprilat in the critically ill.

    PubMed Central

    Boldt, J; Müller, M; Heesen, M; Härter, K; Hempelmann, G

    1995-01-01

    1. Cardiorespiratory effects of long-term, continuous i.v. administration of the ACE inhibitor enalaprilat were studied. 2. Forty-five consecutive critically patients suffering from trauma or postoperative complications were randomly separated into three groups (15 patients in each group) receiving either 0.25 mg h-1 or 0.50 mg h-1 enalaprilat, respectively, or saline solution as placebo (= control group). The infusion was continued for 5 days. 3. Haemodynamic and respiratory parameters were intensively monitored on admission to the intensive care unit (= 'baseline' values) and daily during the next 5 days. 4. Mean arterial blood pressure (MAP) decreased significantly only in the enalaprilat-treated patients, whereas heart rate (HR) remained unchanged in these patients. 5. Pulmonary capillary wedge pressure (PCWP) and pulmonary artery pressure (PAP) were decreased by enalaprilat (0.50 mg h-1: PAP (mean +/- s.d.) decreased from 28.0 +/- 4.1 to 24.0 +/- 3.0 mm Hg) and remained significantly lower than in the control group. In the untreated control group, cardiac index (CI), oxygen consumption (VO2I) and oxygen delivery (DO2I) significantly decreased, which was blunted by enalaprilat infusion. Oxygen extraction (O2-extr) increased in both enalaprilat groups (0.25 mg h-1: from 26.1 +/- 5.5 to 30.4 +/- 4.0%; 0.50 mg h-1: 25.2 +/- 5.6 to 30.9 +/- 4.4%) and decreased in the control patients. 6. Right ventricular haemodynamics improved by enalaprilat infusion (0.50 mg h-1: RVEF increased from 40.0 +/- 3.5 to 45.5 +/- 4.0%). Lactate plasma concentrations decreased in the group with 0.50 mg h-1 enalaprilat (from 1.9 +/- 1.0 to 1.3 +/- 0.3 mg dl-1) and increased in the control patients. 7. Continuous infusion of the ACE inhibitor enalaprilat exerted beneficial cardiorespiratory effects in the critically ill. The widespread common risk of altered perfusion with decreased CI, DO2, VO2, O2-extr and increased lactate concentration was blunted by enalaprilat infusion. 8. Although

  5. 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

  6. 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

  7. ACE Inhibitor and Angiotensin Receptor-II Antagonist Prescribing and Hospital Admissions with Acute Kidney Injury: A Longitudinal Ecological Study

    PubMed Central

    Tomlinson, Laurie A.; Abel, Gary A.; Chaudhry, Afzal N.; Tomson, Charles R.; Wilkinson, Ian B.; Roland, Martin O.; Payne, Rupert A.

    2013-01-01

    Background ACE Inhibitors (ACE-I) and Angiotensin-Receptor Antagonists (ARAs) are commonly prescribed but can cause acute kidney injury (AKI) during intercurrent illness. Rates of hospitalization with AKI are increasing. We aimed to determine whether hospital AKI admission rates are associated with increased ACE-I/ARA prescribing. Methods and Findings English NHS prescribing data for ACE-I/ARA prescriptions were matched at the level of the general practice to numbers of hospital admissions with a primary diagnosis of AKI. Numbers of prescriptions were weighted for the demographic characteristics of general practices by expressing prescribing as rates where the denominator is Age, Sex, and Temporary Resident Originated Prescribing Units (ASTRO-PUs). We performed a mixed-effect Poisson regression to model the number of admissions for AKI occurring in each practice for each of 4 years from 1/4/2007. From 2007/8-2010/11, crude AKI admission rates increased from 0.38 to 0.57 per 1000 patients (51.6% increase), and national annual ACE-I/ARA prescribing rates increased by 0.032 from 0.202 to 0.234 (15.8% increase). There was strong evidence (p<0.001) that increases in practice-level prescribing of ACE-I/ARA over the study period were associated with an increase in AKI admission rates. The increase in prescribing seen in a typical practice corresponded to an increase in admissions of approximately 5.1% (rate ratio = 1.051 for a 0.03 per ASTRO-PU increase in annual prescribing rate, 95%CI 1.047-1.055). Using the regression model we predict that 1,636 (95%CI 1,540-1,780) AKI admissions would have been avoided if prescribing rates were at the 2007/8 level, equivalent to 14.8% of the total increase in AKI admissions. Conclusion In this ecological analysis, up to 15% of the increase in AKI admissions in England over a 4-year time period is potentially attributable to increased prescribing of ACE-I and ARAs. However, these findings are limited by the lack of patient level

  8. 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

  9. [Liver damage in a patient treated with a vitamin K antagonist, a statin and an ACE inhibitor].

    PubMed

    Bruggisser, M; Terraciano, L; Rätz Bravo, A; Haschke, M

    2010-10-20

    We report the case of a 71-year-old male patient who presented at the emergency room with episodes of epistaxis and jaundice. The patient was on therapy with phenprocoumon, atorvastatin and perindopril. Findings on admission included prominent elevation of transaminases and bilirubin and a high INR due to impaired liver function and oral anticoagulation. After exclusion of other causes like viral or autoimmune hepatitis and after having obtained a liver biopsy, a diagnosis of drug induced liver damage (DILI) was made. Epidemiology, pathophysiology and clinical signs of DILI are discussed with a special focus on coumarines, statins and ACE-inhibitors. PMID:20960395

  10. Individualised therapy of angiotensin converting enzyme (ACE) inhibitors in stable coronary artery disease: overview of the primary results of the PERindopril GENEtic association (PERGENE) study.

    PubMed

    Brugts, J J; de Maat, M P M; Danser, A H J; Boersma, E; Simoons, M L

    2012-01-01

    In patients with stable coronary artery disease (CAD) without overt heart failure, ACE inhibitors are among the most commonly used drugs as these agents have been proven effective in reducing the risk of cardiovascular events. Considerable individual variations in the blood pressure response to ACE inhibitors are observed and as such heterogeneity in clinical treatment effect would be likely as well. Assessing the consistency of treatment benefit is essential for the rational and cost-effective prescription of ACE inhibitors. Information on heterogeneities in treatment effect between subgroups of patients could be used to develop an evidence-based guidance for the installation of ACE-inhibitor therapy. Obviously, therapy should only be applied in those patients who most likely will benefit. Attempts to develop such treatment guidance by using clinical characteristics have been unsuccessful. No heterogeneity in risk reduction by ACE inhibitors has been observed in relation to relevant clinical characteristics. A new approach to such 'guided-therapy' could be to integrate more patient-specific characteristics such as the patients' genetic information. If proven feasible, pharmacogenetic profiling could optimise patients' benefit of treatment and reduce unnecessary treatment of patients. Cardiovascular pharmacogenetic research of ACE inhibitors in coronary artery disease patients is in a formative stage and studies are limited. The PERGENE study is a large pharmacogenetic substudy of the EUROPA trial, aimed to assess the achievability of pharmacogenetic profiling. We provide an overview of the main results of the PERGENE study in terms of the genetic determinants of treatment benefit and blood pressure response. The main results of the PERGENE study show a pharmacogenetic profile related to the treatment benefit of perindopril identifying responders and non-responders to treatment. PMID:21688035

  11. Ventricular dilatation in the absence of ACE inhibitors: influence of haemodynamic and neurohormonal variables following myocardial infarction

    PubMed Central

    Walsh, J; Batin, P; Hawkins, M; McEntegart, D; Cowley, A

    1999-01-01

    Objective—To examine the relation between patterns of ventricular remodelling and haemodynamic and neurohormonal variables, at rest and during symptom limited exercise, in the year following acute myocardial infarction in patients not receiving angiotensin converting enzyme (ACE) inhibitors.
Design—A prospective observational study.
Patients—65 patients recruited following hospital admission with a transmural anterior myocardial infarction.
Methods—Central haemodynamics and neurohormonal activation at rest and during symptom limited treadmill exercise were measured at baseline before hospital discharge, one month later, and at three monthly intervals thereafter. Patients were classified according to individual patterns of change in left ventricular end diastolic volumes at rest, assessed at each visit using transthoracic echocardiography.
Results—In most patients (n = 43, 66%) ventricular volumes were unchanged or reduced. Mean (SEM) treadmill exercise capacity and peak exercise cardiac index increased at month 12 by 200 (24) seconds (p < 0.001 v baseline) and by 0.8 (0.4) l/min/m2 (p<0.05 v baseline), respectively, in this group. In patients with limited ventricular dilatation (n = 11, 17%) exercise capacity increased by 259 (52) seconds (p < 0.001 v baseline) and peak exercise cardiac index improved by 0.8 (0.7) l/min/m2 (NS). In the remaining 11 patients with progressive left ventricular dilatation, exercise capacity increased by 308 (53) seconds (p< 0.001 v baseline) and peak exercise cardiac index similarly improved by 1.3 (0.7) l/min/m2 (NS). There were trends towards increased atrial natriuretic factor (ANF) secretion at rest and at peak exercise in this group.
Conclusions—Ventricular dilatation after acute myocardial infarction is a heterogeneous process that is progressive in only a minority of patients. Compensatory mechanisms, including ANF release, appear capable of maintaining and improving exercise capacity in

  12. 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.

  13. Interactions of angiotensin-converting enzyme, kinins and nitric oxide in circulation and the beneficial effects of ACE inhibitors in cardiovascular diseases.

    PubMed

    Magen, E; Viskoper, R J

    2000-12-01

    Renin-angiotensin-aldosterone systems play a critical role in the development and progression of cardiovascular diseases, and inhibitors of angiotensin-converting enzyme have proven effective for the treatment of these diseases. Since angiotensin II receptor antagonists can inhibit the effects of angiotensin II via ACE-independent pathways, e.g., chymase, they were considered to be more effective than ACEIs. On the other hand, ACE inhibitors can increase bradykinin, and thus, nitric oxide, which may cause potent cardioprotection, inhibition of smooth muscle proliferation and attenuation of inflammation mechanisms. It appears that angiotensin II receptor antagonists and ACEIs may mediate cardioprotection in different ways. This is the rationale to explore the possibility of a combined administration of both drugs for the treatment of chronic heart failure and other cardiovascular pathology. In this review we try to analyze the role of ACE, kinins and chymase inhibition in the pathophysiology and treatment of cardiovascular diseases.

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

    PubMed Central

    2011-01-01

    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. PMID:22828053

  15. 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

  16. 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.

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

    PubMed

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

    2015-07-01

    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

  18. 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

  19. 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

  20. 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…

  1. High Incidence of ACE/PAI-1 in Association to a Spectrum of Other Polymorphic Cardiovascular Genes Involving PBMCs Proinflammatory Cytokines in Hypertensive Hypercholesterolemic Patients: Reversibility with a Combination of ACE Inhibitor and Statin

    PubMed Central

    Mouawad, Charbel; Haddad, Katia; Hamoui, Samar; Azar, Albert; Fajloun, Ziad; Makdissy, Nehman

    2015-01-01

    Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects. Two genes were significantly associated with HH: ACE (OR: 9.20, P<0.0001) and PAI-1 (OR: 2.29, P = 0.007), respectively with the occurrence of the risky alleles “Del” and “4G”. The frequencies of the Del and 4G alleles were found to be 0.98 and 0.90 in the HH group versus 0.84 and 0.79 in the healthy group, respectively. Serum ACE activity and PAI-I increased significantly with Del/Del and 4G/5G genotypes. The co-expression of Del/4G(+/+) was detected in 113 out of 171 (66.0%) controls and 125 out of 144 (86.8%) HH subjects. Del/4G(-/-) was detected in only 6 (3.5%) controls and undetected in the HH group. Three venous thrombosis related genes [FV(Leiden), MTHFR(A1298C) and FXIII(V34L)] were significantly related to the prominence of the co-expression of Del/4G(+/+). A range of 2 to 8 combined polymorphisms co-expressed per subject where 5 mutations were the most detected. In Del/4G(+/+) subjects, peripheral blood mononuclear cells (PBMCs) produced significant elevated levels of IFN-γ and TNF-α contrary to IL-10, and no variations occurred for IL-4. ACE inhibitor (ramipril) in combination with statin (atorvastatin) and not alone reversed significantly the situation. This first report from Lebanon sheds light on an additional genetic predisposition of a complex spectrum of genes involved in CVD and suggests that the most requested gene FVL by physicians may not be sufficient to diagnose eventual future problems that can occur in the cardiovascular system. Subjects expressing the double mutations

  2. Non-disulfide-bridged peptides from Tityus serrulatus venom: Evidence for proline-free ACE-inhibitors.

    PubMed

    Pucca, Manuela Berto; Cerni, Felipe Augusto; Pinheiro-Junior, Ernesto Lopes; Zoccal, Karina Furlani; Bordon, Karla de Castro Figueiredo; Amorim, Fernanda Gobbi; Peigneur, Steve; Vriens, Kim; Thevissen, Karin; Cammue, Bruno Philippe Angelo; Júnior, Ronaldo Bragança Martins; Arruda, Eurico; Faccioli, Lúcia Helena; Tytgat, Jan; Arantes, Eliane Candiani

    2016-08-01

    The present study purifies two T. serrulatus non-disulfide-bridged peptides (NDBPs), named venom peptides 7.2 (RLRSKG) and 8 (KIWRS) and details their synthesis and biological activity, comparing to the synthetic venom peptide 7.1 (RLRSKGKK), previously identified. The synthetic replicate peptides were subjected to a range of biological assays: hemolytic, antifungal, antiviral, electrophysiological, immunological and angiotensin-converting enzyme (ACE) inhibition activities. All venom peptides neither showed to be cytolytic nor demonstrated significant antifungal or antiviral activities. Interestingly, peptides were able to modulate macrophages' responses, increasing IL-6 production. The three venom peptides also demonstrated potential to inhibit ACE in the following order: 7.2>7.1>8. The ACE inhibition activity was unexpected, since peptides that display this function are usually proline-rich peptides. In attempt to understand the origin of such small peptides, we discovered that the isolated peptides 7.2 and 8 are fragments of the same molecule, named Pape peptide precursor. Furthermore, the study discusses that Pape fragments could be originated from a post-splitting mechanism resulting from metalloserrulases and other proteinases cleavage, which can be seen as a clever mechanism used by the scorpion to enlarge its repertoire of venom components. Scorpion venom remains as an interesting source of bioactive proteins and this study advances our knowledge about three NDBPs and their biological activities. PMID:27221550

  3. ACE inhibition with spirapril improves diastolic function at rest independent of vasodilation during treatment with spirapril in mild to moderate hypertension.

    PubMed

    Petersen, J R; Drabaek, H; Gleerup, G; Mehlsen, J; Petersen, L J; Winther, K

    1996-03-01

    The effects of the ACE inhibitor spirapril and of hydrochlorothiazide on left ventricular diastolic function were studied. Thirteen patients with mild to moderate essential hypertension completed this randomized, double-blinded, placebo-controlled, crossover study. After a three-week run-in period the patients entered three periods lasting four weeks each, wherein they were treated with placebo, spirapril, or hydrochlorothiazide. Blood pressure, hemodynamic variables (stroke volume, heart rate, cardiac output, index of contractility, and systemic vascular resistance), echocardiography (left ventricular mass), and Doppler-derived atrial to early (A/E)-ratio velocity time integrals (VTI) were measured at the end of each of the four periods. Spirapril lowered the A/E-ratio VTIs (0.57, 0.12-1.00) (P < 0.02) as compared with both placebo (0.80, 0.50-2.67) and hydrochlorothiazide (0.83, 0.44-1.25), and the drug normalized the A/E-ratio VTI in those patients with elevated values. The hemodynamic variables, left ventricular mass, and end-systolic wall stress were unchanged during all three treatments. There were no significant changes in mean blood pressure during the treatment periods. These results indicate that spirapril lowers A/E ratio within four weeks in patients with mild to moderate essential hypertension. It thereby seems able to improve left ventricular diastolic function. The effect is not dependent upon changes in hemodynamic variables, blood pressure, left ventricular mass, or end-systolic wall stress.

  4. Angiotensin-converting enzyme inhibitors in veterinary medicine.

    PubMed

    Lefebvre, H P; Brown, S A; Chetboul, V; King, J N; Pouchelon, J-L; Toutain, P L

    2007-01-01

    Angiotensin-converting enzyme (ACE) inhibitors represent one of the most commonly used categories of drugs in canine and feline medicine. ACE inhibitors currently approved for use in veterinary medicine are benazepril, enalapril, imidapril and ramipril. They are all pro-drugs administered by oral route. A physiologically based model taking into account the saturable binding to ACE has been developed for pharmacokinetic analysis. The bioavailability of the active compounds from their respective pro-drug is low. The active metabolites are eliminated by renal, hepatorenal or biliary excretion, according to the drug. The elimination half-life of the free fraction of the active compounds is very short (ranging from approximately 10 min to 2 h). ACE inhibitors are generally well tolerated. Benazepril, enalapril, imidapril and ramipril are approved for dogs with chronic heart failure (CHF). The efficacy of ACE inhibitors has been convincingly demonstrated in dogs with CHF, especially in those with chronic valvular disease. In such clinical settings, ACE inhibitors improve hemodynamics and clinical signs, and increase survival time. In cats with cardiovascular disease, little information is available except for reports of some benefit in cats with hypertrophic cardiomyopathy in two non-controlled investigations. ACE inhibitors have also a mild to moderate hypotensive effect. There is also evidence to recommend ACE inhibitors in dogs and cats with chronic renal failure (CRF). They decrease the glomerular capillary pressure, have antiproteinuric effects, tend to delay the progression of CRF and to limit the extent of renal lesions. PMID:17506720

  5. Comparison of the Efficacy and Safety of Different ACE Inhibitors in Patients With Chronic Heart Failure: A PRISMA-Compliant Network Meta-Analysis.

    PubMed

    Sun, WeiPing; Zhang, HaiBin; Guo, JinCheng; Zhang, XueKun; Zhang, LiXin; Li, ChunLei; Zhang, Ling

    2016-02-01

    Heart failure is a public health problem and a great economic burden for patients and healthcare systems. Suppression of the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE)-inhibitors remains the mainstay of treatment for heart failure. However, the abundance of ACE inhibitors makes it difficult for doctors to choose.We performed this network meta-analysis of ACEIs in patients with heart failure in order to address this area of uncertainty.We searched PubMed, Embase, CENTRAL, and Medline.Any randomized controlled trial evaluating the efficacy and safety of captopril, enalapril, lisinopril, ramipril, or trandolapril or combined interventions of 2 or more of these drugs.Two reviewers extracted the data and made the quality assessment. At first, we used Stata software (version 12.0, StataCorp, College Station, TX) to make traditional pairwise meta-analyses for studies that directly compared different interventions. Then, network meta-analysis was performed using WinBUGS (version 1.4.3, MRC Biostatistics Unit, Cambridge, UK).A total of 29 studies were included. Lisinopril was associated with a higher rate of all-cause mortality compared with placebo (odds ratio 65.9, 95% credible interval 1.91 to 239.6) or ramipril (14.65, 1.23 to 49.5). Enalapril significantly reduced systolic blood pressure when compared with placebo (standardized mean differences -0.6, 95% credible interval -1.03 to -0.18). Both captopril (odds ratio 76.2, 95% credible interval 1.56 to 149.3) and enalapril (274.4, 2.4 to 512.9) were associated with a higher incidence of cough compared to placebo.Some important outcomes such as rehospitalization and cardiac death were not included. The sample size and the number of studies were limited, especially for ramipril.Our results suggest that enalapril might be the best option when considering factors such as increased ejection fraction, stroke volume, and decreased mean arterial pressure. However, enalapril was associated with the

  6. Membrane-associated zinc peptidase families: comparing ACE and ACE2.

    PubMed

    Guy, J L; Lambert, D W; Warner, F J; Hooper, N M; Turner, A J

    2005-08-01

    In contrast to the relatively ubiquitous angiotensin-converting enzyme (ACE), expression of the mammalian ACE homologue, ACE2, was initially described in the heart, kidney and testis. ACE2 is a type I integral membrane protein with its active site domain exposed to the extracellular surface of endothelial cells and the renal tubular epithelium. Here ACE2 is poised to metabolise circulating peptides which may include angiotensin II, a potent vasoconstrictor and the product of angiotensin I cleavage by ACE. To this end, ACE2 may counterbalance the effects of ACE within the renin-angiotensin system (RAS). Indeed, ACE2 has been implicated in the regulation of heart and renal function where it is proposed to control the levels of angiotensin II relative to its hypotensive metabolite, angiotensin-(1-7). The recent solution of the structure of ACE2, and ACE, has provided new insight into the substrate and inhibitor profiles of these two key regulators of the RAS. As the complexity of this crucial pathway is unravelled, there is a growing interest in the therapeutic potential of agents that modulate the activity of ACE2.

  7. 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.

  8. 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. PMID:25439533

  9. Fosinopril and zofenopril, two angiotensin-converting enzyme (ACE) inhibitors, potentiate the anticonvulsant activity of antiepileptic drugs against audiogenic seizures in DBA/2 mice.

    PubMed

    Sarro, Giovambattista De; Paola, Eugenio Donato Di; Gratteri, Santo; Gareri, Pietro; Rispoli, Vincenzo; Siniscalchi, Antonio; Tripepi, Giovanni; Gallelli, Luca; Citraro, Rita; Russo, Emilio

    2012-03-01

    The renin-angiotensin system (RAS) exists in the brain and it may be involved in pathogenesis of neurological and psychiatric disorders including seizures. The aim of the present research was to evaluate the effects of some angiotensin-converting enzyme inhibitors (ACEi; captopril, enalapril, fosinopril and zofenopril), commonly used as antihypertensive agents, in the DBA/2 mice animal model of generalized tonic-clonic seizures. Furthermore, the co-administration of these compounds with some antiepileptic drugs (AEDs; carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate and valproate) was studied in order to identify possible positive interactions in the same model. All ACEi were able to decrease the severity of audiogenic seizures with the exception of enalapril up to the dose of 100mg/kg, the rank order of activity was as follows: fosinopril>zofenopril>captopril. The co-administration of ineffective doses of all ACE inhibitors with AEDs, generally increased the potency of the latter. Fosinopril was the most active in potentiating the activity of AEDs and the combination of ACEi with lamotrigine and valproate was the most favorable, whereas, the co-administrations with diazepam and phenobarbital seemed to be neutral. The increase in potency was generally associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of AEDs with ACEi was predominantly more favorable than control. ACEi administration did not influence plasma and brain concentrations of the AEDs studied excluding pharmacokinetic interactions and concluding that it is of pharmacodynamic nature. In conclusion, fosinopril, zofenopril, enalapril and captopril showed an additive anticonvulsant effect when co-administered with some AEDs, most notably carbamazepine, felbamate, lamotrigine, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.

  10. 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. PMID:26169577

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

    PubMed Central

    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

    2016-01-01

    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. PMID:26169577

  12. Selective imidazoline agonist moxonidine plus the ACE inhibitor ramipril in hypertensive patients with impaired insulin sensitivity: partners in a successful MARRIAGE?

    PubMed

    Rayner, Brian

    2004-03-01

    Hypertension in combination with clinically overt diabetes mellitus is recognized as a particularly powerful combination of risk factors that greatly increases cardiovascular vulnerability. There is also evidence that presumed pre-diabetic conditions such as insulin resistance, hyperinsulinaemia and compensatory hyperglycaemia may amplify overall cardiovascular risk in patients with hypertension, especially when encountered as part of the condition known as metabolic syndrome X (Reaven's syndrome). The long-term benefits of antihypertensive therapy may be compromised if these drugs exert adverse effects on metabolic parameters such as insulin sensitivity, or if they promote a transition from pre-diabetes to overt diabetes. Class differences in the effects of antihypertensives on metabolic indices may therefore be an important consideration when choosing treatment for patients who exhibit these characteristics. Experience from clinical trials suggests that drugs that target the renin-angiotensin system may have metabolic advantages over drugs such as beta-blockers and diuretics, but this conclusion has not been proved definitively. Moxonidine, which selectively targets imidazoline type-1 receptors in the sympathetic vasomotor centres of the rostral-ventrolateral medulla, is an effective antihypertensive and has been reported to exert favourable metabolic effects in preclinical and clinical studies. The MARRIAGE study (Moxonidine And Ramipril Regarding Insulin And Glucose Evaluation) will extend these preliminary observations by comparing the effects of moxonidine and the ACE inhibitor ramipril--and the combination of both drugs--on metabolic and haemodynamic parameters in patients with hypertension and impaired fasting glycaemia. A description is provided of the design and conduct of MARRIAGE.

  13. 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.

  14. Dual ACE-inhibition and angiotensin II AT1 receptor antagonism with curcumin attenuate maladaptive cardiac repair and improve ventricular systolic function after myocardial infarctionin rat heart.

    PubMed

    Pang, Xue-Fen; Zhang, Li-Hui; Bai, Feng; Wang, Ning-Ping; Ijaz Shah, Ahmed; Garner, Ron; Zhao, Zhi-Qing

    2015-01-01

    Curcumin has been shown to improve cardiac function by reducing degradation of extracellular matrix and inhibiting synthesis of collagen after ischemia. This study tested the hypothesis that attenuation of maladaptive cardiac repair with curcumin is associated with a dual ACE-inhibition and angiotensin II AT1 receptor antagonism after myocardial infarction. Sprague-Dawley rats were subjected to 45min ischemia followed by 7 and 42 days of reperfusion, respectively. Curcumin was fed orally at a dose of 150mg/kg/day only during reperfusion. Relative to the control animals, dietary treatment with curcumin significantly reduced levels of ACE and AT1 receptor protein as determined by Western blot assay, coincident with less locally-expressed ACE and AT1 receptor in myocardium and coronary vessels as identified by immunohistochemistry. Along with this inhibition, curcumin significantly increased protein level of AT2 receptor and its expression compared with the control. As evidenced by less collagen deposition in fibrotic myocardium, curcumin also reduced the extent of collagen-rich scar and increased mass of viable myocardium detected by Masson׳s trichrome staining. Echocardiography showed that the wall thickness of the infarcted anterior septum in the curcumin group was significantly greater than that in the control group. Cardiac contractile function was improved in the curcumin treated animals as measured by fraction shortening and ejection fraction. In cultured cardiac muscle cells, curcumin inhibited oxidant-induced AT1 receptor expression and promoted cell survival. These results suggest that curcumin attenuates maladaptive cardiac repair and enhances cardiac function, primarily mediated by a dual ACE-inhibition and AT1 receptor antagonism after myocardial infarction.

  15. Atrial overexpression of angiotensin-converting enzyme 2 improves the canine rapid atrial pacing-induced structural and electrical remodeling. Fan, ACE2 improves atrial substrate remodeling.

    PubMed

    Fan, Jinqi; Zou, Lili; Cui, Kun; Woo, Kamsang; Du, Huaan; Chen, Shaojie; Ling, Zhiyu; Zhang, Quanjun; Zhang, Bo; Lan, Xianbin; Su, Li; Zrenner, Bernhard; Yin, Yuehui

    2015-01-01

    The purpose of this study was to investigate whether atrial overexpression of angiotensin-converting enzyme 2 (ACE2) by homogeneous transmural atrial gene transfer can reverse atrial remodeling and its mechanisms in a canine atrial-pacing model. Twenty-eight mongrel dogs were randomly divided into four groups: Sham-operated, AF-control, gene therapy with adenovirus-enhanced green fluorescent protein (Ad-EGFP) and gene therapy with Ad-ACE2 (Ad-ACE2) (n = 7 per subgroup). AF was induced in all dogs except the Sham-operated group by rapid atrial pacing at 450 beats/min for 2 weeks. Ad-EGFP and Ad-ACE2 group then received epicardial gene painting. Three weeks after gene transfer, all animals except the Sham group underwent rapid atrial pacing for another 3 weeks and then invasive electrophysiological, histological and molecular studies. The Ad-ACE2 group showed an increased ACE2 and Angiotensin-(1-7) expression, and decreased Angiotensin II expression in comparison with Ad-EGFP and AF-control group. ACE2 overexpression attenuated rapid atrial pacing-induced increase in activated extracellular signal-regulated kinases and mitogen-activated protein kinases (MAPKs) levels, and decrease in MAPK phosphatase 1(MKP-1) level, resulting in attenuation of atrial fibrosis collagen protein markers and transforming growth factor-β1. Additionally, ACE2 overexpression also modulated the tachypacing-induced up-regulation of connexin 40, down-regulation of connexin 43 and Kv4.2, and significantly decreased the inducibility and duration of AF. ACE2 overexpression could shift the renin-angiotensin system balance towards the protective axis, attenuate cardiac fibrosis remodeling associated with up-regulation of MKP-1 and reduction of MAPKs activities, modulate tachypacing-induced ion channels and connexin remodeling, and subsequently reduce the inducibility and duration of AF.

  16. [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. PMID:27071265

  17. 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

  18. [A Case of Life-Threatening Angioedema Occurred During Prolonged Angiotensin-Converting Enzyme Inhibitor Treatment].

    PubMed

    Nakamura, Rintaro; Nihei, Shun-Ichi; Arai, Hideaki; Nagata, Keiji; Isa, Yasuki; Harayama, Nobuya; Aibara, Keiji; Kamochi, Msayuki

    2016-03-01

    Although angiotensin-converting enzyme (ACE) inhibitors are widely used as the first choice drug for treating hypertension, we have only a superficial understanding of their relationship to angioedema. We report a case of life-threatening angioedema. The case was a 60-year-old man who had been taking an ACE inhibitor for hypertension for 11 years. He visited his home doctor for dyspnea, and tongue and neck swelling. He was transported to our hospital because of the possibility of airway obstruction. On admission, his tongue and neck swelling became more severe. We performed an intubation using an endoscope and started airway management. We also stopped his ACE inhibitor. The severe tongue and neck swelling improved gradually and he was extubated on day 3. On the fifth day he was discharged. We diagnosed angioedema caused by an ACE inhibitor. Although the risk of airway obstruction with ACE inhibitors is acknowledged, we have only a superficial understanding of how prolonged ACE inhibitor treatment induces angioedema. So we should consider angioedema in cases of taking ACE inhibitors, especially in cases of prolonged treatment. PMID:26972946

  19. 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…

  20. Investigation of the energy barrier to the rotation of amide CN bonds in ACE inhibitors by NMR, dynamic HPLC and DFT.

    PubMed

    Bouabdallah, S; Ben Dhia, M T; Driss, M R; Touil, S

    2016-09-01

    The isomerizations of Enalapril, Perindopril, Enalaprilat and Lisinopril have been investigated using NMR spectroscopic, dynamic chromatographic, unified equation and DFT theoretical calculations. The thermodynamic parameters (ΔH, ΔS and ΔG) were determined by varying the temperature in the NMR experiments. At the coalescence temperature, we can evaluate the isomerization barrier to the rotation (ΔG(≠)) around the amide bond. Using dynamics chromatography and an unified equation introduced by Trap, we can determine isomerization rate constants and Gibbs activation energies. Molecular mechanics calculations also provided evidence for the presence of low energy conformers for the ACE due to restricted amide rotation. With the value of barriers (ΔE) between them of the order of (20kJmol(-1)), which is in agreement with the dynamic NMR results and DFT calculations.

  1. Investigation of the energy barrier to the rotation of amide CN bonds in ACE inhibitors by NMR, dynamic HPLC and DFT.

    PubMed

    Bouabdallah, S; Ben Dhia, M T; Driss, M R; Touil, S

    2016-09-01

    The isomerizations of Enalapril, Perindopril, Enalaprilat and Lisinopril have been investigated using NMR spectroscopic, dynamic chromatographic, unified equation and DFT theoretical calculations. The thermodynamic parameters (ΔH, ΔS and ΔG) were determined by varying the temperature in the NMR experiments. At the coalescence temperature, we can evaluate the isomerization barrier to the rotation (ΔG(≠)) around the amide bond. Using dynamics chromatography and an unified equation introduced by Trap, we can determine isomerization rate constants and Gibbs activation energies. Molecular mechanics calculations also provided evidence for the presence of low energy conformers for the ACE due to restricted amide rotation. With the value of barriers (ΔE) between them of the order of (20kJmol(-1)), which is in agreement with the dynamic NMR results and DFT calculations. PMID:27344631

  2. ACES: Final performance report

    NASA Astrophysics Data System (ADS)

    Baxter, V. D.

    1981-04-01

    The performance of the ACES in a single family residence near Knoxville, Tennessee was compared with that of two different air to air heat pumps in an identical house. Results show that energy was saved for the testing years. In addition to reducing consumption, the ACES significantly reduced integrated peak utility demands. Reinsulation of the ice storage bin reduced heat leakage rates by about 40 percent and resulted in increasing ground temperatures by an average of 5.60 C over first year levels. The demonstration project and the ACES concept are described. Data acquisition procedures, system modifications, steady state performance, annual cycle performance, and effects of modifications are discussed.

  3. ACE blood test

    MedlinePlus

    Serum angiotensin-converting enzyme; SACE ... Chernecky CC, Berger BJ. Angiotensin-converting enzyme (ACE) - blood. In: Chernecky CC, Berger BJ, eds. Laboratory Tests and Diagnostic Procedures . 6th ed. Philadelphia, PA: Elsevier Saunders; 2013:138-139.

  4. Difluoromethane, a New and Improved Inhibitor of Methanotrophy

    PubMed Central

    Miller, Laurence G.; Sasson, Caleb; Oremland, Ronald 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. PMID:9797290

  5. Improving Viral Protease Inhibitors to Counter Drug Resistance.

    PubMed

    Kurt Yilmaz, Nese; Swanstrom, Ronald; Schiffer, Celia A

    2016-07-01

    Drug resistance is a major problem in health care, undermining therapy outcomes and necessitating novel approaches to drug design. Extensive studies on resistance to viral protease inhibitors, particularly those of HIV-1 and hepatitis C virus (HCV) protease, revealed a plethora of information on the structural and molecular mechanisms underlying resistance. These insights led to several strategies to improve viral protease inhibitors to counter resistance, such as exploiting the essential biological function and leveraging evolutionary constraints. Incorporation of these strategies into structure-based drug design can minimize vulnerability to resistance, not only for viral proteases but for other quickly evolving drug targets as well, toward designing inhibitors one step ahead of evolution to counter resistance with more intelligent and rational design. PMID:27090931

  6. 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.

  7. 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 Central

    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 NG-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. PMID:27143859

  8. 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.

  9. Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules.

    PubMed

    Das, Undurti N

    2008-01-01

    Lowering plasma low density lipoprotein-cholesterol (LDL-C), blood pressure, homocysteine, and preventing platelet aggregation using a combination of a statin, three blood pressure lowering drugs such as a thiazide, a beta blocker, and an angiotensin converting enzyme (ACE) inhibitor each at half standard dose; folic acid; and aspirin-called as polypill- was estimated to reduce cardiovascular events by approximately 80%. Essential fatty acids (EFAs) and their long-chain metabolites: gamma-linolenic acid (GLA), dihomo-GLA (DGLA), arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and other products such as prostaglandins E1 (PGE1), prostacyclin (PGI2), PGI3, lipoxins (LXs), resolvins, protectins including neuroprotectin D1 (NPD1) prevent platelet aggregation, lower blood pressure, have anti-arrhythmic action, reduce LDL-C, ameliorate the adverse actions of homocysteine, show anti-inflammatory actions, activate telomerase, and have cytoprotective properties. Thus, EFAs and their metabolites show all the classic actions expected of the "polypill". Unlike the proposed "polypill", EFAs are endogenous molecules present in almost all tissues, have no significant or few side effects, can be taken orally for long periods of time even by pregnant women, lactating mothers, and infants, children, and adults; and have been known to reduce the incidence cardiovascular diseases including stroke. In addition, various EFAs and their long-chain metabolites not only enhance nitric oxide generation but also react with nitric oxide to yield their respective nitroalkene derivatives that produce vascular relaxation, inhibit neutrophil degranulation and superoxide formation, inhibit platelet activation, and possess PPAR-gamma ligand activity and release NO, thus prevent platelet aggregation, thrombus formation, atherosclerosis, and cardiovascular diseases. Based on these evidences, I propose that a rational combination of omega-3 and omega-6 fatty acids and the

  10. Providing Size-Resolved Mixing State Inputs to Improve Aerosol Optics Models: Comparison of ACE-Asia Aerosol Chemical Measurements for Different Source Regions With Simultaneous Optical Measurements

    NASA Astrophysics Data System (ADS)

    Sullivan, R. C.; Poon, G.; Guazzotti, S.; Sodeman, D.; Holecek, J.; Spencer, M.; Prather, K.

    2005-12-01

    Measurements made of the aerodynamic size and chemical composition of single aerosol particles on board the R/V Ronald H. Brown sailing between Hawaii and the Sea of Japan during ACE-Asia in 2001 revealed a complex mixture of mineral dust, organic carbon, elemental carbon, sulfates, nitrates, chloride, ammonium, and sea salt. The air mass source regions included influences from the Pacific Ocean, Miyakejima volcano, Gobi and Taklimakan Deserts, Shanghai, Japan, and Korea. The particle composition sampled from each of these regions showed unique changes in the aerosol's mixing state. This complexity presents major challenges in accurately modeling the optical properties of the Asian aerosol. The degree of closure between the measured chemical and optical properties of this aerosol and those predicted by models has been presented by Quinn et al. [JGR, 109, D19S01, doi: 10.1029/2003JD004010, 2004]. Differences between measured and calculated aerosol absorption coefficients were partly attributed to the assumption of internally mixed homogeneous spheres for the aerosol population. Good correlations between measured and calculated aerosol mass and light scattering were found but relied on particle shapes not confirmed by measurements. To better our understanding of the relationship between aerosol chemistry and optical measurements, and provide more detailed inputs to improve the predictions of optical models, we present size-resolved single-particle mixing state results obtained by an ATOFMS for the seven air mass source regions described by Quinn et al. (2004). Our results do not support the assumption of a homogeneous internally mixed aerosol population for many of the source regions. Particular focus is given to the mixing state and chemical associations of sulfate, nitrate, chloride, ammonium, OC, EC, dust, and sea salt. We demonstrate the segregation of ammonium, sulfate, and nitrate within individual particles throughout the study and discuss the different

  11. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism

    PubMed Central

    2004-01-01

    In the RAS (renin–angiotensin system), Ang I (angiotensin I) is cleaved by ACE (angiotensin-converting enzyme) to form Ang II (angiotensin II), which has effects on blood pressure, fluid and electrolyte homoeostasis. We have examined the kinetics of angiotensin peptide cleavage by full-length human ACE, the separate N- and C-domains of ACE, the homologue of ACE, ACE2, and NEP (neprilysin). The activity of the enzyme preparations was determined by active-site titrations using competitive tight-binding inhibitors and fluorogenic substrates. Ang I was effectively cleaved by NEP to Ang (1–7) (kcat/Km of 6.2×105 M−1·s−1), but was a poor substrate for ACE2 (kcat/Km of 3.3×104 M−1·s−1). Ang (1–9) was a better substrate for NEP than ACE (kcat/Km of 3.7×105 M−1·s−1 compared with kcat/Km of 6.8×104 M−1·s−1). Ang II was cleaved efficiently by ACE2 to Ang (1–7) (kcat/Km of 2.2×106 M−1·s−1) and was cleaved by NEP (kcat/Km of 2.2×105 M−1·s−1) to several degradation products. In contrast with a previous report, Ang (1–7), like Ang I and Ang (1–9), was cleaved with a similar efficiency by both the N- and C-domains of ACE (kcat/Km of 3.6×105 M−1·s−1 compared with kcat/Km of 3.3×105 M−1·s−1). The two active sites of ACE exhibited negative co-operativity when either Ang I or Ang (1–7) was the substrate. In addition, a range of ACE inhibitors failed to inhibit ACE2. These kinetic data highlight that the flux of peptides through the RAS is complex, with the levels of ACE, ACE2 and NEP dictating whether vasoconstriction or vasodilation will predominate. PMID:15283675

  12. 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…

  13. Strong suppression of the renin-angiotensin system has a renal-protective effect in hypertensive patients: high-dose ARB with ACE inhibitor (Hawaii) study.

    PubMed

    Ohishi, Mitsuru; Takeya, Yasushi; Tatara, Yuji; Yamamoto, Koichi; Onishi, Miyuki; Maekawa, Yoshihiro; Kamide, Kei; Rakugi, Hiromi

    2010-11-01

    The principal means for reducing proteinuria in patients with chronic kidney disease are strong blockade of the renin-angiotensin system and strict regulation of blood pressure (BP). This study compared the efficacy of the maximum permissible doses of two common angiotensin receptor blockers (ARBs), namely valsartan (maximum dose=160 mg per day) and olmesartan (maximum dose=40 mg per day). We also investigated whether a high-dose ARB or the combination of an angiotensin-converting enzyme inhibitor with a high-dose ARB would be more renal protective. We recruited 87 poorly controlled hypertensive patients. In the first study, 50 patients without proteinuria were switched from valsartan (160 mg per day) to olmesartan (40 mg per day) for 4 months. In the second study, 37 patients with proteinuria were randomized to either switch from valsartan 160 mg per day to 40 mg per day olmesartan (n=19; Olm-G) or addition of 2.5-10 mg per day imidapril (stepped up by 2.5 mg per month) to valsartan at 160 mg per day (n=18; Imi-G). After 4 months, the BP level decreased (first study) from 157/88 mm Hg to 145/82 mm Hg (P<0.001) and (second study) from 149/86 mm Hg to 135/77 mm Hg and 145/82 mm Hg for Olm-G and Imi-G, respectively. Furthermore, in the second study, urinary protein/creatinine excretion was reduced from 2.0±1.8 g g⁻¹ to 0.8±0.8 g g⁻¹ (P=0.0242) in Olm-G and from 1.4±1.3 g g⁻¹ to 0.9±1.0 g g⁻¹ (P=0.0398) in Imi-G. The significance persisted after adjustment for BP or other risk factors. Our results suggested that the maximum dose of olmesartan was more effective than that of valsartan and comparable with the combination of valsartan and imidapril for reducing BP and proteinuria in poorly controlled hypertensive patients. PMID:20703230

  14. Affinity purification of angiotensin converting enzyme inhibitory peptides using immobilized ACE.

    PubMed

    Megías, Cristina; Pedroche, Justo; Yust, María del Mar; Alaiz, Manuel; Girón-Calle, Julio; Millan, Francisco; Vioque, Javier

    2006-09-20

    A lung extract rich in angiotensin converting enzyme (ACE) and pure ACE were immobilized by reaction with the activated support 4 BCL glyoxyl-agarose. These immobilized ACE derivatives were used for purification of ACE inhibitory peptides by affinity chromatography. The immobilized lung extract was used to purify inhibitory peptides from sunflower and rapeseed protein hydrolysates that had been obtained by treatment of protein isolates with alcalase. The ACE binding peptides that were retained by the derivatives were specifically released by treatment with the ACE inhibitor captopril and further purified by reverse-phase C18 HPLC chromatography. Inhibitory peptides with IC50 50 and 150 times lower than those of the original sunflower and rapeseed hydrolysates, respectively, were obtained. The derivative prepared using pure ACE was used for purification of ACE inhibitory peptides from the same type of sunflower protein hydrolysate. ACE binding peptides were released from the ACE-agarose derivatives by treatment with 1 M NaCl and had an IC50 a little higher than those obtained using immobilized extract and elution with captopril. Affinity chromatography facilitated the purification of ACE inhibitory peptides and potentially other bioactive peptides present in food proteins.

  15. The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study

    PubMed Central

    Altmaier, Elisabeth; Menni, Cristina; Heier, Margit; Meisinger, Christa; Thorand, Barbara; Quell, Jan; Kobl, Michael; Römisch-Margl, Werner; Valdes, Ana M.; Mangino, Massimo; Waldenberger, Melanie; Strauch, Konstantin; Illig, Thomas; Adamski, Jerzy; Spector, Tim; Gieger, Christian; Suhre, Karsten; Kastenmüller, Gabi

    2016-01-01

    Angiotensin-I-converting enzyme (ACE) inhibitors are an important class of antihypertensives whose action on the human organism is still not fully understood. Although it is known that ACE especially cleaves COOH-terminal dipeptides from active polypeptides, the whole range of substrates and products is still unknown. When analyzing the action of ACE inhibitors, effects of genetic variation on metabolism need to be considered since genetic variance in the ACE gene locus was found to be associated with ACE-concentration in blood as well as with changes in the metabolic profiles of a general population. To investigate the interactions between genetic variance at the ACE-locus and the influence of ACE-therapy on the metabolic status we analyzed 517 metabolites in 1,361 participants from the KORA F4 study. We replicated our results in 1,964 individuals from TwinsUK. We observed differences in the concentration of five dipeptides and three ratios of di- and oligopeptides between ACE inhibitor users and non-users that were genotype dependent. Such changes in the concentration affected major homozygotes, and to a lesser extent heterozygotes, while minor homozygotes showed no or only small changes in the metabolite status. Two of these resulting dipeptides, namely aspartylphenylalanine and phenylalanylserine, showed significant associations with blood pressure which qualifies them—and perhaps also the other dipeptides—as readouts of ACE-activity. Since so far ACE activity measurement is substrate specific due to the usage of only one oligopeptide, taking several dipeptides as potential products of ACE into account may provide a broader picture of the ACE activity. PMID:27120469

  16. The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study.

    PubMed

    Altmaier, Elisabeth; Menni, Cristina; Heier, Margit; Meisinger, Christa; Thorand, Barbara; Quell, Jan; Kobl, Michael; Römisch-Margl, Werner; Valdes, Ana M; Mangino, Massimo; Waldenberger, Melanie; Strauch, Konstantin; Illig, Thomas; Adamski, Jerzy; Spector, Tim; Gieger, Christian; Suhre, Karsten; Kastenmüller, Gabi

    2016-01-01

    Angiotensin-I-converting enzyme (ACE) inhibitors are an important class of antihypertensives whose action on the human organism is still not fully understood. Although it is known that ACE especially cleaves COOH-terminal dipeptides from active polypeptides, the whole range of substrates and products is still unknown. When analyzing the action of ACE inhibitors, effects of genetic variation on metabolism need to be considered since genetic variance in the ACE gene locus was found to be associated with ACE-concentration in blood as well as with changes in the metabolic profiles of a general population. To investigate the interactions between genetic variance at the ACE-locus and the influence of ACE-therapy on the metabolic status we analyzed 517 metabolites in 1,361 participants from the KORA F4 study. We replicated our results in 1,964 individuals from TwinsUK. We observed differences in the concentration of five dipeptides and three ratios of di- and oligopeptides between ACE inhibitor users and non-users that were genotype dependent. Such changes in the concentration affected major homozygotes, and to a lesser extent heterozygotes, while minor homozygotes showed no or only small changes in the metabolite status. Two of these resulting dipeptides, namely aspartylphenylalanine and phenylalanylserine, showed significant associations with blood pressure which qualifies them-and perhaps also the other dipeptides-as readouts of ACE-activity. Since so far ACE activity measurement is substrate specific due to the usage of only one oligopeptide, taking several dipeptides as potential products of ACE into account may provide a broader picture of the ACE activity. PMID:27120469

  17. 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.

  18. Possible involvement of ATP-dependent K-channel related mechanisms in the antihypertensive and cough suppressant effects of the novel ACE inhibitor (2S, 3aS, 7aS)-1-(N2-nicotinoyl-L-lysyl-gamma-D-glutamyl)octahydro-1H- indole-2-carboxylic acid.

    PubMed

    Nagata, S; Takeyama, K; Hosoki, K; Karasawa, T

    1997-06-01

    The antihypertensive and cough suppressant mechanisms of DU-1777 ((2S,3aS,7aS)-1-(N2-nicotinoyl-L-lsyl-gamma-D-glutamyl )octahydro-1H-indole-2 -carboxylic acid, CAS 116662-73-8), a new long-acting angiotensin-1-converting enzyme (ACE) inhibitor, were investigated in vivo and in vitro. The antihypertensive effects of DU-1777 at 10 mg/kg p.o. and cromakalim at 0.3 mg/kg p.o. were partially (about 60%) or fully antagonized by glibenclamide at 10 mg/kg i.v. in 2-kidney, 1-clip renal hypertensive rats (2K-1C RHR). The antihypertensive effects of a Ca blocker (nifedipine) and other ACE inhibitors (captopril, alacepril, enalapril, lisinopril, imidapril and quanapril) were not antagonized by glibenclamide. In deoxycorticosterone acetate-salt hypertensive rats (DOCA-HR), the antihypertensive effects of DU-1777 at 3-30 mg/kg p.o. were fully antagonized by glibenclamide. However, in vitro, DU-1777 (10(-6)-10(-3) mol/l) did not affect aortic ring contractions induced by high K (30 mmol/l). In guinea pig, citric acid induced cough was increased by ACE inhibitors, captopril, alacepril, enalapril and lisinopril (10 and 30 mg/kg p.o.). DU-1777 had a tendency to decrease citric acid induced cough and the effect was antagonized by glibenclamide. These results suggest that while DU-1777 itself does not open ATP-dependent K channel, it indirectly produces these effects through unknown mechanisms in vivo. Moreover, these effects contributed to the antihypertensive effect in DOCA-HR and cough suppressant effect in guinea pigs. PMID:9239450

  19. 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

  20. 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

  1. Inhibitors

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  2. 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.

  3. ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis.

    PubMed

    Simões E Silva, Ana Cristina; Teixeira, Mauro Martins

    2016-05-01

    The Renin Angiotensin System (RAS) is a pivotal physiological regulator of heart and kidney homeostasis, but also plays an important role in the pathophysiology of heart and kidney diseases. Recently, new components of the RAS have been discovered, including angiotensin converting enzyme 2 (ACE2), Angiotensin(Ang)-(1-7), Mas receptor, Ang-(1-9) and Alamandine. These new components of RAS are formed by the hydrolysis of Ang I and Ang II and, in general, counteract the effects of Ang II. In experimental models of heart and renal diseases, Ang-(1-7), Ang-(1-9) and Alamandine produced vasodilation, inhibition of cell growth, anti-thrombotic, anti-inflammatory and anti-fibrotic effects. Recent pharmacological strategies have been proposed to potentiate the effects or to enhance the formation of Ang-(1-7) and Ang-(1-9), including ACE2 activators, Ang-(1-7) in hydroxypropyl β-cyclodextrin, cyclized form of Ang-(1-7) and nonpeptide synthetic Mas receptor agonists. Here, we review the role and effects of ACE2, ACE2 activators, Ang-(1-7) and synthetic Mas receptor agonists in the control of inflammation and fibrosis in cardiovascular and renal diseases and as counter-regulators of the ACE-Ang II-AT1 axis. We briefly comment on the therapeutic potential of the novel members of RAS, Ang-(1-9) and alamandine, and the interactions between classical RAS inhibitors and new players in heart and kidney diseases. PMID:26995300

  4. ACE to Ulysses Coherences

    NASA Astrophysics Data System (ADS)

    Thomson, D. J.; Maclennan, C. G.; Lanzerotti, L. J.

    2006-12-01

    The EPAM charged particle instrument on ACE is the backup for the HISCALE instrument on Ulysses making the two ideally suited for spatial coherence studies over large heliosphere distances. Fluxes of low-energy ( ~50 - 200 keV) electrons are detected in eight spatial sectors on both spacecraft. A spherical harmonic description of the particle flux as a function of time using only the l=0 and l=1 degree coefficients describes most of the observed flux. Here we concentrate on the three l=1 coefficients for the 60--100 kev electrons.Between the two spacecraft these result in nine coherence estimates that are all typically moderately coherent, but the fact that the different coefficients at each spacecraft are also coherent with each other makes interpretation difficult. To avoid this difficulty we estimated the canonical coherences between the two groups of three series. This, in effect, chooses an optimum coordinate system at each spacecraft and for each frequency and estimates the coherence in this frame. Using one--minute data, we find that the canonical coherences are generally larger at high frequencies (3 mHz and above) than they are at low frequencies. This appears to be generally true and does not depend particularly on time, range, etc. However, if the data segment is chosen too long, say > 30 days with 1--minute sampling, the coherence at high frequencies drops. This may be because the spatial and temporal features of the mode are confounded, or possibly because the solar modes p--modes are known to change frequency with solar activity, so do not appear coherent on long blocks.The coherences are not smooth functions of frequency, but have a bimodal distribution particularly in the 100 μHz to 5 mHz range. Classifying the data at frequencies where the canonical coherences are high in terms of apparent polarization and orientation, we note two major families of modes that appear to be organized by the Parker spiral. The magnetic field data on the two

  5. ALTUS Cumulus Electrification Study (ACES)

    NASA Technical Reports Server (NTRS)

    Kim, Tony; Blakeslee, Richard; Russell, Larry W. (Technical Monitor)

    2002-01-01

    The ALTUS Cumulus Electrification Study (ACES) is an uninhabited aerial vehicle (UAV)-based project that will investigate thunderstorms in the vicinity of the Florida Everglades in August 2002. ACES is being conducted to both investigate storm electrical activity and its relationship to storm morphology, and validate Tropical Rainfall Measurement Mission (TRMM) satellite measurements. In addition, as part of NASA's UAV-based science demonstration program, this project will provide a scientifically useful demonstration of the utility and promise of UAV platforms for Earth science and applications observations. Part of the demonstration involves getting approvals from the Federal Aviation Administration and the NASA airworthiness flight safety review board. ACES will employ the ALTUS II aircraft, built by General Atomics - Aeronautical Systems, Inc. Key science objectives simultaneously addressed by ACES are to: (1) investigate lightning-storm relationships, (2) study storm electrical budgets, and (3) provide Lightning Imaging Sensor validation. The ACES payload, already developed and flown on ALTUS, includes electrical, magnetic, and optical sensors to remotely characterize the lightning activity and the electrical environment within and around thunderstorms. ACES will contribute important electrical and optical measurements not available from other sources. Also, the high altitude vantage point of the UAV observing platform (up to 55,000 feet) offers a useful 'cloud-top' perspective. By taking advantage of its slow flight speed (70 to 100 knots), long endurance, and high altitude flight, the ALTUS will be flown near, and when possible, above (but never into) thunderstorms for long periods of time, allowing investigations to be conducted over entire storm life cycles. In addition, concurrent ground-based observations will enable the UAV measurements to be more completely interpreted and evaluated in the context of the thunderstorm structure, evolution, and

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

    PubMed

    Nguyen, Binh Cao Quan; Tawata, Shinkichi

    2015-01-01

    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. PMID:26287130

  7. ACEE program rationale and implementation

    SciTech Connect

    Aiken, W.S. Jr.; Petersen, R.H.

    1982-08-01

    The impact of the Aircraft Energy Efficiency program (ACEE) on commercial aviation is examined. In addition to the emphasis on air transport fuel efficiency, topics such as airline operating costs, air transport effects on U.S. trade, and fuel price forecasts are addressed. An overview of the program and its contribution to aviation technology is included.

  8. Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties.

    PubMed

    Sloman, David L; Noucti, Njamkou; Altman, Michael D; Chen, Dapeng; Mislak, Andrea C; Szewczak, Alexander; Hayashi, Mansuo; Warren, Lee; Dellovade, Tammy; Wu, Zhenhua; Marcus, Jacob; Walker, Deborah; Su, Hua-Poo; Edavettal, Suzanne C; Munshi, Sanjeev; Hutton, Michael; Nuthall, Hugh; Stanton, Matthew G

    2016-09-01

    Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer's disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility. PMID:27491711

  9. 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

  10. 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.

  11. 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.

  12. Improved low molecular weight Myc-Max inhibitors.

    PubMed

    Wang, Huabo; Hammoudeh, Dalia I; Follis, Ariele Viacava; Reese, Brian E; Lazo, John S; Metallo, Steven J; Prochownik, Edward V

    2007-09-01

    Compounds that selectively prevent or disrupt the association between the c-Myc oncoprotein and its obligate heterodimeric partner Max (Myc-Max compounds) have been identified previously by high-throughput screening of chemical libraries. Although these agents specifically inhibit the growth of c-Myc-expressing cells, their clinical applicability is limited by their low potency. We describe here several chemical modifications of one of these original compounds, 10058-F4, which result in significant improvements in efficacy. Compared with the parent structure, these analogues show enhanced growth inhibition of c-Myc-expressing cells in a manner that generally correlates with their ability to disrupt c-Myc-Max association and DNA binding. Furthermore, we show by use of a sensitive fluorescence polarization assay that both 10058-F4 and its active analogues bind specifically to monomeric c-Myc. These studies show that improved Myc-Max compounds can be generated by a directed approach involving deliberate modification of an index compound. They further show that the compounds specifically target c-Myc, which exists in a dynamic and relatively unstructured state with only partial and transient alpha-helical content.

  13. 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…

  14. 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.

  15. Shedding of the germinal angiotensin I-converting enzyme (gACE) involves a serine protease and is activated by epididymal fluid.

    PubMed

    Thimon, Véronique; Métayer, Sonia; Belghazi, Maya; Dacheux, Françoise; Dacheux, Jean-Louis; Gatti, Jean-Luc

    2005-11-01

    The present report describes how the soluble germinal angiotensin I-converting enzyme (gACE) appears in the epididymal fluid, where it has been identified in some laboratory rodents and domestic ungulates. We showed that this gACE results from an active proteolytic process that releases the enzyme's extracellular domain from sperm in a precise spatiotemporal location during epididymal transit and that this process involves serine protease activity. Using polyclonal antibodies against the C-terminal intracellular sequence of ACE, a fragment of approximately 10 kDa was detected on the sperm extract only in the epididymal region, where the gACE release occurs. The fluid enzyme was purified, and the cleavage site was determined by mass spectrometry to be between Arg622 and Leu623 of the mature sheep gACE sequence (equivalent to Arg627 and Arg1203 of the human mature gACE and somatic ACE sequences, respectively). Thereafter, the C-terminal Arg was removed, leaving Ala621 as a C-terminal. Using an in vitro assay, gACE cleavage from sperm was strongly increased by the presence of epididymal fluid from the release zone, and this increase was inhibited specifically by the serine protease-inhibitor AEBSF but not by para-aminobenzamidine. None of the other inhibitors tested, such as metallo- or cystein-protease inhibitors, had a similar effect on release. It was also found that this process did not involve changes in gACE phosphorylation. PMID:15987822

  16. Targeted in-vivo computed tomography (CT) imaging of tissue ACE using concentrated lisinopril-capped gold nanoparticle solutions

    NASA Astrophysics Data System (ADS)

    Daniel, Marie-Christine; Aras, Omer; Smith, Mark F.; Nan, Anjan; Fleiter, Thorsten

    2010-04-01

    The development of cardiac and pulmonary fibrosis have been associated with overexpression of angiotensin-converting enzyme (ACE). Moreover, ACE inhibitors, such as lisinopril, have shown a benificial effect for patients diagnosed with heart failure or systemic hypertension. Thus targeted imaging of the ACE is of crucial importance for monitoring of the tissue ACE activity as well as the treatment efficacy in heart failure. In this respect, lisinopril-capped gold nanoparticles were prepared to provide a new type of probe for targeted molecular imaging of ACE by tuned K-edge computed tomography (CT) imaging. Concentrated solutions of these modified gold nanoparticles, with a diameter around 16 nm, showed high contrast in CT imaging. These new targeted imaging agents were thus used for in vivo imaging on rat models.

  17. Highly improved antiparasitic activity after introduction of an N-benzylimidazole moiety on protein farnesyltransferase inhibitors.

    PubMed

    Bosc, Damien; Mouray, Elisabeth; Cojean, Sandrine; Franco, Caio Haddad; Loiseau, Philippe M; Freitas-Junior, Lucio H; Moraes, Carolina Borsoi; Grellier, Philippe; Dubois, Joëlle

    2016-02-15

    In our search for new protein farnesyltransferase inhibitors with improved antiparasitic activities, we modified our previously developed 3-arylthiophene series of inhibitors by replacing the thioisopropyl group by different substituted imidazolylmethanamino moieties. Twenty four new derivatives were synthesized and evaluated against human and parasite farnesyltransferases, and their anti-parasitic activity was determined against Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani. Introduction of a N-p-substituted-benzylimidazole led to significantly increase the inhibition of parasite proliferation in the submicromolar range. The structure of the best inhibitors was parasite dependent. Three compounds possess IC50 values at the same range as the reference miltefosine against L. donovani proliferation and other new derivatives display high level of anti-trypanosomal activity against T. cruzi, higher or in the same order of magnitude as the reference compounds benznidazole and nifurtimox. PMID:26774924

  18. 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.

  19. Angiotensin converting enzyme inhibitors produced by Streptomyces chromofuscus. Discovery, taxonomy and fermentation.

    PubMed

    Nakatsukasa, W M; Wilgus, R M; Thomas, D N; Mertz, F P; Boeck, L D

    1985-08-01

    Culture A58365.1, NRRL 15098, identified as a new strain of Streptomyces chromofuscus, was found to produce two novel angiotensin converting enzyme (ACE) inhibitors, A58365A and A58365B. Fermentation medium studies afforded an increase in ACE inhibitor titers from less than 1 microgram/ml to greater than 20 micrograms/ml. Proline was the obligatory supplement for ACE inhibitor biosynthesis.

  20. 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.

  1. Structure-Guided Development of Deoxycytidine Kinase Inhibitors with Nanomolar Affinity and Improved Metabolic Stability

    PubMed Central

    2015-01-01

    Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers. PMID:25341194

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

    PubMed Central

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

    2011-01-01

    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 Kd and IC50 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. PMID:22169600

  3. Improvement of a microbial fuel cell performance as a BOD sensor using respiratory inhibitors.

    PubMed

    Chang, In Seop; Moon, Hyunsoo; Jang, Jae Kyung; Kim, Byung Hong

    2005-03-15

    Studies were made to improve the performance of a microbial fuel cell (MFC) as a biochemical oxygen demand (BOD) sensor. The signal from MFCs decreased in the presence of electron acceptors of higher redox potential such as nitrate and oxygen. The addition of azide and cyanide did not change the signal in the absence of the electron acceptors. The respiratory inhibitors eliminated the inhibitory effects of the electron acceptors on the current generation from MFCs. Similar results were obtained using oligotrophic MFCs fed with an environmental sample that contained nitrate. The use of the respiratory inhibitors is therefore recommended for the accurate BOD measurement of environmental samples containing nitrate and/or oxygen with an MFC-type BOD sensor.

  4. Expression of Magnaporthe grisea Avirulence Gene ACE1 Is Connected to the Initiation of Appressorium-Mediated Penetration▿

    PubMed Central

    Fudal, Isabelle; Collemare, Jérôme; Böhnert, Heidi U.; Melayah, Delphine; Lebrun, Marc-Henri

    2007-01-01

    Magnaporthe grisea is responsible for a devastating fungal disease of rice called blast. Current control of this disease relies on resistant rice cultivars that recognize M. grisea signals corresponding to specific secreted proteins encoded by avirulence genes. The M. grisea ACE1 avirulence gene differs from others, since it controls the biosynthesis of a secondary metabolite likely recognized by rice cultivars carrying the Pi33 resistance gene. Using a transcriptional fusion between ACE1 promoter and eGFP, we showed that ACE1 is only expressed in appressoria during fungal penetration into rice and barley leaves, onion skin, and cellophane membranes. ACE1 is almost not expressed in appressoria differentiated on Teflon and Mylar artificial membranes. ACE1 expression is not induced by cellophane and plant cell wall components, demonstrating that it does not require typical host plant compounds. Cyclic AMP (cAMP) signaling mutants ΔcpkA and Δmac1 sum1-99 and tetraspanin mutant Δpls1::hph differentiate melanized appressoria with normal turgor but are unable to penetrate host plant leaves. ACE1 is normally expressed in these mutants, suggesting that it does not require cAMP signaling or a successful penetration event. ACE1 is not expressed in appressoria of the buf1::hph mutant defective for melanin biosynthesis and appressorial turgor. The addition of hyperosmotic solutes to buf1::hph appressoria restores appressorial development and ACE1 expression. Treatments of young wild-type appressoria with actin and tubulin inhibitors reduce both fungal penetration and ACE1 expression. These experiments suggest that ACE1 appressorium-specific expression does not depend on host plant signals but is connected to the onset of appressorium-mediated penetration. PMID:17142568

  5. Angiotensin-converting enzyme inhibitors: measurement of relative inhibitory potency and serum drug levels by radioinhibitor binding displacement assay

    SciTech Connect

    Jackson, B.; Cubela, R.; Johnston, C.I.

    1987-06-01

    Radioinhibitor binding displacement, a new method for the measurement of angiotensin-converting enzyme (ACE) competitive inhibitors, has been used to assess the relative potency of nine synthetic ACE inhibitors. MK351A, tyrosyl derivative of enalaprilic acid was iodinated with /sup 125/I and used as the radioligand. (/sup 125/I)MK351A bound to human serum ACE in a concentration-dependent manner. It was displaced in a concentration-dependent manner by all ACE inhibitors tested. Fifty percent displacement of bound (/sup 125/I)MK351A (DD50) for each ACE inhibitor correlated well with inhibitor potency ID50, estimated using an ACE enzymatic activity assay using Hip-His-Leu as substrate (r = 0.96, p less than 0.001; n = 9). The radioinhibitor binding displacement assay was used to measure serum concentration of enalaprilic acid (MK422) in human serum samples. Drug concentration estimated by radioinhibitor binding displacement assay correlated closely (r = 0.96, p less than 0.001; n = 22) with the drug concentration measured by a specific radioimmunoassay. The radioinhibitor binding displacement technique using (/sup 125/I)MK351A as the ligand for human serum ACE has general application to all competitive ACE inhibitors, allowing comparison of in vitro ACE inhibitor potencies and estimation of serum ACE inhibitor concentrations.

  6. Calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors: Effectiveness in combination with diuretics or β-blockers for treating hypertension

    PubMed Central

    Bisognano, John D; McLaughlin, Trent; Roberts, Craig S; Tang, Simon SK

    2007-01-01

    This retrospective database analysis compared the effectiveness of dihydropyridine calcium channel blockers (DHPs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) added to diuretics or β-blockers. Adults with hypertension treated with diuretic or β-blocker monotherapy between 1998 and 2001 were identified from a large US electronic medical records database of primary care practices. Patients were required to have a baseline blood pressure (BP) ≥140/90 mmHg (≥130/80 mmHg for diabetes mellitus) and recorded BP measurements within 6 months before and 1–12 months following index date. Patients were matched 1:1:1 by propensity score to correct for differences in baseline characteristics. 1875 patients met study criteria and 660 (220 in each cohort) were matched based on propensity scores. Matched cohorts had no significant differences in baseline characteristics. Mean changes in systolic/diastolic BP were −17.5/−8.8, −15.7/−6.3, and −13.0/−8.0 mmHg with DHPs, ACE inhibitors, and ARBs, respectively. Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High BP 6/7 goal attainment for each regimen was 47.3%, 40.0%, and 32.2%, respectively. DHPs, ACE inhibitors, and ARBs improved BP when added to patients’ β-blocker or diuretic therapy. The greatest benefits were observed with DHPs, followed by ACE inhibitors, then ARBs. PMID:18078009

  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. 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

  9. Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats.

    PubMed

    Rodefer, Joshua S; Saland, Samantha K; Eckrich, Samuel J

    2012-03-01

    A number of selective phosphodiesterase (PDE) inhibitors have been demonstrated to improve learning in several rodent models of cognition. Given that schizophrenia is associated with impairments in frontal lobe-dependent cognitive functions (e.g., working memory and cognitive flexibility), we examined whether PDE inhibitors would attenuate cognitive deficits associated with schizophrenia. Persistent suppression of N-methyl-D-aspartate (NMDA) receptor function produces enduring structural changes in neocortical and limbic regions in a pattern similar to changes reported in schizophrenia. This similarity suggests that subchronic treatment with NMDA receptor antagonists (e.g., phencyclidine, PCP) may represent a useful preclinical model of neurobiological and related cognitive deficits associated with schizophrenia. We treated male Long-Evans rats with subchronic PCP (5 mg/kg, ip, BID, 7 d) or saline and then examined the effects of acute treatment with selected doses of PDE inhibitors that have been demonstrated to regulate both intracellular levels of cAMP and/or cGMP, and to improve cognitive function. We used an extradimensional-intradimensional (ED/ID) test of cognitive flexibility similar to those used in humans and non-human primates for assessing executive function. Subchronic treatment with PCP produced a selective impairment on ED shift (EDS) performance without significant impairment on any other discrimination problem when compared to saline-treated control animals. Selected doses of the four PDEIs evaluated (PDE2: BAY 60-7550; PDE4: rolipram; PDE5: sildenafil; PDE10A: papaverine) were able to significantly attenuate this cognitive deficit in EDS performance. This suggests that this rodent model of executive function was sensitive to pro-cognitive effects of intracellular effects resulting from PDE inhibition. Together, these data suggest that inhibition of PDE activity may represent valuable therapeutic targets to improve cognition associated with

  10. 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 ...

  11. 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

  12. Crosstalk between ACE2 and PLGF regulates vascular permeability during acute lung injury

    PubMed Central

    Wang, Lantao; Li, Yong; Qin, Hao; Xing, Dong; Su, Jie; Hu, Zhenjie

    2016-01-01

    Angiotensin converting enzyme 2 (ACE2) treatment suppresses the severity of acute lung injury (ALI), through antagonizing hydrolyzing angiotensin II (AngII) and the ALI-induced apoptosis of pulmonary endothelial cells. Nevertheless, the effects of ACE2 on vessel permeability and its relationship with placental growth factor (PLGF) remain ill-defined. In the current study, we examined the relationship between ACE2 and PLGF in ALI model in mice. We used a previously published bleomycin method to induce ALI in mice, and treated the mice with ACE2. We analyzed the levels of PLGF in these mice. The mouse lung vessel permeability was determined by a fluorescence pharmacokinetic assay following i.v. injection of 62.5 µg/kg Visudyne. PLGF pump or soluble Flt-1 (sFlt-1) pump was given to augment or suppress PLGF effects, respectively. The long-term effects on lung function were determined by measurement of lung resistance using methacholine. We found that ACE2 treatment did not alter PLGF levels in lung, but antagonized the effects of PLGF on increases of lung vessel permeability. Ectogenic PLGF abolished the antagonizing effects of ACE2 on the vessel permeability against PLGF. On the other hand, suppression of PLGF signaling mimicked the effects of ACE2 on the vessel permeability against PLGF. The suppression of vessel permeability resulted in improvement of lung function after ALI. Thus, ACE2 may antagonize the PLGF-mediated increases in lung vessel permeability during ALI, resulting in improvement of lung function after ALI. PMID:27158411

  13. 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. PMID:27517126

  14. 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.

  15. 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 Central

    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

    2011-01-01

    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, activation of poly(ADP-ribose) polymerase in the lung and in circulating leukocytes. Female, adult sheep (28–40 kg) were divided into 3 groups. After tracheostomy and under deep anesthesia both vehicle-control (n=5) and captopril (20 mg/kg/d, iv., starting 0.5 hour before the injury) treated (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 TGF-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 ROS-induced PARP over-activation. ACE inhibition may also exert additional beneficial effects by inhibiting the expression of the pro-fibrotic mediator TGF-β. PMID:21701415

  16. 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. PMID:27613825

  17. 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.

  18. 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.

  19. [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. PMID:22849951

  20. [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.

  1. Proteinase inhibitor gene families: strategies for transformation to improve plant defenses against herbivores.

    PubMed

    Ryan, C A

    1989-01-01

    Recent evidence indicates that the presence of serine proteinase inhibitors in plant leaves can reduce predation by insects. Plants can now be transformed with proteinase inhibitor genes with strong promoters to express the inhibitor proteins in relatively high levels at specific times. Inhibitors having variable specificities against digestive proteinases of insects and pathogens can now be assessed for their possible role(s) in natural plant defense and for their potential usefulness in protecting crop plants against herbivores.

  2. An inhibitor of the protein kinases TBK1/IKKε improves obesity-related metabolic dysfunctions

    PubMed Central

    Reilly, Shannon M.; Chiang, Shian-Huey; Decker, Stuart J.; Chang, Louise; Uhm, Maeran; Larsen, Martha J.; Rubin, John R.; Mowers, Jonathan; White, Nicole M.; Hochberg, Irit; Downes, Michael; Yu, Ruth; Liddle, Christopher; Evans, Ronald M.; Oh, Dayoung; Li, Pingping; Olefsky, Jerrold M.; Saltiel, Alan R.

    2013-01-01

    Emerging evidence suggests that inflammation provides a link between obesity and insulin resistance. The noncanonical IκB kinases IKKε and TANK-binding kinase 1 (TBK1) are induced in liver and fat after high fat diet by NF-κB activation, and in turn initiate a program of counter-inflammation that preserves energy storage. Here, we report the discovery of a small molecule inhibitor of these kinases called amlexanox. Treatment of obese mice with amlexanox elevates energy expenditure through increased thermogenesis, producing weight loss, improved insulin sensitivity and decreased steatosis in obese mice. Because of its record of safety in patients, amlexanox may be an interesting candidate for clinical evaluation in the treatment of obesity and related disorders. PMID:23396211

  3. Benzothiophene inhibitors of MK2. Part 2: improvements in kinase selectivity and cell potency.

    PubMed

    Anderson, David R; Meyers, Marvin J; Kurumbail, Ravi G; Caspers, Nicole; Poda, Gennadiy I; Long, Scott A; Pierce, Betsy S; Mahoney, Matthew W; Mourey, Robert J; Parikh, Mihir D

    2009-08-15

    Optimization of kinase selectivity for a set of benzothiophene MK2 inhibitors provided analogs with potencies of less than 500 nM in a cell based assay. The selectivity of the inhibitors can be rationalized by examination of X-ray crystal structures of inhibitors bound to MK2.

  4. 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

  5. Improving compliance and persistence to adjuvant tamoxifen and aromatase inhibitor therapy.

    PubMed

    Hadji, Peyman

    2010-02-01

    Better compliance and persistence with therapy are associated with improved patient outcomes. As more and more patients survive breast cancer, compliance with adjuvant therapy becomes increasingly important. In clinical trials, compliance with adjuvant endocrine therapy among women with breast cancer is usually high. Retrospective analyses of databases and medical records from clinical practice, insurance databases of prescription refills, and survey data show a significant decrease in persistence after 12 months of therapy. With ongoing therapy, a further decline in persistence of up to 50% has been reported. A consistent methodology is needed to measure patient behavior and identify patients who are not adhering to therapy. Promising strategies for enhancing adherence to treatment in clinical practice include improving access to health care, increasing patient satisfaction, managing side effects, patient education, and better communication between the patient and health care provider. Positive relationships between patients and their health care providers, and frequent monitoring and feedback, may be most effective. While the lack of conformity across studies in measuring makes cross-study comparisons difficult, this review evaluates the available data regarding compliance and persistence with adjuvant endocrine therapies for breast cancer (tamoxifen and aromatase inhibitors) and presents strategies for improving adherence.

  6. Angiotensin converting enzyme inhibitors and the reduced risk of Alzheimer's disease in the absence of apolipoprotein E4 allele.

    PubMed

    Qiu, Wei Qiao; Mwamburi, Mkaya; Besser, Lilah M; Zhu, Haihao; Li, Huajie; Wallack, Max; Phillips, Leslie; Qiao, Liyan; Budson, Andrew E; Stern, Robert; Kowall, Neil

    2013-01-01

    Our cross-sectional study showed that the interaction between apolipoprotein E4 (ApoE4) and angiotensin converting enzyme (ACE) inhibitors was associated with Alzheimer's disease (AD). The aim of this longitudinal study was to differentiate whether ACE inhibitors accelerate or reduce the risk of AD in the context of ApoE alleles. Using the longitudinal data from the National Alzheimer's Coordinating Center (NACC) with ApoE genotyping and documentation of ACE inhibitors use, we found that in the absence of ApoE4, subjects who had been taking central ACE inhibitor use (χ2 test: 21% versus 27%, p = 0.0002) or peripheral ACE inhibitor use (χ2 test: 13% versus 27%, p < 0.0001) had lower incidence of AD compared with those who had not been taking an ACE inhibitor. In contrast, in the presence of ApoE4, there was no such association between ACE inhibitor use and the risk of AD. After adjusting for the confounders, central ACE inhibitor use (OR = 0.68, 95% CI = 0.55, 0.83, p = 0.0002) or peripheral ACE inhibitor use (OR = 0.33, 95% CI = 0.33, 0.68, p < 0.0001) still remained inversely associated with a risk of developing AD in ApoE4 non-carriers. In conclusion, ACE inhibitors, especially peripherally acting ones, were associated with a reduced risk of AD in the absence of ApoE4, but had no such effect in those carrying the ApoE4 allele. A double-blind clinical trial should be considered to determine the effect of ACE inhibitors on prevention of AD in the context of ApoE genotype.

  7. The role of ACE2 in cardiovascular physiology.

    PubMed

    Oudit, Gavin Y; Crackower, Michael A; Backx, Peter H; Penninger, Josef M

    2003-04-01

    The renin-angiotensin system (RAS) is critically involved in cardiovascular and renal function and in disease conditions, and has been shown to be a far more complex system than initially thought. A recently discovered homologue of angiotensin-converting enzyme (ACE)--ACE2--appears to negatively regulate the RAS. ACE2 cleaves Ang I and Ang II into the inactive Ang 1-9 and Ang 1-7, respectively. ACE2 is highly expressed in kidney and heart and is especially confined to the endothelium. With quantitative trait locus (QTL) mapping, ACE2 was defined as a QTL on the X chromosome in rat models of hypertension. In these animal models, kidney ACE2 messenger RNA and protein expression were markedly reduced, making ACE2 a candidate gene for this QTL. Targeted disruption of ACE2 in mice failed to elicit hypertension, but resulted in severe impairment in myocardial contractility with increased angiotensin II levels. Genetic ablation of ACE in the ACE2 null mice rescued the cardiac phenotype. These genetic data show that ACE2 is an essential regulator of heart function in vivo. Basal renal morphology and function were not altered by the inactivation of ACE2. The novel role of ACE2 in hydrolyzing several other peptides-such as the apelin peptides, opioids, and kinin metabolites-raises the possibility that peptide systems other than angiotensin and its derivatives also may have an important role in regulating cardiovascular and renal function.

  8. Ticagrelor--a new platelet aggregation inhibitor in patients with acute coronary syndromes. An improvement of other inhibitors?

    PubMed

    Kowalczyk, Mariusz; Banach, Maciej; Mikhailidis, Dimitri P; Hannam, Simon; Rysz, Jacek

    2009-12-01

    Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Clopidogrel, is a pro-drug that needs to be metabolized in the liver and intestines to form active metabolites. Prasugrel, a third generation thienopyridine, was approved for use in Europe in February 2009, and is currently available in the United Kingdom. All thienopyridines however, have pharmacological limitations that lead to a search for more effective non-thienopyridine P2Y12 inhibitors. Promising results have been reported with ticagrelor, an oral first reversible, direct-acting inhibitor of the P2Y12 receptor. Ticagrelor is the first oral P2Y12 receptor binding antagonist that does not require metabolic activation. Furthermore, ticagrelor has at last 1 active metabolite, which has very similar pharmacokinetics to the parent compound. Therefore, ticagrelor has more rapid onset and more pronounced platelet inhibition than other antiplatelet agents. The safety and efficacy of ticagrelor compared with clopidogrel in ACS patient has been recently evaluated by the PLATelet inhibition and patient Outcomes (PLATO) trial. Ticagrelor compared with clopidogrel had a significantly greater reduction in the death rate from vascular causes, myocardial infarction, or stroke without major bleeding. There was however, an increase in non-procedure related bleeding, dyspnoea and ventricular pauses in the first week of treatment. Further studies on new antiplatelet agents are needed to establish a new "gold standard" antiplatelet therapy. PMID:19946242

  9. Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress.

    PubMed

    AbdAlla, Said; El Hakim, Ahmed; Abdelbaset, Ahmed; Elfaramawy, Yasser; Quitterer, Ursula

    2015-01-01

    With increasing life expectancy, Alzheimer's disease (AD) and other types of age-associated dementia are on the rise worldwide. Treatment approaches for dementia are insufficient and novel therapies are not readily available. In this context repurposing of established drugs appears attractive. A well-established class of cardiovascular drugs, which targets the angiotensin II system, is such a candidate, which currently undergoes a paradigm shift with regard to the potential benefit for treatment of neurodegenerative symptoms. In search for additional evidence, we subjected aged rats to chronic unpredictable mild stress, which is known to enhance the development of AD-related neuropathological features. We report here that four weeks of chronic mild stress induced a strong upregulation of the hippocampal angiotensin-converting enzyme (Ace) at gene expression and protein level. Concomitantly, tau protein hyperphosphorylation developed. Signs of neurodegeneration were detected by the significant downregulation of neuronal structure proteins such as microtubule-associated protein 2 (Map2) and synuclein-gamma (Sncg). Ace was involved in neurodegenerative symptoms because treatment with the brain-penetrating ACE inhibitor, captopril, retarded tau hyperphosphorylation and signs of neurodegeneration. Moreover, ACE inhibitor treatment could counteract glutamate neurotoxicity by preventing the downregulation of glutamate decarboxylase 2 (Gad2). Taken together, ACE inhibition targets neurodegeneration triggered by environmental stress. PMID:26697495

  10. Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress

    PubMed Central

    AbdAlla, Said; el Hakim, Ahmed; Abdelbaset, Ahmed; Elfaramawy, Yasser; Quitterer, Ursula

    2015-01-01

    With increasing life expectancy, Alzheimer's disease (AD) and other types of age-associated dementia are on the rise worldwide. Treatment approaches for dementia are insufficient and novel therapies are not readily available. In this context repurposing of established drugs appears attractive. A well-established class of cardiovascular drugs, which targets the angiotensin II system, is such a candidate, which currently undergoes a paradigm shift with regard to the potential benefit for treatment of neurodegenerative symptoms. In search for additional evidence, we subjected aged rats to chronic unpredictable mild stress, which is known to enhance the development of AD-related neuropathological features. We report here that four weeks of chronic mild stress induced a strong upregulation of the hippocampal angiotensin-converting enzyme (Ace) at gene expression and protein level. Concomitantly, tau protein hyperphosphorylation developed. Signs of neurodegeneration were detected by the significant downregulation of neuronal structure proteins such as microtubule-associated protein 2 (Map2) and synuclein-gamma (Sncg). Ace was involved in neurodegenerative symptoms because treatment with the brain-penetrating ACE inhibitor, captopril, retarded tau hyperphosphorylation and signs of neurodegeneration. Moreover, ACE inhibitor treatment could counteract glutamate neurotoxicity by preventing the downregulation of glutamate decarboxylase 2 (Gad2). Taken together, ACE inhibition targets neurodegeneration triggered by environmental stress. PMID:26697495

  11. Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy.

    PubMed

    Kharatmal, Shivsharan B; Singh, Jitendra N; Sharma, Shyam S

    2015-10-01

    Calpain plays an important role in the pathophysiology of neurological and cardiovascular complications, but its functional association in diabetic neuropathy is not yet elucidated. Therefore, we investigated the role of calpain in modulation of tetrodotoxin-resistant sodium channels (TTX-R Na(+) channels) in dorsal root ganglion (DRG) neurons using a pharmacological approach. The effects of a calpain inhibitor, MDL 28170 (3 and 10 mg/kg, i.p.) on TTX-R Na(+) channels in DRG neurons of streptozotocin-induced diabetic rats were assessed by using whole-cell patch-clamp technique. In addition to this biochemical, functional and behavioral deficits were also measured. Diabetic rats demonstrated the mechanical allodynia and thermal hyperalgesia with reduced nerve perfusion and conduction velocity as compared to control. MDL 28170 treatments significantly recovered these functional and nociceptive deficits. Moreover, diabetic rats exhibited increased calpain activation, lipid peroxidation and proinflammatory cytokines as compared to control. Drug treatment significantly improved these biochemical deficits. Additionally, DRG neurons from diabetic rats illustrated a significant increase in TTX-R sodium current (INa) density as compared to control. MDL 28170 treatments in diabetic rats significantly blocked the altered channel kinetics with hyperpolarizing shift in voltage-dependence of steady-state activation and inactivation curves. All together, our study provides evidence that calpain activation is directly associated with alterations in TTX-R Na(+) channels and triggers functional, nociceptive and biochemical deficits in experimental diabetic neuropathy. The calpain inhibitor, MDL 28710 have shown beneficial effects in alleviating diabetic neuropathy via modulation of TTX-R Na(+) channel kinetics and reduction of oxidative stress and neuro-inflammation.

  12. 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

  13. 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

  14. 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.

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

    PubMed

    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.

  16. Optimization of the choline transporter (CHT) inhibitor ML352: Development of VU6001221, an improved in vivo tool compound.

    PubMed

    Bertron, Jeanette L; Ennis, Elizabeth A; Tarr, Christopher J; Wright, Jane; Dickerson, Jonathan W; Locuson, Charles W; Blobaum, Anna L; Rook, Jerri M; Blakely, Randy D; Lindsley, Craig W

    2016-10-01

    This Letter describes the further lead optimization of the CHT inhibitor probe, ML352 (VU0476201), and the development of VU6001221, an improved in vivo tool. A multi-dimensional optimization effort encountered steep SAR, and ultimately, subtle tuning of the electronics of the central phenyl core provided VU6001221, a CHT inhibitor with comparable potency for choline uptake inhibition as ML352, yet improved PK and CNS penetration. Moreover, VU6001221 enabled evaluation, for the first time, of a CHT inhibitor in a standard preclinical rodent cognition model, novel object recognition (NOR). We observed VU6001221 to elicit a dose-responsive increase in NOR, raising the possibility of agonism of synaptic α7 nicotinic ACh receptors by elevated extracellular choline, that if confirmed would represent a novel molecular strategy to enhance cognition. PMID:27575469

  17. Visual hallucinations related to angiotensin-converting enzyme inhibitor use: case reports and review.

    PubMed

    Doane, John; Stults, Barry

    2013-04-01

    Four patients experienced visual hallucinations that appear to have been precipitated by lisinopril. Other cases of visual hallucinations have been reported with other angiotensin-converting enzyme (ACE) inhibitors. Older patients, particularly those with a history of either dementia or mild cognitive impairment, may be at higher risk. Hallucinations resolved within 1 to 30 days after cessation of ACE inhibitors. Development of visual hallucinations after initiation of ACE inhibitors should prompt discontinuation of therapy. Visual hallucinations have been reported in one case involving an ARB. Visual hallucinations have not been associated with direct renin inhibitors. Consideration should be given to use of alternative, unrelated antihypertensive drug classes.

  18. 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…

  19. 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.

  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. 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.

  2. Role of ACE and PAI-1 Polymorphisms in the Development and Progression of Diabetic Retinopathy.

    PubMed

    Saleem, Saba; Azam, Aisha; Maqsood, Sundus Ijaz; Muslim, Irfan; Bashir, Shaheena; Fazal, Nosheen; Riaz, Moeen; Ali, Syeda Hafiza Benish; Niazi, Muhammad Khizar; Ishaq, Mazhar; Waheed, Nadia Khalida; Qamar, Raheel; Azam, Maleeha

    2015-01-01

    In the present study we determined the association of angiotensin converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms with diabetic retinopathy (DR) and its sub-clinical classes in Pakistani type 2 diabetic patients. A total of 353 diabetic subjects including 160 DR and 193 diabetic non retinopathy (DNR) as well as 198 healthy controls were genotyped by allele specific polymerase chain reaction (PCR) for ACE Insertion/Deletion (ID) polymorphism, rs4646994 in intron 16 and PAI-1 4G/5G (deletion/insertion) polymorphism, rs1799768 in promoter region of the gene. To statistically assess the genotype-phenotype association, multivariate logistic regression analysis was applied to the genotype data of DR, DNR and control individuals as well as the subtypes of DR. The ACE genotype ID was found to be significantly associated with DR (p = 0.009, odds ratio (OR) 1.870 [95% confidence interval (CI) = 1.04-3.36]) and its sub-clinical class non-proliferative DR (NPDR) (p = 0.006, OR 2.250 [95% CI = 1.098-4.620]), while PAI polymorphism did not show any association with DR in the current cohort. In conclusion in Pakistani population the ACE ID polymorphism was observed to be significantly associated with DR and NPDR, but not with the severe form of the disease i.e. proliferative DR (PDR). PMID:26658948

  3. Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin.

    PubMed

    White, William B; Wilson, Craig A; Bakris, George L; Bergenstal, Richard M; Cannon, Christopher P; Cushman, William C; Heller, Simon K; Mehta, Cyrus R; Nissen, Steven E; Zannad, Faiez; Kupfer, Stuart

    2016-09-01

    Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors. PMID:27480840

  4. 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.

  5. Cardiac and renal distribution of ACE and ACE-2 in rats with heart failure.

    PubMed

    Cohen-Segev, Ravit; Francis, Bahaa; Abu-Saleh, Niroz; Awad, Hoda; Lazarovich, Aviva; Kabala, Aviva; Aronson, Doron; Abassi, Zaid

    2014-10-01

    Congestive heart failure is often associated with impaired kidney function. Over-activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid salt and water retention in heart failure. While the expression of angiotensin converting enzyme (ACE), a key enzyme in the synthesis of angiotensin II (Ang II), is well established, the expression of angiotensin converting enzyme-2 (ACE-2), an enzyme responsible for angiotensin 1-7 generation, is largely unknown. This issue is of a special interest since angiotensin 1-7 counteracts many of the proliferative and hypertensive effects of angiotensin II. Therefore, the present study was designed to investigate the expression of both enzymes in the kidney and heart of rats with heart failure. Heart failure (CHF) was induced in male Sprague Dawley rats (n=9) by the creation of a surgical aorto-caval fistula. Sham-operated rats served as controls (n=8). Two weeks after surgery, the animals were sacrificed and their hearts and kidneys were harvested for assessment of cardiac remodeling and ACE and ACE-2 immunoreactivity by immunohistochemical staining. ACE immunostaining was significantly increased in the kidneys (4.34 ± 0.39% vs. 2.96 ± 0.40%, P<0.05) and hearts (4.57 ± 0.54% vs. 2.19 ± 0.37%, P<0.01) of CHF rats as compared with their sham controls. In a similar manner, ACE-2 immunoreactivity was also elevated in the kidneys (4.65 ± 1.17% vs. 1.75 ± 0.29%, P<0.05) and hearts (5.48 ± 1.11% vs. 1.13 ± 0.26%, P<0.01) of CHF rats as compared with their healthy controls. This study showed that both ACE and ACE-2 are overexpressed in the cardiac and renal tissues of animals with heart failure as compared with their sham controls. The increased expression of the beneficial ACE-2 in heart failure may serve as a compensatory response to the over-activity of the deleterious isoform, namely, angiotensin converting enzyme 1(ACE-1).

  6. 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

  7. Structural basis of resistance to anti-cytochrome bc₁ complex inhibitors: implication for drug improvement.

    PubMed

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

    2014-01-01

    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 reductionsite 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.

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

    PubMed

    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.

  9. Validation of ozone measurements from the Atmospheric Chemistry Experiment (ACE)

    NASA Astrophysics Data System (ADS)

    Dupuy, E.; Walker, K. A.; Kar, J.; Boone, C. D.; McElroy, C. T.; Bernath, P. F.; Drummond, J. R.; Skelton, R.; McLeod, S. D.; Hughes, R. C.; Nowlan, C. R.; Dufour, D. G.; Zou, J.; Nichitiu, F.; Strong, K.; Baron, P.; Bevilacqua, R. M.; Blumenstock, T.; Bodeker, G. E.; Borsdorff, T.; Bourassa, A. E.; Bovensmann, H.; Boyd, I. S.; Bracher, A.; Brogniez, C.; Burrows, J. P.; Catoire, V.; Ceccherini, S.; Chabrillat, S.; Christensen, T.; Coffey, M. T.; Cortesi, U.; Davies, J.; de Clercq, C.; Degenstein, D. A.; de Mazière, M.; Demoulin, P.; Dodion, J.; Firanski, B.; Fischer, H.; Forbes, G.; Froidevaux, L.; Fussen, D.; Gerard, P.; Godin-Beekmann, S.; Goutail, F.; Granville, J.; Griffith, D.; Haley, C. S.; Hannigan, J. W.; Höpfner, M.; Jin, J. J.; Jones, A.; Jones, N. B.; Jucks, K.; Kagawa, A.; Kasai, Y.; Kerzenmacher, T. E.; Kleinböhl, A.; Klekociuk, A. R.; Kramer, I.; Küllmann, H.; Kuttippurath, J.; Kyrölä, E.; Lambert, J.-C.; Livesey, N. J.; Llewellyn, E. J.; Lloyd, N. D.; Mahieu, E.; Manney, G. L.; Marshall, B. T.; McConnell, J. C.; McCormick, M. P.; McDermid, I. S.; McHugh, M.; McLinden, C. A.; Mellqvist, J.; Mizutani, K.; Murayama, Y.; Murtagh, D. P.; Oelhaf, H.; Parrish, A.; Petelina, S. V.; Piccolo, C.; Pommereau, J.-P.; Randall, C. E.; Robert, C.; Roth, C.; Schneider, M.; Senten, C.; Steck, T.; Strandberg, A.; Strawbridge, K. B.; Sussmann, R.; Swart, D. P. J.; Tarasick, D. W.; Taylor, J. R.; Tétard, C.; Thomason, L. W.; Thompson, A. M.; Tully, M. B.; Urban, J.; Vanhellemont, F.; Vigouroux, C.; von Clarmann, T.; von der Gathen, P.; von Savigny, C.; Waters, J. W.; Witte, J. C.; Wolff, M.; Zawodny, J. M.

    2009-01-01

    This paper presents extensive {bias determination} analyses of ozone observations from the Atmospheric Chemistry Experiment (ACE) satellite instruments: the ACE Fourier Transform Spectrometer (ACE-FTS) and the Measurement of Aerosol Extinction in the Stratosphere and Troposphere Retrieved by Occultation (ACE-MAESTRO) instrument. Here we compare the latest ozone data products from ACE-FTS and ACE-MAESTRO with coincident observations from nearly 20 satellite-borne, airborne, balloon-borne and ground-based instruments, by analysing volume mixing ratio profiles and partial column densities. The ACE-FTS version 2.2 Ozone Update product reports more ozone than most correlative measurements from the upper troposphere to the lower mesosphere. At altitude levels from 16 to 44 km, the average values of the mean relative differences are nearly all within +1 to +8%. At higher altitudes (45-60 km), the ACE-FTS ozone amounts are significantly larger than those of the comparison instruments, with mean relative differences of up to +40% (about +20% on average). For the ACE-MAESTRO version 1.2 ozone data product, mean relative differences are within ±10% (average values within ±6%) between 18 and 40 km for both the sunrise and sunset measurements. At higher altitudes ( 35-55 km), systematic biases of opposite sign are found between the ACE-MAESTRO sunrise and sunset observations. While ozone amounts derived from the ACE-MAESTRO sunrise occultation data are often smaller than the coincident observations (with mean relative differences down to -10%), the sunset occultation profiles for ACE-MAESTRO show results that are qualitatively similar to ACE-FTS, indicating a large positive bias (mean relative differences within +10 to +30%) in the 45-55 km altitude range. In contrast, there is no significant systematic difference in bias found for the ACE-FTS sunrise and sunset measurements.

  10. Validation of ozone measurements from the Atmospheric Chemistry Experiment (ACE)

    NASA Astrophysics Data System (ADS)

    Dupuy, E.; Walker, K. A.; Kar, J.; Boone, C. D.; McElroy, C. T.; Bernath, P. F.; Drummond, J. R.; Skelton, R.; McLeod, S. D.; Hughes, R. C.; Nowlan, C. R.; Dufour, D. G.; Zou, J.; Nichitiu, F.; Strong, K.; Baron, P.; Bevilacqua, R. M.; Blumenstock, T.; Bodeker, G. E.; Borsdorff, T.; Bourassa, A. E.; Bovensmann, H.; Boyd, I. S.; Bracher, A.; Brogniez, C.; Burrows, J. P.; Catoire, V.; Ceccherini, S.; Chabrillat, S.; Christensen, T.; Coffey, M. T.; Cortesi, U.; Davies, J.; de Clercq, C.; Degenstein, D. A.; de Mazière, M.; Demoulin, P.; Dodion, J.; Firanski, B.; Fischer, H.; Forbes, G.; Froidevaux, L.; Fussen, D.; Gerard, P.; Godin-Beekman, S.; Goutail, F.; Granville, J.; Griffith, D.; Haley, C. S.; Hannigan, J. W.; Höpfner, M.; Jin, J. J.; Jones, A.; Jones, N. B.; Jucks, K.; Kagawa, A.; Kasai, Y.; Kerzenmacher, T. E.; Kleinböhl, A.; Klekociuk, A. R.; Kramer, I.; Küllmann, H.; Kuttippurath, J.; Kyrölä, E.; Lambert, J.-C.; Livesey, N. J.; Llewellyn, E. J.; Lloyd, N. D.; Mahieu, E.; Manney, G. L.; Marshall, B. T.; McConnell, J. C.; McCormick, M. P.; McDermid, I. S.; McHugh, M.; McLinden, C. A.; Mellqvist, J.; Mizutani, K.; Murayama, Y.; Murtagh, D. P.; Oelhaf, H.; Parrish, A.; Petelina, S. V.; Piccolo, C.; Pommereau, J.-P.; Randall, C. E.; Robert, C.; Roth, C.; Schneider, M.; Senten, C.; Steck, T.; Strandberg, A.; Strawbridge, K. B.; Sussmann, R.; Swart, D. P. J.; Tarasick, D. W.; Taylor, J. R.; Tétard, C.; Thomason, L. W.; Thompson, A. M.; Tully, M. B.; Urban, J.; Vanhellemont, F.; von Clarmann, T.; von der Gathen, P.; von Savigny, C.; Waters, J. W.; Witte, J. C.; Wolff, M.; Zawodny, J. M.

    2008-02-01

    This paper presents extensive validation analyses of ozone observations from the Atmospheric Chemistry Experiment (ACE) satellite instruments: the ACE Fourier Transform Spectrometer (ACE-FTS) and the Measurement of Aerosol Extinction in the Stratosphere and Troposphere Retrieved by Occultation (ACE-MAESTRO) instrument. The ACE satellite instruments operate in the mid-infrared and ultraviolet-visible-near-infrared spectral regions using the solar occultation technique. In order to continue the long-standing record of solar occultation measurements from space, a detailed quality assessment is required to evaluate the ACE data and validate their use for scientific purposes. Here we compare the latest ozone data products from ACE-FTS and ACE-MAESTRO with coincident observations from satellite-borne, airborne, balloon-borne and ground-based instruments, by analysing volume mixing ratio profiles and partial column densities. The ACE-FTS version 2.2 Ozone Update product reports more ozone than most correlative measurements from the upper troposphere to the lower mesosphere. At altitude levels from 16 to 44 km, the mean differences range generally between 0 and +10% with a slight but systematic positive bias (typically +5%). At higher altitudes (45-60 km), the ACE-FTS ozone amounts are significantly larger than those of the comparison instruments by up to ~40% (typically +20%). For the ACE-MAESTRO version 1.2 ozone data product, agreement within ±10% (generally better than ±5%) is found between 18 and 40 km for the sunrise and sunset measurements. At higher altitudes (45-55 km), systematic biases of opposite sign are found between the ACE-MAESTRO sunrise and sunset observations. While ozone amounts derived from the ACE-MAESTRO sunrise occultation data are often smaller than the coincident observations (by as much as -10%), the sunset occultation profiles for ACE-MAESTRO show results that are qualitatively similar to ACE-FTS and indicate a large positive bias (+10 to +30

  11. 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.

  12. The appropriate dose of angiotensin‐converting‐enzyme inhibitors or angiotensin receptor blockers in patients with dilated cardiomyopathy. The higher, the better?

    PubMed Central

    Konishi, Masaaki; von Haehling, Stephan

    2015-01-01

    Abstract Heart failure is a major public issue, and dilated cardiomyopathy (DCM) is one of the common etiologies of heart failure. DCM is generally progressive, and some patients with DCM need heart transplant despite optimal medical and mechanical therapy. Current guidelines recommend inhibitors of renin–angiotensin–aldosterone system, namely angiotensin‐converting‐enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), and mineralocorticoid receptor antagonist as well as beta‐blockers for the medical treatment of heart failure with reduced ejection fraction, including DCM. Furthermore, because they have beneficial effects on the outcome of heart failure in a dose‐related fashion, they should be titrated to the target dose. In clinical practice, the underuse and under‐dose of these agents matter; however, the efficacy and safety of supramaximal dose of ACE inhibitor or ARB have never been investigated in the patients with DCM. In this issue of ESC Heart Failure, it is demonstrated that benazepril or valsartan at supramaximal dose improved left ventricular function and reduced cardiovascular events compared with each drug at low dose, respectively. In this editorial, the current evidence concerning the use of ACE inhibitor or ARB in patients with HF and future prospective will be discussed.

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

    PubMed

    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.

  14. Febuxostat, a novel xanthine oxidoreductase inhibitor, improves hypertension and endothelial dysfunction in spontaneously hypertensive rats.

    PubMed

    Shirakura, Takashi; Nomura, Johji; Matsui, Chieko; Kobayashi, Tsunefumi; Tamura, Mizuho; Masuzaki, Hiroaki

    2016-08-01

    Xanthine oxidase (XO) is an enzyme responsible for the production of uric acid. XO produces considerable amount of oxidative stress throughout the body. To date, however, its pathophysiologic role in hypertension and endothelial dysfunction still remains controversial. To explore the possible involvement of XO-derived oxidative stress in the pathophysiology of vascular dysfunction, by use of a selective XO inhibitor, febuxostat, we investigated the impact of pharmacological inhibition of XO on hypertension and vascular endothelial dysfunction in spontaneously hypertensive rats (SHRs). Sixteen-week-old SHR and normotensive Wistar-Kyoto (WKY) rats were treated with tap water (control) or water containing febuxostat (3 mg/kg/day) for 6 weeks. Systolic blood pressure (SBP) in febuxostat-treated SHR (220 ± 3 mmHg) was significantly (P < 0.05) decreased compared with the control SHR (236 ± 4 mmHg) while SBP in febuxostat-treated WKY was constant. Acetylcholine-induced endothelium-dependent relaxation in aortas from febuxostat-treated SHR was significantly (P < 0.05) improved compared with the control SHR, whereas relaxation in response to sodium nitroprusside was not changed. Vascular XO activity and tissue nitrotyrosine level, a representative indicator of local oxidative stress, were considerably elevated in the control SHR compared with the control WKY, and this increment was abolished by febuxostat. Our results suggest that exaggerated XO activity and resultant increase in oxidative stress in this experimental model contribute to the hypertension and endothelial dysfunction, thereby supporting a notion that pharmacological inhibition of XO is valuable not only for hyperuricemia but also for treating hypertension and related endothelial dysfunction in human clinics.

  15. Farnesyl pyrophosphate synthase inhibitor, ibandronate, improves endothelial function in spontaneously hypertensive rats

    PubMed Central

    HAN, JIE; JIANG, DONG-MEI; YE, YANG; DU, CHANG-QING; YANG, JIAN; HU, SHEN-JIANG

    2016-01-01

    Reactive oxygen species (ROS), originating predominantly from vascular smooth muscle cells (VSMCs), lead to vascular damage and endothelial dysfunction in rats with hypertension. The downstream signaling pathways of farnesyl pyrophosphate (FPP) synthase, Ras-related C3 botulinum toxin substrate 1 (Rac1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, mediate the generation of ROS. The present study investigated the effect of the FPP synthase inhibitor, ibandronate, on ROS production, the possible beneficial effect on endothelial dysfunction and the underlying mechanisms in spontaneously hypertensive rats (SHRs). The SHRs were treated with ibandronate for 30 days. Endothelium-dependent and independent vasorelaxation were measured in isolated aortic rings. Additionally, VSMCs from the SHRs and Wistar-Kyoto (WKY) rats were cultured. The production of ROS and activation of NADPH oxidase were determined using fluorescence and chemiluminescence, respectively, in vivo and in vitro. Angiotensin II (Ang II) increased ROS production in the cultured VSMCs from the WKY rats and SHRs, in a concentration-dependent manner. The Ang II-induced responses were more marked in the SHR VSMCs, compare with those in the WKY VSMCs, however, the response decreased significantly following ibandronate pretreatment. Treatment with ibandronate significantly decreased the production of ROS, translocation of NADPH oxidase subunit p47phox, and activities of NADPH oxidase and Rac1 in the aorta and VSMCs, and improved the impaired endothelium-dependent vasodilation in the SHRs. Adding geranylgeraniol, but not farnesol or mevalonate, reversed the inhibitory effects of ibandronate. In addition, inhibiting geranylgeranyl-transferase mimicked the effect of ibandronate on the excess oxidative response. Ibandronate exerted cellular antioxidant effects through the Rac1/NADPH oxidase pathway. These effects may have contributed to the vasoprotective effects on the impaired endothelium in

  16. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model.

    PubMed

    Komla-Ebri, Davide; Dambroise, Emilie; Kramer, Ina; Benoist-Lasselin, Catherine; Kaci, Nabil; Le Gall, Cindy; Martin, Ludovic; Busca, Patricia; Barbault, Florent; Graus-Porta, Diana; Munnich, Arnold; Kneissel, Michaela; Di Rocco, Federico; Biosse-Duplan, Martin; Legeai-Mallet, Laurence

    2016-05-01

    Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3-encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3Y367C/+ mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH. PMID:27064282

  17. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model

    PubMed Central

    Dambroise, Emilie; Kramer, Ina; Benoist-Lasselin, Catherine; Kaci, Nabil; Le Gall, Cindy; Martin, Ludovic; Busca, Patricia; Barbault, Florent; Graus-Porta, Diana; Munnich, Arnold; Kneissel, Michaela; Di Rocco, Federico; Biosse-Duplan, Martin

    2016-01-01

    Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3–encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3Y367C/+ mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH. PMID:27064282

  18. Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation.

    PubMed

    Yang, Shao H; Qiao, Xin; Fong, Loren G; Young, Stephen G

    2008-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a progeroid syndrome characterized by multiple aging-like disease phenotypes. We recently reported that a protein farnesyltransferase inhibitor (FTI) improved several disease phenotypes in mice with a HGPS mutation (Lmna(HG/+)). Here, we investigated the impact of an FTI on the survival of Lmna(HG/+) mice. The FTI significantly improved the survival of both male and female Lmna(HG/+) mice. Treatment with the FTI also improved body weight curves and reduced the number of spontaneous rib fractures. This study provides further evidence for a beneficial effect of an FTI in HGPS.

  19. 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.

  20. Regulation of alveolar epithelial cell survival by the ACE-2/angiotensin 1–7/Mas axis

    PubMed Central

    Li, Xiaopeng; Xue, Anita; Gao, Xu; Abdul-Hafez, Amal

    2011-01-01

    Earlier work from this laboratory demonstrated that apoptosis of alveolar epithelial cells (AECs) requires autocrine generation of angiotensin (ANG) II. More recent studies showed that angiotensin converting enzyme-2 (ACE-2), which degrades ANGII to form ANG1–7, is protective but severely downregulated in human and experimental lung fibrosis. Here it was theorized that ACE-2 and its product ANG1–7 might therefore regulate AEC apoptosis. To evaluate this hypothesis, the AEC cell line MLE-12 and primary cultures of rat AECs were exposed to the profibrotic apoptosis inducers ANGII or bleomycin (Bleo). Markers of apoptosis (caspase-9 or -3 activation and nuclear fragmentation), steady-state ANGII and ANG1–7, and JNK phosphorylation were measured thereafter. In the absence of Bleo, inhibition of ACE-2 by small interfering RNA or by a competitive inhibitor (DX600 peptide) caused a reciprocal increase in autocrine ANGII and corresponding decrease in ANG1–7 in cell culture media (both P < 0.05) and, moreover, induced AEC apoptosis. At baseline (without inhibitor), ANG1–7 in culture media was 10-fold higher than ANGII (P < 0.01). Addition of purified ANGII or bleomycin-induced caspase activation, nuclear fragmentation, and JNK phosphorylation in cultured AECs. However, preincubation with ANG1–7 (0.1 μM) prevented JNK phosphorylation and apoptosis. Moreover, pretreatment with A779, a specific blocker of the ANG1–7 receptor mas, prevented ANG1–7 blockade of JNK phosphorylation, caspase activation, and nuclear fragmentation. These data demonstrate that ACE-2 regulates AEC survival by balancing the proapoptotic ANGII and its antiapoptotic degradation product ANG1–7. They also suggest that ANG1–7 inhibits AEC apoptosis through the ANG1–7 receptor mas. PMID:21665960

  1. Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich's Ataxia: A New Synthetic Route

    PubMed Central

    Xu, Chunping; Soragni, Elisabetta; Jacques, Vincent; Rusche, James R.; Gottesfeld, Joel M.

    2011-01-01

    Friedreich's ataxia (FRDA) is caused by transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin. Based on the hypothesis that the acetylation state of the histone proteins is responsible for gene silencing in FRDA, previous work in our lab identified a first generation of HDAC inhibitors (pimelic o-aminobenzamides), which increase FXN mRNA in lymphocytes from FRDA patients. Importantly, these compounds also function in a FRDA mouse model to increase FXN mRNA levels in the brain and heart. While the first generation of HDAC inhibitors hold promise as potential therapeutics for FRDA, they have two potential problems: less than optimal brain penetration and metabolic instability in acidic conditions. Extensive optimization focusing on modifying the left benzene ring, linker and the right benzene ring lead to a novel class of HDAC inhibitors that have optimized pharmacological properties (increased brain penetration and acid stability) compared to the previous HDAC inhibitors. This article will describe the chemical synthesis and pharmacological properties of these new HDAC inhibitors.

  2. 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

  3. 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

  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. Advances in bypassing agent therapy for hemophilia patients with inhibitors to close care gaps and improve outcomes.

    PubMed

    Shapiro, Amy D; Hedner, Ulla

    2011-10-01

    In the past, patients with hemophilia and inhibitors have had less-than-optimal treatment and have experienced more orthopedic complications than patients without inhibitors. Bypassing agents offer the potential to close treatment gaps between inhibitor and noninhibitor patients by helping the former better attain key treatment goals, including: facilitating early initiation of treatment and hemostatic control in hemarthroses; providing effective treatment in serious hemorrhagic episodes; and performance of major surgery. Effective treatment with a bypassing agent minimizes joint and/or muscle damage and potentially can serve as an effective prophylactic agent to minimize the number of hemarthroses experienced per year, thereby mitigating the development of arthropathy. The reported efficacy of the currently available bypassing agents ranges from approximately 50-80% (50-64% in controlled studies) for plasma-derived activated prothrombin complex concentrate (pd-aPCC) and 81-91% (in controlled studies) for recombinant activated factor VII (rFVIIa), including use in major orthopedic surgery. Both bypassing agents have undergone key improvements in their formulation and/or properties in recent years. The nanofiltered, vapor-heated formulation of pd-aPCC has diminished the risk of acquiring blood-borne viral infections and the room temperature stable formulation of rFVIIa allows more convenient storage, increased ease to dissolve and inject, and smaller volumes, thereby increasing overall ease of administration. Use of recommended dosing has been demonstrated to provide effective hemostasis with a minimal number of injections for both agents. In this paper, we review the individual characteristics of pd-aPCC and rFVIIa and discuss clinical data from studies conducted in inhibitor patients that demonstrate the potential benefits of these bypassing agents in this difficult-to-treat population, and underscore the potential opportunities to close the gap in care between

  6. Discovery and optimization of potent and selective benzonaphthyridinone analogs as small molecule mTOR inhibitors with improved mouse microsome stability

    PubMed Central

    Liu, Qingsong; Wang, Jinhua; Kang, Seong A.; Thoreen, Carson C.; Hur, Wooyoung; Choi, Hwan Geun; Waller, David L.; Sim, Taebo; Sabatini, David M.; Gray, Nathanael S.

    2014-01-01

    Starting from small molecule mTOR inhibitor Torin1, replacement of the piperazine ring with a phenyl ring resulted in a new series of mTOR inhibitors (as exemplified by 10) that showed superior potency and selectivity for mTOR, along with significantly improved mouse liver microsome stability and a longer in vivo half-life. PMID:21621413

  7. 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%.

  8. 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.

  9. Global regulator engineering significantly improved Escherichia coli tolerances toward inhibitors of lignocellulosic hydrolysates.

    PubMed

    Wang, Jianqing; Zhang, Yan; Chen, Yilu; Lin, Min; Lin, Zhanglin

    2012-12-01

    Lignocellulosic biomass is regarded as the most viable source of feedstock for industrial biorefinery, but the harmful inhibitors generated from the indispensable pretreatments prior to fermentation remain a daunting technical hurdle. Using an exogenous regulator, irrE, from the radiation-resistant Deinococcus radiodurans, we previously showed that a novel global regulator engineering (GRE) approach significantly enhanced tolerances of Escherichia coli to alcohol and acetate stresses. In this work, an irrE library was subjected to selection under various stresses of furfural, a typical hydrolysate inhibitor. Three furfural tolerant irrE mutants including F1-37 and F2-1 were successfully obtained. The cells containing these mutants reached OD(600) levels of 4- to 16-fold of that for the pMD18T cells in growth assay under 0.2% (v/v) furfural stress. The cells containing irrE F1-37 and F2-1 also showed considerably reduced intracellular oxygen species (ROS) levels under furfural stress. Moreover, these two irrE mutants were subsequently found to confer significant cross tolerances to two other most common inhibitors, 5-hydroxymethyl-2-furaldehyde (HMF), vanillin, as well as real lignocellulosic hydrolysates. When evaluated in Luria-Bertani (LB) medium supplemented with corn stover cellulosic hydrolysate (prepared with a solid loading of 30%), the cells containing the mutants exhibited lag phases markedly shortened by 24-44 h in comparison with the control cells. This work thus presents a promising step forward to resolve the inhibitor problem for E. coli. From the view of synthetic biology, irrE can be considered as an evolvable "part" for various stresses. Furthermore, this GRE approach can be extended to exploit other exogenous global regulators from extremophiles, and the native counterparts in E. coli, for eliciting industrially useful phenotypes.

  10. Biodistribution of Fracture-Targeted GSK3β Inhibitor-Loaded Micelles for Improved Fracture Healing.

    PubMed

    Low, Stewart A; Galliford, Chris V; Yang, Jiyuan; Low, Philip S; Kopeček, Jindřich

    2015-10-12

    Bone fractures constitute a major cause of morbidity and mortality especially in the elderly. Complications associated with osteoporosis drugs and the age of the patient slow bone turnover and render such fractures difficult to heal. Increasing the speed of fracture repair by administration of a fracture-targeted bone anabolic agent could find considerable application. Aspartic acid oligopeptides are negatively charged molecules at physiological pH that adsorb to hydroxyapatite, the mineral portion of bone. This general adsorption is the strongest where bone turnover is highest or where hydroxyapatite is freshly exposed. Importantly, both of these conditions are prominent at fracture sites. GSK3β inhibitors are potent anabolic agents that can promote tissue repair when concentrated in a damaged tissue. Unfortunately, they can also cause significant toxicity when administered systemically and are furthermore difficult to deliver due to their strong hydrophobicity. In this paper, we solve both problems by conjugating the hydrophobic GSK3β inhibitor to a hydrophilic aspartic acid octapeptide using a hydrolyzable bond, thereby generating a bone fracture-targeted water-soluble form of the drug. The resulting amphiphile is shown to assemble into micelles, extending its circulation time while maintaining its fracture-targeting abilities. For measurement of pharmacokinetics, an 125I was introduced at the location of the bromine in the GSK3β inhibitor to minimize any structural differences. Biodistribution studies demonstrate a greater than 4-fold increase in fracture accumulation over healthy bone. PMID:26331790

  11. Biodistribution of fracture-targeted GSK3β inhibitor-loaded micelles for improved fracture healing

    PubMed Central

    Low, Stewart A.; Galliford, Chris V.; Yang, Jiyuan; Low, Philip S.; Kopeček, Jindřich

    2016-01-01

    Bone fractures constitute a major cause of morbidity and mortality especially in the elderly. Complications associated with osteoporosis drugs and the age of the patient slow bone turnover and render such fractures difficult to heal. Increasing the speed of fracture repair by administration of a fracture-targeted bone anabolic agent could find considerable application. Aspartic acid oligopeptides are negatively charged molecules at physiological pH that adsorb to hydroxyapatite, the mineral portion of bone. This general adsorption is the strongest where bone turnover is highest or where hydroxyapatite is freshly exposed. Importantly, both of these conditions are prominent at fracture sites. GSK3β inhibitors are potent anabolic agents that can promote tissue repair when concentrated in a damaged tissue. Unfortunately, they can also cause significant toxicity when administered systemically and are furthermore difficult to deliver due to their strong hydrophobicity. In this paper, we solve both problems by conjugating the hydrophobic GSK3β inhibitor to a hydrophilic aspartic acid octapeptide using a hydrolyzable bond, thereby generating a bone fracture-targeted water-soluble form of the drug. The resulting amphiphile is shown to assemble into micelles, extending its circulation time while maintaining its fracture-targeting abilities. For measurement of pharmacokinetics, an 125I was introduced at the location of the bromine in the GSK3β inhibitor to minimize any structural differences. Biodistribution studies demonstrate a greater than 4-fold increase in fracture accumulation over healthy bone. PMID:26331790

  12. Metformin combined with p38 MAPK inhibitor improves cisplatin sensitivity in cisplatin-resistant ovarian cancer

    PubMed Central

    XIE, YA; PENG, ZHENG; SHI, MINGXING; JI, MEI; GUO, HONGJUN; SHI, HUIRONG

    2014-01-01

    The aim of the present study was to determine the effects of metformin, combined with a p38 mitogen-activated protein kinase (MAPK) inhibitor, on the sensitivity of cisplatin-resistant ovarian cancer to cisplatin. The expression and distribution of phosphorylated p38 MAPK (P-p38 MAPK) was confirmed in drug-resistant and primary ovarian cancer tissues by immunohistochemistry and western blotting. A bromodeoxyuridine ELISA kit was used to analyze the effects of metformin, SB203580, a p38 MAPK inhibitor, and metformin combined with SB203580, on the cell proliferation of SKOV3/DDP cisplatin-resistant ovarian cancer cells. The protein expression of P-p38 MAPK was significantly higher in cisplatin-resistant ovarian cancer, as compared with the primary ovarian cancer tissues. Metformin combined with SB203580 significantly enhanced the sensitivity of SKOV3/DDP cells to cisplatin. In conclusion, the p38 MAPK signaling pathway may be associated with cisplatin-resistant ovarian cancer. Metformin, combined with the p38 MAPK inhibitor, significantly increased the sensitivity of SKOV3/DDP cells to cisplatin treatment. PMID:25118792

  13. 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.

  14. Antioxidant activity and ACE-inhibitory of Class II hydrophobin from wild strain Trichoderma reesei.

    PubMed

    Khalesi, Mohammadreza; Jahanbani, Raheleh; Riveros-Galan, David; Sheikh-Hassani, Vahid; Sheikh-Zeinoddin, Mahmoud; Sahihi, Mehdi; Winterburn, James; Derdelinckx, Guy; Moosavi-Movahedi, Ali Akbar

    2016-10-01

    There are several possible uses of the Class II hydrophobin HFBII in clinical applications. To fully understand and exploit this potential however, the antioxidant activity and ACE-inhibitory potential of this protein need to be better understood and have not been previously reported. In this study, the Class II hydrophobin HFBII was produced by the cultivation of wild type Trichoderma reesei. The crude hydrophobin extract obtained from the fermentation process was purified using reversed-phase liquid chromatography and the identity of the purified HFBII verified by MALDI-TOF (molecular weight: 7.2kDa). Subsequently the antioxidant activities of different concentrations of HFBII (0.01-0.40mg/mL) were determined. The results show that for HFBII concentrations of 0.04mg/mL and upwards the protein significantly reduced the presence of ABTS(+) radicals in the medium, the IC50 value found to be 0.13mg/mL. Computational modeling highlighted the role of the amino acid residues located in the conserved and exposed hydrophobic patch on the surface of the HFBII molecule and the interactions with the aromatic rings of ABTS. The ACE-inhibitory effect of HFBII was found to occur from 0.5mg/mL and upwards, making the combination of HFBII with strong ACE-inhibitors attractive for use in the healthcare industry. PMID:27211298

  15. Acute Kidney Injury in Elderly Patients With Chronic Kidney Disease: Do Angiotensin-Converting Enzyme Inhibitors Carry a Risk?

    PubMed

    Chaumont, Martin; Pourcelet, Aline; van Nuffelen, Marc; Racapé, Judith; Leeman, Marc; Hougardy, Jean-Michel

    2016-06-01

    In contrast to angiotensin receptor blockers (ARBs), mainly excreted by the liver, the dosage of angiotensin-converting enzyme (ACE) inhibitors, cleared by the kidney, must be adapted to account for renal clearance in patients with chronic kidney disease (CKD) to avoid acute kidney injury (AKI). Community-acquired AKI and the use of ACE inhibitors or ARBs in the emergency department were retrospectively assessed in 324 patients with baseline stage 3 or higher CKD. After stepwise regression analysis, the use of ACE inhibitors (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.1; P=.02) and the presence of dehydration (OR, 30.8; 95% CI, 3.9-239.1) were associated with AKI. A total of 45% of patients using ACE inhibitors experienced overdosing, which causes most of the excess risk of AKI. These results suggest that dosage adjustment of ACE inhibitors to renal function or substitution of ACE inhibitors with ARBs could reduce the incidence of AKI. Moreover, ACE inhibitors and ARBs should be stopped in cases of dehydration. PMID:27080620

  16. Preoperative angiotensin converting enzyme inhibitor usage in patients with chronic subdural hematoma: Associations with initial presentation and clinical outcome.

    PubMed

    Neidert, Marian C; Schmidt, Tobias; Mitova, Tatyana; Fierstra, Jorn; Bellut, David; Regli, Luca; Burkhardt, Jan-Karl; Bozinov, Oliver

    2016-06-01

    The aim of this study is to analyze the association of preoperative usage of angiotensin converting enzyme (ACE) inhibitors with the initial presentation and clinical outcome of patients with chronic subdural hematoma (cSDH). Patients treated for cSDH between 2009 and 2013 at our institution were included in this retrospective case-control study. Medical charts were reviewed retrospectively and data were analyzed using descriptive and inferential statistics. Out of 203 patients (58 females, mean age 73.2years), 53 (26%) patients were on ACE inhibitors before their presentation with cSDH. Median initial hematoma volume in individuals with ACE inhibitors (179.2±standard error of the mean [SEM] 13.0ml) was significantly higher compared to patients without ACE inhibitors (140.4±SEM 6.2ml; p=0.007). There was an increased probability of surgical reintervention in the ACE inhibitor group (12/53, 23% versus 19/153, 12%; p=0.079), especially in patients older than 80years (6/23, 26% versus 3/45, 7%; p=0.026). ACE inhibitors are associated with higher hematoma volume in patients with cSDH and with a higher frequency of recurrences requiring surgery (especially in the very old). We hypothesize that these effects are due to ACE inhibitor induced bradykinin elevation causing increased vascular permeability of the highly vascularized neomembranes in cSDH. PMID:26898577

  17. Identification of novel Saccharomyces cerevisiae proteins with nuclear export activity: cell cycle-regulated transcription factor ace2p shows cell cycle-independent nucleocytoplasmic shuttling.

    PubMed

    Jensen, T H; Neville, M; Rain, J C; McCarthy, T; Legrain, P; Rosbash, M

    2000-11-01

    Nuclear export of proteins containing leucine-rich nuclear export signals (NESs) is mediated by the NES receptor CRM1/Crm1p. We have carried out a yeast two-hybrid screen with Crm1p as a bait. The Crm1p-interacting clones were subscreened for nuclear export activity in a visual assay utilizing the Crm1p-inhibitor leptomycin B (LMB). This approach identified three Saccharomyces cerevisiae proteins not previously known to have nuclear export activity. These proteins are the 5' RNA triphosphatase Ctl1p, the cell cycle-regulated transcription factor Ace2p, and a protein encoded by the previously uncharacterized open reading frame YDR499W. Mutagenesis analysis show that YDR499Wp contains an NES that conforms to the consensus sequence for leucine-rich NESs. Mutagenesis of Ctl1p and Ace2p were unable to identify specific NES residues. However, a 29-amino-acid region of Ace2p, rich in hydrophobic residues, contains nuclear export activity. Ace2p accumulates in the nucleus at the end of mitosis and activates early-G(1)-specific genes. We now provide evidence that Ace2p is nuclear not only in late M-early G(1) but also during other stages of the cell cycle. This feature of Ace2p localization explains its ability to activate genes such as CUP1, which are not expressed in a cell cycle-dependent manner.

  18. 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; Wang, Qian; Xu, Wei; Su, Shan; Sun, Zhiwu; Yu, Fei; Liu, Qi; Wang, Chao; et al

    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

  19. Sex Hormones Promote Opposite Effects on ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously Hypertensive Rats

    PubMed Central

    Dalpiaz, P. L. M.; Lamas, A. Z.; Caliman, I. F.; Ribeiro, R. F.; Abreu, G. R.; Moyses, M. R.; Andrade, T. U.; Gouvea, S. A.; Alves, M. F.; Carmona, A. K.; Bissoli, N. S.

    2015-01-01

    Background There is growing interest in sex differences and RAS components. However, whether gender influences cardiac angiotensin I-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity is still unknown. In the present work, we determined the relationship between ACE and ACE2 activity, left ventricular function and gender in spontaneously hypertensive rats (SHRs). Methodology / Principal Findings Twelve-week-old female (F) and male (M) SHRs were divided into 2 experimental groups (n = 7 in each group): sham (S) and gonadectomized (G). Fifty days after gonadectomy, we measured positive and negative first derivatives (dP/dt maximum left ventricle (LV) and dP/dt minimum LV, respectively), hypertrophy (morphometric analysis) and ACE and ACE2 catalytic activity (fluorimetrically). Expression of calcium handling proteins was measured by western blot. Male rats exhibited higher cardiac ACE and ACE2 activity as well as hypertrophy compared to female rats. Orchiectomy decreased the activity of these enzymes and hypertrophy, while ovariectomy increased hypertrophy and ACE2, but did not change ACE activity. For cardiac function, the male sham group had a lower +dP/dt than the female sham group. After gonadectomy, the +dP/dt increased in males and reduced in females. The male sham group had a lower -dP/dt than the female group. After gonadectomy, the -dP/dt increased in the male and decreased in the female groups when compared to the sham group. No difference was observed among the groups in SERCA2a protein expression. Gonadectomy increased protein expression of PLB (phospholamban) and the PLB to SERCA2a ratio in female rats, but did not change in male rats. Conclusion Ovariectomy leads to increased cardiac hypertrophy, ACE2 activity, PLB expression and PLB to SERCA2a ratio, and worsening of hemodynamic variables, whereas in males the removal of testosterone has the opposite effects on RAS components. PMID:26010093

  20. ACE: A Collaborative School Consultation Program for Secondary School Teachers

    ERIC Educational Resources Information Center

    Couture, Caroline; Massé, Line

    2014-01-01

    This article presents a description of ACE (Accompagnement collaboratif des enseignants (Collaborative teacher accompaniment)), a new program designed to guide secondary school teachers in integrating students with behavioral problems in their classrooms. ACE proposes collaborative accompaniment inspired by behavioral and mental health…

  1. 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. PMID:23145508

  2. Genetic influences of angiotensin-converting enzyme inhibitor response: an opportunity for personalizing therapy?

    PubMed

    Brugts, Jasper J; Simoons, Maarten L

    2012-08-01

    The angiotensin-converting enzyme (ACE) inhibitors are a cornerstone drug therapy in the current treatment of patients with hypertension, stable coronary artery disease and heart failure. Individualizing therapy of ACE inhibitors with clinical risk factors in low-risk patients with stable coronary artery disease is not feasible. The concept of pharmacogenetics, by studying patient factors more individually, offers a first glimpse in the quest for the 'holy grail' of personalized medicine. As such, genetic targets in the direct pharmacodynamic pathway of ACE inhibitors, the renin-angiotensin-aldosterone system, is a plausible candidate for such an approach. In the past few decades, results of pharmacogenetic studies were scarce and inconsistent. However, recently the first reports of larger pharmacogenetic studies are now confirming that the 'pharmacogenetic approach' might be feasible in the future. The current review focuses on the recent developments in pharmacogenetic research in response to ACE inhibitors in patients with stable coronary artery disease. PMID:23030290

  3. 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

    2014-03-01

    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.

  4. 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

  5. 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

  6. 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.

  7. NAAG peptidase inhibitor improves motor function and reduces cognitive dysfunction in a model of TBI with secondary hypoxia.

    PubMed

    Gurkoff, Gene G; Feng, Jun-Feng; Van, Ken C; Izadi, Ali; Ghiasvand, Rahil; Shahlaie, Kiarash; Song, Minsoo; Lowe, David A; Zhou, Jia; Lyeth, Bruce G

    2013-06-17

    Immediately following traumatic brain injury (TBI) and TBI with hypoxia, there is a rapid and pathophysiological increase in extracellular glutamate, subsequent neuronal damage and ultimately diminished motor and cognitive function. N-acetyl-aspartyl glutamate (NAAG), a prevalent neuropeptide in the CNS, is co-released with glutamate, binds to the presynaptic group II metabotropic glutamate receptor subtype 3 (mGluR3) and suppresses glutamate release. However, the catalytic enzyme glutamate carboxypeptidase II (GCP II) rapidly hydrolyzes NAAG into NAA and glutamate. Inhibition of the GCP II enzyme with NAAG peptidase inhibitors reduces the concentration of glutamate both by increasing the duration of NAAG activity on mGluR3 and by reducing degradation into NAA and glutamate resulting in reduced cell death in models of TBI and TBI with hypoxia. In the following study, rats were administered the NAAG peptidase inhibitor PGI-02776 (10mg/kg) 30 min following TBI combined with a hypoxic second insult. Over the two weeks following injury, PGI-02776-treated rats had significantly improved motor function as measured by increased duration on the rota-rod and a trend toward improved performance on the beam walk. Furthermore, two weeks post-injury, PGI-02776-treated animals had a significant decrease in latency to find the target platform in the Morris water maze as compared to vehicle-treated animals. These findings demonstrate that the application of NAAG peptidase inhibitors can reduce the deleterious motor and cognitive effects of TBI combined with a second hypoxic insult in the weeks following injury. PMID:23562458

  8. A Selective Dopamine Reuptake Inhibitor Improves Prefrontal Cortex-Dependent Cognitive Function: Potential Relevance to Attention Deficit Hyperactivity Disorder

    PubMed Central

    Schmeichel, Brooke E.; Zemlan, Frank P.; Berridge, Craig W.

    2012-01-01

    Drugs used to treat attention deficit hyperactivity disorder (ADHD) improve prefrontal cortex (PFC)-dependent cognitive function. The majority of ADHD-related treatments act either as dual norepinephrine (NE) and dopamine (DA) reuptake inhibitors (psychostimulants) or selective NE reuptake inhibitors (SNRIs). Certain benztropine analogs act as highly selective DA reuptake inhibitors while lacking the reinforcing actions, and thus abuse potential, of psychostimulants. To assess the potential use of these compounds in the treatment of ADHD, we examined the effects of a well-characterized benztropine analog, AHN 2-005, on performance of rats in a PFC-dependent delayed-alternation task of spatial working memory. Similar to that seen with all drugs currently approved for ADHD, AHN 2-005 dose-dependently improved performance in this task. Clinically-relevant doses of psychostimulants and SNRIs elevate NE and DA preferentially in the PFC. Despite the selectivity of this compound for the DA transporter, additional microdialysis studies demonstrated that a cognition-enhancing dose of AHN 2-005 that lacked locomotor activating effects increased extracellular levels of both DA and NE in the PFC. AHN 2-005 produced a larger increase in extracellular DA in the nucleus accumbens, although the magnitude of this was well below that seen with motor activating doses of psychostimulants. Collectively, these observations suggest that benztropine analogs may be efficacious in the treatment of ADHD or other disorders associated with PFC dysfunction. These studies provide a strong rationale for future research focused on the neural mechanisms contributing to the cognition-enhancing actions and the potential clinical utility of AHN 2-005 and related compounds. PMID:22796428

  9. Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1-FoxM1 complex.

    PubMed

    Yang, Jin; Feng, Xuhui; Zhou, Qiong; Cheng, Wei; Shang, Ching; Han, Pei; Lin, Chiou-Hong; Chen, Huei-Sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin

    2016-09-20

    Genes encoding angiotensin-converting enzymes (Ace and Ace2) are essential for heart function regulation. Cardiac stress enhances Ace, but suppresses Ace2, expression in the heart, leading to a net production of angiotensin II that promotes cardiac hypertrophy and fibrosis. The regulatory mechanism that underlies the Ace2-to-Ace pathological switch, however, is unknown. Here we report that the Brahma-related gene-1 (Brg1) chromatin remodeler and forkhead box M1 (FoxM1) transcription factor cooperate within cardiac (coronary) endothelial cells of pathologically stressed hearts to trigger the Ace2-to-Ace enzyme switch, angiotensin I-to-II conversion, and cardiac hypertrophy. In mice, cardiac stress activates the expression of Brg1 and FoxM1 in endothelial cells. Once activated, Brg1 and FoxM1 form a protein complex on Ace and Ace2 promoters to concurrently activate Ace and repress Ace2, tipping the balance to Ace2 expression with enhanced angiotensin II production, leading to cardiac hypertrophy and fibrosis. Disruption of endothelial Brg1 or FoxM1 or chemical inhibition of FoxM1 abolishes the stress-induced Ace2-to-Ace switch and protects the heart from pathological hypertrophy. In human hypertrophic hearts, BRG1 and FOXM1 expression is also activated in endothelial cells; their expression levels correlate strongly with the ACE/ACE2 ratio, suggesting a conserved mechanism. Our studies demonstrate a molecular interaction of Brg1 and FoxM1 and an endothelial mechanism of modulating Ace/Ace2 ratio for heart failure therapy.

  10. Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1-FoxM1 complex.

    PubMed

    Yang, Jin; Feng, Xuhui; Zhou, Qiong; Cheng, Wei; Shang, Ching; Han, Pei; Lin, Chiou-Hong; Chen, Huei-Sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin

    2016-09-20

    Genes encoding angiotensin-converting enzymes (Ace and Ace2) are essential for heart function regulation. Cardiac stress enhances Ace, but suppresses Ace2, expression in the heart, leading to a net production of angiotensin II that promotes cardiac hypertrophy and fibrosis. The regulatory mechanism that underlies the Ace2-to-Ace pathological switch, however, is unknown. Here we report that the Brahma-related gene-1 (Brg1) chromatin remodeler and forkhead box M1 (FoxM1) transcription factor cooperate within cardiac (coronary) endothelial cells of pathologically stressed hearts to trigger the Ace2-to-Ace enzyme switch, angiotensin I-to-II conversion, and cardiac hypertrophy. In mice, cardiac stress activates the expression of Brg1 and FoxM1 in endothelial cells. Once activated, Brg1 and FoxM1 form a protein complex on Ace and Ace2 promoters to concurrently activate Ace and repress Ace2, tipping the balance to Ace2 expression with enhanced angiotensin II production, leading to cardiac hypertrophy and fibrosis. Disruption of endothelial Brg1 or FoxM1 or chemical inhibition of FoxM1 abolishes the stress-induced Ace2-to-Ace switch and protects the heart from pathological hypertrophy. In human hypertrophic hearts, BRG1 and FOXM1 expression is also activated in endothelial cells; their expression levels correlate strongly with the ACE/ACE2 ratio, suggesting a conserved mechanism. Our studies demonstrate a molecular interaction of Brg1 and FoxM1 and an endothelial mechanism of modulating Ace/Ace2 ratio for heart failure therapy. PMID:27601681

  11. 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

  12. 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.

  13. C1 inhibitor treatment improves host defense in pneumococcal meningitis in rats and mice.

    PubMed

    Zwijnenburg, Petra J G; van der Poll, Tom; Florquin, Sandrine; Polfliet, Machteld M J; van den Berg, Timo K; Dijkstra, Christine D; Roord, John J; Hack, C Erik; van Furth, A Marceline

    2007-07-01

    In spite of antibiotic treatment, pneumococcal meningitis continues to be associated with significant morbidity and mortality. The complement system is a key component of innate immunity against invading pathogens. However, activation of complement is also involved in tissue damage, and complement inhibition by C1 inhibitor (C1-inh) is beneficial in animal models of endotoxemia and sepsis. In the present study, we demonstrate classical pathway complement activation during pneumococcal meningitis in rats. We also evaluate the effect of C1-inh treatment on clinical illness, bacterial clearance, and inflammatory responses in rats and mice with pneumococcal meningitis. C1-inh treatment was associated with reduced clinical illness, a less-pronounced inflammatory infiltrate around the meninges, and lower brain levels of proinflammatory cytokines and chemokines. C1-inh treatment increased bacterial clearance, possibly through an up-regulation of CR3. Hence, C1-inh may be a useful agent in the treatment of pneumococcal meningitis.

  14. Angiotensin-converting enzyme inhibition studies by natural leech inhibitors by capillary electrophoresis and competition assay.

    PubMed

    Deloffre, Laurence; Sautiere, Pierre-Eric; Huybrechts, Roger; Hens, Korneel; Vieau, Didier; Salzet, Michel

    2004-06-01

    A protocol to follow the processing of angiotensin I into angiotensin II by rabbit angiotensin-converting enzyme (ACE) and its inhibition by a novel natural antagonist, the leech osmoregulator factor (LORF) using capillary zonal electrophoresis is described. The experiment was carried out using the Beckman PACE system and steps were taken to determine (a) the migration profiles of angiotensin and its yielded peptides, (b) the minimal amount of angiotensin II detected, (c) the use of different electrolytes and (d) the concentration of inhibitor. We demonstrated that LORF (IPEPYVWD), a neuropeptide previously found in leech brain, is able to inhibit rabbit ACE with an IC(50) of 19.8 micro m. Interestingly, its cleavage product, IPEP exhibits an IC(50) of 11.5 micro m. A competition assay using p-benzoylglycylglycylglycine and insect ACE established that LORF and IPEP fragments are natural inhibitors for invertebrate ACE. Fifty-four percent of insect ACE activity is inhibited with 50 micro m IPEP and 35% inhibition with LORF (25 mm). Extending the peptide at both N- and C-terminus (GWEIPEPYVWDES) and the cleavage of IPEP in IP abolished the inhibitory activity of both peptides. Immunocytochemical data obtained with antisera raised against LORF and leech ACE showed a colocalization between the enzyme and its inhibitor in the same neurons. These results showed that capillary zonal electrophoresis is a useful technique for following enzymatic processes with small amounts of products and constitutes the first evidence of a natural ACE inhibitor in invertebrates.

  15. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury.

    PubMed

    Yang, Penghui; Gu, Hongjing; Zhao, Zhongpeng; Wang, Wei; Cao, Bin; Lai, Chengcai; Yang, Xiaolan; Zhang, LiangYan; Duan, Yueqiang; Zhang, Shaogeng; Chen, Weiwen; Zhen, Wenbo; Cai, Maosheng; Penninger, Josef M; Jiang, Chengyu; Wang, Xiliang

    2014-11-13

    Since March 2013, the emergence of an avian-origin influenza A (H7N9) virus has raised concern in China. Although most infections resulted in respiratory illness, some severe cases resulted in acute respiratory distress syndrome (ARDS), which is a severe form of acute lung injury (ALI) that further contributes to morbidity. To date, no effective drugs that improve the clinical outcome of influenza A (H7N9) virus-infected patients have been identified. Angiotensin-converting enzyme (ACE) and ACE2 are involved in several pathologies such as cardiovascular functions, renal disease, and acute lung injury. In the current study, we report that ACE2 could mediate the severe acute lung injury induced by influenza A (H7N9) virus infection in an experimental mouse model. Moreover, ACE2 deficiency worsened the disease pathogenesis markedly, mainly by targeting the angiotensin II type 1 receptor (AT1). The current findings demonstrate that ACE2 plays a critical role in influenza A (H7N9) virus-induced acute lung injury, and suggest that might be a useful potential therapeutic target for future influenza A (H7N9) outbreaks.

  16. 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

  17. 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.

  18. Direct thrombin inhibitor-bivalirudin functionalized plasma polymerized allylamine coating for improved biocompatibility of vascular devices.

    PubMed

    Yang, Zhilu; Tu, Qiufen; Maitz, Manfred F; Zhou, Shuo; Wang, Jin; Huang, Nan

    2012-11-01

    The direct thrombin inhibitor of bivalirudin (BVLD), a short peptide derived from hirudin, has drawn an increasing attention in clinical application because it is safer and more effective than heparin for diabetic patients with moderate- or high-risk for acute coronary syndromes (ACS). In this study, BVLD was covalently conjugated on plasma polymerized allylamine (PPAam) coated 316L stainless steel (SS) to develop an anticoagulant surface. QCM-D real time monitoring result shows that 565±20 ng/cm2 of BVLD was bound to the PPAam surface. Infrared spectroscopy (IR) and X-ray photoelectron spectroscopy (XPS) confirmed the immobilization of BVLD. The conjugation of BVLD onto the PPAam coating led to enhanced binding of thrombin, and the activity of the thrombin adsorbed on its surface was effectively inhibited. As a result, the BVLD immobilized PPAam (BVLD-PPAam) substrate prolonged the clotting times, and exhibited inhibition in adhesion and activation of platelets and fibrinogen. We also found that the BVLD-PPAam coating significantly enhanced endothelial cell adhesion, proliferation, migration and release of nitric oxide (NO) and secretion of prostaglandin I2 (PGI2). In vivo results indicate that the BVLD-PPAam surface restrained thrombus formation by rapidly growing a homogeneous and intact endothelium on its surface. These data suggest the potential of this multifunctional BVLD-PPAam coating for the application not only in general vascular devices such as catheters, tubes, oxygenator, hemodialysis membranes but also vascular grafts and stents.

  19. Histone deacetylase inhibitor, trichostatin A, improves learning and memory in high-fat diet-induced cognitive deficits in mice.

    PubMed

    Sharma, Sorabh; Taliyan, Rajeev; Ramagiri, Shruti

    2015-05-01

    Metabolic syndrome is increasingly recognized for its effects on cognitive health. Recent studies have highlighted the role of histone deacetylases (HDACs) in metabolic syndrome and cognitive functions. The present study was designed to investigate the possible therapeutic role of a HDAC inhibitor, trichostatin A (TSA), in cognitive impairment associated with metabolic syndrome. To ascertain the mechanisms involved, we fed mice with high-fat diet (HFD) for 4 weeks and examined changes in behavioral and biochemical/oxidative stress markers. Mice subjected to HFD exhibited characteristic features of metabolic disorder, viz., hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and lower high-density lipoprotein (HDL) cholesterol levels. Moreover, these mice showed severe deficits in learning and memory as assessed by the Morris water maze and passive avoidance tasks along with elevated oxidative stress and inflammatory markers in brain homogenates. The observed changes occurred concurrently with reduced brain-derived neurotrophic factor (BDNF). In contrast, the mice treated with the HDAC inhibitor, TSA (0.5 and 1 mg/kg, i.p.), showed a significant and dose-dependent reduction in serum glucose, triglycerides, and total cholesterol along with improvement in HDL-cholesterol levels and learning and memory performance. TSA treatment also results in alleviation of oxidative stress and neuroinflammatory markers. Moreover, TSA significantly augmented the BDNF levels in HFD-fed mice. Thus, based upon these observations, it may be suggested that HDAC inhibition could be a novel therapeutic strategy to combat cognitive impairment associated with metabolic syndrome.

  20. Combined administration of FVIII and rFVIIa improves haemostasis in haemophilia A patients with high-responding inhibitors--a thrombin generation-guided pilot study.

    PubMed

    Livnat, T; Martinowitz, U; Azar-Avivi, S; Zivelin, A; Brutman-Barazani, T; Lubetsky, A; Kenet, G

    2013-09-01

    Treatment of haemophilia A patients with inhibitors is challenging, and may require individually tailored regimens. Whereas low titre inhibitor patients may respond to high doses of factor VIII (FVIII), high-responding inhibitor patients render replacement therapy ineffective and often require application of bypassing agents. Thrombin generation (TG) assays may be used to monitor haemostasis and/or predict patients' response to bypass agents. In this study we defined by TG, the potential contribution of FVIII to recombinant activated factor VII (rFVIIa)-induced haemostasis in inhibitor plasma. Based upon results, prospectively designed individual regimens of coadministration of rFVIIa and FVIII were applied. Plasma samples from 14 haemophilia patients with inhibitors (including high titre inhibitors) were tested. The response to increasing concentrations of FVIII, rFVIIa or both was assayed by TG. Eight patients, chosen following consent and at physician's discretion, comprised the combined FVIII-rFVIIa therapy clinical study cohort. Combined spiking with FVIII/rFVIIa improved TG induced by rFVIIa alone in all inhibitor plasmas. Combined rFVIIa and FVIII therapy was applied during bleeding or immune tolerance to eight patients, for a total of 393 episodes. Following a single combined dose, 90% haemostasis was documented and neither thrombosis nor any complications evolved. During study period decline of inhibitor levels and bleeding frequency were noted. Pre-analytical studies enabled us to prospectively tailor individual therapy regimens. We confirmed for the first time that the in vitro advantage of combining FVIII and rFVIIa, indeed accounts for improved haemostasis and may safely be applied to inhibitor patients.

  1. 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

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

    PubMed

    Mishra, S; Bedja, D; Amuzie, C; Foss, C A; Pomper, M G; Bhattacharya, R; Yarema, K J; Chatterjee, S

    2015-09-01

    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 (125)I-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.

  3. Hemojuvelin Modulates Iron Stress During Acute Kidney Injury: Improved by Furin Inhibitor

    PubMed Central

    Young, Guang-Huar; Huang, Tao-Min; Wu, Che-Hsiung; Lai, Chun-Fu; Hou, Chun-Cheng; Peng, Kang-Yung; Liang, Chan-Jung; Lin, Shuei-Liong; Chang, Shih-Chung; Tsai, Pi-Ru; Wu, Kwan-Dun

    2014-01-01

    Abstract Aims: Free iron plays an important role in the pathogenesis of acute kidney injury (AKI) via the formation of hydroxyl radicals. Systemic iron homeostasis is controlled by the hemojuvelin-hepcidin-ferroportin axis in the liver, but less is known about this role in AKI. Results: By proteomics, we identified a 42 kDa soluble hemojuvelin (sHJV), processed by furin protease from membrane-bound hemojuvelin (mHJV), in the urine during AKI after cardiac surgery. Biopsies from human and mouse specimens with AKI confirm that HJV is extensively increased in renal tubules. Iron overload enhanced the expression of hemojuvelin-hepcidin signaling pathway. The furin inhibitor (FI) decreases furin-mediated proteolytic cleavage of mHJV into sHJV and augments the mHJV/sHJV ratio after iron overload with hypoxia condition. The FI could reduce renal tubule apoptosis, stabilize hypoxic induced factor-1, prevent the accumulation of iron in the kidney, and further ameliorate ischemic-reperfusion injury. mHJV is associated with decreasing total kidney iron, secreting hepcidin, and promoting the degradation of ferroportin at AKI, whereas sHJV does the opposite. Innovation: This study suggests the ratio of mHJV/sHJV affects the iron deposition during acute kidney injury and sHJV could be an early biomarker of AKI. Conclusion: Our findings link endogenous HJV inextricably with renal iron homeostasis for the first time, add new significance to early predict AKI, and identify novel therapeutic targets to reduce the severity of AKI using the FI. Antioxid. Redox Signal. 20, 1181–1194. PMID:23901875

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. Rational Design of Coumarin Derivatives as CK2 Inhibitors by Improving the Interaction with the Hinge Region.

    PubMed

    Zhang, Na; Chen, Wen-Juan; Zhou, Yue; Zhao, Hongtao; Zhong, Ru-Gang

    2016-01-01

    Design of novel coumarin derivatives as CK2 inhibitors were attempted by targeting the interaction with the hinge region. A set of substituents capable of forming a hydrogen bond or halogen bond with the hinge region were screened in silico, and trifluoromethyl emerges as a promising motif by forming favorable electrostatic interaction and a presumable halogen bond with the hinge region. As proof of concept, three trifluoromethyl derivatives of coumarin were synthesized and tested in vitro. The results indicated that replacement of methyl by trifluoromethyl leads to a modest 5-fold improvement in potency, with the most active compound being 0.4 µM. The newly designed compounds were further screened on one lung cancer cell line A549, showing low micromolar anti-proliferative activity.

  9. 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.

  10. 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.

  11. First science observations with the ACES echelle spectrograph

    NASA Astrophysics Data System (ADS)

    Reynolds, Robert O.; Lloyd-Hart, Michael

    2004-09-01

    The use of spectrographs with telescopes having high order adaptive optics (AO) systems offers the possibility of achieving near diffraction-limited spectral resolution with ground-based telescopes, as well as important advantages for instrument design. The use of an optical fiber to couple the instrument to the telescope affords additional advantages such as flexibility in the placement of the instrument and improved homogeneity of the input illumination function. In the case of Steward Observatory's Adaptively Coupled Echelle Spectrograph (ACES), the instrument is normally coupled to the telescope with an 8 micron diameter near single-mode optical fiber, although the instrument can be used at fixed focus locations without the fiber for telescopes so equipped. The use of a fiber coupler results in the phenomenon known as 'modal noise', where the transmission of multiple modes in the fiber leads to a wavelength-dependent variation in illumination that limits flat fielding precision. We have largely eliminated this effect through the use of an automated fiber stretcher device. We report here on improvements to the fiber feed optics and on interim observations made with the instrument at a conventional telescope not equipped with adaptive optics.

  12. 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.

  13. Investigating the Selectivity of Metalloenzyme Inhibitors

    PubMed Central

    Day, Joshua A.; Cohen, Seth M.

    2013-01-01

    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 Fe3+ from holo-transferrin to gauge the ability of the inhibitors to access Fe3+ 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. PMID:24074025

  14. Molecular dynamics simulation and molecular docking studies of Angiotensin converting enzyme with inhibitor lisinopril and amyloid Beta Peptide.

    PubMed

    Jalkute, Chidambar Balbhim; Barage, Sagar Hindurao; Dhanavade, Maruti Jayram; Sonawane, Kailas Dasharath

    2013-06-01

    Angiotensin converting enzyme (ACE) cleaves amyloid beta peptide. So far this cleavage mechanism has not been studied in detail at atomic level. Keeping this view in mind, we performed molecular dynamics simulation of crystal structure complex of testis truncated version of ACE (tACE) and its inhibitor lisinopril along with Zn(2+) to understand the dynamic behavior of active site residues of tACE. Root mean square deviation results revealed the stability of tACE throughout simulation. The residues Ala 354, Glu 376, Asp 377, Glu 384, His 513, Tyr 520 and Tyr 523 of tACE stabilized lisinopril by hydrogen bonding interactions. Using this information in subsequent part of study, molecular docking of tACE crystal structure with Aβ-peptide has been made to investigate the interactions of Aβ-peptide with enzyme tACE. The residues Asp 7 and Ser 8 of Aβ-peptide were found in close contact with Glu 384 of tACE along with Zn(2+). This study has demonstrated that the residue Glu 384 of tACE might play key role in the degradation of Aβ-peptide by cleaving peptide bond between Asp 7 and Ser 8 residues. Molecular basis generated by this attempt could provide valuable information towards designing of new therapies to control Aβ concentration in Alzheimer's patient.

  15. 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. PMID:23261432

  16. 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.

  17. 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.

  18. Potential of protease inhibitor in 3-nitropropionic acid induced Huntington's disease like symptoms: mitochondrial dysfunction and neurodegeneration.

    PubMed

    Hariharan, Ashwini; Shetty, Shruthi; Shirole, Trupti; Jagtap, Aarti G

    2014-12-01

    Huntington's disease (HD) is a genetic, neurodegenerative disorder mainly characterized by motor dysfunction, cognitive decline and psychiatric disturbances. 3-Nitropropionic acid (3-NP) is an inhibitor of succinate dehydrogenase (Complex II) of the mitochondrial respiratory chain, which thereby reduces production of ATP. It induces neurotoxicity by causing striatal degeneration, energy deficit and oxidative stress. Angiotensin converting enzyme (ACE) is an important protease in the renin angiotensin system (RAS) responsible for the conversion of Angiotensin I to Angiotensin II. Angiotensin-II stimulates mitochondrial oxidant release leading to depression of energy metabolism. ACE inhibitors have shown promise in disorders like stress, anxiety, and depression in addition to showing beneficial effects in cognitive disorders like Alzheimer's. Angiotensin-II inhibition enhances energy production by lowering mitochondrial oxidant production, and hence protects mitochondrial structure. Trandolapril is a centrally active ACE inhibitor. 3-NP administered systematically (20mg/kg, i.p) for 4 days consecutively induced HD like symptoms - loss of body weight, neurobehavioral alterations like memory dysfunction (elevated plus maze, Morris water maze performance), Hind-limb impairment (Narrow beam test), motor incoordination (locomotor activity). Biochemical studies on brain tissue showed increased lipid peroxidation, nitrite levels and acetylcholinesterase activity along with decreased levels of reduced glutathione, catalase activity. Mitochondrial enzyme complex activities (I, II, IV and MTT assay) were found to be significantly lowered in brain mitochondria. Administration of Trandolapril (4 and 6 mg/kg, p.o) daily for 12 days showed significant improvement in body weight, neurobehavioral parameters, oxidative stress and mitochondrial enzyme activities in rat brain. These findings were further confirmed by histopathological studies which showed improvement in 3-NP induced

  19. Potential of protease inhibitor in 3-nitropropionic acid induced Huntington's disease like symptoms: mitochondrial dysfunction and neurodegeneration.

    PubMed

    Hariharan, Ashwini; Shetty, Shruthi; Shirole, Trupti; Jagtap, Aarti G

    2014-12-01

    Huntington's disease (HD) is a genetic, neurodegenerative disorder mainly characterized by motor dysfunction, cognitive decline and psychiatric disturbances. 3-Nitropropionic acid (3-NP) is an inhibitor of succinate dehydrogenase (Complex II) of the mitochondrial respiratory chain, which thereby reduces production of ATP. It induces neurotoxicity by causing striatal degeneration, energy deficit and oxidative stress. Angiotensin converting enzyme (ACE) is an important protease in the renin angiotensin system (RAS) responsible for the conversion of Angiotensin I to Angiotensin II. Angiotensin-II stimulates mitochondrial oxidant release leading to depression of energy metabolism. ACE inhibitors have shown promise in disorders like stress, anxiety, and depression in addition to showing beneficial effects in cognitive disorders like Alzheimer's. Angiotensin-II inhibition enhances energy production by lowering mitochondrial oxidant production, and hence protects mitochondrial structure. Trandolapril is a centrally active ACE inhibitor. 3-NP administered systematically (20mg/kg, i.p) for 4 days consecutively induced HD like symptoms - loss of body weight, neurobehavioral alterations like memory dysfunction (elevated plus maze, Morris water maze performance), Hind-limb impairment (Narrow beam test), motor incoordination (locomotor activity). Biochemical studies on brain tissue showed increased lipid peroxidation, nitrite levels and acetylcholinesterase activity along with decreased levels of reduced glutathione, catalase activity. Mitochondrial enzyme complex activities (I, II, IV and MTT assay) were found to be significantly lowered in brain mitochondria. Administration of Trandolapril (4 and 6 mg/kg, p.o) daily for 12 days showed significant improvement in body weight, neurobehavioral parameters, oxidative stress and mitochondrial enzyme activities in rat brain. These findings were further confirmed by histopathological studies which showed improvement in 3-NP induced

  20. 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.

  1. 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.

  2. Validation of ACE and OSIRIS ozone and NO2 measurements using ground-based instruments at 80° N

    NASA Astrophysics Data System (ADS)

    Adams, C.; Strong, K.; Batchelor, R. L.; Bernath, P. F.; Brohede, S.; Boone, C.; Degenstein, D.; Daffer, W. H.; Drummond, J. R.; Fogal, P. F.; Farahani, E.; Fayt, C.; Fraser, A.; Goutail, F.; Hendrick, F.; Kolonjari, F.; Lindenmaier, R.; Manney, G.; McElroy, C. T.; McLinden, C. A.; Mendonca, J.; Park, J.-H.; Pavlovic, B.; Pazmino, A.; Roth, C.; Savastiouk, V.; Walker, K. A.; Weaver, D.; Zhao, X.

    2012-05-01

    -based ozone total columns with mean relative differences of 0.1-7.3%. For NO2, partial columns from 17 km upward were scaled to noon using a photochemical model. Mean relative differences between OSIRIS, ACE-FTS and ground-based NO2 measurements do not exceed 20%. ACE-MAESTRO measures more NO2 than the other instruments, with mean relative differences of 25-52%. Seasonal variation in the differences between NO2 partial columns is observed, suggesting that there are systematic errors in the measurements and/or the photochemical model corrections. For ozone spring-time measurements, additional coincidence criteria based on stratospheric temperature and the location of the polar vortex were found to improve agreement between some of the instruments. For ACE-FTS v2.2 minus Bruker FTIR, the 2007-2009 spring-time mean relative difference improved from -5.0 ± 0.4% to -3.1 ± 0.8% with the dynamical selection criteria. This was the largest improvement, likely because both instruments measure direct sunlight and therefore have well-characterized lines-of-sight compared with scattered sunlight measurements. For NO2, the addition of a ±1° latitude coincidence criterion improved spring-time intercomparison results, likely due to the sharp latitudinal gradient of NO2 during polar sunrise. The differences between satellite and ground-based measurements do not show any obvious trends over the missions, indicating that both the ACE and OSIRIS instruments continue to perform well.

  3. Validation of ACE and OSIRIS ozone and NO2 measurements using ground-based instruments at 80° N

    NASA Astrophysics Data System (ADS)

    Adams, C.; Strong, K.; Batchelor, R. L.; Bernath, P. F.; Brohede, S.; Boone, C.; Degenstein, D.; Daffer, W. H.; Drummond, J. R.; Fogal, P. F.; Farahani, E.; Fayt, C.; Fraser, A.; Goutail, F.; Hendrick, F.; Kolonjari, F.; Lindenmaier, R.; Manney, G.; McElroy, C. T.; McLinden, C. A.; Mendonca, J.; Park, J.-H.; Pavlovic, B.; Pazmino, A.; Roth, C.; Savastiouk, V.; Walker, K. A.; Weaver, D.; Zhao, X.

    2012-01-01

    columns with mean relative differences of 0.1-7.3%. For NO2, partial columns from 17 km upward were scaled to noon using a photochemical model. Mean relative differences between OSIRIS, ACE-FTS and ground-based NO2 measurements do not exceed 20%. ACE-MAESTRO measures more NO2 than the other instruments, with mean relative differences of 25-52%. Seasonal variation in the differences between partial columns is observed, suggesting that there are systematic errors in the measurements, the photochemical model corrections, and/or in the coincidence criteria. For ozone spring-time measurements, additional coincidence criteria based on stratospheric temperature and the location of the polar vortex were found to improve agreement between some of the instruments. For ACE-FTS v2.2 minus Bruker FTIR, the 2007-2009 spring-time mean relative difference improved from -5.0 ± 0.4% to -3.1 ± 0.8% with the dynamical selection criteria. This was the largest improvement, likely because both instruments measure direct sunlight and therefore have well-characterized lines-of-sight compared with scattered sunlight measurements. For NO2, the addition of a ±1° latitude coincidence criterion improved spring-time intercomparison results, likely due to the sharp latitudinal gradient of NO2 during polar sunrise. The differences between satellite and ground-based measurements do not show any obvious trends over the missions, indicating that both the ACE and OSIRIS instruments continue to perform well.

  4. Effects of angiotensin converting enzyme inhibitors in hypertensive patients with aortic valve stenosis: a drug withdrawal study

    PubMed Central

    Jiménez-Candil, J; Bermejo, J; Yotti, R; Cortina, C; Moreno, M; Cantalapiedra, J L; García-Fernández, M A

    2005-01-01

    Objective: To determine the effects of angiotensin converting enzyme (ACE) inhibitors in hypertensive patients with aortic valve stenosis (AS). Design: Observational, drug withdrawal, single blinded study, with randomisation of the order of tests. Setting: Hypertension and asymptomatic AS. Patients and interventions: 20 patients (aged 73 (9) years, valve area 0.7 (0.3) cm2, left ventricular ejection fraction ⩾ 45%) were enrolled. Each patient underwent two sets of tests (with and without taking the drug), each of which included clinical evaluation, Doppler echocardiogram, and symptom limited exercise echocardiography. Main outcome measures: Functional and haemodynamic variables while taking and not taking ACE inhibitors. Results: Drug intervention induced no change in patients’ subjective functional class. While taking ACE inhibitors, patients had a lower systolic blood pressure (140 (18) mm Hg with ACE inhibitors v 159 (12) mm Hg without ACE inhibitors, p  =  0.02), a higher mean pressure gradient (34 (15) mm Hg v 28 (18) mm Hg, p  =  0.037), and a higher left ventricular stroke work loss (19 (6)% v 14 (10)%, p  =  0.009). Other baseline functional and haemodynamic parameters were unmodified. Five patients had an abnormal blood pressure response during one of the exercise tests (two patients while taking the drug and three patients while not taking the drug). When taking ACE inhibitors, patients had a higher stroke volume at peak stress (59 (11) ml v 54 (25) ml, p  =  0.046). All other stress variables remained constant. Conclusions: In AS, the afterload relief caused by ACE inhibitors is blunted by a parallel increase in the pressure gradient. However, ACE inhibitors favourably affect stress haemodynamic function in most hypertensive patients with AS and should not be discontinued. PMID:16162624

  5. Hydroxyl fasudil, an inhibitor of Rho signaling, improves erectile function in diabetic rats: a role for neuronal ROCK

    PubMed Central

    Sezen, Sena F.; Lagoda, Gwen; Musicki, Biljana; Burnett, Arthur L.

    2014-01-01

    Introduction The pathogenesis of diabetic erectile dysfunction (ED) includes neuropathy, but the molecular basis for neurogenic ED is incompletely understood. The RhoA/ROCK pathway has been implicated in diabetic neuropathy and in ED, but its role in diabetic neurogenic ED is not known. Aims The aim of this study was to determine whether hydroxyl fasudil, an ROCK inhibitor, affects diabetic neuropathy-related ED. Methods Type 1 diabetes mellitus was induced in male rats by streptozotocin (75 mg/kg, intraperitoneally). After 8 weeks, diabetic rats were administered hydroxyl fasudil, a selective ROCK inhibitor (10 mg/kg/day, intraperitoneally) or vehicle, for 4 weeks. Age-matched control, nondiabetic, rats were treated intraperitoneally for 4 weeks with saline. At week 12, after a 2 day wash-out, neuro-stimulated erectile function was evaluated. Major pelvic ganglia (MPG) were collected for western blot analysis of RhoA, ROCK-1, ROCK-2, phospho (P)-AKT (Ser473), and P-phosphatase and tensin homolog (P-PTEN) (Ser380/Thr382/383). Main outcome measures Effect of ROCK inhibitor hydroxyl fasudil on erectile function and ROCK/P-AKT/P-PTEN pathway in the MPG of diabetic rats. Results Erectile response was significantly (P<0.05) reduced in diabetic compared with nondiabetic rats, and was preserved (P<0.05) in diabetic rats treated with hydroxyl fasudil. In diabetic rats, RhoA and ROCK-2 protein expressions in MPG were increased (P<0.05) and remained increased in hydroxyl fasudil-treated rats. P-AKT (Ser473) expression was decreased (P<0.05), while P-PTEN (Ser380/Thr382/383) expression was increased (P<0.05) in MPG of diabetic compared to nondiabetic rats, and both were reversed (P<0.05) in diabetic rats treated with hydroxyl fasudil. Conclusion Improved erectile function and restored P-AKT and P-PTEN in the MPG with hydroxyl fasudil treatment suggest the role of Rho signaling via PTEN/AKT pathway in neurogenic diabetic ED. PMID:24919622

  6. Climate-active Trace Gases from ACE Satellite Observations

    NASA Astrophysics Data System (ADS)

    Bernath, P. F.; Brown, A.; Harrison, J.; Chipperfield, M.; Boone, C.; Wilson, C.; Walker, K. A.

    2011-12-01

    ACE (also known as SCISAT) is making a comprehensive set of simultaneous measurements of more than 30 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. A high-resolution (0.02 cm-1) infrared Fourier Transform Spectrometer (FTS) operating from 2 to 13 microns (750-4400 cm-1) is measuring the vertical distribution of trace gases, and the meteorological variables of temperature and pressure. Launched by NASA in August 2003 for a nominal two-year mission, ACE performance remains excellent after 8 years in orbit. Volume mixing ratio (VMR) profiles of sixteen halogenated trace gases are routinely retrieved from ACE-FTS atmospheric spectra: CCl4, CF4, CCl3F (CFC-11), CCl2F2 (CFC-12), C2Cl3F3 (CFC-113), CH3Cl, ClONO2, COF2, COCl2, COClF, CHF2Cl (HCFC-22), CH3CCl2F (HCFC-141b), CH3CClF2 (HCFC-142b), HCl, HF and SF6. ACE also provides VMR profiles for CH4, N2O and OCS; HCFC-23 (CHF3) is a recent research product. ACE-FTS measurements were compared to surface measurements made by the AGAGE network and output from the SLIMCAT three-dimensional (3-D) chemical transport model, which is constrained by similar surface data. ACE-FTS measurements of CFCs (and HCl) show declining trends which agree with both AGAGE and SLIMCAT values. The concentrations of HCFCs are increasing with ACE-FTS, SLIMCAT and AGAGE all showing positive trends. These results illustrate the success of the Montreal Protocol in reducing ozone depleting substances. The replacement of CFCs with HCFCs has led to an increase in the VMR of HF in the stratosphere. As chlorine containing compounds continue to be phased out and replaced by fluorine-containing molecules, it is likely that total atmospheric fluorine will continue increasing in the near future. These species are all powerful greenhouse gases. ACE provides near global VMR

  7. Significant improvement in cloning efficiency of an inbred miniature pig by histone deacetylase inhibitor treatment after somatic cell nuclear transfer.

    PubMed

    Zhao, Jianguo; Ross, Jason W; Hao, Yanhong; Spate, Lee D; Walters, Eric M; Samuel, Melissa S; Rieke, August; Murphy, Clifton N; Prather, Randall S

    2009-09-01

    The National Institutes of Health (NIH) miniature pig was developed specifically for xenotransplantation and has been extensively used as a large-animal model in many other biomedical experiments. However, the cloning efficiency of this pig is very low (<0.2%), and this has been an obstacle to the promising application of these inbred swine genetics for biomedical research. It has been demonstrated that increased histone acetylation in somatic cell nuclear transfer (SCNT) embryos, by applying a histone deacetylase (HDAC) inhibitor such as trichostatin A (TSA), significantly enhances the developmental competence in several species. However, some researchers also reported that TSA treatment had various detrimental effects on the in vitro and in vivo development of the SCNT embryos. Herein, we report that treatment with 500 nM 6-(1,3-dioxo-1H, 3H-benzo[de]isoquinolin-2-yl)-hexanoic acid hydroxyamide (termed scriptaid), a novel HDAC inhibitor, significantly enhanced the development of SCNT embryos to the blastocyst stage when NIH inbred fetal fibroblast cells (FFCs) were used as donors compared with the untreated group (21% vs. 9%, P < 0.05). Scriptaid treatment resulted in eight pregnancies from 10 embryo transfers (ETs) and 14 healthy NIH miniature pigs from eight litters, while no viable piglets (only three mummies) were obtained from nine ETs in the untreated group. Thus, scriptaid dramatically increased the cloning efficiency when using inbred genetics from 0.0% to 1.3%. In contrast, scriptaid treatment decreased the blastocyst rate in in vitro fertilization embryos (from 37% to 26%, P < 0.05). In conclusion, the extremely low cloning efficiency in the NIH miniature pig may be caused by its inbred genetic background and can be improved by alteration of genomic histone acetylation patterns.

  8. 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.

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

    PubMed

    Passalacqua, Karla D; Charbonneau, Marie-Eve; Donato, Nicholas J; Showalter, Hollis D; Sun, Duxin; Wen, Bo; He, Miao; Sun, Hanshi; O'Riordan, Mary X D; Wobus, Christiane E

    2016-07-01

    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

  10. 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. PMID:27246933

  11. Mind the gap: delayed manifestation of long-term object memory improvement by phosphodiesterase inhibitors.

    PubMed

    Akkerman, S; Blokland, A; Prickaerts, J

    2014-03-01

    We examined the temporal profile of pharmacologically enhanced episodic memory, using the object recognition task. Male Wistar rats were tested at different retention intervals ranging from 1 h to 24 h. The object discrimination performance of all groups (untreated, placebo, drug treatment) gradually decreased up to an interval (8 h). Interestingly, only after this 8 h interval the memory improving effects of vardenafil and rolipram started to emerge. This time-dependent memory performance shows similarities with the Kamin effect. The delayed manifestation of drug-enhanced memory suggests that two separate memory mechanisms are at play, a quick transient form of memory and a more stable memory form that requires several hours to develop. It is important to take this into account when testing treatments intended for long-term memory enhancement.

  12. 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.

  13. 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.

  14. Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome

    PubMed Central

    Lysenko, Larisa V.; Kim, Jeesun; Henry, Cassandra; Tyrtyshnaia, Anna; Kohnz, Rebecca A.; Madamba, Francisco; Simon, Gabriel M.; Kleschevnikova, Natalia E.; Nomura, Daniel K.; Ezekowitz, R . Alan B.; Kleschevnikov, Alexander M.

    2014-01-01

    Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS. PMID:25474204

  15. Novel Inhibitors of Neurotropic Alphavirus Replication That Improve Host Survival in a Mouse Model of Acute Viral Encephalitis

    PubMed Central

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

    2012-01-01

    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 analog 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. PMID:22428985

  16. 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

  17. Celastrol, an NF-κB Inhibitor, Improves Insulin Resistance and Attenuates Renal Injury in db/db Mice

    PubMed Central

    Kim, Jung Eun; Lee, Mi Hwa; Nam, Deok Hwa; Song, Hye Kyoung; Kang, Young Sun; Lee, Ji Eun; Kim, Hyun Wook; Cha, Jin Joo; Hyun, Young Youl; Han, Sang Youb; Han, Kum Hyun; Han, Jee Young; Cha, Dae Ryong

    2013-01-01

    The NF-κB pathway plays an important role in chronic inflammatory and autoimmune diseases. Recently, NF-κB has also been suggested as an important mechanism linking obesity, inflammation, and metabolic disorders. However, there is no current evidence regarding the mechanism of action of NF-κB inhibition in insulin resistance and diabetic nephropathy in type 2 diabetic animal models. We investigated the effects of the NF-κB inhibitor celastrol in db/db mice. The treatment with celastrol for 2 months significantly lowered fasting plasma glucose (FPG), HbA1C and homeostasis model assessment index (HOMA-IR) levels. Celastrol also exhibited significant decreases in body weight, kidney/body weight and adiposity. Celastrol reduced insulin resistance and lipid abnormalities and led to higher plasma adiponectin levels. Celastrol treatment also significantly mitigated lipid accumulation and oxidative stress in organs including the kidney, liver and adipose tissue. The treated group also exhibited significantly lower creatinine levels and urinary albumin excretion was markedly reduced. Celastrol treatment significantly lowered mesangial expansion and suppressed type IV collagen, PAI-1 and TGFβ1 expressions in renal tissues. Celastrol also improved abnormal lipid metabolism, oxidative stress and proinflammatory cytokine activity in the kidney. In cultured podocytes, celastrol treatment abolished saturated fatty acid-induced proinflammatory cytokine synthesis. Taken together, celastrol treatment not only improved insulin resistance, glycemic control and oxidative stress, but also improved renal functional and structural changes through both metabolic and anti-inflammatory effects in the kidney. These results suggest that targeted therapy for NF-κB may be a useful new therapeutic approach for the management of type II diabetes and diabetic nephropathy. PMID:23637966

  18. 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.

  19. 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.

  20. Improving patient outcomes in hereditary angioedema: reducing attack frequency using routine prevention with C1 inhibitor concentrate

    PubMed Central

    Dominas, Nina; Hoffmann, Thomas K; Bas, Murat; Greve, Jens

    2014-01-01

    Hereditary angioedema (HAE) is a rare inherited disorder, characterised by recurrent oedema attacks in various regions of the body. In HAE, mutations in the C1 esterase inhibitor (C1-INH) gene result in decreased C1-INH concentrations (type I HAE) or functionally deficient C1-INH (type II HAE), leading to inappropriate activation of the kallikrein–kinin system and release of vasoactive mediators. Treatment of HAE aims to manage acute attacks (using replacement C1-INH or bradykinin B2 receptor antagonist) or prevent attacks through prophylaxis (using C1-INH or attenuated androgens). We present a case of a 67-year-old man with HAE who suffered a high number of breakthrough HAE attacks while undergoing long-term prophylaxis with attenuated androgens. Androgen therapy was safely discontinued and routine prevention therapy with C1-INH (1000 U) introduced as part of an individualised management approach, in line with published clinical trial data, which improved patient outcomes in terms of HAE attack frequency and severity. PMID:24850548

  1. High-throughput sequence analysis reveals structural diversity and improved potency among RNA inhibitors of HIV reverse transcriptase

    PubMed Central

    Ditzler, Mark A.; Lange, Margaret J.; Bose, Debojit; Bottoms, Christopher A.; Virkler, Katherine F.; Sawyer, Andrew W.; Whatley, Angela S.; Spollen, William; Givan, Scott A.; Burke, Donald H.

    2013-01-01

    Systematic evolution of ligands through exponential enrichment (SELEX) is a well-established method for generating nucleic acid populations that are enriched for specified functions. High-throughput sequencing (HTS) enhances the power of comparative sequence analysis to reveal details of how RNAs within these populations recognize their targets. We used HTS analysis to evaluate RNA populations selected to bind type I human immunodeficiency virus reverse transcriptase (RT). The populations are enriched in RNAs of independent lineages that converge on shared motifs and in clusters of RNAs with nearly identical sequences that share common ancestry. Both of these features informed inferences of the secondary structures of enriched RNAs, their minimal structural requirements and their stabilities in RT-aptamer complexes. Monitoring population dynamics in response to increasing selection pressure revealed RNA inhibitors of RT that are more potent than the previously identified pseudoknots. Improved potency was observed for inhibition of both purified RT in enzymatic assays and viral replication in cell-based assays. Structural and functional details of converged motifs that are obscured by simple consensus descriptions are also revealed by the HTS analysis. The approach presented here can readily be generalized for the efficient and systematic post-SELEX development of aptamers for down-stream applications. PMID:23241386

  2. Protein kinase inhibitors substantially improve the physical detection of T-cells with peptide-MHC tetramers.

    PubMed

    Lissina, Anna; Ladell, Kristin; Skowera, Ania; Clement, Matthew; Edwards, Emily; Seggewiss, Ruth; van den Berg, Hugo A; Gostick, Emma; Gallagher, Kathleen; Jones, Emma; Melenhorst, J Joseph; Godkin, Andrew J; Peakman, Mark; Price, David A; Sewell, Andrew K; Wooldridge, Linda

    2009-01-01

    Flow cytometry with fluorochrome-conjugated peptide-major histocompatibility complex (pMHC) tetramers has transformed the study of antigen-specific T-cells by enabling their visualization, enumeration, phenotypic characterization and isolation from ex vivo samples. Here, we demonstrate that the reversible protein kinase inhibitor (PKI) dasatinib improves the staining intensity of human (CD8+ and CD4+) and murine T-cells without concomitant increases in background staining. Dasatinib enhances the capture of cognate pMHC tetramers from solution and produces higher intensity staining at lower pMHC concentrations. Furthermore, dasatinib reduces pMHC tetramer-induced cell death and substantially lowers the T-cell receptor (TCR)/pMHC interaction affinity threshold required for cell staining. Accordingly, dasatinib permits the identification of T-cells with very low affinity TCR/pMHC interactions, such as those that typically predominate in tumour-specific responses and autoimmune conditions that are not amenable to detection by current technology.

  3. Entrapment of an EGFR inhibitor into nanostructured lipid carriers (NLC) improves its antitumor activity against human hepatocarcinoma cells

    PubMed Central

    2014-01-01

    Background In hepatocellular carcinoma (HCC), different signaling pathways are de-regulated, and among them, the expression of the epidermal growth factor receptor (EGFR). Tyrphostin AG-1478 is a lipophilic low molecular weight inhibitor of EGFR, preferentially acting on liver tumor cells. In order to overcome its poor drug solubility and thus improving its anticancer activity, it was entrapped into nanostructured lipid carriers (NLC) by using safe ingredients for parenteral delivery. Results Nanostructured lipid carriers (NLC) carrying tyrphostin AG-1478 were prepared by using the nanoprecipitation method and different matrix compositions. The best system in terms of mean size, PDI, zeta potential, drug loading and release profile was chosen to evaluate the anti-proliferative effect of drug-loaded NLC versus free drug on human hepatocellular carcinoma HA22T/VGH cells. Conclusions Thanks to the entrapment into NLC systems, tyrphostin AG-1478 shows an enhanced in vitro anti-tumor activity compared to free drug. These finding raises hope of future drug delivery strategy of tyrphostin AG-1478 -loaded NLC targeted to the liver for the HCC treatment. PMID:24886097

  4. The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats

    PubMed Central

    Krupka, Jennifer; May, Frauke; Weimer, Thomas; Pragst, Ingo; Kleinschnitz, Christoph; Stoll, Guido; Panousis, Con; Dickneite, Gerhard; Nolte, Marc W.

    2016-01-01

    Background and Purpose Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach. Methods For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation. Results Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis. Conclusions With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury. PMID:26815580

  5. 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.

  6. Inhibitor of neuronal nitric oxide synthase improves gas exchange in ventilator-induced lung injury after pneumonectomy

    PubMed Central

    2012-01-01

    Background Mechanical ventilation with high tidal volumes may cause ventilator-induced lung injury (VILI) and enhanced generation of nitric oxide (NO). We demonstrated in sheep that pneumonectomy followed by injurious ventilation promotes pulmonary edema. We wished both to test the hypothesis that neuronal NOS (nNOS), which is distributed in airway epithelial and neuronal tissues, could be involved in the pathogenesis of VILI and we also aimed at investigating the influence of an inhibitor of nNOS on the course of VILI after pneumonectomy. Methods Anesthetized sheep underwent right pneumonectomy, mechanical ventilation with tidal volumes (VT) of 6 mL/kg and FiO2 0.5, and were subsequently randomized to a protectively ventilated group (PROTV; n = 8) keeping VT and FiO2 unchanged, respiratory rate (RR) 25 inflations/min and PEEP 4 cm H2O for the following 8 hrs; an injuriously ventilated group with VT of 12 mL/kg, zero end-expiratory pressure, and FiO2 and RR unchanged (INJV; n = 8) and a group, which additionally received the inhibitor of nNOS, 7-nitroindazole (NI) 1.0 mg/kg/h intravenously from 2 hours after the commencement of injurious ventilation (INJV + NI; n = 8). We assessed respiratory, hemodynamic and volumetric variables, including both the extravascular lung water index (EVLWI) and the pulmonary vascular permeability index (PVPI). We measured plasma nitrite/nitrate (NOx) levels and examined lung biopsies for lung injury score (LIS). Results Both the injuriously ventilated groups demonstrated a 2–3-fold rise in EVLWI and PVPI, with no significant effects of NI. In the INJV group, gas exchange deteriorated in parallel with emerging respiratory acidosis, but administration of NI antagonized the derangement of oxygenation and the respiratory acidosis significantly. NOx displayed no significant changes and NI exerted no significant effect on LIS in the INJV group. Conclusion Inhibition of nNOS improved gas exchange, but did not

  7. Deletion of the aceE gene (encoding a component of pyruvate dehydrogenase) attenuates Salmonella enterica serovar Enteritidis.

    PubMed

    Pang, Ervinna; Tien-Lin, Chang; Selvaraj, Madhan; Chang, Jason; Kwang, Jimmy

    2011-10-01

    Salmonella enterica serovar Enteritidis (S. Enteritidis) is a major food-borne pathogen. From a transposon insertion mutant library created previously using S. Enteritidis 10/02, one of the mutants was identified to have a 50% lethal dose (LD(50) ) at least 100 times that of the parental strain in young chicks, with an attenuation in a poorly studied gene encoding a component of pyruvate dehydrogenase, namely the aceE gene. Evaluation of the in vitro virulence characteristics of the ΔaceE∷kan mutant revealed that it was less able to invade epithelial cells, less resistant to reactive oxygen intermediate, less able to survive within a chicken macrophage cell line and had a retarded growth rate compared with the parental strain. Young chicks vaccinated with 2 × 10(9) CFU of the ΔaceE∷kan mutant were protected from the subsequent challenge of the parental strain, with the mutant colonized in the liver and spleen in a shorter time than the group infected with the parental strain. In addition, compared with the parental strain, the ΔaceE∷kan mutant did not cause persistent eggshell contamination of vaccinated hens.

  8. Targeting of plasminogen activator inhibitor 1 improves fibrinolytic therapy for tetracycline-induced pleural injury in rabbits.

    PubMed

    Florova, Galina; Azghani, Ali; Karandashova, Sophia; Schaefer, Chris; Koenig, Kathleen; Stewart-Evans, Kris; Declerck, Paul J; Idell, Steven; Komissarov, Andrey A

    2015-04-01

    Endogenous active plasminogen activator inhibitor 1 (PAI-1) was targeted in vivo with monoclonal antibodies (mAbs) that redirect its reaction with proteinases to the substrate branch. mAbs were used as an adjunct to prourokinase (single-chain [sc] urokinase [uPA]) intrapleural fibrinolytic therapy (IPFT) of tetracycline-induced pleural injury in rabbits. Outcomes of scuPA IPFT (0.25 or 0.0625 mg/kg) with 0.5 mg/kg of mouse IgG or mAbs (MA-33H1F7 and MA-8H9D4) were assessed at 24 hours. Pleural fluid (PF) was collected at 0, 10, 20, and 40 minutes and 24 hours after IPFT and analyzed for plasminogen activating (PA), uPA, fibrinolytic activities, levels of total plasmin/plasminogen, α-macroglobulin (αM), mAbs/IgG antigens, free active uPA, and αM/uPA complexes. Anti-PAI-1 mAbs, but not mouse IgG, delivered with an eightfold reduction in the minimal effective dose of scuPA (from 0.5 to 0.0625 mg/kg), improved the outcome of IPFT (P < 0.05). mAbs and IgG were detectable in PFs at 24 hours. Compared with identical doses of scuPA alone or with IgG, treatment with scuPA and anti-PAI-1 mAbs generated higher PF uPA amidolytic and PA activities, faster formation of αM/uPA complexes, and slower uPA inactivation. However, PAI-1 targeting did not significantly affect intrapleural fibrinolytic activity or levels of total plasmin/plasminogen and αM antigens. Targeting PAI-1 did not induce bleeding, and rendered otherwise ineffective doses of scuPA able to improve outcomes in tetracycline-induced pleural injury. PAI-1-neutralizing mAbs improved IPFT by increasing the durability of intrapleural PA activity. These results suggest a novel, well-tolerated IPFT strategy that is tractable for clinical development.

  9. Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo

    PubMed Central

    de J García-Rivas, G; Carvajal, K; Correa, F; Zazueta, C

    2006-01-01

    Background and purpose: The mitochondrial permeability transition pore (mPTP), an energy-dissipating channel activated by calcium, contributes to reperfusion damage by depolarizing the mitochondrial inner membrane potential. As mitochondrial Ca2+ overload is a main inductor of mPTP opening, we examined the effect of Ru360, a selective inhibitor of the mitochondrial calcium uptake system against myocardial damage induced by reperfusion in a rat model. Experimental approach: Myocardial reperfusion injury was induced by a 5-min occlusion of the left anterior descending coronary artery, followed by a 5-min reperfusion in anaesthetized open-chest rats. We measured reperfusion-induced arrhythmias and functions indicative of unimpaired mitochondrial integrity to evaluate the effect of Ru360 treatment. Key results: Reperfusion elicited a high incidence of arrhythmias, haemodynamic dysfunction and loss of mitochondrial integrity. A bolus intravenous injection of Ru360 (15-50 nmol kg−1), given 30-min before ischaemia, significantly improved the above mentioned variables in the ischaemic/reperfused myocardium. Calcium uptake in isolated mitochondria from Ru360-treated ventricles was partially diminished, suggesting an interaction of this compound with the calcium uniporter. Conclusions and implications: We showed that Ru360 treatment abolishes the incidence of arrhythmias and haemodynamic dysfunction elicited by reperfusion in a whole rat model. Ru360 administration partially inhibits calcium uptake, preventing mitochondria from depolarization by the opening of the mPTP. We conclude that myocardial damage could be a consequence of failure of the mitochondrial network to maintain the membrane potential at reperfusion. Hence, it is plausible that Ru360 could be used in reperfusion therapy to prevent the occurrence of arrhythmia. PMID:17031386

  10. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Angiotensin converting enzyme (A.C.E.) test system... Test Systems § 862.1090 Angiotensin converting enzyme (A.C.E.) test system. (a) Identification. An angiotensin converting enzyme (A.C.E.) test system is a device intended to measure the activity of...

  11. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Angiotensin converting enzyme (A.C.E.) test system... Test Systems § 862.1090 Angiotensin converting enzyme (A.C.E.) test system. (a) Identification. An angiotensin converting enzyme (A.C.E.) test system is a device intended to measure the activity of...

  12. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Angiotensin converting enzyme (A.C.E.) test system... Test Systems § 862.1090 Angiotensin converting enzyme (A.C.E.) test system. (a) Identification. An angiotensin converting enzyme (A.C.E.) test system is a device intended to measure the activity of...

  13. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Angiotensin converting enzyme (A.C.E.) test system... Test Systems § 862.1090 Angiotensin converting enzyme (A.C.E.) test system. (a) Identification. An angiotensin converting enzyme (A.C.E.) test system is a device intended to measure the activity of...

  14. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Angiotensin converting enzyme (A.C.E.) test system... Test Systems § 862.1090 Angiotensin converting enzyme (A.C.E.) test system. (a) Identification. An angiotensin converting enzyme (A.C.E.) test system is a device intended to measure the activity of...

  15. Young & ACE: Young Unemployed People and Adult and Community Education.

    ERIC Educational Resources Information Center

    Adult, Community, and Further Education Board, Melbourne (Australia).

    Pilot projects designed to increase the access of young unemployed Australians to adult and community education (ACE) were undertaken in one rural and one metropolitan adult, community and further education region with significant rates of unemployment among individuals aged 15-24 years. Two consortia were selected to conduct the pilot programs,…

  16. The Economics of ACE Delivery. A Research Report.

    ERIC Educational Resources Information Center

    McIntyre, John; Brown, Tony; Ferrier, Fran

    The financial operations of providers of adult and community education (ACE) in New South Wales, Australia, were examined in a conceptual and empirical study. Enrollment data were analyzed and case studies of three community colleges and two community adult education centers in metropolitan, coastal, and rural communities were conducted. Four…

  17. POMB/ACE chemotherapy for mediastinal germ cell tumours.

    PubMed

    Bower, M; Brock, C; Holden, L; Nelstrop, A; Makey, A R; Rustin, G J; Newlands, E S

    1997-05-01

    Mediastinal germ cell tumours (MGCT) are rare and most published series reflect the experiences of individual institutions over many years. Since 1979, we have treated 16 men (12 non-seminomatous germ cell tumours and 4 seminomas) with newly diagnosed primary MGCT with POMB/ACE chemotherapy and elective surgical resection of residual masses. This approach yielded complete remissions in 15/16 (94%) patients. The median follow-up was 6.0 years and no relapses occurred more than 2 years after treatment. The 5 year overall survival in the non-seminomatous germ cell tumours (NSGCT) is 73% (95% confidence interval 43-90%). One patient with NSGCT developed drug-resistant disease and died without achieving remission and 2 patients died of relapsed disease. In addition, 4 patients with bulky and/or metastatic seminoma were treated with POMB/ACE. One died of treatment-related neutropenic sepsis in complete remission and one died of relapsed disease. Finally, 4 patients (2 NSGCT and 2 seminomas) referred at relapse were treated with POMB/ACE and one was successfully salvaged. The combination of POMB/ACE chemotherapy and surgery is effective management for MGCT producing high long-term survival rates.

  18. Improving the In Vivo Profile of Minigastrin Radiotracers: A Comparative Study Involving the Neutral Endopeptidase Inhibitor Phosphoramidon.

    PubMed

    Kaloudi, Aikaterini; Nock, Berthold A; Lymperis, Emmanouil; Krenning, Eric P; de Jong, Marion; Maina, Theodosia

    2016-02-01

    Minigastrin radiotracers, such as [(111)In-DOTA]MG0 ([(111)In-DOTA-DGlu(1)]minigastrin), have been considered for diagnostic imaging and radionuclide therapy of CCK2R-positive human tumors, such as medullary thyroid carcinoma. However, the high kidney retention assigned to the pentaGlu(2-6) repeat in the peptide sequence has compromised their clinical applicability. On the other hand, truncated des(Glu)(2-6)-analogs, such as [(111)In-DOTA]MG11 ([(111)In-DOTA-DGlu(10),desGlu(2-6)]minigastrin), despite their low renal uptake, show poor bioavailability and tumor targeting. [(111)In]CP04 ([(111)In-DOTA-DGlu(1-6)]minigastrin) acquired by Glu(2-6)/DGlu(2-6) substitution showed promising tumor-to-kidney ratios in rodents. In the present study, we compare the biological profiles of [(111)In]CP04, [(111)In-DOTA]MG11, and [(111)In-DOTA]MG0 during in situ neutral endopeptidase (NEP) inhibition, recently shown to improve the bioavailability of several peptide radiotracers. After coinjection of the NEP inhibitor, phosphoramidon (PA), the stability of [(111)In]CP04 and [(111)In-DOTA]MG0 in peripheral mouse blood increased, with an exceptional >14-fold improvement monitored for [(111)In-DOTA]MG11. In line with these findings, PA treatment increased the uptake of [(111)In]CP04 (8.5 ± 0.4%ID/g to 16.0 ± 2.3%ID/g) and [(111)In-DOTA]MG0 (11.9 ± 2.2%ID/g to 17.2 ± 0.9%ID/g) in A431-CCK2R(+) tumors at 4 hours postinjection, whereas the respective increase for [(111)In-DOTA]MG11 was >6-fold (2.5 ± 0.9%ID/g to 15.1 ± 1.7%ID/g). Interestingly, kidney uptake remained lowest for [(111)In-DOTA]MG11, but unfavorably increased by PA treatment for [(111)In-DOTA]MG0. Thus, overall, the most favorable in vivo profile was displayed by [(111)In-DOTA]MG11 during NEP inhibition, highlighting the need to validate this promising concept in the clinic. PMID:26844849

  19. 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

  20. 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.

  1. 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

  2. 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. PMID:27045751

  3. Enhanced histone acetylation in somatic cells induced by a histone deacetylase inhibitor improved inter-generic cloned leopard cat blastocysts.

    PubMed

    Lee, Hyo-Sang; Yu, Xian-Feng; Bang, Jae-Il; Cho, Su-Jin; Deb, Gautam Kumar; Kim, Byeong-Woo; Kong, Il-Keun

    2010-11-01

    The objective was to determine whether alterations of histone acetylation status in donor cells affected inter-generic SCNT (igSCNT)-cloned embryo development. Leopard cat cells were treated with trichostatin A (TSA; a histone deacetylase inhibitor) for 48 h, and then donor cells were transferred into enucleated oocytes from domestic cats. Compared to non-treated cells, the acetylated histone 3 at lysine 9 (AcH3K9) and histone 4 at lysine 5 (AcH4K5) in the TSA group increased for up to 48 h (P < 0.05). The AcH3K9 signal ratios of igSCNT group was higher than control group 3 h after activation (P < 0.05). Treatment with TSA significantly increased total cell number of blastocysts (109.1 ± 6.9 vs. 71.8 ± 2.9, mean ± SEM), with no significant effects on rates of cleavage or blastocyst development (71.1 ± 2.8 vs. 67.6 ± 2.9 and 12.2 ± 2.6 vs. 11.0 ± 2.6, respectively). When igSCNT cloned embryos were transferred into a domestic cat oviduct and recovered after 8 d, blastocyst development rates and total cell numbers were greater in the TSA-igSCNT group (20.7 ± 3.0% and 2847.6 ± 37.2) than in the control igSCNT group (5.7 ± 2.2% and 652.1 ± 17.6, P < 0.05). Average total cell numbers of blastocysts were approximately 4.4-fold higher in the TSA-igSCNT group (2847.6 ± 37.2, n = 10) than in the control group (652.1 ± 17.6, n = 8; P < 0.05), but were ∼2.9-fold lower than in vivo cat blastocysts produced by intrauterine insemination (8203.8 ± 29.6, n = 5; P < 0.001). Enhanced histone acetylation levels of donor cells improved in vivo developmental competence and quality of inter-generic cloned embryos; however, fewer cells in blastocysts derived from igSCNT than blastocysts produced by insemination may reduce development potential following intergeneric cloning (none of the cloned embryos were maintained to term).

  4. 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.

  5. 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

  6. Results of ACE 1, ACE 2, AEROSOLS99, INDOEX, TARFOX, and NEAQS: What Have We Learned? Where Do We Go From Here?

    NASA Astrophysics Data System (ADS)

    Quinn, P. K.; Bates, T. S.

    2003-12-01

    Since 1995, a series of international field experiments has focused on the measurement of aerosol properties in marine regions downwind of continental emissions. A goal of these experiments has been the characterization of regional aerosol properties and their controlling processes in order to improve estimates of aerosol direct and indirect radiative forcing. The first Aerosol Characterization Experiment (ACE 1) purposefully steered clear of any continental plumes in order to characterize the "background" aerosol upon which anthropogenic perturbations could be imposed. ACE 2 focused on the European plume, INDOEX (Indian Ocean Experiment) on the plume emanating from the Indian subcontinent, ACE Asia on the Asian plume, and TARFOX (Tropospheric Aerosol Radiative Forcing Observational Experiment) and NEAQS (New England Air Quality Study) on the eastern U.S. plume. In addition, measurements of dust and biomass burning aerosols from Africa were made the Atlantic Aerosols99 cruise. With the exception of TARFOX, all experiments included the shipboard sampling of aerosol chemical, physical, and optical properties. The shipboard sampling was done with standardized protocols to minimize sampling biases and to make the data from the different regions directly comparable. Regional aerosol properties from the North American, European, African, Asian, and Indian plumes will be compared and the major findings from these experiments will be presented. Properties that will be compared include the relative contribution of the dominant chemical components to aerosol mass and light extinction, the absolute concentrations of the chemical components, light scattering and absorption by the aerosol, single scattering albedo, and aerosol optical depth. Since TARFOX was an aircraft study we include only data collected at altitudes less than 300 m. In addition to using standardized sampling protocols on the ship, over-determined data sets were collected so that a measured aerosol property

  7. 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.

  8. 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.

  9. A mutant trypsin-like enzyme from Streptomyces fradiae, created by site-directed mutagenesis, improves affinity chromatography for protein trypsin inhibitors.

    PubMed

    Katoh, T; Kikuchi, N; Nagata, K; Yoshida, N

    1996-08-01

    The Ser-170 residue of a trypsin-like enzyme from Streptomyces fradiae (SFT), which is considered to be the active-site serine, was replaced with alanine by site-directed mutagenesis to improve the affinity chromatography step for a Kazal-type trypsin inhibitor pancreatic secretory trypsin inhibitor (PSTI). The resulting mutant SFT, designated as [S170A]SFT, was expressed in Streptomyces lividans and purified to homogeneity. [S170A]SFT was catalytically inactive, but still had the ability to bind tightly to PSTI and to soybean trypsin inhibitor with dissociation constants of 3.1 x 10(-7) M and 1.9 x 10(-8) M respectively. We further demonstrated that recombinant human PSTI secreted into Saccharomyces cerevisiae culture broth could be purified to homogeneity with a one-step [S170A]SFT-affinity column. The purified PSTI contained no molecules intramolecularly cleaved by active trypsin, which are found when trypsin-affinity chromatography is used for the purification. This eliminated the need for further separation of intact PSTI from intramolecularly cleaved PSTI by high-performance liquid chromatography, thus simplifying and improving its purification process.

  10. 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.

  11. Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles.

    PubMed

    Court, John J; Poisson, Carl; Ardzinski, Andrzej; Bilimoria, Darius; Chan, Laval; Chandupatla, Kishan; Chauret, Nathalie; Collier, Philip N; Das, Sanjoy Kumar; Denis, Francois; Dorsch, Warren; Iyer, Ganesh; Lauffer, David; L'Heureux, Lucille; Li, Pan; Luisi, Brian S; Mani, Nagraj; Nanthakumar, Suganthi; Nicolas, Olivier; Rao, B Govinda; Ronkin, Steven; Selliah, Subajini; Shawgo, Rebecca S; Tang, Qing; Waal, Nathan D; Yannopoulos, Constantin G; Green, Jeremy

    2016-07-14

    The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound 23, a compound with comparable potency and improved physicochemical properties.

  12. Regional aerosol properties: Comparisons of boundary layer measurements from ACE 1, ACE 2, Aerosols99, INDOEX, ACE Asia, TARFOX, and NEAQS

    NASA Astrophysics Data System (ADS)

    Quinn, Patricia K.; Bates, Timothy S.

    2005-07-01

    Means and variability of aerosol chemical composition and optical properties are compared for the first and second Aerosol Characterization Experiments (ACE 1 and ACE 2), a cruise across the Atlantic (Aerosols99), the Indian Ocean Experiment (INDOEX), the Asian Aerosol Characterization Experiment (ACE Asia), the Tropospheric Aerosol Radiative Forcing Observational Experiment (TARFOX), and the New England Air Quality Study (NEAQS). These experiments were focused either on the remote marine atmosphere (ACE 1) or areas downwind of continental aerosol source regions including western Europe, North America, Africa, India, and Asia. Presented here are size-segregated concentrations of aerosol mass, sea salt, non-sea-salt (nss) SO4=, NH4+, NO3-, dust, organic carbon (OC), elemental carbon (EC), and nss K+, as well as mass ratios that are commonly used to identify aerosol sources and to assess aerosol processing (Cl- to Na+, OC to nss SO4=, EC to total carbon (TC), EC to nss SO4=, nss K+ to EC, Fe to Al, and Si to Al). Optical properties that are compared include size-segregated scattering, backscattering, and absorption coefficients, and single-scattering albedo at 550 nm. Size-segregated mass scattering and mass absorption efficiencies for the total aerosol and mass extinction efficiencies for the dominant chemical components also are compared. In addition, we present the contribution to light extinction by the dominant chemical components for each region. All data are based on shipboard measurements performed at a relative humidity of 55 ± 5%. Scattering coefficients and single-scattering albedos also are reported at ambient relative humidity (RH) using published values of f(RH). Finally, aerosol optical depths from each region are compared. Identical sampling protocols were used in all experiments in order to eliminate sampling biases and to make the data directly comparable. Major findings include (1) nss SO4= makes up only 16 to 46% of the submicron aerosol mass

  13. 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).

  14. Curriculum innovation in an accelerated BSN program: the ACE Model.

    PubMed

    Suplee, Patricia D; Glasgow, Mary Ellen

    2008-01-01

    As the demand for registered nurses continues to rise, so too has the creation of accelerated baccalaureate nursing programs for second-degree students. This article describes an 11-month Accelerated Career Entry (ACE) Nursing Program's innovative curriculum design, which has a heavy emphasis on technology, professional socialization, and the use of a standardized patient experience as a form of summative evaluation. In addition, challenges of this program are presented. Since 2002, the ACE Program has graduated over 500 students with an average first-time NCLEX pass rate of 95-100%. Although the number of graduates from accelerated programs does not solve the severe nursing shortage, the contributions of these intelligent, assertive, pioneering graduates are important for health care.

  15. ACE-FTS instrument: activities in preparation for launch

    NASA Astrophysics Data System (ADS)

    Soucy, Marc-Andre; Walker, Kaley A.; Fortin, Serge; Deutsch, Christophe

    2003-11-01

    The Atmospheric Chemistry Experiment (ACE) is the mission selected by the Canadian Space Agency for its next science satellite, SCISAT-1. ACE consists of a suite of instruments in which the primary element is an infrared Fourier Transform Spectrometer (FTS) coupled with an auxiliary 2-channel visible (525 nm) and near infrared imager (1020 nm). A secondary instrument, MAESTRO, provides spectrographic data from the near ultra-violet to the near infrared, including the visible spectral range. In combination the instrument payload covers the spectral range from 0.25 to 13.3 micron. A comprehensive set of simultaneous measurements of trace gases, thin clouds, aerosols and temperature will be made by solar occultation from a satellite in low earth orbit. The ACE mission will measure and analyse the chemical and dynamical processes that control the distribution of ozone in the upper troposphere and stratosphere. A high inclination (74 degrees), low earth orbit (650 km) allows coverage of tropical, mid-latitude and polar regions. This paper presents the instrument-related activities in preparation for launch. In particular, activities related to the integration of instrument to spacecraft are presented as well as tests of the instrument on-board the SciSat-1 bus. Environmental qualification activities at spacecraft-level are described. An overview of the characterization and calibration campaign is presented. Activities for integration and verification at launch site are also covered. The latest status of the spacecraft is also presented.

  16. 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.

  17. ACE inhibition prevents diastolic Ca2+ overload and loss of myofilament Ca2+ sensitivity after myocardial infarction

    PubMed Central

    Zalvidea, Santiago; Andre, Lucas; Loyer, Xavier; Cassan, Cécile; Sainte-Marie, Yannis; Thireau, Jérôme; Sjaastad, Ivar; Heymes, Christophe; Pasquié, Jean-Luc; Cazorla, Olivier; Aimond, Franck; Richard, Sylvain

    2012-01-01

    Prevention of adverse cardiac remodeling after myocardial infarction (MI) remains a therapeutic challenge. Angiotensin-converting enzyme inhibitors (ACE-I) are a well-established first-line treatment. ACE-I delay fibrosis, but little is known about their molecular effects on cardiomyocytes. We investigated the effects of the ACE-I delapril on cardiomyocytes in a mouse model of heart failure (HF) after MI. Mice were randomly assigned to three groups: Sham, MI, and MI-D (6 weeks of treatment with a non-hypotensive dose of delapril started 24h after MI). Echocardiography and pressure-volume loops revealed that MI induced hypertrophy and dilatation, and altered both contraction and relaxation of the left ventricle. At the cellular level, MI cardiomyocytes exhibited reduced contraction, slowed relaxation, increased diastolic Ca2+ levels, decreased Ca2+-transient amplitude, and diminished Ca2+ sensitivity of myofilaments. In MI-D mice, however, both mortality and cardiac remodeling were decreased when compared to non-treated MI mice. Delapril maintained cardiomyocyte contraction and relaxation, prevented diastolic Ca2+ overload and retained the normal Ca2+ sensitivity of contractile proteins. Delapril maintained SERCA2a activity through normalization of P-PLB/PLB (for both Ser16-PLB and Thr17-PLB) and PLB/SERCA2a ratios in cardiomyocytes, favoring normal reuptake of Ca2+ in the sarcoplasmic reticulum. In addition, delapril prevented defective cTnI function by normalizing the expression of PKC, enhanced in MI mice. In conclusion, early therapy with delapril after MI preserved the normal contraction/relaxation cycle of surviving cardiomyocytes with multiple direct effects on key intracellular mechanisms contributing to preserve cardiac function. PMID:22280358

  18. An intercomparison study of isotopic ozone profiles from the ACE-FTS, JEM-SMILES, and Odin-SMR instruments

    NASA Astrophysics Data System (ADS)

    Jones, A.; Walker, K. A.; Suzuki, M.; Kasai, Y.; Shiotani, M.; Urban, J.; Bernath, P. F.; Manney, G. L.

    2012-12-01

    Observations of various atmospheric isotopologue species are a valuable source of information, as they can improve our current understanding of the atmosphere. For example, isotopic signatures in atmospheric profiles can be used to investigate atmospheric dynamical processes, while differences in the isotopic composition of atmospheric trace gases can be traced to effects due to their sources and sinks. This study focuses on the intercomparison of three satellite missions that provide measurements of isotopic species. The Atmospheric Chemistry Experiment-Fourier Transform Spectrometer (ACE-FTS) aboard the Canadian satellite SCISAT (launched in August 2003) was designed to investigate the composition of the upper troposphere, stratosphere, and mesosphere. ACE-FTS utilizes solar occultation to measure temperature, pressure, and vertical profiles of over thirty chemical species, including isotopologue profiles for; O3, H2O, CH4, N2O, CO, CO2 and NO. Global coverage for each species is obtained approximately over one year and with a vertical resolution of typically 3-4 km. ACE-FTS O3 isotopologue volume mixing ratio profiles are firstly compared to data measured by the Superconducting Sub-Millimeter-wave Limb Emission Sounder (SMILES), onboard the Japanese Experiment Module (JEM) of the International Space Station (ISS), and the Sub-Millimetre Radiometer (SMR) aboard the Swedish Odin satellite. Secondly, we intercompare the isotopic fractionation profiles for each ozone isotopologue product measured by the three instruments to further ascertain a level of confidence in the measurements.

  19. User`s guide for the Augmented Computer Exercise for Inspection Training (ACE-IT) software

    SciTech Connect

    Dobranich, P.R.; Horak, K.E.; Hagan, D.; Evanko, D.; Nelson, J.; Ryder, C.; Hedlund, D.

    1997-09-01

    The on-site inspection provisions in many current and proposed arms control agreements require extensive preparation and training on the part of both the Inspection Teams (inspectors) and Inspected Parties (host). Current training techniques include table-top inspections and practice inspections. The Augmented Computer Exercise for Inspection Training (ACE-IT), an interactive computer training tool, increases the utility of table-top inspections. ACE-IT has been designed to provide training for challenge inspections under the Chemical Weapons Convention (CWC); however, this training tool can be modified for other inspection regimes. Although ACE-IT provides training from notification of an inspection through post-inspection activities, the primary emphasis of ACE-IT is in the inspection itself--particularly with the concept of managed access. ACE-IT also demonstrates how inspection provisions impact compliance determination and the protection of sensitive information. This User`s Guide describes the use of the ACE-IT training software.

  20. Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

    PubMed Central

    Chattopadhyay, Shrikanta; Stewart, Alison L.; Mukherjee, Siddhartha; Huang, Cherrie; Hartwell, Kimberly A.; Miller, Peter G.; Subramanian, Radhika; Carmody, Leigh C.; Yusuf, Rushdia Z.; Sykes, David B.; Paulk, Joshiawa; Vetere, Amedeo; Vallet, Sonia; Santo, Loredana; Cirstea, Diana D.; Hideshima, Teru; Dančík, Vlado; Majireck, Max M.; Hussain, Mahmud M.; Singh, Shambhavi; Quiroz, Ryan; Iaconelli, Jonathan; Karmacharya, Rakesh; Tolliday, Nicola J.; Clemons, Paul A.; Moore, Malcolm A.S.; Stern, Andrew M.; Shamji, Alykhan F.; Ebert, Benjamin L.; Golub, Todd R.; Raje, Noopur S.; Scadden, David T.; Schreiber, Stuart L.

    2015-01-01

    Summary Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876's mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets. PMID:25660025

  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. 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.

  3. A review of the preclinical cardiovascular pharmacology of cilazapril, a new angiotensin converting enzyme inhibitor.

    PubMed

    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 (approximately 76%) in the rat as 0.25 mg kg-1 enalapril. Cilazapril (0.25 mg kg-1 p.o.) inhibited plasma ACE by greater than 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 (1.5x) 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 2-4.5x 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 greater than or equal to 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

  4. 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

  5. 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.

  6. 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

  7. 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 Central

    Suh, Jung-Won; 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. PMID:20052342

  8. 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. PMID:20660065

  9. 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.

  10. 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

  11. Selective small molecule Stat3 inhibitor reduces breast cancer tumor-initiating cells and improves recurrence free survival in a human-xenograft model.

    PubMed

    Dave, Bhuvanesh; Landis, Melissa D; Tweardy, David J; Chang, Jenny C; Dobrolecki, Lacey E; Wu, Meng-Fen; Zhang, Xiaomei; Westbrook, Thomas F; Hilsenbeck, Susan G; Liu, Dan; Lewis, Michael T

    2012-01-01

    Metastasis and disease relapse are hypothesized to result from tumor initiating cells (TICs). Previously, we have defined a CD44+/CD24-/low mammosphere-forming tumorigenic 493-gene signature in breast cancer. Stat3 was identified as a critical node in self-renewal based on an ongoing lentiviral shRNA screen being conducted in two breast cancer cell lines SUM159 and BT549. In corroborating work, targeting the SH2 domain of Stat3 with a novel small molecule decreased the percentage of cells expressing TIC markers (CD44+/CD24-/low and ALDH+) and mammosphere formation in p-Stat3 overexpressing human breast cancer xenografts in SCID-beige mice. Importantly, we observed a four-fold improvement in the 30-day recurrence-free survival relative to docetaxel alone with the addition of the Stat3 inhibitor in the chemoresistant tumor model. Thus, these findings provide a strong impetus for the development of selective Stat3 inhibitors in order to improve survival in patients with p-Stat3 overexpressing tumors. PMID:22879872

  12. 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.

  13. 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. PMID:26200391

  14. New antimuscarinic agents for improved treatment of poisoning by cholinesterase inhibitors. Annual report, 1 November 1983-1 August 1984

    SciTech Connect

    Stubbins, J.F.

    1984-08-01

    The object of this project is to find a more effective antimuscarinic agent than atropine for use as an antidote for poisoning by organophosphate cholinesterase inhibitors. To start this search, 30 structurally diverse antimuscarinic agents have been selected for initial testing. These compounds are to be evaluated for peripheral and central antimuscarinic activity in a variety of in vitro and in vivo tests in addition to determining their effectiveness as antidotes (in combination with an oxime reactivator) for poisoning by soman. Twenty-two of the compounds have now been evaluated for their ability to block acetylcholine-induced contractions in guinea pig intestinal smooth muscle when compared to atropine. Ability to displace radiolabeled quinuclidinyl benzilate from muscarinic receptors of mouse brain homogenate has been determined for atropine, hyoscine and 26 of the compounds. Only triflupromazine appeared to have a distinctly greater affinity for brain receptors than muscle receptors to atropine. Intestinal smooth muscle blockade; oxotremorine tremor inhibition; muscarinic receptor subtypes.

  15. 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.

  16. 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. PMID:17518357

  17. New pyripyropene A derivatives, highly SOAT2-selective inhibitors, improve hypercholesterolemia and atherosclerosis in atherogenic mouse models.

    PubMed

    Ohshiro, Taichi; Ohtawa, Masaki; Nagamitsu, Tohru; Matsuda, Daisuke; Yagyu, Hiroaki; Davis, Matthew A; Rudel, Lawrence L; Ishibashi, Shun; Tomoda, Hiroshi

    2015-11-01

    Sterol O-acyltransferase 2 (SOAT2; also known as ACAT2) is considered as a new therapeutic target for the treatment or prevention of hypercholesterolemia and atherosclerosis. Fungal pyripyropene A (PPPA: 1,7,11-triacyl type), the first SOAT2-selective inhibitor, proved orally active in vivo using atherogenic mouse models. The purpose of the present study was to demonstrate that the PPPA derivatives (PRDs) prove more effective in the mouse models than PPPA. Among 196 semisynthetic PPPA derivatives, potent, SOAT2-selective, and stable PRDs were selected. In vivo antiatherosclerotic activity of selected PRDs was tested in apolipoprotein E knockout (Apoe(-/-)) mice or low-density lipoprotein receptor knockout (Ldlr(-/-)) mice fed a cholesterol-enriched diet (0.2% cholesterol and 21% fat) for 12 weeks. During the PRD treatments, no detrimental side effects were observed. Among three PRDs, Apoe(-/-) mice treated with PRD125 (1-,11-O-benzylidene type) at 1 mg/kg/day had significantly lower total plasma cholesterol concentration by 57.9 ± 9.3%; further, the ratio of cholesteryl oleate to cholesteryl linoleate in low-density lipoprotein was lower by 55.6 ± 7.5%, respectively. The hepatic cholesteryl ester levels and SOAT2 activity in the small intestines and livers of the PRD-treated mice were selectively lowered. The atherosclerotic lesion areas in the aortae of PRD125-treated mice were significantly lower at 62.2 ± 13.1%, respectively. Furthermore, both PRDs were also orally active in atherogenic Ldlr(-/-) mice. Among the PRDs tested, PRD125 was the most potent in both mouse models. These results suggest that SOAT2-selective inhibitors such as PRD125 have a high potential as poststatin agents for treatment and/or prevention in patients with atherosclerosis and hypercholesterolemia. PMID:26338984

  18. Aerodynamically controlled expansion (ACE) nozzle for short takeoff and vertical landing aircraft

    NASA Astrophysics Data System (ADS)

    Terrier, Douglas Anthony

    2000-10-01

    An Aerodynamically Controlled Expansion (ACE) propulsion nozzle that improves hover thrust performance by 2.5 percent in a short take off and vertical landing (STOVL) aircraft has been developed. The ACE concept employs a carefully defined step in the nozzle internal contour that interacts with the boundary layer to induce flow separation in the divergent section, thereby relieving over-expansion losses during hover. This study specifies design parameters for a passive boundary layer control step for application on the Joint Strike Fighter (JSF). In addition, parametric performance predictions presented herein provide a basic understanding of how the step concept can be applied to overcome undesirable over-expansion in generalized supersonic nozzle flows. The aerodynamic phenomena governing the interaction of the step with the nozzle flow were investigated in an extensive, parametric CFD analysis. The CFD analysis matrix consists of thirty-three axi-symmetric nozzle cases including expansion area ratios (A9/A 8) of 1.1, 1.3 and 1.5, slot area ratios (A s/A8) of 1.0 (baseline), 1.1 and 1.2, and covering the nozzle pressure ratio (NPR) range of 2.0 to 8.0. The CFD results define the NPR at which flow separation occurs as a function of A9/A8, and A s/A8, and the effect of the step on nozzle performance. Results indicate that the onset of separation occurs at higher NPR with increasing A9/A 8 and increasing As/A 8. For the case of the JSF nozzle with A9/ A8 = 1.3, the CFD analysis predicted that a nozzle having an As/A8 = 1.1 produces an improvement of approximately 2.5 percent in hover thrust relative to the baseline with a minimal adverse impact at other design conditions. Twelve percent scale models representing the baseline, and step sizes of 1.1 and 1.2 were tested in the Lockheed Martin Thrust Measurement Facility (TMF). Test results showed excellent agreement with CFD predictions and validated the step performance. Preliminary design integration studies support

  19. Discovery of triazolopyridinone GS-462808, a late sodium current inhibitor (Late INai) of the cardiac Nav1.5 channel with improved efficacy and potency relative to ranolazine.

    PubMed

    Koltun, Dmitry O; Parkhill, Eric Q; Elzein, Elfatih; Kobayashi, Tetsuya; Jiang, Robert H; Li, Xiaofen; Perry, Thao D; Avila, Belem; Wang, Wei-Qun; Hirakawa, Ryoko; Smith-Maxwell, Catherine; Wu, Lin; Dhalla, Arvinder K; Rajamani, Sridharan; Mollova, Nevena; Stafford, Brian; Tang, Jennifer; Belardinelli, Luiz; Zablocki, Jeff A

    2016-07-01

    Previously we disclosed the discovery of potent Late INa current inhibitor 2 (GS-458967, IC50 of 333nM) that has a good separation of late versus peak Nav1.5 current, but did not have a favorable CNS safety window due to high brain penetration (3-fold higher partitioning into brain vs plasma) coupled with potent inhibition of brain sodium channel isoforms (Nav1.1, 1.2, 1.3). We increased the polar surface area from 50 to 84Å(2) by adding a carbonyl to the core and an oxadiazole ring resulting in 3 GS-462808 that had lower brain penetration and serendipitously lower activity at the brain isoforms. Compound 3 has an improved CNS window (>20 rat and dog) relative to 2, and improved anti-ischemic potency relative to ranolazine. The development of 3 was not pursued due to liver lesions in 7day rat toxicology studies. PMID:27038498

  20. Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility.

    PubMed

    Zak, Mark; Liederer, Bianca M; Sampath, Deepak; Yuen, Po-Wai; Bair, Kenneth W; Baumeister, Timm; Buckmelter, Alexandre J; Clodfelter, Karl H; Cheng, Eric; Crocker, Lisa; Fu, Bang; Han, Bingsong; Li, Guangkun; Ho, Yen-Ching; Lin, Jian; Liu, Xiongcai; Ly, Justin; O'Brien, Thomas; Reynolds, Dominic J; Skelton, Nicholas; Smith, Chase C; Tay, Suzanne; Wang, Weiru; Wang, Zhongguo; Xiao, Yang; Zhang, Lei; Zhao, Guiling; Zheng, Xiaozhang; Dragovich, Peter S

    2015-02-01

    Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.

  1. The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but does not enhance the efficacy of doxorubicin, despite improving tumor perfusion and radiation response in mice.

    PubMed

    Ali, Majid; Kamjoo, Marzieh; Thomas, Huw D; Kyle, Suzanne; Pavlovska, Ivanda; Babur, Muhammed; Telfer, Brian A; Curtin, Nicola J; Williams, Kaye J

    2011-12-01

    AG014699 was the first inhibitor of the DNA repair enzyme PARP-1 to enter clinical trial in cancer patients. In addition to enhancing the cytotoxic effect of DNA-damaging chemotherapies, we have previously shown that AG014699 is vasoactive, thereby having the potential to improve drug biodistribution. The effectiveness of the clinical agent doxorubicin is confounded both by poor tumor penetration and cardiotoxicity elicited via PARP hyperactivation. In this study, we analyzed the impact of AG014699 on doxorubicin tolerance and response in breast (MDA-MB-231) and colorectal (SW620, LoVo) tumor models in vitro and in vivo. As anticipated, AG014699 did not potentiate the response to doxorubicin in vitro. In vivo, AG014699 did not influence the pharmacokinetics of doxorubicin; however, it did ameliorate cardiotoxicity. Both toxicity and extent of amelioration were more pronounced in male than in female mice. AG014699 improved vessel perfusion in both MDA-MB-231 and SW620 tumors; however, this neither led to improved tumor-accumulation of doxorubicin nor enhanced therapeutic response. In contrast, when combined with radiotherapy, AG014699 significantly enhanced response both in vitro and in vivo. Real-time assessment of tumor vessel function and companion histologic studies indicate that doxorubicin causes a profound antivascular effect that counters the positive effect of AG014699 on perfusion. These data indicate that although AG014699 can enhance response to some chemotherapeutic drugs via improved delivery, this does not apply to doxorubicin. PARP inhibitors may still be of use to counter doxorubicin toxicity, and if the gender effect translates from rodents to humans, this would have greater effect in males. PMID:21926192

  2. Validation of NO2 and NO from the Atmospheric Chemistry Experiment (ACE)

    NASA Astrophysics Data System (ADS)

    Kerzenmacher, T.; Wolff, M. A.; Strong, K.; Dupuy, E.; Walker, K. A.; Amekudzi, L. K.; Batchelor, R. L.; Bernath, P. F.; Berthet, G.; Blumenstock, T.; Boone, C. D.; Bramstedt, K.; Brogniez, C.; Brohede, S.; Burrows, J. P.; Catoire, V.; Dodion, J.; Drummond, J. R.; Dufour, D. G.; Funke, B.; Fussen, D.; Goutail, F.; Griffith, D. W. T.; Haley, C. S.; Hendrick, F.; Höpfner, M.; Huret, N.; Jones, N.; Kar, J.; Kramer, I.; Llewellyn, E. J.; López-Puertas, M.; Manney, G.; McElroy, C. T.; McLinden, C. A.; Melo, S.; Mikuteit, S.; Murtagh, D.; Nichitiu, F.; Notholt, J.; Nowlan, C.; Piccolo, C.; Pommereau, J.-P.; Randall, C.; Raspollini, P.; Ridolfi, M.; Richter, A.; Schneider, M.; Schrems, O.; Silicani, M.; Stiller, G. P.; Taylor, J.; Tétard, C.; Toohey, M.; Vanhellemont, F.; Warneke, T.; Zawodny, J. M.; Zou, J.

    2008-10-01

    Vertical profiles of NO2 and NO have been obtained from solar occultation measurements by the Atmospheric Chemistry Experiment (ACE), using an infrared Fourier Transform Spectrometer (ACE-FTS) and (for NO2) an ultraviolet-visible-near-infrared spectrometer, MAESTRO (Measurement of Aerosol Extinction in the Stratosphere and Troposphere Retrieved by Occultation). In this paper, the quality of the ACE-FTS version 2.2 NO2 and NO and the MAESTRO version 1.2 NO2 data are assessed using other solar occultation measurements (HALOE, SAGE II, SAGE III, POAM III, SCIAMACHY), stellar occultation measurements (GOMOS), limb measurements (MIPAS, OSIRIS), nadir measurements (SCIAMACHY), balloon-borne measurements (SPIRALE, SAOZ) and ground-based measurements (UV-VIS, FTIR). Time differences between the comparison measurements were reduced using either a tight coincidence criterion, or where possible, chemical box models. ACE-FTS NO2 and NO and the MAESTRO NO2 are generally consistent with the correlative data. The ACE-FTS and MAESTRO NO2 volume mixing ratio (VMR) profiles agree with the profiles from other satellite data sets to within about 20% between 25 and 40 km, with the exception of MIPAS ESA (for ACE-FTS) and SAGE II (for ACE-FTS (sunrise) and MAESTRO) and suggest a negative bias between 23 and 40 km of about 10%. MAESTRO reports larger VMR values than the ACE-FTS. In comparisons with HALOE, ACE-FTS NO VMRs typically (on average) agree to ±8% from 22 to 64 km and to +10% from 93 to 105 km, with maxima of 21% and 36%, respectively. Partial column comparisons for NO2 show that there is quite good agreement between the ACE instruments and the FTIRs, with a mean difference of +7.3% for ACE-FTS and +12.8% for MAESTRO.

  3. ACE2 overexpression inhibits acquired platinum resistance-induced tumor angiogenesis in NSCLC.

    PubMed

    Cheng, Qijian; Zhou, Ling; Zhou, Jianping; Wan, Huanying; Li, Qingyun; Feng, Yun

    2016-09-01

    Angiotensin II (AngII) is a multifunctional bioactive peptide in the renin-angiotensin system (RAS). Angiotensin-converting enzyme 2 (ACE2) is a newly identified component of RAS. We previously reported that ACE2 overexpression may inhibit cell growth and vascular endothelial growth factor (VEGF) production in vitro and in vivo. In the present study, we investigated the effect of ACE2 on tumor-associated angiogen-esis after the development of acquired platinum resistance in non-small cell lung cancer (NSCLC). Four NSCLC cell lines, A549, LLC, A549-DDP and LLC-DDP, were used in vitro, while A549 and A549-DDP cells were used in vivo. A549-DDP and LLC-DDP cells were newly established at our institution as acquired platinum-resistant sublines by culturing the former parent cells in cisplatin (CDDP)-containing conditioned medium for 6 months. These platinum-resistant cells showed significantly higher angiotensin II type 1 receptor (AT1R), ACE and VEGF production and lower ACE2 expression than their corresponding parent cells. We showed that ACE2 overexpression inhibited the production of VEGF in vitro and in vivo compared to their corresponding parent cells. We also found that ACE2 overexpression reduced the expression of AT1R and ACE. Additionally, we confirmed that ACE2 overexpres-sion inhibited cell growth and VEGF production while simultaneously suppressing ACE and AT1R expression in human lung cancer xenografts. Our findings indicate that ACE2 overexpression may potentially suppress angiogenesis in NSCLC after the development of acquired platinum resistance. PMID:27460845

  4. 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.

  5. Differential systemic and regional hemodynamic profiles of four angiotensin-I converting-enzyme inhibitors in the rat.

    PubMed

    Richer, C; Doussau, M P; Giudicelli, J F

    1989-12-01

    Angiotensin-converting enzyme (ACE) inhibitors decrease blood pressure by reducing systemic vascular resistance. That the peripheral vasodilating properties of ACE inhibitors might not be homogeneously distributed in all vascular beds and might differ from one drug to another has been investigated in the normotensive rat by the pulsed Doppler technique using the active components of four different ACE inhibitors: captopril, enalapril, perindopril, and ramipril. Systemic (cardiac output and blood pressure) and regional (kidney, mesentery, hindquarter) hemodynamic responses to saline or to cumulative bolus injections (0.01-1 mg/kg) of captopril, enalaprilat, perindoprilat, or ramiprilat were continuously monitored. The effects of successive bolus injections (0.3-300 ng/kg) of angiotensinII were also investigated. The four ACE inhibitors produced an almost complete blockade of plasma angiotensin-II converting-enzyme activity (83%, 100%, 100%, and 100%, respectively), induced dose-dependent decreases in mean blood pressure, did not significantly affect cardiac output, and reduced total peripheral and mesenteric vascular resistances to the same extent. Hindlimb vascular resistance was identically decreased, but to a lower extent than total peripheral resistance by enalaprilat, perindoprilat, and ramiprilat, whereas it was increased by captopril at low doses only. Renal resistance was markedly decreased by the four drugs, and especially by captopril. The decreasing rank order for ACE-inhibitor-induced vasodilation is exactly the same (renal greater than total peripheral = mesenteric greater than hindlimb vascular resistances) as that of angiotensin-H-induced regional vasoconstriction, indicating that the vasodilator properties of ACE inhibitors are mainly due to angiotensin-II vasomotor tone suppression. None of the investigated compounds significantly affected mesenteric and hindlimb blood flows, except captopril, which lowered the latter significantly

  6. Ethane, ethyne and carbon monoxide concentrations in the upper troposphere and lower stratosphere from ACE and GEOS-Chem: a comparison study

    NASA Astrophysics Data System (ADS)

    González Abad, G.; Allen, N. D. C.; Bernath, P. F.; Boone, C. D.; McLeod, S. D.; Manney, G. L.; Toon, G. C.; Carouge, C.; Wang, Y.; Wu, S.; Barkley, M. P.; Palmer, P. I.; Xiao, Y.; Fu, T. M.

    2011-09-01

    Near global upper tropospheric concentrations of carbon monoxide (CO), ethane (C2H6) and ethyne (C2H2) from ACE (Atmospheric Chemistry Experiment) Fourier transform spectrometer on board the Canadian satellite SCISAT-1 are presented and compared with the output from the Chemical Transport Model (CTM) GEOS-Chem. The retrievals of ethane and ethyne from ACE have been improved for this paper by using new sets of microwindows compared with those for previous versions of ACE data. With the improved ethyne retrieval we have been able to produce a near global upper tropospheric distribution of C2H2 from space. Carbon monoxide, ethane and ethyne concentrations retrieved using ACE spectra show the expected seasonality linked to variations in the anthropogenic emissions and destruction rates as well as seasonal biomass burning activity. The GEOS-Chem model was run using the dicarbonyl chemistry suite, an extended chemical mechanism in which ethyne is treated explicitly. Seasonal cycles observed from satellite data are well reproduced by the model output, however the simulated CO concentrations are found to be systematically biased low over the Northern Hemisphere. An average negative global mean bias of 12% and 7% of the model relative to the satellite observations has been found for CO and C2H6 respectively and a positive global mean bias of 1% has been found for C2H2. ACE data are compared for validation purposes with MkIV spectrometer data and Global Tropospheric Experiment (GTE) TRACE-A campaign data showing good agreement with all of them.

  7. Treating High Blood Pressure: Is an ACE Inhibitor Drug Right for You?

    MedlinePlus

    ... scientific review by the Oregon Health and Science University-based Drug Effectiveness Review Project. This is a summary of a longer, more detailed report you can find at www.CRBestBuyDrugs.org . Best Buy Generic Name Brand Name A Pills per Average Cost & Strength Day B per Month C Benazepril 20 ...

  8. 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.

  9. Signatures of interchange reconnection: STEREO, ACE and Hinode observations combined

    NASA Astrophysics Data System (ADS)

    Baker, D.; Rouillard, A. P.; van Driel-Gesztelyi, L.; Démoulin, P.; Harra, L. K.; Lavraud, B.; Davies, J. A.; Opitz, A.; Luhmann, J. G.; Sauvaud, J.-A.; Galvin, A. B.

    2009-10-01

    Combining STEREO, ACE and Hinode observations has presented an opportunity to follow a filament eruption and coronal mass ejection (CME) on 17 October 2007 from an active region (AR) inside a coronal hole (CH) into the heliosphere. This particular combination of "open" and closed magnetic topologies provides an ideal scenario for interchange reconnection to take place. With Hinode and STEREO data we were able to identify the emergence time and type of structure seen in the in-situ data four days later. On the 21st, ACE observed in-situ the passage of an ICME with "open" magnetic topology. The magnetic field configuration of the source, a mature AR located inside an equatorial CH, has important implications for the solar and interplanetary signatures of the eruption. We interpret the formation of an "anemone" structure of the erupting AR and the passage in-situ of the ICME being disconnected at one leg, as manifested by uni-directional suprathermal electron flux in the ICME, to be a direct result of interchange reconnection between closed loops of the CME originating from the AR and "open" field lines of the surrounding CH.

  10. 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.

  11. Uncertainty quantification for accident management using ACE surrogates

    SciTech Connect

    Varuttamaseni, A.; Lee, J. C.; Youngblood, R. W.

    2012-07-01

    The alternating conditional expectation (ACE) regression method is used to generate RELAP5 surrogates which are then used to determine the distribution of the peak clad temperature (PCT) during the loss of feedwater accident coupled with a subsequent initiation of the feed and bleed (F and B) operation in the Zion-1 nuclear power plant. The construction of the surrogates assumes conditional independence relations among key reactor parameters. The choice of parameters to model is based on the macroscopic balance statements governing the behavior of the reactor. The peak clad temperature is calculated based on the independent variables that are known to be important in determining the success of the F and B operation. The relationship between these independent variables and the plant parameters such as coolant pressure and temperature is represented by surrogates that are constructed based on 45 RELAP5 cases. The time-dependent PCT for different values of F and B parameters is calculated by sampling the independent variables from their probability distributions and propagating the information through two layers of surrogates. The results of our analysis show that the ACE surrogates are able to satisfactorily reproduce the behavior of the plant parameters even though a quasi-static assumption is primarily used in their construction. The PCT is found to be lower in cases where the F and B operation is initiated, compared to the case without F and B, regardless of the F and B parameters used. (authors)

  12. 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

  13. Structure-Based Evaluation of Non-nucleoside Inhibitors with Improved Potency and Solubility That Target HIV Reverse Transcriptase Variants

    PubMed Central

    2015-01-01

    The development of novel non-nucleoside inhibitors (NNRTIs) with activity against variants of HIV reverse transcriptase (RT) is crucial for overcoming treatment failure. The NNRTIs bind in an allosteric pocket in RT ∼10 Å away from the active site. Earlier analogues of the catechol diether compound series have picomolar activity against HIV strains with wild-type RT but lose potency against variants with single Y181C and double K103N/Y181C mutations. As guided by structure-based and computational studies, removal of the 5-Cl substitution of compound 1 on the catechol aryl ring system led to a new analogue compound 2 that maintains greater potency against Y181C and K103N/Y181C variants and better solubility (510 μg/mL). Crystal structures were determined for wild-type, Y181C, and K103N/Y181C RT in complex with both compounds 1 and 2 to understand the structural basis for these findings. Comparison of the structures reveals that the Y181C mutation destabilizes the binding mode of compound 1 and disrupts the interactions with residues in the pocket. Compound 2 maintains the same conformation in wild-type and mutant structures, in addition to several interactions with the NNRTI binding pocket. Comparison of the six crystal structures will assist in the understanding of compound binding modes and future optimization of the catechol diether series. PMID:25700160

  14. 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

  15. 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. PMID:25578823

  16. 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…

  17. 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.

  18. Validation of NO2 and NO from the Atmospheric Chemistry Experiment (ACE)

    NASA Astrophysics Data System (ADS)

    Kerzenmacher, T.; Wolff, M. A.; Stong, K.; Dupuy, E.; Walker, K. A.; Amekudzi, L. K.; Batchelor, R. L.; Bernath, P. F.; Berthet, G.; Blumenstock, T.; Boone, C. D.; Bramstedt, K.; Brogniez, C.; Brohede, S.; Burrows, J. P.; Catoire, V.; Dodion, J.; Drummond, J. R.; Dufour, D. G.; Funke, B.; Fussen, D.; Goutail, F.; Griffith, D. W. T.; Haley, C. S.; Hendrick, F.; Höpfner, M.; Huret, N.; Jones, N.; Kar, J.; Kramer, I.; Llewellyn, E. J.; López-Puertas, M.; Manney, G.; McElroy, C. T.; McLinden, C. A.; Melo, S.; Mikuteit, S.; Murthag, D.; Nichitiu, F.; Notholt, J.; Nowlan, C.; Piccolo, C.; Pommereau, J.-P.; Randall, C.; Raspollini, P.; Ridolfi, M.; Richter, A.; Schneider, M.; Schrems, O.; Silicani, M.; Stiller, G. P.; Taylor, J.; Tétard, C.; Toohey, M.; Vanhellemont, F.; Warneke, T.; Zawodny, J. M.; Zou, J.

    2008-02-01

    Vertical profiles of NO2 and NO have been obtained from solar occultation measurements by the Atmospheric Chemistry Experiment (ACE), using an infrared Fourier Transform Spectrometer, ACE-FTS, and an ultraviolet-visible-near-infrared spectrometer, MAESTRO (Measurement of Aerosol Extinction in the Stratosphere and Troposphere Retrieved by Occultation). In this paper, the quality of the ACE-FTS version 2.2 NO2 and NO and the MAESTRO version 1.2 NO2 data are assessed using other solar occultation measurements (HALOE, SAGE II, SAGE III, POAM III, SCIAMACHY), stellar occultation measurements (GOMOS), limb measurements (MIPAS, OSIRIS), nadir measurements (SCIAMACHY), balloon measurements (SPIRALE, SAOZ) and ground-based measurements (UV-VIS, FTIR). Time differences between the comparison measurements were reduced using either a tight coincidence criterion, or where possible, chemical box models. ACE-FTS NO2 and NO and the MAESTRO NO2 are generally consistent with the correlative data. The ACE-FTS NO2 VMRs agree with the satellite data sets to within about 20% between 25 and 40 km, and suggest a negative bias between 23 and 40 km of about textminus10%. In comparisons with HALOE, ACE-FTS NO VMRs typically agree to ±8% from 22 to 64 km and to +10% from 93 to 105 km. Partial column comparisons for NO2 show that there is fair agreement between the ACE instruments and the FTIRs, with a mean difference of +7.3% for ACE-FTS and +12.8% for MAESTRO.

  19. 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.

  20. 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,...

  1. 77 FR 20835 - National Customs Automation Program (NCAP) Test Concerning Automated Commercial Environment (ACE...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-06

    ... Portal Accounts and Subsequent Revision Notices: 67 FR 21800 (May 1, 2002); 70 FR 5199 (February 1, 2005); 69 FR 5360 and 69 FR 5362 (February 4, 2004); 69 FR 54302 (September 8, 2004). ACE System of Records Notice: 71 FR 3109 (January 19, 2006). Terms/Conditions for Access to the ACE Portal and...

  2. 76 FR 34246 - Automated Commercial Environment (ACE); Announcement of National Customs Automation Program Test...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-13

    ..., 2003, CBP published a final rule in the Federal Register (68 FR 68140) to effectuate the provisions of... 27, 2006 (71 FR 62922), CBP designated the ACE Truck Manifest System as the approved system for... in which CBP had planned to require the use of ACE. See, 72 FR 53789, September 20, 2007....

  3. Absence of cell surface expression of human ACE leads to perinatal death.

    PubMed

    Michaud, Annie; Acharya, K Ravi; Masuyer, Geoffrey; Quenech'du, Nicole; Gribouval, Olivier; Morinière, Vincent; Gubler, Marie-Claire; Corvol, Pierre

    2014-03-15

    Renal tubular dysgenesis (RTD) is a recessive autosomal disease characterized most often by perinatal death. It is due to the inactivation of any of the major genes of the renin-angiotensin system (RAS), one of which is the angiotensin I-converting enzyme (ACE). ACE is present as a tissue-bound enzyme and circulates in plasma after its solubilization. In this report, we present the effect of different ACE mutations associated with RTD on ACE intracellular trafficking, secretion and enzymatic activity. One truncated mutant, R762X, responsible for neonatal death was found to be an enzymatically active, secreted form, not inserted in the plasma membrane. In contrast, another mutant, R1180P, was compatible with life after transient neonatal renal insufficiency. This mutant was located at the plasma membrane and rapidly secreted. These results highlight the importance of tissue-bound ACE versus circulating ACE and show that the total absence of cell surface expression of ACE is incompatible with life. In addition, two missense mutants (W594R and R828H) and two truncated mutants (Q1136X and G1145AX) were also studied. These mutants were neither inserted in the plasma membrane nor secreted. Finally, the structural implications of these ACE mutations were examined by molecular modelling, which suggested some important structural alterations such as disruption of intra-molecular non-covalent interactions (e.g. salt bridges).

  4. SCORE/ACE Counselor Handbook. Service Corps of Retired Executives. Active Corps of Executives.

    ERIC Educational Resources Information Center

    Landsverk, Arvel; And Others

    This counselor handbook is intended to help Service Corps of Retired Executives/Active Corps of Executives (SCORE/ACE) counselors to plan and conduct counseling services more effectively. Included in the introductory section are an overview of the SCORE/ACE counseling program, a discussion of what the counselor does, directions for completing…

  5. Education for 2001 and Beyond: Imperatives and Possibilities. Outcomes from the ACE "Education 2000" International Conference.

    ERIC Educational Resources Information Center

    Unicorn: Journal of the Australian College of Education, 2000

    2000-01-01

    This issue of "Unicorn," the journal of the Australian College of Education (ACE), contains extracts and summaries of 13 presentations given at the international ACE conference, "Education 2000: Priorities for the New Millennium." The papers not only address the five themes of the conference (priorities for learning, priorities for supporting…

  6. 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.

  7. 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 Central

    Darewicz, Małgorzata; Borawska, Justyna; Vegarud, Gerd E.; Minkiewicz, Piotr; Iwaniak, Anna

    2014-01-01

    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. PMID:25123137

  8. 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.

  9. Diminazene Aceturate Improves Cardiac Fibrosis and Diastolic Dysfunction in Rats with Kidney Disease

    PubMed Central

    Velkoska, Elena; Patel, Sheila K.; Griggs, Karen

    2016-01-01

    Angiotensin converting enzyme (ACE) 2 is a negative regulator of the renin angiotensin system (RAS) through its role to degrade angiotensin II. In rats with subtotal nephrectomy (STNx), adverse cardiac remodelling occurs despite elevated cardiac ACE2 activity. We hypothesised that diminazene aceturate (DIZE), which has been described as having an off-target effect to activate ACE2, would have beneficial cardiac effects in STNx rats. STNx led to hypertension, diastolic dysfunction, left ventricular hypertrophy, cardiac fibrosis, and increased cardiac ACE, ACE2, Ang II and Ang 1–7 levels. Cardiac gene expression of ADAM17 was also increased. In STNx, two-weeks of subcutaneous DIZE (15mg/kg/d) had no effect on blood pressure but improved diastolic dysfunction and cardiac fibrosis, reduced ADAM17 mRNA and shifted the cardiac RAS balance to a cardioprotective profile with reduced ACE and Ang II. There was no change in cardiac ACE2 activity or in cardiac Ang 1–7 levels with DIZE. In conclusion, our results suggest that DIZE exerts a protective effect on the heart under the pathological condition of kidney injury. This effect was not due to improved kidney function, a fall in blood pressure or a reduction in LVH but was associated with a reduction in cardiac ACE and cardiac Ang II levels. As in vitro studies showed no direct effect of DIZE on ACE2 or ACE activity, the precise mechanism of action of DIZE remains to be determined. PMID:27571511

  10. Diminazene Aceturate Improves Cardiac Fibrosis and Diastolic Dysfunction in Rats with Kidney Disease.

    PubMed

    Velkoska, Elena; Patel, Sheila K; Griggs, Karen; Burrell, Louise M

    2016-01-01

    Angiotensin converting enzyme (ACE) 2 is a negative regulator of the renin angiotensin system (RAS) through its role to degrade angiotensin II. In rats with subtotal nephrectomy (STNx), adverse cardiac remodelling occurs despite elevated cardiac ACE2 activity. We hypothesised that diminazene aceturate (DIZE), which has been described as having an off-target effect to activate ACE2, would have beneficial cardiac effects in STNx rats. STNx led to hypertension, diastolic dysfunction, left ventricular hypertrophy, cardiac fibrosis, and increased cardiac ACE, ACE2, Ang II and Ang 1-7 levels. Cardiac gene expression of ADAM17 was also increased. In STNx, two-weeks of subcutaneous DIZE (15mg/kg/d) had no effect on blood pressure but improved diastolic dysfunction and cardiac fibrosis, reduced ADAM17 mRNA and shifted the cardiac RAS balance to a cardioprotective profile with reduced ACE and Ang II. There was no change in cardiac ACE2 activity or in cardiac Ang 1-7 levels with DIZE. In conclusion, our results suggest that DIZE exerts a protective effect on the heart under the pathological condition of kidney injury. This effect was not due to improved kidney function, a fall in blood pressure or a reduction in LVH but was associated with a reduction in cardiac ACE and cardiac Ang II levels. As in vitro studies showed no direct effect of DIZE on ACE2 or ACE activity, the precise mechanism of action of DIZE remains to be determined. PMID:27571511

  11. 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

  12. 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. PMID:25931305

  13. Improved symptom relief and duodenal ulcer healing with lansoprazole, a new proton pump inhibitor, compared with ranitidine.

    PubMed Central

    Hawkey, C J; Long, R G; Bardhan, K D; Wormsley, K G; Cochran, K M; Christian, J; Moules, I K

    1993-01-01

    The purpose of this study was to compare duodenal ulcer healing, symptom relief, and safety of lansoprazole (a new proton pump inhibitor) given at doses of 30 mg and 60 mg, in the morning with ranitidine 300 mg at bedtime. Two hundred and eighty nine patients were enrolled over a 20 month period in a double blind randomised parallel group comparative study set in outpatient endoscopy units of six United Kingdom medical centres. Patients were randomised to receive lansoprazole 30 mg in the morning (n = 95), 60 mg in the morning (n = 96), or ranitidine 300 mg at bedtime (n = 98) for four weeks. Efficacy was assessed by gastroscopy at study entry and after two and four weeks of treatment. Symptom relief was monitored by patient diaries and physician review at two and four weeks. Both doses of lansoprazole resulted in significantly greater ulcer healing than ranitidine after two and four weeks. Respective healing rates on lansoprazole 30 mg, 60 mg, and ranitidine 300 mg were 78%, 80%, and 60% after two weeks and 93%, 97%, and 81% after four weeks. Patients on lansoprazole 30 mg (p = 0.002) and lansoprazole 60 mg (p = 0.026) also recorded greater relief of night time pain in the diary cards during the first seven days of treatment than those on ranitidine. Patients on lansoprazole 60 mg reported significantly better pain relief at their two week visit compared with those receiving ranitidine (p = 0.007). There were no differences between treatment groups in the occurrence or pattern of adverse drug reactions during the trial. It is concluded that for patients with duodenal ulcer, lansoprazole 30 mg or 60 mg is associated with faster ulcer healing and better symptom relief than ranitidine 300 mg at bedtime. There were no significant differences between lansoprazole 30 mg and 60 mg. These data indicate that lansoprazole should be used at a once daily dose of 30 mg for the treatment of duodenal ulcer. PMID:8244121

  14. 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

  15. 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

  16. Adolescent parents and their children: a multifaceted approach to prevention of adverse childhood experiences (ACE).

    PubMed

    Mayer, Lynn Milgram; Thursby, Ellen

    2012-01-01

    Childhood experiences can have long-term effects. Research shows that children who undergo adverse childhood experiences (ACE) often have negative health and mental health outcomes later in life. Children of adolescent parents with high ACE Scores are at greater risk of ACE. As such, an intergenerational approach to preventing ACE is proposed in this article, addressing the needs of both the adolescent parent and their children. A review of the literature indicates that a public health perspective can guide the development of a prevention model aimed at reducing the effects of ACE. The current article proposes a universal, multifaceted, and interdisciplinary prevention science model that has two targets: adolescent parents and their children. Schools and early childhood programs can be mobilized to offer community prevention strategies across realms to include the individual, community, provider, coalitions/networks, organizational practices, and policy/legislation. PMID:22970783

  17. 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.

  18. 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

  19. Proteasome inhibitors.

    PubMed

    Teicher, Beverly A; Tomaszewski, Joseph E

    2015-07-01

    Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications. PMID:25935605

  20. Cell permeable peptide of JNK inhibitor prevents islet apoptosis immediately after isolation and improves islet graft function.

    PubMed

    Noguchi, Hirofumi; Nakai, Yusuke; Matsumoto, Shinichi; Kawaguchi, Miho; Ueda, Michiko; Okitsu, Teru; Iwanaga, Yasuhiro; Yonekawa, Yukihide; Nagata, Hideo; Minami, Kohtaro; Masui, Yumi; Futaki, Shiroh; Tanaka, Koichi

    2005-08-01

    Although application of the Edmonton protocol has markedly improved outcomes for pancreatic islet transplantation, the insulin independence rate after islet transplantation from one donor pancreas has proven to remain low. During the isolation process and subsequent clinical transplantation, islets are subjected to severe adverse conditions that impair survival and ultimately contribute to graft failure. Pancreas preservation with the two-layer method (TLM) has proven to improve transplant results by protecting isolated islets against apoptosis through the mitochondrial pathway. However, pancreas storage with TLM cannot protect against activation of c-Jun NH2-terminal kinase (JNK) in isolated islets. This study investigated whether delivery of a JNK inhibitory peptide (JNKI) via the protein transduction system can prevent apoptosis of islet cells immediately after isolation. For efficient delivery of the (JNKI into isolated islets, we synthesized JNKI as a C-terminal fusion peptide with the 11-arginine protein transduction domain (11R-JNKI). 11R efficiently delivered the JNKI into isolated islets and 11R-JNKI prevented islet apoptosis immediately after isolation and improved islet graft function. These findings suggest that peptide drugs could be useful for the prevention of the impairment of islet cells and lead to improvement in the outcomes for pancreatic islet transplantation.

  1. Polar Vortex Structure with ACE and OSIRIS Ozone Data

    NASA Astrophysics Data System (ADS)

    Evans, W. F.

    2005-12-01

    The polar vortex is the dominant feature of stratospheric wind field. The ACE instrument on SCISAT-1 can map ozone fields from 8 to 50 km in 16 days. The OSIRIS instrument on ODIN can map the ozone fields at 2 km intervals from 10 km to over 65 km on a daily basis. They can also provide aerosol maps at the lower levels. These can be used for dynamical studies such as vortex breakdown. Four years of ozone data from the OSIRIS instrument on ODIN have been processed using the Kerr three wavelength algorithm. The OSIRIS ozone data is on the web as orbital slices. TOMS like maps have been formed at 2 km intervals from 10 km to 42 km by mapping the OSIRIS ozone product onto polar map projections. This mapset allows investigations of the vertical structure and evolution of the vortex. The downward motion in the vortex is clearly demonstrated by aerosol maps which show a clean vortex due to the descent within the vortex. The Antarctic vortex and the Arctic vortex were investigated using the ACE profiles and the OSIRIS ozone product. OSIRIS data is available from Oct 1, 2001 to April 30, 2005 as maps at 2km intervals from 10 km to 42 km. An example is demonstrated using the split vortex event of September 25, 2002; the split extends from 14 km up to 42 km. However, the 10 km and 12 km levels showed no vortex during the split. There is a close relationship of vortex ozone with PV and hence to the vortex wind. These maps are used to study the vortex in the Arctic and the Antarctic. In particular, the vortex breakdown in the two hemispheres is compared. The ozone vortex extends up to 55 km at the wind null region. There are significant differences in the hemispheres in the vortex below 24 km. A comparison of the features of the Arctic and Antarctic vorticies was conducted. The Antarctic vortex usually extends from 10 km up to over 42 km whereas in the Arctic, the vortex is only obvious from 16 km to 42km. The main hemispheric differences seem to be in the lower stratosphere

  2. Update on TNF Inhibitors.

    PubMed

    Kerdel, Francisco A

    2016-06-01

    The introduction of tumor necrosis factor (TNF)-α inhibitors dramatically improved the management of psoriasis. Some newer or investigational biologics with different mechanisms of action have demonstrated noninferiority or superiority to etanercept, the first self-injectable anti-TNF-α agent to become available in the United States. Nonetheless, TNF-α inhibitors are likely to remain a mainstay of therapy for many years.

  3. P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile

    SciTech Connect

    Nair, Latha G.; Sannigrahi, Mousumi; Bogen, Stephane; Pinto, Patrick; Chen, Kevin X.; Prongay, Andrew; Tong, Xiao; Cheng, K.-C.; Girijavallabhann, Viyyoor; Njoroge, F. George

    2010-09-03

    SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4,4-dimethyl lactam as the new P4 cap unit with improved potency (K*{sub i}, EC 90 = 70 nM) and pharmacokinetic properties (Rat AUC (PO) = 3.52 {micro}M h) compared to 1.

  4. Platelet Inhibitors.

    PubMed

    Shifrin, Megan M; Widmar, S Brian

    2016-03-01

    Antithrombotic medications have become standard of care for management of acute coronary syndrome. Platelet adhesion, activation, and aggregation are essential components of platelet function; platelet-inhibiting medications interfere with these components and reduce incidence of thrombosis. Active bleeding is a contraindication for administration of platelet inhibitors. There is currently no reversal agent for platelet inhibitors, although platelet transfusion may be used to correct active bleeding after administration of platelet inhibitors. PMID:26897422

  5. 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.

  6. 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. PMID:25306378

  7. 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.

  8. 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

  9. Economic evaluation of the Annual Cycle Energy System (ACES). Volume II. Detailed results. Final report

    SciTech Connect

    Not Available

    1980-05-01

    The energy effectiveness and the economic viability of the ACES concept are examined. ACES is studied in a variety of different applications and compared to a number of conventional systems. The different applications are studied in two groups: the class of building into which the ACES is incorporated and the climatic region in which the ACES is located. Buildings investigated include single-family and multi-family residences and a commercial office building. The application of ACES to each of these building types is studied in Minneapolis, Atlanta, and Philadelphia. The economic evaluation of the ACES is based on a comparison of the present worth of the ACES to the present worth of conventional systems; namely, electric resistance heating, electric air conditioning, and electric domestic water heating; air-to-air heat pump and electric domestic water heating; oil-fired furnace, electric air conditioning, and electric domestic water heating; and gas-fired furnace, electric air conditioning, and gas domestic water heating.

  10. Long-lasting neuroprotection and neurological improvement in stroke models with new, potent and brain permeable inhibitors of poly(ADP-ribose) polymerase

    PubMed Central

    Moroni, F; Cozzi, A; Chiarugi, A; Formentini, L; Camaioni, E; Pellegrini-Giampietro, DE; Chen, Y; Liang, S; Zaleska, MM; Gonzales, C; Wood, A; Pellicciari, R

    2012-01-01

    BACKGROUND AND PURPOSES Thienyl-isoquinolone (TIQ-A) is a relatively potent PARP inhibitor able to reduce post-ischaemic neuronal death in vitro. Here we have studied, in different stroke models in vivo, the neuroprotective properties of DAMTIQ and HYDAMTIQ, two TIQ-A derivatives able to reach the brain and to inhibit PARP-1 and PARP-2. EXPERIMENTAL APPROACH Studies were carried out in (i) transient (2 h) middle cerebral artery occlusion (tMCAO), (ii) permanent MCAO (pMCAO) and (iii) electrocoagulation of the distal portion of MCA in conjunction with transient (90 min) bilateral carotid occlusion (focal cortical ischaemia). KEY RESULTS In male rats with tMCAO, HYDAMTIQ (0.1–10 mg·kg−1) injected i.p. three times, starting 4 h after MCAO, reduced infarct volumes by up to 70%, reduced the loss of body weight by up to 60% and attenuated the neurological impairment by up to 40%. In age-matched female rats, HYDAMTIQ also reduced brain damage. Protection, however, was less pronounced than in the male rats. In animals with pMCAO, HYDAMTIQ administered 30 min after MCAO reduced infarct volumes by approximately 40%. In animals with focal cortical ischaemia, HYDAMTIQ treatment decreased post-ischaemic accumulation of PAR (the product of PARP activity) and the presence of OX42-positive inflammatory cells in the ischaemic cortex. It also reduced sensorimotor deficits for up to 90 days after MCAO. CONCLUSION AND IMPLICATIONS Our results show that HYDAMTIQ is a potent PARP inhibitor that conferred robust neuroprotection and long-lasting improvement of post-stroke neurological deficits. PMID:21913897

  11. Corrosion inhibitor

    SciTech Connect

    Wisotsky, M.J.; Metro, S.J.

    1989-10-31

    A corrosion inhibitor for use in synthetic ester lubricating oils is disclosed. It comprises an effective amount of: at least one aromatic amide; and at least one hydroxy substituted aromatic compound. The corrosion inhibitor thus formed is particularly useful in synthetic ester turbo lubricating oils.

  12. Statins, HMG-CoA Reductase Inhibitors, Improve Neovascularization by Increasing the Expression Density of CXCR4 in Endothelial Progenitor Cells

    PubMed Central

    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. 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 starting PDE5i at an outpatient clinic after discharge (PDE5i group, n=56), and patients taking no medication (non-PDE5i group, n=40). Using self-administered questionnaires, the proportion of patients who did not require incontinence pads (pad-free patients) was calculated preoperatively and at 1, 3, 6, 12, 18, and 24 months after BNSRP. Severity of incontinence was determined based on the pad numbers and then compared among the 3 groups. Results Proportions of pad-free patients and severity of incontinence initially deteriorated in all of the groups to the lowest values soon after undergoing BNSRP, with gradual improvement noted thereafter. The deterioration was most prominent in the immediate PDE5i group. As compared to the non-PDE5i group, both the PDE5i and immediate PDE5i groups exhibited a better final continence status. Conclusions PDE5i improves final continence status. However, administration of PDE5i immediately after surgery causes a distinct temporary deterioration in urinary incontinence.

  14. Improvement of ethanol productivity and energy efficiency by degradation of inhibitors using recombinant Zymomonas mobilis (pHW20a-fdh).

    PubMed

    Dong, Hong-Wei; Fan, Li-Qiang; Luo, Zichen; Zhong, Jian-Jiang; Ryu, Dewey D Y; Bao, Jie

    2013-09-01

    Toxic compounds, such as formic acid, furfural, and hydroxymethylfurfural (HMF) generated during pretreatment of corn stover (CS) at high temperature and low pH, inhibit growth of Zymomonas mobilis and lower the conversion efficiency of CS to biofuel and other products. The inhibition of toxic compounds is considered as one of the major technical barriers in the lignocellulose bioconversion. In order to detoxify and/or degrade these toxic compounds by the model ethanologenic strain Z. mobilis itself in situ the fermentation medium, we constructed a recombinant Z. mobilis ZM4 (pHW20a-fdh) strain that is capable of degrading toxic inhibitor, formate. This is accomplished by cloning heterologous formate dehydrogenase gene (fdh) from Saccharomyces cerevisiae and by coupling this reaction of NADH regeneration reaction system with furfural and HMF degradation in the recombinant Z. mobilis strain. The NADH regeneration reaction also improved both the energy efficiency and cell physiological activity of the recombinant organism, which were definitely confirmed by the improved cell growth, ethanol yield, and ethanol productivity during fermentation with CS hydrolysate.

  15. 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 starting PDE5i at an outpatient clinic after discharge (PDE5i group, n=56), and patients taking no medication (non-PDE5i group, n=40). Using self-administered questionnaires, the proportion of patients who did not require incontinence pads (pad-free patients) was calculated preoperatively and at 1, 3, 6, 12, 18, and 24 months after BNSRP. Severity of incontinence was determined based on the pad numbers and then compared among the 3 groups. Results Proportions of pad-free patients and severity of incontinence initially deteriorated in all of the groups to the lowest values soon after undergoing BNSRP, with gradual improvement noted thereafter. The deterioration was most prominent in the immediate PDE5i group. As compared to the non-PDE5i group, both the PDE5i and immediate PDE5i groups exhibited a better final continence status. Conclusions PDE5i improves final continence status. However, administration of PDE5i immediately after surgery causes a distinct temporary deterioration in urinary incontinence. PMID:27617318

  16. 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.

  17. JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitor, improves glucose metabolism in diet-induced obesity and genetic T2DM mice.

    PubMed

    Tomimoto, Daisuke; Okuma, Chihiro; Ishii, Yukihito; Kobayashi, Akio; Ohta, Takeshi; Kakutani, Makoto; Imanaka, Tsuneo; Ogawa, Nobuya

    2015-09-01

    Type 2 diabetes mellitus (T2DM) arises primarily due to lifestyle factors and genetics. A number of lifestyle factors are known to be important in the development of T2DM, including obesity. JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase 1 inhibitor, reduced body weight depending on dietary fat in diet-induced obesity (DIO) rats in our previous study. Here, the effect of JTT-553 on glucose metabolism was evaluated using body weight reduction in T2DM mice. JTT-553 was repeatedly administered to DIO and KK-A(y) mice. JTT-553 reduced body weight gain and fat weight in both mouse models. In DIO mice, JTT-553 decreased insulin, non-esterified fatty acid (NEFA), total cholesterol (TC), and liver triglyceride (TG) plasma concentrations in non-fasting conditions. JTT-553 also improved insulin-dependent glucose uptake in adipose tissues and glucose intolerance in DIO mice. In KK-A(y) mice, JTT-553 decreased glucose, NEFA, TC and liver TG plasma concentrations in non-fasting conditions. JTT-553 also decreased glucose, insulin, and TC plasma concentrations in fasting conditions. In addition, JTT-553 decreased TNF-α mRNA levels and increased GLUT4 mRNA levels in adipose tissues in KK-A(y) mice. These results suggest that JTT-553 improves insulin resistance in adipose tissues and systemic glucose metabolism through reductions in body weight.

  18. Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice

    PubMed Central

    Gallo, Linda A.; Ward, Micheal S.; Fotheringham, Amelia K.; Zhuang, Aowen; Borg, Danielle J.; Flemming, Nicole B.; Harvie, Ben M.; Kinneally, Toni L.; Yeh, Shang-Ming; McCarthy, Domenica A.; Koepsell, Hermann; Vallon, Volker; Pollock, Carol; Panchapakesan, Usha; Forbes, Josephine M.

    2016-01-01

    Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db/db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta. Other molecular (collagen IV and connective tissue growth factor) and histological (tubulointerstitial total collagen and glomerular collagen IV accumulation) benefits were seen upon dual therapy with metformin. Albuminuria, urinary markers of tubule damage (kidney injury molecule-1, KIM-1 and neutrophil gelatinase-associated lipocalin, NGAL), kidney growth, and glomerulosclerosis, however, were not improved with empagliflozin or metformin, and plasma and intra-renal renin activity was enhanced with empagliflozin. In this model, blood glucose lowering with empagliflozin attenuated some molecular and histological markers of fibrosis but, as per treatment with metformin, did not provide complete renoprotection. Further research to refine the treatment regimen in type 2 diabetes and nephropathy is warranted. PMID:27226136

  19. The Ace locus of Drosophila melanogaster: structural gene for acetylcholinesterase with an unusual 5' leader.

    PubMed Central

    Hall, L M; Spierer, P

    1986-01-01

    The Ace locus of Drosophila melanogaster has been mapped at the molecular level. cDNA clones from the locus have been isolated and their sequence determined, confirming that Ace forms the structural gene for acetylcholinesterase (AChE). The cDNAs have a 1950 nucleotide open reading frame from which the complete amino acid sequence of AChE has been deduced. The Drosophila enzyme is found to have extensive homology to the known sequence of Torpedo AChE. Ace cDNAs have an unusual structure with a long 5' leader and several short upstream open reading frames. Images Fig. 2. PMID:3024971

  20. 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.

  1. Improved synthesis of lysine- and arginine-derived Amadori and Heyns products and in vitro measurement of their angiotensin I-converting enzyme inhibitory activity.

    PubMed

    Srinivas, Sudhanva M; Harohally, Nanishankar V

    2012-02-15

    The L-lysine- and L-arginine-derived Amadori and Heyns products consisting of N-(1-deoxy-d-fructos-1-yl)amino acid and N-(2-deoxy-d-glucos-2-yl)amino acid were prepared by reaction of d-fructose and d-glucose with l-lysine hydrochloride and l-arginine hydrochloride using commercial zinc powder as deprotonating reagent and also as catalyst precursor in a simple synthetic route in high yield. These compounds were screened for angiotensin I-converting enzyme (ACE) inhibitory activity using a high-throughput colorimetric assay (utilizing porcine kidney ACE). The IC(50) values fall in the range of 1030-1175 μM, with N(α)-(1-deoxy-d-fructos-1-yl)arginine showing the best IC(50) value (1030 ± 38 μM). This study demonstrates an improved synthetic method for simple Amadori and Heyns products and their moderate ACE inhibitor activity. PMID:22242891

  2. Deactivating Cochlear Implant Electrodes Based on Pitch Information for Users of the ACE Strategy.

    PubMed

    Vickers, Deborah; Degun, Aneeka; Canas, Angela; Stainsby, Thomas; Vanpoucke, Filiep

    2016-01-01

    There is a wide range in performance for cochlear implant (CI) users and there is some evidence to suggest that implant fitting can be modified to improve performance if electrodes that do not provide distinct pitch information are de-activated. However, improvements in performance may not be the same for users of all CI devices; in particular for those with Cochlear devices using n-of-m strategies (ACE or SPEAK).The goal of this research was to determine for users of Cochlear devices (CP810 or CP900 series processors) if speech perception could be improved when indiscriminable electrodes were de-activated and this was also compared to when the same number of discriminable electrodes were de-activated.A cross-over study was conducted with 13 adult CI users who received experimental maps with de-activated channels for a minimum of 2 months and these were compared to optimised clinical maps.The findings showed that there were no significant benefits of electrode de-activation on speech perception and that there was a significant deterioration in spectro-temporal ripple perception when electrodes were switched off. There were no significant differences between de-activation of discriminable or indiscriminable electrodes.These findings suggest that electrode de-activation with n-of-m strategies may not be beneficial. PMID:27080652

  3. Deactivating Cochlear Implant Electrodes Based on Pitch Information for Users of the ACE Strategy.

    PubMed

    Vickers, Deborah; Degun, Aneeka; Canas, Angela; Stainsby, Thomas; Vanpoucke, Filiep

    2016-01-01

    There is a wide range in performance for cochlear implant (CI) users and there is some evidence to suggest that implant fitting can be modified to improve performance if electrodes that do not provide distinct pitch information are de-activated. However, improvements in performance may not be the same for users of all CI devices; in particular for those with Cochlear devices using n-of-m strategies (ACE or SPEAK).The goal of this research was to determine for users of Cochlear devices (CP810 or CP900 series processors) if speech perception could be improved when indiscriminable electrodes were de-activated and this was also compared to when the same number of discriminable electrodes were de-activated.A cross-over study was conducted with 13 adult CI users who received experimental maps with de-activated channels for a minimum of 2 months and these were compared to optimised clinical maps.The findings showed that there were no significant benefits of electrode de-activation on speech perception and that there was a significant deterioration in spectro-temporal ripple perception when electrodes were switched off. There were no significant differences between de-activation of discriminable or indiscriminable electrodes.These findings suggest that electrode de-activation with n-of-m strategies may not be beneficial.

  4. 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.

  5. Improvement of mouse cloning using nuclear transfer-derived embryonic stem cells and/or histone deacetylase inhibitor.

    PubMed

    Wakayama, Sayaka; Wakayama, Teruhiko

    2010-01-01

    Nuclear transfer-derived ES (ntES) cell lines can be established from somatic cell nuclei with a relatively high success rate. Although ntES cells have been shown to be equivalent to ES cells, there are ethical objections concerning human cells, such as the use of fresh oocyte donation from young healthy woman. In contrast, the use of induced pluripotent stem (iPS) cells for cloning poses few ethical problems and is a relatively easy technique compared with nuclear transfer. Therefore, although there are several reports proposing the use of ntES cells as a model of regenerative medicine, the use of these cells in preliminary medical research is waning. However, in theory, 5 to 10 donor cells can establish one ntES cell line and, once established, these cells will propagate indefinitely. These cells can be used to generate cloned animals from ntES cell lines using a second round of NT. Even in infertile and "unclonable" strains of mice, we can generate offspring from somatic cells by combining cloning with ntES technology. Moreover, cloned offspring can be generated potentially even from the nuclei of dead bodies or freeze-dried cells via ntES cells, such as from an extinct frozen animal. Currently, only the ntES technology is available for this purpose, because all other techniques, including iPS cell derivation, require significant numbers of living donor cells. This review describes how to improve the efficiency of cloning, the establishment of clone-derived embryonic stem cells and further applications.

  6. Improvement of robustness and ethanol production of ethanologenic Saccharomyces cerevisiae under co-stress of heat and inhibitors.

    PubMed

    Lu, Ying; Cheng, Yan-Fei; He, Xiu-Ping; Guo, Xue-Na; Zhang, Bo-Run

    2012-01-01

    Bioethanol is an attractive alternative to fossil fuels. Saccharomyces cerevisiae is the most important ethanol producer. However, yeast cells are challenged by various environmental stresses during the industrial process of ethanol production. The robustness under heat, acetic acid, and furfural stresses was improved for ethanologenic S. cerevisiae in this work using genome shuffling. Recombinant yeast strain R32 could grow at 45°C, and resist 0.55% (v/v) acetic acid and 0.3% (v/v) furfural at 40°C. When ethanol fermentation was conducted at temperatures ranging from 30 to 42°C, recombinant strain R32 always gave high ethanol production. After 42 h of fermentation at 42°C, 187.6 ± 1.4 g/l glucose was utilized by recombinant strain R32 to produce 81.4 ± 2.7 g/l ethanol, which were respectively 3.4 and 4.1 times those of CE25. After 36 h of fermentation at 40°C with 0.5% (v/v) acetic acid, 194.4 ± 1.2 g/l glucose in the medium was utilized by recombinant strain R32 to produce 84.2 ± 4.6 g/l of ethanol. The extent of glucose utilization and ethanol concentration of recombinant strain R32 were 6.3 and 7.9 times those of strain CE25. The ethanol concentration produced by recombinant strain R32 was 8.9 times that of strain CE25 after fermentation for 48 h under 0.2% (v/v) furfural stress at 40°C. The strong physiological robustness and fitness of yeast strain R32 support its potential application for industrial production of bioethanol from renewable resources such as lignocelluloses.

  7. 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

  8. Role of the Renin-Angiotensin-Aldosterone System and Its Pharmacological Inhibitors in Cardiovascular Diseases: Complex and Critical Issues.

    PubMed

    Borghi, Claudio; Rossi, Francesco

    2015-12-01

    Hypertension is one of the major risk factor able to promote development and progression of several cardiovascular diseases, including left ventricular hypertrophy and dysfunction, myocardial infarction, stroke, and congestive heart failure. Also, it is one of the major driven of high cardiovascular risk profile in patients with metabolic complications, including obesity, metabolic syndrome and diabetes, as well as in those with renal disease. Thus, effective control of hypertension is a key factor for any preventing strategy aimed at reducing the burden of hypertension-related cardiovascular diseases in the clinical practice. Among various regulatory and contra-regulatory systems involved in the pathogenesis of cardiovascular and renal diseases, renin-angiotensin system (RAS) plays a major role. However, despite the identification of renin and the availability of various assays for measuring its plasma activity, the specific pathophysiological role of RAS has not yet fully characterized. In the last years, however, several notions on the RAS have been improved by the results of large, randomized clinical trials, performed in different clinical settings and in different populations treated with RAS inhibiting drugs, including angiotensin converting enzyme (ACE) inhibitors and antagonists of the AT1 receptor for angiotensin II (ARBs). These findings suggest that the RAS should be considered to have a central role in the pathogenesis of different cardiovascular diseases, for both therapeutic and preventive purposes, without having to measure its level of activation in each patient. The present document will discuss the most critical issues of the pathogenesis of different cardiovascular diseases with a specific focus on RAS blocking agents, including ACE inhibitors and ARBs, in the light of the most recent evidence supporting the use of these drugs in the clinical management of hypertension and hypertension-related cardiovascular diseases.

  9. 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

  10. Angiotensin I-converting enzyme inhibitor peptides derived from the endostatin-containing NC1 fragment of human collagen XVIII.

    PubMed

    Farias, Shirley L; Sabatini, Regiane A; Sampaio, Tatiana C; Hirata, Izaura Y; Cezari, Maria Helena S; Juliano, Maria A; Sturrock, Edward D; Carmona, Adriana K; Juliano, Luiz

    2006-05-01

    Extracellular matrix and soluble plasma proteins generate peptides that regulate biological activities such as cell growth, differentiation and migration. Bradykinin, a peptide released from kininogen by kallikreins, stimulates vasodilatation and endothelial cell proliferation. Various classes of substances can potentiate these biological actions of bradykinin. Among them, the best studied are bradykinin potentiating peptides (BPPs) derived from snake venom, which can also strongly inhibit angiotensin I-converting enzyme (ACE) activity. We identified and synthesized sequences resembling BPPs in the vicinity of potential proteolytic cleavage sites in the collagen XVIII molecule, close to endostatin. These peptides were screened as inhibitors of human recombinant wild-type ACE containing two intact functional domains; two full-length ACE mutants containing only a functional C- or N-domain catalytic site; and human testicular ACE, a natural form of the enzyme that only contains the C-domain. The BPP-like peptides inhibited ACE in the micromolar range and interacted preferentially with the C-domain. The proteolytic activity involved in the release of BPP-like peptides was studied in human serum and human umbilical-vein endothelial cells. The presence of enzymes able to release these peptides in blood led us to speculate on a physiological mechanism for the control of ACE activities.

  11. An Improved High Yield Total Synthesis and Cytotoxicity Study of the Marine Alkaloid Neoamphimedine: An ATP-Competitive Inhibitor of Topoisomerase IIα and Potent Anticancer Agent

    PubMed Central

    Li, Linfeng; Abraham, Adedoyin D.; Zhou, Qiong; Ali, Hadi; O’Brien, Jeremy V.; Hamill, Brayden D.; Arcaroli, John J.; Messersmith, Wells A.; LaBarbera, Daniel V.

    2014-01-01

    Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase IIα. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been access to sufficient amounts of material for biological testing. Although there are two reported syntheses of neo, both require 12 steps with low overall yields (≤6%). In this article, we report an improved total synthesis of neo achieved in 10 steps with a 25% overall yield. In addition, we report an expanded cytotoxicity study using a panel of human cancer cell lines, including: breast, colorectal, lung, and leukemia. Neo displays potent cytotoxicity (nM IC50 values) in all, with significant potency against colorectal cancer (lowest IC50 = 6 nM). We show that neo is cytotoxic not cytostatic, and that neo exerts cytotoxicity by inducing G2-M cell cycle arrest and apoptosis. PMID:25244109

  12. Improvement of the Rett Syndrome Phenotype in a Mecp2 Mouse Model Upon Treatment with Levodopa and a Dopa-Decarboxylase Inhibitor

    PubMed Central

    Szczesna, Karolina; de la Caridad, Olga; Petazzi, Paolo; Soler, Marta; Roa, Laura; Saez, Mauricio A; Fourcade, Stéphane; Pujol, Aurora; Artuch-Iriberri, Rafael; Molero-Luis, Marta; Vidal, August; Huertas, Dori; Esteller, Manel

    2014-01-01

    Rett Syndrome is a neurodevelopmental autism spectrum disorder caused by mutations in the gene coding for methyl CpG-binding protein (MeCP2). The disease is characterized by abnormal motor, respiratory, cognitive impairment, and autistic-like behaviors. No effective treatment of the disorder is available. Mecp2 knockout mice have a range of physiological and neurological abnormalities that resemble the human syndrome and can be used as a model to interrogate new therapies. Herein, we show that the combined administration of Levodopa and a Dopa-decarboxylase inhibitor in RTT mouse models is well tolerated, diminishes RTT-associated symptoms, and increases life span. The amelioration of RTT symptomatology is particularly significant in those features controlled by the dopaminergic pathway in the nigrostratium, such as mobility, tremor, and breathing. Most important, the improvement of the RTT phenotype upon use of the combined treatment is reflected at the cellular level by the development of neuronal dendritic growth. However, much work is required to extend the duration of the benefit of the described preclinical treatment. PMID:24917201

  13. ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension.

    PubMed

    Mendoza-Torres, Evelyn; Oyarzún, Alejandra; Mondaca-Ruff, David; Azocar, Andrés; Castro, Pablo F; Jalil, Jorge E; Chiong, Mario; Lavandero, Sergio; Ocaranza, María Paz

    2015-08-01

    The renin-angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE-Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling.

  14. ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension.

    PubMed

    Mendoza-Torres, Evelyn; Oyarzún, Alejandra; Mondaca-Ruff, David; Azocar, Andrés; Castro, Pablo F; Jalil, Jorge E; Chiong, Mario; Lavandero, Sergio; Ocaranza, María Paz

    2015-08-01

    The renin-angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE-Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling. PMID:26275770

  15. Early genes induction in spontaneously hypertensive rats left ventricle with angiotensin-converting enzyme inhibitors but not hydralazine

    SciTech Connect

    Susic, D.; Aristizabal, D.J.; Prakash, O.; Nunez, E.; Frohlich, E.D.

    1995-12-01

    Spontaneously hypertensive rats were given an angiotensin-converting enzyme (ACE) inhibitor (benazepril or quinapril) or hydralazine and were left for up to 6 hr. To examine whether administration of antihypertensive agents affects expression of immediate early genes in left ventricular myocardium, groups of rats were sacrificed at 1, 3, and 6 hr after dosing; total RNA was extracted from left ventricular tissue and analyzed by blot hybridization technique using labeled probes for c-myc, c-fos, and GAPDH mRNA. All three antihypertensive agents reduced pressure similarly, and treatment with the two ACE inhibitors increased c-fos and c-myc mRNA expression in left ventriculum. By contrast, hydralazine did not increase steady-state mRNA expression of either proto-oncogene. Thus, in parallel with the pressure fall, acute administration of the ACE inhibitors induced expression of c-fos and c-myc mRNAs in the left ventricle. Since the equidepressor dose of hyralazine did not affect expression of these proto-oncogenes, this effect of ACE inhibitors is independent of their hemodynamic action. 27 refs., 1 fig., 2 tabs.

  16. Helping Students Process a Simulated Death Experience: Integration of an NLN ACE.S Evolving Case Study and the ELNEC Curriculum.

    PubMed

    Kopka, Judith A; Aschenbrenner, Ann P; Reynolds, Mary B

    2016-01-01

    The nursing literature supports the need for end-of-life (EOL) education, but the ability to provide quality clinical experience in this area is limited by the availability of patients and nursing instructors' and preceptors' comfort and expertise in teaching EOL care. Clinical simulation allows faculty to provide the same quality EOL experience to all students. This article discusses an effective teaching strategy integrating End-of-Life Nursing Education Consortium core content with National League for Nursing ACE.S unfolding case studies, clinical simulation, and social media. PMID:27405204

  17. GPS Antenna Characterization Experiment (ACE): Receiver Design and Initial Results

    NASA Technical Reports Server (NTRS)

    Martzen, Phillip; Highsmith, Dolan E.; Valdez, Jennifer E.; Parker, Joel J. K.; Moreau, Michael C.

    2015-01-01

    The GPS Antenna Characterization Experiment (ACE) is a research collaboration between Aerospace and NASA Goddard to characterize the gain patterns of the GPS L1 transmit antennas. High altitude GPS observations are collected at a ground station through a transponder-based or "bent-pipe" architecture where the GPS L1 RF spectrum is received at a platform in geosynchronous orbit and relayed to the ground for processing. The focus of this paper is the unique receiver algorithm design and implementation. The high-sensitivity GPS C/A-code receiver uses high fidelity code and carrier estimates and externally supplied GPS message bit data in a batch algorithm with settings for a 0 dB-Hz threshold. The resulting carrier-to-noise measurements are used in a GPS L1 transmit antenna pattern reconstruction. This paper shows initial transmit gain patterns averaged over each block of GPS satellites, including comparisons to available pre-flight gain measurements from the GPS vehicle contractors. These results provide never-before-seen assessments of the full, in-flight transmit gain patterns.

  18. Operation Heli-STAR - Atlanta Communications Experiment (ACE). Volume 9

    NASA Technical Reports Server (NTRS)

    1996-01-01

    Operation Heli-STAR (Helicopter Short-Haul Transportation and Aviation Research) was established and operated in Atlanta, Georgia, during the period of the 1996 Centennial Olympic Games. Heli-STAR had three major thrusts: (1) the establishment and operation of a helicopter-based cargo transportation system, (2) the management of low-altitude air traffic in the airspace of an urban area, and (3) the collection and analysis of research and development data associated with items 1 and 2. Heli-STAR was a cooperative industry/government program that included parcel package shippers and couriers in the Atlanta area, the helicopter industry, aviation electronics manufacturers, the Federal Aviation Administration (FAA), the National Aeronautics and Space Administration (NASA), and support contractors. Several detailed reports have been produced as a result of Operation Heli-STAR. These include four reports on acoustic measurements and associated analyses, and reports on the Heli-STAR tracking data including the data processing and retrieval system, the Heli-STAR cargo simulation, and the community response system. In addition, NASA's Advanced General Aviation Transport Experiments (AGATE) program has produced a report describing the Atlanta Communications Experiment (ACE) which produced the avionics and ground equipment using automatic dependent surveillance-broadcast (ADS-B) technology. This latter report is restricted to organizations belonging to NASA's AGATE industry consortium. A complete list of these reports is shown on the following page.

  19. ACE Observatory Control System - 16 years of remote intercontinental observing

    NASA Astrophysics Data System (ADS)

    Mack, Peter

    2011-03-01

    The ACE Observatory Control System has been used for remote control since 1995. The system was designed for use at isolated observatories with no-one present on the mountain-top. The software provides complete diagnostic feedback to the astronomer and is supplemented by live audio-visual. Accessories include environmental sensors (weather station, all-sky camera, constellation cameras), automated mirror covers and remote power control. This gives the astronomer the same experience as being present at the observatory. The system is installed on 30 telescopes and many of them are used for routine nightly intercontinental observations, such as Taejeon (S. Korea) to Mt. Lemmon (Arizona) and southeast USA to KPNO and CTIO. The system has fully integrated autoguider acquisition and science camera control. We describe the building blocks of the system and the accessories including automated mirror covers, weather station, all sky camera, remote power control and dome control. Future plans are presented for a fully autonomous platform-independent scheduler and robot for use on multiple telescopes.

  20. Technical manual for the Augmented Computer Exercise for Inspection Training (ACE-IT) software

    SciTech Connect

    Dobranich, P.R.; Horak, K.E.; Hagan, D.; Evanko, D.; Nelson, J.; Ryder, C.; Hedlund, D.

    1997-09-01

    The on-site inspection provisions in many current and proposed arms control agreements require extensive preparation and training on the part of both the Inspection Teams (inspectors) and Inspected Parties (host). Current training techniques include table-top inspections and practice inspections. The Augmented Computer Exercise for Inspection Training (ACE-IT), an interactive computer training tool, increases the utility of table-top inspections. ACE-IT has been designed to provide training for challenge inspections under the Chemical Weapons Convention (CWC); however, this training tool can be modified for other inspection regimes. Although ACE-IT provides training from notification of an inspection through post-inspection activities, the primary emphasis of ACE-IT is in the inspection itself--particularly with the concept of managed access. ACE-IT also demonstrates how inspection provisions impact compliance determination and the protection of sensitive information. This Technical Manual describes many of the technical aspects of the ACE-IT training software.

  1. Hamsters vaccinated with Ace-mep-7 DNA vaccine produced protective immunity against Ancylostoma ceylanicum infection.

    PubMed

    Wiśniewski, Marcin; Jaros, Sławomir; Bąska, Piotr; Cappello, Michael; Długosz, Ewa; Wędrychowicz, Halina

    2016-04-01

    Hookworms are intestinal nematodes that infect up to 740 million people, mostly in tropical and subtropical regions. Adult worms suck blood from damaged vessels in the gut mucosa, digesting hemoglobin using aspartic-, cysteine- and metalloproteases. Targeting aspartic hemoglobinases using drugs or vaccines is therefore a promising approach to ancylostomiasis control. Based on homology to metalloproteases from other hookworm species, we cloned the Ancylostoma ceylanicum metalloprotease 7 cDNA (Ace-mep-7). The corresponding Ace-MEP-7 protein has a predicted molecular mass of 98.8 kDa. The homology to metallopeptidases from other hookworm species and its predicted transmembrane region support the hypothesis that Ace-MEP-7 may be involved in hemoglobin digestion in the hookworm gastrointestinal tract, especially that our analyses show expression of Ace-mep-7 in the adult stage of the parasite. Immunization of Syrian golden hamsters with Ace-mep-7 cDNA resulted in 50% (p < 0.01) intestinal worm burden reduction. Additionally 78% (p < 0.05) egg count reduction in both sexes was observed. These results suggest that immunization with Ace-mep-7 may contribute to reduction in egg count released into the environment during the A. ceylanicum infection. PMID:26795262

  2. Exercise manual for the Augmented Computer Exercise for Inspection Training (ACE-IT) software

    SciTech Connect

    Dobranich, P.R.; Widney, T.W.; Goolsby, P.T.; Nelson, J.D.; Evanko, D.A.

    1997-09-01

    The on-site inspection provisions in many current and proposed arms control agreements require extensive preparation and training on the part of both the Inspected Party and the Inspection Team. Current training techniques include table-top inspections and practice inspections. The Augmented Computer Exercise for Inspection Training (ACE-IT), an interactive computer training tool, increases the utility of table-top inspections. ACE-IT has been designed to provide training for a hypothetical challenge inspection under the Chemical Weapons Convention (CWC); however, this training tool can be modified for other inspection regimes. Although ACE-IT provides training from notification of an inspection through post-inspection activities, the primary emphasis of ACE-IT is in the inspection itself--particularly with the concept of managed access. ACE-IT also demonstrates how inspection provisions impact compliance determination and the protection of sensitive information. The Exercise Manual supplements the ACE-IT software by providing general information on on-site inspections and detailed information for the CWC challenge inspection exercise. The detailed information includes the pre-inspection briefing, maps, list of sensitive items, medical records, and shipping records.

  3. The Atmospheric Chemistry Experiment (ace): CO, CH_4 and N_2O Isotopologues

    NASA Astrophysics Data System (ADS)

    Bernath, Peter F.; Buzan, Eric M.; Beale, Christopher A.; Yousefi, Mahdi; Boone, Chris

    2016-06-01

    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 orbit 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 in the 750--4400 cm-1 region, which provides the vertical distribution of trace gases, and the meteorological variables of temperature and pressure. Aerosols and clouds are being monitored through the extinction of solar radiation using two filtered imagers as well as by their infrared spectra. Although now in its thirteenth year, the ACE-FTS is still operating nominally. A short introduction and overview of the ACE mission will be presented (see http://www.ace.uwaterloo.ca for more information). This talk will focus on ACE observations of the CO, CH_4 and N_2O isotopologues, and comparisons with chemical transport models.

  4. Targeting the ACE2 and Apelin Pathways Are Novel Therapies for Heart Failure: Opportunities and Challenges

    PubMed Central

    Kazemi-Bajestani, Seyyed M. R.; Patel, Vaibhav B.; Wang, Wang; Oudit, Gavin Y.

    2012-01-01

    Angiotensin-converting enzyme 2 (ACE2)/Ang II/Ang 1–7 and the apelin/APJ are two important peptide systems which exert diverse effects on the cardiovascular system. ACE2 is a key negative regulator of the renin-angiotensin system (RAS) where it metabolizes angiotensin (Ang) II into Ang 1–7, an endogenous antagonist of Ang II. Both the prolonged activation of RAS and the loss of ACE2 can be detrimental as they lead to functional deterioration of the heart and progression of cardiac, renal, and vascular diseases. Recombinant human ACE2 in an animal model of ACE2 knockout mice lowers Ang II. These interactions neutralize the pressor and subpressor pathologic effects of Ang II by producing Ang 1–7 levels in vivo, that might be cardiovascular protective. ACE2 hydrolyzes apelin to Ang II and, therefore, is responsible for the degradation of both peptides. Apelin has emerged as a promising peptide biomarker of heart failure. The serum level of apelin in cardiovascular diseases tends to be decreased. Apelin is recognized as an imperative controller of systemic blood pressure and myocardium contractility. Dysregulation of the apelin/APJ system may be involved in the predisposition to cardiovascular diseases, and enhancing apelin action may have important therapeutic effects. PMID:22655211

  5. SB203580, a p38 Inhibitor, Improved Cardiac Function but Worsened Lung Injury and Survival During Escherichia coli Pneumonia in Mice

    PubMed Central

    Su, Junwu; Cui, Xizhong; Li, Yan; Mani, Haresh; Ferreyra, Gabriela A.; Danner, Robert L.; Hsu, Lewis L.; Fitz, Yvonne; Eichacker, Peter Q.

    2012-01-01

    Background Supporting its therapeutic application in sepsis, p38 mitogen-activated protein kinase (MAPK) inhibition decreases cardiopulmonary injury and lethality with lipopolysaccharide challenge. However, only one preclinical study has reported the survival effects of a p38 inhibitor (SB203580, 100 mg/kg) during infection. We therefore tested SB203580 in mice (n = 763) challenged with intratracheal Escherichia coli and treated with antibiotics and fluids. Methods and Results Compared with placebo, high dose SB203580 (100 mg/kg) pretreatment increased the hazards ratio of death (95% confidence interval) (3.6 [2.1, 6.1], p < 0.0001). Decreasing doses (10, 1, or 0.1 mg/kg) went from being harmful to having no significant effect (p < 0.0001 for the effect of decreasing dose). At 48 hours, but not 24 hours after E. coli, high and low dose SB203580 pretreatment decreased cardiac phosphorylated p38 MAPK levels and improved cardiac output either (p ≤ 0.07). Low dose SB203580 did not alter lung neutrophils significantly but increased lung injury at 48 hours (p = 0.05). High dose decreased lung neutrophils and injury at 24 hours (p = 0.09 and 0.01, respectively) but then increased them at 48 hours (both p ≤ 0.01). Lung injury was greater with high versus low dose at 48 hours (p = 0.002). Conclusion Thus, SB203580 had divergent effects on cardiac and lung function in E. coli challenged mice. Furthermore, high dose worsened survival and low dose did not improve it. Altogether, these findings suggest that clearly defining the risks and benefits of p38 MAPK inhibition is important before such treatment is applied in patients with or at risk of serious infection. PMID:20068480

  6. Design, synthesis, and analysis of a polyethelene glycol-modified (PEGylated) small molecule inhibitor of integrin {alpha}4{beta}1 with improved pharmaceutical properties.

    PubMed

    Pepinsky, R B; Lee, W-C; Cornebise, M; Gill, A; Wortham, K; Chen, L L; Leone, D R; Giza, K; Dolinski, B M; Perper, S; Nickerson-Nutter, C; Lepage, D; Chakraborty, A; Whalley, E T; Petter, R C; Adams, S P; Lobb, R R; Scott, D M

    2005-02-01

    Integrin alpha4beta1 plays an important role in inflammatory processes by regulating the migration of leukocytes into inflamed tissues. Previously, we identified BIO5192 [2(S)-{[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino}-4-[4-methyl-2(S)-(methyl-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-pentanoylamino]-butyric acid], a highly selective and potent (K(D) of 9 pM) small molecule inhibitor of alpha4beta1. Although BIO5192 is efficacious in various animal models of inflammatory disease, high doses and daily treatment of the compound are needed to achieve a therapeutic effect because of its relatively short serum half-life. To address this issue, polyethylene glycol modification (PEGylation) was used as an approach to improve systemic exposure. BIO5192 was PEGylated by a targeted approach in which derivatizable amino groups were incorporated into the molecule. Two sites were identified that could be modified, and from these, five PEGylated compounds were synthesized and characterized. One compound, 2a-PEG (K(D) of 19 pM), was selected for in vivo studies. The pharmacokinetic and pharmacodynamic properties of 2a-PEG were dramatically improved relative to the unmodified compound. The PEGylated compound was efficacious in a rat model of experimental autoimmune encephalomyelitis at a 30-fold lower molar dose than the parent compound and required only a once-a-week dosing regimen compared with a daily treatment for BIO5192. Compound 2a-PEG was highly selective for alpha4beta1. These studies demonstrate the feasibility of PEGylation of alpha4beta1-targeted small molecules with retention of activity in vitro and in vivo. 2a-PEG, and related compounds, will be valuable reagents for assessing alpha4beta1 biology and may provide a new therapeutic approach to treatment of human inflammatory diseases.

  7. The Angiotensin Converting Enzyme Inhibitor Lisinopril Improves Muscle Histopathology but not Contractile Function in a Mouse Model of Duchenne Muscular Dystrophy

    PubMed Central

    Lowe, Jeovanna; Wodarcyk, Andrew J.; Floyd, Kyle T.; Rastogi, Neha; Schultz, Eric J.; Swager, Sarah A.; Chadwick, Jessica A.; Tran, Tam; Raman, Subha V.

    2016-01-01

    Background Angiotensin converting enzyme inhibitors (ACEi) are the current standard of care treatment for cardiac dysfunction in Duchenne muscular dystrophy patients. We previously showed treatment with an ACEi plus mineralocorticoid receptor (MR) antagonist improves limb and respiratory skeletal muscles, in addition to cardiac muscles, in a dystrophic mouse model at 20 weeks-of-age. Objective To determine whether previously observed preclinical benefits of an ACEi plus MR antagonist on dystrophic skeletal muscles can be reproduced by increasing ACEi dosage alone. We also compared functional and histological outcome measures at 10 and 20 weeks-of-age. Methods Dystrophin deficient utrophin haplo-insufficient (utrn+/−; mdx) “het” mice were treated with 10, 20, or 50 mg/kg × day of the ACEi lisinopril from 4 to 10 weeks-of-age via water bottles and compared with C57BL/10 wild-type control mice and untreated hets. Data from 10 week-old het mice were also compared to data collected from an untreated het group at 20 weeks-old. In vivo cardiac and grip strength measurements, in vitro diaphragm and extensor digitorum longus muscle force measurements, and histopathological analyses were performed. One-way ANOVA followed by Dunnett post hoc comparison was used to determine significance. Results ACEi treatment reduced skeletal muscle damage but had no significant effect on muscle force. Body weight, heart rate, grip strength and blood pressure were unaffected by treatment. Limb muscle histopathology was more informative at 10 than 20 weeks-of-age. Conclusions These results suggest increased ACEi dosage alone cannot improve all dystrophic parameters. Further optimization of MR antagonists in 20 week-old mice is warranted. PMID:27110493

  8. Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage

    PubMed Central

    Nowicka-Sans, Beata; Protack, Tricia; Lin, Zeyu; Li, Zhufang; Zhang, Sharon; Sun, Yongnian; Samanta, Himadri; Terry, Brian; Liu, Zheng; Chen, Yan; Sin, Ny; Sit, Sing-Yuen; Swidorski, Jacob J.; Chen, Jie; Venables, Brian L.; Healy, Matthew; Meanwell, Nicholas A.; Cockett, Mark; Hanumegowda, Umesh; Regueiro-Ren, Alicia; Krystal, Mark

    2016-01-01

    BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC50], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library (n = 87) of gag/pr recombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC50 of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC50s similar to those for the wild-type virus. A 5.4-fold reduction in EC50 occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to an in vitro measurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally, in vitro combination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potent in vitro anti-HIV-1

  9. Resolution of refractory hypotension and anuria in a premature newborn with loss-of-function of ACE.

    PubMed

    Richer, Julie; Daoud, Hussein; Geier, Pavel; Jarinova, Olga; Carson, Nancy; Feberova, Jana; Ben Fadel, Nadya; Fadfel, Nadya Ben; Unrau, Jennifer; Bareke, Eric; Khatchadourian, Karine; Bulman, Dennis E; Majewski, Jacek; Boycott, Kym M; Dyment, David A

    2015-07-01

    We present the investigation and management of a premature, hypotensive neonate born after a pregnancy complicated by anhydramnios to highlight the impact of early and informed management for rare kidney disease. Vasopressin was used to successfully treat refractory hypotension and anuria in the neonate born at 27 weeks of gestation. Next generation sequencing of a targeted panel of genes was then performed in the neonate and parents. Subsequently, two compound heterozygous deletions leading to frameshift mutations were identified in the angiotensin 1-converting enzyme gene ACE; exon 5:c.820_821delAG (p.Arg274Glyfs*117) and exon24: c.3521delG (p.Gly1174Alafs*12), consistent with a diagnosis of renal tubular dysgenesis. In light of the molecular diagnosis, identification, and treatment of associated low aldosterone level resulted in further improvement in renal function and only mild residual chronic renal failure is present at 14 months of age. Truncating alterations in ACE most often result in fetal demise during gestation or in the first days of life and typically as a result of the Potter sequence. The premature delivery, and serendipitous early treatment with vasopressin, and then later fludrocortisone, resulted in an optimal outcome in an otherwise lethal condition.

  10. [Aural Stimulation with Capsaicin Ointment Improved the Swallowing Function in Patients with Dysphagia: Evaluation by the SMRC Scale].

    PubMed

    Kondo, Eiji; Jinnouchi, Osamu; Ohnishi, Hiroki; Kawata, Ikuji; Takeda, Noriaki

    2015-11-01

    Cough and swallowing reflexes are important airway-protective mechanisms against aspiration. Angiotensin-converting enzyme (ACE) inhibitors, one of the side effects of which is cough, have been reported to reduce the incidence of aspiration pneumonia in hypertensive patients with stroke. ACE inhibitors have also been reported to improve the swallowing function in post-stroke patients. On the other hand, stimulation of the Arnold nerve, the auricular branch of the vagus, triggers the cough reflex (Arnold's ear-cough reflex). Capsaicin, an agonist of Transient Receptor Potential Vanilloid 1 (TRPV1), has been shown to activate the peripheral sensory C-fibers. Stimulation of the sensory branches of the vagus in the laryngotracheal mucosa with capsaicin induces the cough reflex and has been reported to improve the swallowing function in patients with dysphagia. In our previous study, we showed that aural stimulation of the Arnold nerve with 0.025% capsaicin ointment improved the swallowing function, as evaluated by the endoscopic swallowing score, in 26 patients with dysphagia. In the present study, the video images of swallowing recorded in the previous study were re-evaluated using the SMRC scale by an independent otolaryngologist who was blinded to the information about the patients and the endoscopic swallowing score. The SMRC scale is used to evaluate four aspects of the swallowing function: 1) Sensory: the initiation of the swallowing reflex as assessed by the white-out timing; 2) Motion: the ability to hold blue-dyed water in the oral cavity and induce laryngeal elevation; 3) Reflex: glottal closure and the cough reflex induced by touching the epiglottis or arytenoid with the endoscope; 4) Clearance: pharyngeal clearance of the blue-dyed water after swallowing. Accordingly, we demonstrated that a single application of capsaicin ointment to the external auditory canal of patients with dysphagia significantly improved the R, but not the S, M or C scores, and this

  11. Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitors.

    PubMed

    Cho, Yoonsang; Vermeire, Jon J; Merkel, Jane S; Leng, Lin; Du, Xin; Bucala, Richard; Cappello, Michael; Lolis, Elias

    2011-09-23

    The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new pharmacophores. Hookworms are blood-feeding, intestinal nematode parasites that infect up to 600 million people worldwide. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (rAceMIF) provided partial protection from disease, thus establishing a "proof-of-concept" for targeting AceMIF to prevent or treat infection. A high-throughput screen (HTS) against rAceMIF identified six AceMIF-specific inhibitors. A nonsteroidal anti-inflammatory drug (NSAID), sodium meclofenamate, could be tested in an animal model to assess the therapeutic efficacy in treating hookworm disease. Furosemide, an FDA-approved diuretic, exhibited submicromolar inhibition of rAceMIF tautomerase activity. Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity.

  12. Drug Repositioning and Pharmacophore Identification in the Discovery of Hookworm MIF Inhibitors

    SciTech Connect

    Y Cho; J Vermeire; J Merkel; L Leng; X Du; R Bucala; M Cappello; E Lolis

    2011-12-31

    The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new pharmacophores. Hookworms are blood-feeding, intestinal nematode parasites that infect up to 600 million people worldwide. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (rAceMIF) provided partial protection from disease, thus establishing a 'proof-of-concept' for targeting AceMIF to prevent or treat infection. A high-throughput screen (HTS) against rAceMIF identified six AceMIF-specific inhibitors. A nonsteroidal anti-inflammatory drug (NSAID), sodium meclofenamate, could be tested in an animal model to assess the therapeutic efficacy in treating hookworm disease. Furosemide, an FDA-approved diuretic, exhibited submicromolar inhibition of rAceMIF tautomerase activity. Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity.

  13. Binding of the angiotensin-converting enzyme inhibitor, RACX-65, to trout gills

    SciTech Connect

    Olson, K.R.; Evan, A.P.; Ryan, J.W.

    1986-03-01

    Galardy et al. have shown that in rainbow trout, Salmo gairdneri, nearly all of the angiotensin converting enzyme (ACE) activity is found in the gills. In the present study, binding and localization of the angiotensin-converting enzyme inhibitor N-(1(S)-carboxanili-dopropyl)-L-Ala-L-Pro (RAC-X-65) to trout gill was examined in homogenized gill tissues, an isolated perfused gill and by autoradiography. RAC-X-65 inhibited gill ACE as effectively as it inhibits human ACE; the apparent Ki for gill homogenates fell over 15 min from 3 x 10/sup -9/M to 5.5 x 10/sup -10/M. In the arterioarterial pathway (supplying the systematic circulation) of the perfused gill, /sup 3/H-RAC-X-65 extraction (compared to the inert volume maker, /sup 14/C-sucrose) decreased from 72.2 +/- 4.5% after 6 min perfusion to 54.7 +/- 6.8% (14 min) and 38.4 +/- 9.0% after 20 min (N = 6). By 40 min, extraction was less then 10% indicating saturation of ACE binding sites. Relatively little extraction was observed in the gill arteriovenous pathway. Autoradiography of gills perfused with /sup 3/H-RAC-X-65 demonstrated that the pillar cells are the major site of /sup 3/H accumulation and, therefore, probably contain most of the ACE activity.

  14. Drug Repositioning and Pharmacophore Identification in the Discovery of Hookworm MIF Inhibitors

    PubMed Central

    Cho, Yoonsang; Vermeire, Jon J.; Merkel, Jane S.; Leng, Lin; Du, Xin; Bucala, Richard; Cappello, Michael; Lolis, Elias

    2011-01-01

    SUMMARY The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new pharmacophores. Hookworms are blood-feeding, intestinal nematode parasites that infect up to 600 million people worldwide. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (rAceMIF) provided partial protection from disease, thus establishing a “proof-of-concept” for targeting AceMIF to prevent or treat infection. A high-throughput screen (HTS) against rAceMIF identified six AceMIF-specific inhibitors. A nonsteroidal anti-inflammatory drug (NSAID), sodium meclofenamate, could be tested in an animal model to assess the therapeutic efficacy in treating hookworm disease. Furosemide, an FDA-approved diuretic, exhibited submicromolar inhibition of rAceMIF tautomerase activity. Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity. PMID:21944748

  15. Assessment of water vapor isotopologue measurements by ACE-FTS and Odin-SMR

    NASA Astrophysics Data System (ADS)

    Bauer, Ralf; Sheese, Patrick; Walker, Kaley; Urban, Joachim; Murtagh, Donal; Boone, Chris; Bernath, Peter; Manney, Gloria

    2015-04-01

    Knowing the isotopic composition of trace gases can improve our understanding of processes in the Earth's atmosphere causing isotopic fractionation. In many studies, isotopologue (molecules of identical chemical but different isotopic composition) amounts are primarily discussed as δ values, which are defined relative to a standard, e.g.: ( ) 18 (VM RH182 O /VM RH162 O ) δ O (o) = (V-M-R-18-/V-M-R-16-)VSMOW-- 1 * 1000 H2 O H2 O with VSMOW as Vienna Standard Mean Ocean Water. This study targets the water vapor isotopologues H218O and H217O in the stratosphere and lower mesosphere using δ18O and δ17O for the comparison. Over the past decades, H218O and H217O profiles have been measured with balloon-borne (e.g. FIRS-2, Mk IV) and space-borne (e.g. ATMOS/SL3) instruments. The satellite instruments ACE-FTS (Atmospheric Chemistry Experiment - Fourier Transform Spectrometer) on the Canadian satellite SCISAT and SMR (Sub-Millimetre Radiometer) on the Swedish satellite Odin provide a significantly larger number of individual profiles with global coverage. Both instruments are still operational and provide data products for more than 10 years. Assessing their data quality is of key importance before conclusions can be drawn from these results. ACE-FTS on SCISAT is an infrared Fourier Transform Spectrometer with a high spectral resolution of 0.02 cm-1 and a spectral range from 750 to 4400 cm-1. It measures using solar occultation viewing geometry. SCISAT is in a high inclination orbit at an altitude of 650 km. It was launched in August 2003 and has been performing routine measurements since February 2004. SMR on Odin measures millimetre wave emissions from the atmosphere with a 1.1 m telescope in the 486 to 581 GHz range with four tunable radiometers. Odin was launched in February 2001 into a quasi-polar sun-synchronous orbit at about 600 km altitude. Spectral regions for the target trace gases are selected for SMR using different measurement modes and thus not all

  16. Reducing Adverse Childhood Experiences (ACE) by Building Community Capacity: A Summary of Washington Family Policy Council Research Findings

    PubMed Central

    Hall, Judy; Porter, Laura; Longhi, Dario; Becker-Green, Jody; Dreyfus, Susan

    2012-01-01

    Community capacity for organization and collaboration has been shown to be a powerful tool for improving the health and well-being of communities. Since 1994 the Washington State Family Policy Council has supported the development of community capacity in 42 community public health and safety networks. Community networks bring local communities together to restructure natural supports and local resources to meet the needs of families and children, and increase cross-system coordination and flexible funding streams to improve local services and policy. In this study, researchers sought to demonstrate the strong impact of the community networks’ capacity to interrupt health and social problems. Findings suggest that community networks reduce health and safety problems for the entire community population. Further, community networks with high community capacity reduced adverse childhood experiences (ACE) in young adults ages 18–34. PMID:22970785

  17. Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis

    SciTech Connect

    Villard, E.; Soubrier, F.; Tiret, L.; Rakotovao, R. Cambien, F.; Visvikis, S.

    1996-06-01

    Plasma angiotensin I-converting enzyme (ACE) levels are highly genetically determined. A previous segregation-linkage analysis suggested the existence of a functional mutation located within or close to the ACE locus, in almost complete linkage disequilibrium (LD) with the ACE insertion/deletion (I/D) polymorphism and accounting for half the ACE variance. In order to identify the functional variant at the molecular level, we compared ACE gene sequences between four subjects selected for having contrasted ACE levels and I/D genotypes. We identified 10 new polymorphisms, among which 8 were genotyped in 95 healthy nuclear families, in addition to the I/D polymorphism. These polymorphisms could be divided into two groups: five polymorphisms in the 5{prime} region and three in the coding sequence and the 3{prime} UTR. Within each group, polymorphisms were in nearly complete association, whereas polymorphisms from the two groups were in strong negative LD. After adjustment for the I/D polymorphism, all polymorphisms of the 5{prime} group remained significantly associated with ACE levels, which suggests the existence of two quantitative trait loci (QTL) acting additively on ACE levels. Segregation-linkage analyses including one or two ACE-linked QTLs in LD with two ACE markers were performed to test this hypothesis. The two QTLs and the two markers were assumed to be in complete LD. Results supported the existence of two ACE-linked QTLs, which would explain 38% and 49% of the ACE variance in parents and offspring, respectively. One of these QTLs might be the I/D polymorphism itself or the newly characterized 4656(CT){sub 2/3} polymorphism. The second QTL would have a frequency of {approximately}.20, which is incompatible with any of the yet-identified polymorphisms. More extensive sequencing and extended analyses in larger samples and in other populations will be necessary to characterize definitely the functional variants. 30 refs., 1 fig., 6 tabs.

  18. Rapid screening and identification of active ingredients in licorice extract interacting with V3 loop region of HIV-1 gp120 using ACE and CE-MS.

    PubMed

    Li, Zhongjie; Zhao, Yiran; Lin, Weiwei; Ye, Min; Ling, Xiaomei

    2015-01-01

    The binding of envelope protein gp120 to glycosphingolipids is very important during the human immunodeficiency virus entering into the host cell. This step occurs in the V3 loop region in particularly. The conserved core sequence of V3 loop in gp120 was named R15K. Anti-HIV drug targeting to R15K would avoid the drug-resistance caused by HIV-1 genetic diversity. Here, for the first time, affinity capillary electrophoresis (ACE) and capillary electrophoresis-mass spectrometry (CE-MS) were used for establishing a simple, rapid and effective method of screening the licorice extract for biological activity (anti-HIV), which avoided the complicated isolation and purification process. R15K, 3'-sialyllactose (the positive control), and d-galactose (the negative control) were used for the development and validation of ACE method. After the interaction between licorice extract and R15K was confirmed by ACE, the relative active ingredients were isolated by SPE and their structures were determined by CE-ESI-MS online. In this research, two mixtures from licorice extract were found to be active. Furthermore, glycyrrhizin and licorice saponin G2 were verified as the main ingredients that significantly interacted with R15K via CE-MS and LC-MS. The results of quantitative assays showed that the active mixture contained glycyrrhizin of 74.23% and licorice saponin G2 of 9.52%. Calculated by Scatchard analysis method, glycyrrhizin/R15K complex had the highest binding constant (1.69 ± 0.08) × 10(7)L/mol among 27 compounds isolated from licorice extract. The anti-HIV activity of glycyrrhizin was further confirmed by bioactive experiment of cellular level. This strategy might provide a high throughput screening and identifying platform for seeking HIV-1 inhibitors in natural products.

  19. Angiotensin converting enzyme inhibitors mitigate collagen synthesis induced by a single dose of radiation to the whole thorax.

    PubMed

    Kma, Lakhan; Gao, Feng; Fish, Brian L; Moulder, John E; Jacobs, Elizabeth R; Medhora, Meetha

    2012-01-01

    Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m(2)/day) or enalapril (19-28 mg/m(2)/day), but not fosinopril (19-28 mg/m(2)/day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation. PMID:22302041

  20. ACE3P Computations of Wakefield Coupling in the CLIC Two-Beam Accelerator

    SciTech Connect

    Candel, Arno; Li, Z.; Ng, C.; Rawat, V.; Schussman, G.; Ko, K.; Syratchev, I.; Grudiev, A.; Wuensch, W.; /CERN

    2010-10-27

    The Compact Linear Collider (CLIC) provides a path to a multi-TeV accelerator to explore the energy frontier of High Energy Physics. Its novel two-beam accelerator concept envisions rf power transfer to the accelerating structures from a separate high-current decelerator beam line consisting of power extraction and transfer structures (PETS). It is critical to numerically verify the fundamental and higher-order mode properties in and between the two beam lines with high accuracy and confidence. To solve these large-scale problems, SLAC's parallel finite element electromagnetic code suite ACE3P is employed. Using curvilinear conformal meshes and higher-order finite element vector basis functions, unprecedented accuracy and computational efficiency are achieved, enabling high-fidelity modeling of complex detuned structures such as the CLIC TD24 accelerating structure. In this paper, time-domain simulations of wakefield coupling effects in the combined system of PETS and the TD24 structures are presented. The results will help to identify potential issues and provide new insights on the design, leading to further improvements on the novel CLIC two-beam accelerator scheme.

  1. Radiation-induced endothelial dysfunction and fibrosis in rat lung: modification by the angiotensin converting enzyme inhibitor CL242817

    SciTech Connect

    Ward, W.F.; Molteni, A.; Ts'ao, C.H.

    1989-02-01

    The purpose of this study was to evaluate the angiotensin converting enzyme (ACE) inhibitor CL242817 as a modifier of radiation-induced pulmonary endothelial dysfunction and pulmonary fibrosis in rats sacrificed 2 months after a single dose of 60Co gamma rays (0-30 Gy) to the right hemithorax. CL242817 was administered in the feed continuously after irradiation at a regimen of 60 mg/kg/day. Pulmonary endothelial function was monitored by lung ACE activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Pulmonary fibrosis was evaluated by lung hydroxyproline (HP) content. Lung ACE and PLA activities decreased with increasing radiation dose, and cotreatment with CL242817 significantly ameliorated both responses. CL242817 dose-reduction factors (DRF) were 1.3-1.5 for ACE and PLA activity. Lung PGI2 and TXA2 production increased with increasing radiation dose, and CL242817 almost completely prevented both radiation responses. The slope of the radiation dose-response curves in the CL242817-treated rats was essentially zero, precluding calculation of DRF values for PGI2 and TXA2 production. Lung HP content also increased with increasing radiation dose, and CL242817 significantly attenuated this response (DRF = 1.5). These data suggest that the ability of ACE inhibitors to ameliorate radiation-induced pulmonary endothelial dysfunction is not unique to captopril, rather it is a therapeutic action shared by other members of this class of compounds. These data also provide the first evidence that ACE inhibitors exhibit antifibrotic activity in irradiated rat lung.

  2. The onboard imagers for the Canadian ACE SCISAT-1 mission

    NASA Astrophysics Data System (ADS)

    Gilbert, K. L.; Turnbull, D. N.; Walker, K. A.; Boone, C. D.; McLeod, S. D.; Butler, M.; Skelton, R.; Bernath, P. F.; Chateauneuf, F.; Soucy, M.-A.

    2007-06-01

    The Atmospheric Chemistry Experiment (ACE) onboard the Canadian Space Agency's SCISAT-1 satellite has been in orbit since August of 2003. Its broad objective is to study the problem of stratospheric ozone depletion, particularly in the Arctic. The main instruments are two spectrometers, one an infrared Fourier Transform Spectrometer and the other a dual optical spectrophotometer sensitive in the UV and visible. Also included are two filtered imagers used to measure altitude profiles of atmospheric extinction and detect thin clouds. The nominal center wavelengths of the filters are 525 nm for the visible (VIS) imager and 1020 nm for the near-infrared (NIR) imager. With the decommissioning of other satellite instruments used to monitor global aerosols [i.e., Stratospheric Aerosol and Gas Experiment II (SAGE II), SAGE III, Polar Ozone and Aerosol Measurement (POAM) III, Halogen Occultation Experiment (HALOE)], the imagers provide much needed continuity in this data record. The data product from the imagers is still, however, in a preliminary state. Funding restrictions in the prelaunch period were responsible for an incomplete characterization of the imagers' optics and electronics and prevented corrections being made for the problems found during testing. Postlaunch data analysis to correct for image artifacts is ongoing. A comparison with coincidental measurements from SAGE II shows that systematic errors from the preliminary analysis are within 5 and 20% for the VIS and NIR imagers, respectively, for uninverted profiles of optical depth. Despite the preliminary nature of the imager results, a paper describing the imagers and the initial operational data processing code is timely because the data are already being used.

  3. An Improved Model for Predicting Radiation Pneumonitis Incorporating Clinical and Dosimetric Variables;Lung cancer; Radiation pneumonitis; Dose-volume histogram; Angiotensin converting enzyme inhibitor

    SciTech Connect

    Jenkins, Peter; Watts, Joanne

    2011-07-15

    Purpose: Single dose-volume metrics are of limited value for the prediction of radiation pneumonitis (RP) in day-to-day clinical practice. We investigated whether multiparametric models that incorporate clinical and physiologic factors might have improved accuracy. Methods and Materials: The records of 160 patients who received radiation therapy for non-small-cell lung cancer were reviewed. All patients were treated to the same dose and with an identical technique. Dosimetric, pulmonary function, and clinical parameters were analyzed to determine their ability to predict for the subsequent development of RP. Results: Twenty-seven patients (17%) developed RP. On univariate analysis, the following factors were significantly correlated with the risk of pneumonitis: fractional volume of lung receiving >5-20 Gy, absolute volume of lung spared from receiving >5-15 Gy, mean lung dose, craniocaudal position of the isocenter, transfer coefficient for carbon monoxide (KCOc), total lung capacity, coadministration of angiotensin converting enzyme inhibitors, and coadministration of angiotensin receptor antagonists. By combining the absolute volume of lung spared from receiving >5 Gy with the KCOc, we defined a new parameter termed Transfer Factor Spared from receiving >5 Gy (TFS{sub 5}). The area under the receiver operator characteristic curve for TFS{sub 5} was 0.778, increasing to 0.846 if patients receiving modulators of the renin-angiotensin system were excluded from the analysis. Patients with a TFS{sub 5} <2.17 mmol/min/kPa had a risk of RP of 30% compared with 5% for the group with a TFS{sub 5} {>=}2.17. Conclusions: TFS{sub 5} represents a simple parameter that can be used in routine clinical practice to more accurately segregate patients into high- and low-risk groups for developing RP.

  4. The Altus Cumulus Electrification Study (ACES): A UAV-based Investigation of Thunderstorms

    NASA Technical Reports Server (NTRS)

    Blakeslee, Richard; Arnold, James E. (Technical Monitor)

    2001-01-01

    The Altus Cumulus Electrification Study (ACES) is a NASA-sponsored and -led science investigation that utilizes an uninhabited aerial vehicle (UAV) to investigate thunderstorms in the vicinity of the NASA Kennedy Space Center, Florida. As part of NASA's UAV-based science demonstration program, ACES will provide a scientifically useful demonstration of the utility and promise of UAV platforms for Earth science and applications observations. ACES will employ the Altus 11 aircraft, built by General Atomics-Aeronautical Systems, Inc. By taking advantage of its slow flight speed (70 to 100 knots), long endurance, and high-altitude flight (up to 55,000 feet), the Altus will be flown near, and when possible, above (but never into) thunderstorms for long periods of time, allowing investigations to be conducted over entire storm life cycles. Key science objectives simultaneously addressed by ACES are to: (1) investigate lightning-storm relationships, (2) study storm electrical budgets, and (3) provide Lightning Imaging Sensor validation. The ACES payload, already developed and flown on Altus, includes electrical, magnetic, and optical sensors to remotely characterize the lightning activity and the electrical environment within and around thunderstorms. The ACES field campaign will be conducted during July 2002 with a goal of performing 8 to 10 UAV flights. Each flight will require about 4 to 5 hours on station at altitudes from 40,000 ft to 55,000 ft. The ACES team is comprised of scientists from the NASA Marshall Space Flight Center and NASA Goddard Space Flight Centers partnered with General Atomics and IDEA, LLC.

  5. Hypertension and ace gene insertion/deletion polymorphism in pediatric renal transplant patients.

    PubMed

    Serdaroglu, Erkin; Mir, Sevgi; Berdeli, Afig

    2005-10-01

    The objective of the present study was to define the risk factors for hypertension and to analyze the influence of insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) on hypertension in pediatric renal transplant recipients. Twenty-six pediatric renal transplant recipients with stable renal function and treated with the same immunosuppression protocol were included in the study. Their mean age was 12.5 +/- 3.3 yr and mean time after transplantation was 38.5 +/- 39.8 month. Twenty-four hour ambulatory blood pressure monitoring (ABPM) was performed by SpaceLabs (90207) device. The I/D polymorphism of the ACE was determined by PCR and ACE serum level was analyzed by colorimetric method. Hypertension was present in 15 patients (57.7%) by causal blood pressure measurements and 19 patients (73.1%) by ABPM. Twenty-two patients (84.6%) were found to be non-dipper and eight of them had reverse dipping. Only time after transplantation (38 +/- 31 vs. 79 +/-49 month, p = 0.016) and cyclosporin A trough plasma levels (206 +/-78 vs. 119 +/- 83 ng/mL, p = 0.020) influenced the presence of hypertension by multiple logistic regression analysis. The distribution of genotypes were II = 2 (7.7%), ID = 8 (30.8%), DD = 16 (61.5%). There was no effect of ACE gene I/D polymorphism or serum ACE levels on hypertension prevalence and circadian variability of blood pressures. Hypertension was related to the time after transplantation and cyclosporin A levels. The ACE gene I/D polymorphism and serum ACE levels did not influence the blood pressure values or circadian variability of blood pressure among pediatric renal transplant patients. PMID:16176418

  6. Phosphodiesterase-5 inhibitors.

    PubMed

    Cockrill, Barbara A; Waxman, Aaron B

    2013-01-01

    Nitric oxide (NO) signaling plays a key role in modulating vascular tone and remodeling in the pulmonary circulation. The guanylate cyclase/cyclic guanylate monophosphate-signaling pathway primarily mediates nitric oxide signaling. This pathway is critical in normal regulation of the pulmonary vasculature, and is an important target for therapy in patients with pulmonary hypertension. In the pulmonary vasculature, degradation of cGMP is primarily regulated by PDE-5, and inhibition of this enzyme has important effects on pulmonary vasculature smooth muscle tone. Large randomized placebo-controlled trials of PDE-5 inhibitors demonstrated improved exercise capacity, hemodynamics and quality of life in adult patients with PAH. This chapter will discuss the mechanisms of NO signaling in the vasculature, characteristics of the PDE5-inhibitors approved for treatment of PH, and review available data on the use of phosphodiesterase inhibitors in PH. PMID:24092343

  7. Myosin light chain kinase inhibitor ML7 improves vascular endothelial dysfunction via tight junction regulation in a rabbit model of atherosclerosis.

    PubMed

    Cheng, Xiaowen; Wang, Xiaobian; Wan, Yufeng; Zhou, Qing; Zhu, Huaqing; Wang, Yuan

    2015-09-01

    Vascular endothelial dysfunction (VED) is an important factor in the initiation and development of atherosclerosis (AS). Previous studies have demonstrated that endothelial permeability is increased in diet‑induced AS. However, the precise underlying mechanisms remain poorly understood. The present study aimed to analyze whether the myosin light chain kinase (MLCK) inhibitor ML7 is able to improve VED and AS by regulating the expression of the tight junction (TJ) proteins zona occludens (ZO)‑1 and occludin via mechanisms involving MLCK and MLC phosphorylation in high‑fat diet‑fed rabbits. New Zealand white rabbits were randomly divided into three groups: Control group, AS group and ML7 group. The rabbits were fed a standard diet (control group), a high‑fat diet (AS group) or a high‑fat diet supplemented with 1 mg/kg/day ML7 (ML7 group). After 12 weeks, endothelium‑dependent relaxation and endothelium‑independent relaxation were measured using high-frequency ultrasound. Administration of a high‑fat diet significantly increased the levels of serum lipids and inflammatory markers in the rabbits in the AS group, as compared with those in the rabbits in the control group. Furthermore, a high‑fat diet contributed to the formation of a typical atherosclerotic plaque, as well as an increase in endothelial permeability and VED. These symptoms of AS were significantly improved following treatment with ML7, as demonstrated in the ML7 group. Hematoxylin & eosin and immunohistochemical staining indicated that ML7 was able to decrease the expression of MLCK and MLC phosphorylation in the arterial wall of rabbits fed a high‑fat diet. A similar change was observed for the TJ proteins ZO‑1 and occludin. In addition, western blot analysis demonstrated that ML7 increased the expression levels of occludin in the precipitate, but reduced its expression in the supernatant of lysed aortas. These results indicated that occludin, which is a dynamic protein at the TJ

  8. Myosin light chain kinase inhibitor ML7 improves vascular endothelial dysfunction via tight junction regulation in a rabbit model of atherosclerosis

    PubMed Central

    CHENG, XIAOWEN; WANG, XIAOBIAN; WAN, YUFENG; ZHOU, QING; ZHU, HUAQING; WANG, YUAN

    2015-01-01

    Vascular endothelial dysfunction (VED) is an important factor in the initiation and development of atherosclerosis (AS). Previous studies have demonstrated that endothelial permeability is increased in diet-induced AS. However, the precise underlying mechanisms remain poorly understood. The present study aimed to analyze whether the myosin light chain kinase (MLCK) inhibitor ML7 is able to improve VED and AS by regulating the expression of the tight junction (TJ) proteins zona occludens (ZO)-1 and occludin via mechanisms involving MLCK and MLC phosphorylation in high-fat diet-fed rabbits. New Zealand white rabbits were randomly divided into three groups: Control group, AS group and ML7 group. The rabbits were fed a standard diet (control group), a high-fat diet (AS group) or a high-fat diet supplemented with 1 mg/kg/day ML7 (ML7 group). After 12 weeks, endothelium-dependent relaxation and endothelium-independent relaxation were measured using high-frequency ultrasound. Administration of a high-fat diet significantly increased the levels of serum lipids and inflammatory markers in the rabbits in the AS group, as compared with those in the rabbits in the control group. Furthermore, a high-fat diet contributed to the formation of a typical atherosclerotic plaque, as well as an increase in endothelial permeability and VED. These symptoms of AS were significantly improved following treatment with ML7, as demonstrated in the ML7 group. Hematoxylin & eosin and immunohistochemical staining indicated that ML7 was able to decrease the expression of MLCK and MLC phosphorylation in the arterial wall of rabbits fed a high-fat diet. A similar change was observed for the TJ proteins ZO-1 and occludin. In addition, western blot analysis demonstrated that ML7 increased the expression levels of occludin in the precipitate, but reduced its expression in the supernatant of lysed aortas. These results indicated that occludin, which is a dynamic protein at the TJ, is associated with

  9. ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity.

    PubMed

    Patel, Vaibhav B; Mori, Jun; McLean, Brent A; Basu, Ratnadeep; Das, Subhash K; Ramprasath, Tharmarajan; Parajuli, Nirmal; Penninger, Josef M; Grant, Maria B; Lopaschuk, Gary D; Oudit, Gavin Y

    2016-01-01

    Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.

  10. SGLT2 inhibitors.

    PubMed

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. PMID:26362302

  11. Design, synthesis, and biological evaluation of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl derivatives as new irreversible epidermal growth factor receptor inhibitors with improved pharmacokinetic properties.

    PubMed

    Xu, Shilin; Xu, Tianfeng; Zhang, Lianwen; Zhang, Zhang; Luo, Jinfeng; Liu, Yingxue; Lu, Xiaoyun; Tu, Zhengchao; Ren, Xiaomei; Ding, Ke

    2013-11-14

    Structural optimization of a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl compounds, potential new irreversible EGFR inhibitors, was performed to improve pharmacokinetic properties of the compounds. This led to compound 2v with improved aqueous solubility and good pharmacokinetic properties which at the nanomolar level potently inhibits gefitinib-resistant EGFR(L858R/T790M) kinase and displays strong antiproliferative activity against H1975 nonsmall cell lung cancer cells. The new inhibitor also shows promising antitumor efficacy in a murine EGFR(L858R/T790M)-driven H1975 xenograft model without effect on body weight. These studies provide new lead compounds for further development of drugs for treatment of gefitinib-resistant nonsmall cell lung cancer patients.

  12. Angiotensin-converting enzyme (ACE) genotypes and disability in hospitalized older patients.

    PubMed

    Seripa, Davide; Paroni, Giulia; Matera, Maria G; Gravina, Carolina; Scarcelli, Carlo; Corritore, Michele; D'Ambrosio, Luigi P; Urbano, Maria; D'Onofrio, Grazia; Copetti, Massimiliano; Kehoe, Patrick G; Panza, Francesco; Pilotto, Alberto

    2011-09-01

    The association between angiotensin-converting enzyme (ACE) genotypes and functional decline in older adults remains controversial. To assess if ACE gene variations influences functional abilities at older age, the present study explored the association between the common ACE insertion/deletion (I/D) polymorphism and disability measured with activities of daily living (ADL) in hospitalized older patients. We analyzed the frequency of the ACE genotypes (I/I, I/D, and D/D) in a population of 2,128 hospitalized older patients divided according to presence or absence of ADL disability. Logistic regression analysis adjusted for possible confounding factors, identified an association between the I/I genotype with ADL disability (OR=1.54, 95% CI 1.04-2.29). This association was significant in men (OR=2.01, 95% CI 1.07-3.78), but not in women (OR=1.36, 95% CI 0.82-2.25). These results suggested a possible role of the ACE polymorphism as a genetic marker for ADL disability in hospitalized older patients.

  13. ACE Reduces Metabolic Abnormalities in a High-Fat Diet Mouse Model

    PubMed Central

    Lee, Seong-Jong; Han, Jong-Min; Lee, Jin-Seok; Son, Chang-Gue; Im, Hwi-Jin; Jo, Hyun-Kyung; Yoo, Ho-Ryong; Kim, Yoon-Sik; Seol, In-Chan

    2015-01-01

    The medicinal plants Artemisia iwayomogi (A. iwayomogi) and Curcuma longa (C. longa) radix have been used to treat metabolic abnormalities in traditional Korean medicine and traditional Chinese medicine (TKM and TCM). In this study we evaluated the effect of the water extract of a mixture of A. iwayomogi and C. longa (ACE) on high-fat diet-induced metabolic syndrome in a mouse model. Four groups of C57BL/6N male mice (except for the naive group) were fed a high-fat diet freely for 10 weeks. Among these, three groups (except the control group) were administered a high-fat diet supplemented with ACE (100 or 200 mg/kg) or curcumin (50 mg/kg). Body weight, accumulation of adipose tissues in abdomen and size of adipocytes, serum lipid profiles, hepatic steatosis, and oxidative stress markers were analyzed. ACE significantly reduced the body and peritoneal adipose tissue weights, serum lipid profiles (total cholesterol and triglycerides), glucose levels, hepatic lipid accumulation, and oxidative stress markers. ACE normalized lipid synthesis-associated gene expressions (peroxisome proliferator-activated receptor gamma, PPARγ; fatty acid synthase, FAS; sterol regulatory element-binding transcription factor-1c, SREBP-1c; and peroxisome proliferator-activated receptor alpha, PPARα). The results from this study suggest that ACE has the pharmaceutical potential reducing the metabolic abnormalities in an animal model. PMID:26508977

  14. High resolution critical habitat mapping and classification of tidal freshwater wetlands in the ACE Basin

    NASA Astrophysics Data System (ADS)

    Strickland, Melissa Anne

    In collaboration with the South Carolina Department of Natural Resources ACE Basin National Estuarine Research Reserve (ACE Basin NERR), the tidal freshwater ecosystems along the South Edisto River in the ACE Basin are being accurately mapped and classified using a LIDAR-Remote Sensing Fusion technique that integrates LAS LIDAR data into texture images and then merges the elevation textures and multispectral imagery for very high resolution mapping. This project discusses the development and refinement of an ArcGIS Toolbox capable of automating protocols and procedures for marsh delineation and microhabitat identification. The result is a high resolution habitat and land use map used for the identification of threatened habitat. Tidal freshwater wetlands are also a critical habitat for colonial wading birds and an accurate assessment of community diversity and acreage of this habitat type in the ACE Basin will support SCDNR's conservation and protection efforts. The maps developed by this study will be used to better monitor the freshwater/saltwater interface and establish a baseline for an ACE NERR monitoring program to track the rates and extent of alterations due to projected environmental stressors. Preliminary ground-truthing in the field will provide information about the accuracy of the mapping tool.

  15. The association between ace gene variation and aerobic capacity in winter endurance disciplines.

    PubMed

    Orysiak, J; Zmijewski, P; Klusiewicz, A; Kaliszewski, P; Malczewska-Lenczowska, J; Gajewski, J; Pokrywka, A

    2013-12-01

    The aim of the study was to examine the possible relationship between I/D polymorphism of ACE gene and selected indices of aerobic capacity among male and female athletes practising winter endurance sports. Sixty-six well-trained athletes (female n = 26, male n = 40), aged 18.4 ± 2.8 years, representing winter endurance sports (cross-country skiing, n = 48; biathlon, n = 8; Nordic combined, n = 10) participated in the study. Genotyping for ACE I/D polymorphism was performed using polymerase chain reaction. Maximal oxygen consumption (VO2max), maximal running velocity (Vmax) and running velocity at anaerobic threshold (VAT4) were determined in an incremental test to volitional exhaustion on a motorized treadmill. The ACE genotype had no significant effect on absolute VO2max, relative VO2max (divided by body mass or fat free body mass), VAT4 or Vmax. No interaction effect of gender x ACE genotype was found for each of the examined aerobic capacity indices. ACE gene variation was not found to be a determinant of aerobic capacity in either female or male Polish, well-trained endurance athletes participating in winter sports.

  16. Mixed inhibitors of angiotensin-converting enzyme (EC 3.4.15.1) and enkephalinase (EC 3.4.24.11): rational design, properties, and potential cardiovascular applications of glycopril and alatriopril.

    PubMed Central

    Gros, C; Noël, N; Souque, A; Schwartz, J C; Danvy, D; Plaquevent, J C; Duhamel, L; Duhamel, P; Lecomte, J M; Bralet, J

    1991-01-01

    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, we have designed glycoprilat and alatrioprilat [(S)-N-[3-(3,4-methylene-dioxyphenyl)-2-(mercaptomethyl)-1-oxoprop yl] glycine and -alanine, respectively]. 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 (0.2-0.5 mg/kg of body weight, per os). The high potency of these compounds is attributable to interaction of the methylenedioxy group with the S1 subsite of ACE and of the aromatic ring with the S1' 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 125I-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. PMID:1851998

  17. Optimization of the phenylurea moiety in a phosphoinositide 3-kinase (PI3K) inhibitor to improve water solubility and the PK profile by introducing a solubilizing group and ortho substituents.

    PubMed

    Kawada, Hatsuo; Ebiike, Hirosato; Tsukazaki, Masao; Yamamoto, Shun; Koyama, Kohei; Nakamura, Mitsuaki; Morikami, Kenji; Yoshinari, Kiyoshi; Yoshida, Miyuki; Ogawa, Kotaro; Shimma, Nobuo; Tsukuda, Takuo; Ohwada, Jun

    2016-07-01

    Phosphoinositide 3-kinase (PI3K) is a promising anti-cancer target, because various mutations and amplifications are observed in human tumors isolated from cancer patients. Our dihydropyrrolopyrimidine derivative with a phenylurea moiety showed strong PI3K enzyme inhibitory activity, but its pharmacokinetic property was poor because of lack of solubility. Herein, we report how we improved the solubility of our PI3K inhibitors by introducing a solubilizing group and ortho substituents to break molecular planarity. PMID:27189888

  18. Engineering Neurospora crassa for Improved Cellobiose and Cellobionate Production

    PubMed Central

    Hildebrand, Amanda; Szewczyk, Edyta; Lin, Hui; Kasuga, Takao

    2014-01-01

    We report engineering Neurospora crassa to improve the yield of cellobiose and cellobionate from cellulose. A previously engineered strain of N. crassa (F5) with six of seven β-glucosidase (bgl) genes knocked out was shown to produce cellobiose and cellobionate directly from cellulose without the addition of exogenous cellulases. In this study, the F5 strain was further modified to improve the yield of cellobiose and cellobionate from cellulose by increasing cellulase production and decreasing product consumption. The effects of two catabolite repression genes, cre-1 and ace-1, on cellulase production were investigated. The F5 Δace-1 mutant showed no improvement over the wild type. The F5 Δcre-1 and F5 Δace-1 Δcre-1 strains showed improved cellobiose dehydrogenase and exoglucanase expression. However, this improvement in cellulase expression did not lead to an improvement in cellobiose or cellobionate production. The cellobionate phosphorylase gene (ndvB) was deleted from the genome of F5 Δace-1 Δcre-1 to prevent the consumption of cellobiose and cellobionate. Despite a slightly reduced hydrolysis rate, the F5 Δace-1 Δcre-1 ΔndvB strain converted 75% of the cellulose consumed to the desired products, cellobiose and cellobionate, compared to 18% converted by the strain F5 Δace-1 Δcre-1. PMID:25381238

  19. Arctic weather during the FIRE/ACE flights in 1998

    NASA Astrophysics Data System (ADS)

    Wylie, Donald P.

    2001-07-01

    The weather systems, cyclones and anticyclones, along with air trajectories and cloud forms, are compared to past studies of the Arctic to assess compatibility of the 4-month study of FIRE/ACE with past climatologies. The frequency and movement of cyclones (lows) and anticyclones (highs) followed the general eastward and northeastward directions indicated by past studies. Most cyclones (lows) came from eastern Siberia and the Bering Sea to the south and moved north across the Bering Straight or Alaska into the Arctic Ocean. They generally weakened in central pressure as they moved poleward. Anticyclones (highs) were most common in the eastern Beaufort Sea near Canada in June and July, as predicted from previous studies. However, many cyclones and anticyclones moved in westward directions, which is rare in other latitudes. Erratic changes in shape and intensity on a daily basis also were observed. The NOAA National Center for Environmental Prediction (NCEP) analysis generally reflected the SHEBA Ship WMO observations which it used. However, NCEP temperatures were biased warm by 1.0° to 1.5°C in April and early May. In July, when the surface temperatures were at the freezing/thawing point, the NCEP analysis changed to a cold bias of -1.0°C. Dew points had smaller biases except for July where they were biased cold by -1.4°C. Wind speeds had a -2 m/s low bias for the six windiest days. Surface barometric pressures had consistently low biases from -1.2 to -2.8 hPa in all four months. Air parcel historical trajectories were mainly from the south or from local anticyclonic gyres in the Beaufort Sea. Most air came to the SHEBA ship from the North Pacific Ocean or from Alaska and Canada and occasionally from eastern Siberia. Very few trajectories traced back across the pole to Europe and central Asia. Cloud cover was high, as expected, from 69 to 86% of the time. Satellite data also indicate frequent stratus, altostratus, and cirrus clouds (occurring 61% of the time

  20. Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure.

    PubMed

    Patel, Vaibhav B; Zhong, Jiu-Chang; Grant, Maria B; Oudit, Gavin Y

    2016-04-15

    Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.

  1. Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications.

    PubMed

    Tikoo, Kulbhushan; Patel, Gaurang; Kumar, Sandeep; Karpe, Pinakin Arun; Sanghavi, Maitri; Malek, Vajir; Srinivasan, K

    2015-02-01

    Growing body of evidence points out the crucial role of ACE2 in preventing atherosclerosis. However, data on how atherosclerosis affects ACE2 expression in heart and kidney remains unknown. Atherosclerosis was induced by feeding New Zealand White rabbits with high cholesterol diet (HCD - 2%) for 12 weeks and atorvastatin was administered (5mg/kg/day p.o) in last 3 weeks. ACE2 mRNA and protein expression was assessed by Western blotting and real time PCR. HCD fed rabbits developed atherosclerosis as confirmed by increase in plasma total cholesterol, LDL and triglycerides as well as formation atherosclerotic plaques in arch of aorta. The ACE2 protein but not mRNA expression was reduced in heart and kidney of HCD rabbits. Interestingly, atorvastatin increased the ACE2 protein expression in heart and kidney of HCD rabbits. However, atorvastatin increased ACE2 mRNA in heart but not in kidney of HCD rabbits. Atorvastatin increased the occupancy of histone H3 acetylation (H3-Ac) mark on ACE2 promoter region in heart of HCD rabbits indicating direct or indirect epigenetic up-regulation of ACE2 by atorvastatin. Further, atorvastatin suppressed Ang II-induced contractile responses and enhanced AT2 receptor mediated relaxant responses in atherosclerotic aorta. We propose that atherosclerosis is associated with reduced ACE2 expression in heart and kidney. We also show an unexplored potential of atorvastatin to up-regulate ACE2 via epigenetic histone modifications. Our data suggest a novel way of replenishing ACE2 expression for preventing not only atherosclerosis but also other cardiovascular disorders. PMID:25482567

  2. The Delta II with ACE aboard is prepared for liftoff from Pad 17A, CCAS

    NASA Technical Reports Server (NTRS)

    1997-01-01

    The Boeing Delta II expendable launch vehicle carrying the Advanced Composition Explorer (ACE) undergoes final preparations for liftoff in the predawn hours of Aug. 25, 1997, at Launch Complex 17A, Cape Canaveral Air Station. This is the second Delta launch under the Boeing name and the first from Cape Canaveral. The first launch attempt on Aug. 24 was scrubbed by Air Force range safety personnel because two commercial fishing vessels were within the Delta's launch danger area. ACE with its combination of nine sensors and instruments will investigate the origin and evolution of solar phenomenon, the formation of solar corona, solar flares and acceleration of the solar wind. ACE was built for NASA by the Johns Hopkins Applied Physics Laboratory and is managed by the Explorer Project Office at NASA's Goddard Space Flight Center. The lead scientific institution is the California Institute of Technology.

  3. Role of Serratia marcescens ACE2 on diesel degradation and its influence on corrosion.

    PubMed

    Rajasekar, Aruliah; Babu, Thambidurai Ganesh; Pandian, Shunmugiah Thevar Karutha; Maruthamuthu, Sundaram; Palaniswamy, Narayanan; Rajendran, Annamalai

    2007-09-01

    A facultative anaerobic species Serratia marcescens ACE2 isolated from the corrosion products of diesel transporting pipeline in North West, India was identified by 16S rDNA sequence analysis. The role of Serratia marcesens ACE2 on biodegradation of diesel and its influence on the corrosion of API 5LX steel has been elucidated. The degrading strain ACE2 is involved in the process of corrosion of steel API 5LX and also utilizes the diesel as an organic source. The quantitative biodegradation efficiency (BE) of diesel was 58%, calculated by gas-chromatography-mass spectrum analysis. On the basis of gas-chromatography-mass spectrum (GC-MS), Fourier Transform infrared spectroscopy (FTIR) and X-ray diffractometer (XRD), the involvement of Serratia marcescens on degradation and corrosion has been investigated. This basic study will be useful for the development of new approaches for detection, monitoring and control of microbial corrosion.

  4. Serum ACE Level in Sarcoidosis Patients with Typical and Atypical HRCT Manifestation

    PubMed Central

    Kahkouee, Shahram; Samadi, Katayoon; Alai, Ali; Abedini, Atefeh; Rezaiian, Lida

    2016-01-01

    Summary Background Sarcoidosis is an inflammatory disease that affects multiple organs. Before widespread use of computed tomography (CT), the severity of sarcoidosis was assessed based on chest X-ray abnormalities. HRCT can distinguish between active inflammatory changes and irreversible fibrosis. In this study, we analyzed different ACE levels in 148 patients diagnosed with sarcoidosis. Material/Methods We categorized these patients based on their HRCT results into four groups: 1) patients diagnosed with chronic disease; 2) patients diagnosed with non-chronic disease; 3) patients who exhibited typical HRCT changes; and 4) patients who exhibited atypical HRCT changes. Afterward the mean ACE level of each group was calculated and compared. Result The HRCT scans of chronic sarcoidosis patients tended to show more atypical sarcoidosis patterns. Moreover, there was a reverse correlation between chronicity and ACE level (P-value <0.05). Conclusions HRCT is another modality which would be useful when the diagnosis of sarcoidosis is not definite. PMID:27733890

  5. SIGACE Code for Generating High-Temperature ACE Files; Validation and Benchmarking

    NASA Astrophysics Data System (ADS)

    Sharma, Amit R.; Ganesan, S.; Trkov, A.

    2005-05-01

    A code named SIGACE has been developed as a tool for MCNP users within the scope of a research contract awarded by the Nuclear Data Section of the International Atomic Energy Agency (IAEA) (Ref: 302-F4-IND-11566 B5-IND-29641). A new recipe has been evolved for generating high-temperature ACE files for use with the MCNP code. Under this scheme the low-temperature ACE file is first converted to an ENDF formatted file using the ACELST code and then Doppler broadened, essentially limited to the data in the resolved resonance region, to any desired higher temperature using SIGMA1. The SIGACE code then generates a high-temperature ACE file for use with the MCNP code. A thinning routine has also been introduced in the SIGACE code for reducing the size of the ACE files. The SIGACE code and the recipe for generating ACE files at higher temperatures has been applied to the SEFOR fast reactor benchmark problem (sodium-cooled fast reactor benchmark described in ENDF-202/BNL-19302, 1974 document). The calculated Doppler coefficient is in good agreement with the experimental value. A similar calculation using ACE files generated directly with the NJOY system also agrees with our SIGACE computed results. The SIGACE code and the recipe is further applied to study the numerical benchmark configuration of selected idealized PWR pin cell configurations with five different fuel enrichments as reported by Mosteller and Eisenhart. The SIGACE code that has been tested with several FENDL/MC files will be available, free of cost, upon request, from the Nuclear Data Section of the IAEA.

  6. Modelling of the production of ACE inhibitory hydrolysates of horse mackerel using proteases mixtures.

    PubMed

    Pérez-Gálvez, R; Morales-Medina, R; Espejo-Carpio, F; Guadix, A; Guadix, E M

    2016-09-14

    Fish protein hydrolysates from Mediterranean horse mackerel were produced by using a mixture of two commercial endoproteases (i.e. subtilisin and trypsin) at different levels of substrate concentration (2.5 g L(-1), 5 g L(-1), and 7.5 g L(-1) of protein), temperature (40 °C, 47.5 °C, and 55 °C) and percentage of subtilisin in the enzyme mixture (0%, 25%, 50%, 75% and 100%). A crossed mixture process model was employed to predict the degree of hydrolysis (DH) and the ACE inhibitory activity of the final hydrolysates as a function of the experimental factors. Both models were optimized for a maximum DH and ACE inhibition. A maximum DH (17.1%) was predicted at 2.54 g L(-1) of substrate concentration, 40 °C and an enzyme mixture comprising 38.3% of subtilisin and 61.7% of trypsin. Although its proteolytic activity is limited, the presence of trypsin in the enzyme mixture allowed obtaining higher degrees of hydrolysis at low temperatures, which is desirable to minimize thermal deactivation of the proteins. Similarly, a percentage of ACE inhibition above 48% was attained at 2.5 g L(-1) of protein, 40 °C and a 1 : 1 mixture of both proteases. Higher values of ACE inhibition could be attained by increasing both the temperature and the amount of trypsin in the enzyme mixture (e.g. 50% ACE inhibition at 55 °C and 81.5% of trypsin). Finally, those hydrolysates exhibiting the highest levels of ACE inhibition were subjected to simulated gastrointestinal digestion. These assays confirmed the resistance of active fractions against their degradation by digestive enzymes. PMID:27526864

  7. The Altus Cumulus Electrification Study (ACES): A UAV-Based Science Demonstration

    NASA Technical Reports Server (NTRS)

    Blakeslee, R. J.; Croskey, C. L.; Desch, M. D.; Farrell, W. M.; Goldberg, R. A.; Houser, J. G.; Kim, H. S.; Mach, D. M.; Mitchell, J. D.; Stoneburner, J. C.

    2003-01-01

    The Altus Cumulus Electrification Study (ACES) is an unmanned aerial vehicle (UAV)- based project that investigated thunderstorms in the vicinity of the Florida Everglades in August 2002. ACES was conducted to investigate storm electrical activity and its relationship to storm morphology, and to validate satellite-based lightning measurements. In addition, as part of the NASA sponsored UAV-based science demonstration program, this project provided a scientifically useful demonstration of the utility and promise of UAV platforms for Earth science and applications observations. ACES employed the Altus II aircraft, built by General Atomics - Aeronautical Systems, Inc. Key science objectives simultaneously addressed by ACES are to: (1) investigate lightning-storm relationships, (2) study storm electrical budgets, and provide Lightning Imaging Sensor validation. The ACES payload included electrical, magnetic, and optical sensors to remotely characterize the lightning activity and the electrical environment within and around thunderstorms. ACES contributed important electrical and optical measurements not available from other sources. Also, the high altitude vantage point of the UAV observing platform (up to 55,000 feet) provided cloud-top perspective. By taking advantage of its slow flight speed (70 to 100 knots), long endurance, and high altitude flight, the Altus was flown near, and when possible, over (but never into) thunderstorms for long periods of time that allowed investigations to be conducted over entire storm life cycles. An innovative real time weather system was used to identify and vector the aircraft to selected thunderstorms and safely fly around these storms, while, at the same time monitor the weather near our base of operations. In addition, concurrent ground-based observations that included radar (Miami and Key West WSRBD, NASA NPOL), satellite imagery, and lightning (NALDN and Los Alamos EDOT) enable the UAV measurements to be more completely

  8. A cladistic model of ACE sequence variation with implications for myocardial infarction, Alzheimer disease and obesity.

    PubMed

    Katzov, Hagit; Bennet, Anna M; Kehoe, Patrick; Wiman, Björn; Gatz, Margaret; Blennow, Kaj; Lenhard, Boris; Pedersen, Nancy L; de Faire, Ulf; Prince, Jonathan A

    2004-11-01

    Sequence variation in ACE, which encodes angiotensin I converting enzyme, contributes to a large proportion of variability in plasma ACE levels, but the extent to which this impacts upon human disease is unresolved. Most efforts to associate ACE with other heritable traits have involved a single Alu insertion/deletion polymorphism, despite the probable existence of other functional sequence variants with effects that may not be consistently detectable by solely typing the Alu indel. Here, utilizing single nucleotide polymorphisms (SNPs) that differentiate major ACE clades in European populations, we demonstrate a number of significant phenotype associations across more than 4000 Swedish individuals. In a systematic analysis of metabolic phenotypes, effects were detected upon several traits, including fasting plasma glucose levels, insulin levels and measures of obesity (P-values ranging from 0.046 to 8.4 x 10(-6)). Extending cladistic models to the study of myocardial infarction and Alzheimer disease, significant associations were observed with greater effect sizes than those typically obtained in large-scale meta-analyses based on the Alu indel. Population frequencies of ACE genotypes were also found to change with age, congruent with previous data suggesting effects upon longevity. Clade models consistently outperformed those based upon single markers, reinforcing the importance of taking into consideration the possible confounding effects of allelic heterogeneity in this genomic region. Utilizing computational tools, potential functional variants are highlighted that may underlie phenotypic variability, which is discussed along with the broader implications these results may have for studies attempting to link variation in ACE to human disease.

  9. SIGACE Code for Generating High-Temperature ACE Files; Validation and Benchmarking

    SciTech Connect

    Sharma, Amit R.; Ganesan, S.; Trkov, A.

    2005-05-24

    A code named SIGACE has been developed as a tool for MCNP users within the scope of a research contract awarded by the Nuclear Data Section of the International Atomic Energy Agency (IAEA) (Ref: 302-F4-IND-11566 B5-IND-29641). A new recipe has been evolved for generating high-temperature ACE files for use with the MCNP code. Under this scheme the low-temperature ACE file is first converted to an ENDF formatted file using the ACELST code and then Doppler broadened, essentially limited to the data in the resolved resonance region, to any desired higher temperature using SIGMA1. The SIGACE code then generates a high-temperature ACE file for use with the MCNP code. A thinning routine has also been introduced in the SIGACE code for reducing the size of the ACE files. The SIGACE code and the recipe for generating ACE files at higher temperatures has been applied to the SEFOR fast reactor benchmark problem (sodium-cooled fast reactor benchmark described in ENDF-202/BNL-19302, 1974 document). The calculated Doppler coefficient is in good agreement with the experimental value. A similar calculation using ACE files generated directly with the NJOY system also agrees with our SIGACE computed results. The SIGACE code and the recipe is further applied to study the numerical benchmark configuration of selected idealized PWR pin cell configurations with five different fuel enrichments as reported by Mosteller and Eisenhart. The SIGACE code that has been tested with several FENDL/MC files will be available, free of cost, upon request, from the Nuclear Data Section of the IAEA.

  10. Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations

    PubMed Central

    Zhu, Yun; Su, Shan; Qin, Lili; Wang, Qian; Shi, Lei; Ma, Zhenxuan; Tang, Jianchao; Jiang, Shibo; Lu, Lu; Ye, Sheng; Zhang, Rongguang

    2016-01-01

    Peptides derived from the C-terminal heptad repeat (CHR) of HIV gp41 have been developed as effective fusion inhibitors against HIV-1, but facing the challenges of enhancing potency and stability. Here, we report a rationally designed novel HIV-1 fusion inhibitor derived from CHR-derived peptide (Trp628~Gln653, named CP), but with an innovative Ile-Asp-Leu tail (IDL) that dramatically increased the inhibitory activity by up to 100 folds. We also determined the crystal structures of artificial fusion peptides N36- and N43-L6-CP-IDL. Although the overall structures of both fusion peptides share the canonical six-helix bundle (6-HB) configuration, their IDL tails adopt two different conformations: a one-turn helix with the N36, and a hook-like structure with the longer N43. Structural comparison showed that the hook-like IDL tail possesses a larger interaction interface with NHR than the helical one. Further molecular dynamics simulations of the two 6-HBs and isolated CP-IDL peptides suggested that hook-like form of IDL tail can be stabilized by its binding to NHR trimer. Therefore, CP-IDL has potential for further development as a new HIV fusion inhibitor, and this strategy could be widely used in developing artificial fusion inhibitors against HIV and other enveloped viruses. PMID:27666394

  11. Baseline radon detectors for shipboard use: Development and deployment in the First Aerosol Characterization Experiment (ACE 1)

    NASA Astrophysics Data System (ADS)

    Whittlestone, S.; Zahorowski, W.

    1998-01-01

    A new design of two-filter radon detector has been developed for measurement of extremely low levels of radon in the harsh environments on board ships and remote islands. These were needed for the First Aerosol Characterization (ACE 1) multiplatform experiment in the Southern Ocean. By employing an internal recirculation system and a wire mesh screen as the second filter it has been possible to reduce the power consumption by as much as a factor of 10 and the weight and cost by a factor of 2 compared to current designs of comparable sensitivity. A very high efficiency of 0.38 count s-1 Bq-1 radon in the instrument has been achieved by counting while sampling. This is a key parameter because the larger this number, the smaller the volume and power consumption of the detector. Two air flow paths are used to separate the high flow rate needed to prevent loss of radon daughters to the walls of the detector and the lower flow rate needed to change the air sample in the instrument. As a result, the inlet air lines and delay chamber needed to remove thoron are compact. With a volume of 750 L the detectors used on board ships for ACE 1 had a sensitivity of about 0.2 counts s-1 Bq-1 m-3 and a lower limit of detection of 40 mBq m-3 for a 1 hour count. An instrument with a volume of 10 m3 and incorporating improvements made since ACE 1 could be expected to have sensitivity of 3.7 c s-1 Bq-1 m-3 and a lower limit of detection of 2 mBq m-3. At 45 min the time resolution is twice as good as that of instruments using a low internal flow rate, but not as good as instruments with a moving filter, where the sampling period is precisely defined. Dual-flow loop radon detectors with screens have the virtues of simplicity and freedom from routine maintenance. This new technology extends the range of sites at which baseline radon measurements can be made to remote areas with little regular technical support and a harsh environment.

  12. Adaptive coherence estimator (ACE) for explosive hazard detection using wideband electromagnetic induction (WEMI)

    NASA Astrophysics Data System (ADS)

    Alvey, Brendan; Zare, Alina; Cook, Matthew; Ho, Dominic K. C.

    2016-05-01

    The adaptive coherence estimator (ACE) estimates the squared cosine of the angle between a known target vector and a sample vector in a transformed coordinate space. The space is transformed according to an estimation of the background statistics, which directly effects the performance of the statistic as a target detector. In this paper, the ACE detection statistic is used to detect buried explosive hazards with data from a Wideband Electromagnetic Induction (WEMI) sensor. Target signatures are based on a dictionary defined using a Discrete Spectrum of Relaxation Frequencies (DSRF) model. Results are summarized as a receiver operator curve (ROC) and compared to other leading methods.

  13. Experimental demonstration of a classical approach for flexible structure control - The ACES testbed

    NASA Technical Reports Server (NTRS)

    Wie, Bong

    1991-01-01

    This paper describes the results of an active structural control experiment performed for the Advanced Control Evaluation for Structures (ACES) testbed at NASA-Marshall as part of the NASA Control-Structure Interaction Guest Investigator Program. The experimental results successfully demonstrate the effectiveness of a 'dipole' concept for line-of-sight control of a pointing system mounted on a flexible structure. The simplicity and effectiveness of a classical 'single-loop-at-a-time' approach for the active structural control design for a complex structure, such as the ACES testbed, are demonstrated.

  14. VizieR Online Data Catalog: SP_Ace derived data from stellar spectra (Boeche+, 2016)

    NASA Astrophysics Data System (ADS)

    Boeche, C.; Grebel, E. K.

    2015-11-01

    SP_Ace is a software designed to derive stellar parameters and elemental abundances from stellar spectra. In this tables we report the stellar parameters Teff, logg, [M/H], and chemical abundances [El/H] for ten elements derived with the software SP_Ace from spectra of the ELODIE spectral library (Prugniel et al., 2007, Cat. III/251), the benchmark stars (Jofre et al., 2014, Cat. J/A+A/564/A133), and the S4N library (Allende Prieto et al., 2004, Cat. J/A+A/420/183) degraded to spectral resolution R=12,000 and S/N=100. (3 data files).

  15. Comparison of ARAC calculations with surface and airborne measurements for the ACE field trials

    SciTech Connect

    Foster, K.T.; Pobanz, B.

    1996-11-01

    These Atmospheric Collection Equipment (ACE) trials were sponsored by the Air Force Technical Applications Center (AFTAC) for the purpose of investigating specific tracer monitoring methods and equipment. Three different tracers (sulfur hexafluoride and two particulate tracers) were released simultaneously for each experiment. This document provides a brief summary of the sulfur hexafluoride modeling results for three of the remaining four ACE trials (the tracer plume from the fifth trial was not located by the monitoring teams and provided no tracer measurements for model comparison). This summary is followed by a discussion of model results for the two particulate tracers which were co-released with sulfur hexafluoride.

  16. Kidney scintigraphy after ACE inhibition in the diagnosis of renovascular hypertension

    SciTech Connect

    Ghione, S.; Fommei, E.; Palombo, C.; Giaconi, S.; Mantovanelli, A.; Ragazzini, A.; Palla, L.

    1986-01-01

    Suppression of the renin-angiotensin system (RAS) by angiotensin converting enzyme (ACE) inhibition may induce renal failure in patients with bilateral renal artery stenosis. Recent scintigraphic studies with the glomerular tracer technetium-99m-diethylenetriaminepenta-acetate (99m-Tc DTPA) indicate that in patients with unilateral renal artery stenosis, glomerular filtration rate (GFR) may be markedly reduced in the affected kidney after inhibition of ACE. This finding reflects the important role of the RAS in maintaining GFR (by increasing postglomerular resistance) in states of low renal perfusion pressure. Preliminary observations suggest that this scintigraphic test might be useful in the detection of renovascular hypertension.

  17. Angiotensin-converting enzyme (ACE-I/D) polymorphism frequency in Brazilian soccer players.

    PubMed

    Coelho, Daniel Barbosa; Pimenta, Eduardo; Rosse, Izinara Cruz; Veneroso, Christiano; Pussieldi, Guilherme; Becker, Lenice Kapes; Carvalho, Maria-Raquel; Silami-Garcia, Emerson

    2016-06-01

    This study aimed to analyze the angiotensin-converting enzyme (ACE-I/D) allelic and genotypic frequencies in Brazilian soccer players of different ages. The study group comprised 353 players from first-division clubs in the under (U)-14, U-15, U-17, U-20, and professional categories. The allelic and genotypic frequencies did not differ significantly in any of the categories between the group of players and the control group. This was the first study of ACE-I/D polymorphism in Brazilian soccer players. PMID:27232187

  18. Pancreatic angiotensin-converting enzyme 2 improves glycemia in angiotensin II-infused mice

    PubMed Central

    Chhabra, Kavaljit H.; Xia, Huijing; Pedersen, Kim Brint; Speth, Robert C.

    2013-01-01

    An overactive renin-angiotensin system (RAS) is known to contribute to type 2 diabetes mellitus (T2DM). Although ACE2 overexpression has been shown to be protective against the overactive RAS, a role for pancreatic ACE2, particularly in the islets of Langerhans, in regulating glycemia in response to elevated angiotensin II (Ang II) levels remains to be elucidated. This study examined the role of endogenous pancreatic ACE2 and the impact of elevated Ang II levels on the enzyme's ability to alleviate hyperglycemia in an Ang II infusion mouse model. Male C57bl/6J mice were infused with Ang II or saline for a period of 14 days. On the 7th day of infusion, either an adenovirus encoding human ACE2 (Ad-hACE2) or a control adenovirus (Ad-eGFP) was injected into the mouse pancreas. After an additional 7–8 days, glycemia and plasma insulin levels as well as RAS components expression and oxidative stress were assessed. Ang II-infused mice exhibited hyperglycemia, hyperinsulinemia, and impaired glucose-stimulated insulin secretion from pancreatic islets compared with control mice. This phenotype was associated with decreased ACE2 expression and activity, increased Ang II type 1 receptor (AT1R) expression, and increased oxidative stress in the mouse pancreas. Ad-hACE2 treatment restored pancreatic ACE2 expression and compensatory activity against Ang II-mediated impaired glycemia, thus improving β-cell function. Our data suggest that decreased pancreatic ACE2 is a link between overactive RAS and impaired glycemia in T2DM. Moreover, maintenance of a normal endogenous ACE2 compensatory activity in the pancreas appears critical to avoid β-cell dysfunction, supporting a therapeutic potential for ACE2 in controlling diabetes resulting from an overactive RAS. PMID:23462816

  19. [JAK2 inhibitors].

    PubMed

    Hernández Boluda, Juan Carlos; Gómez, Montse; Pérez, Ariadna

    2016-07-15

    Pharmacological inhibition of the kinase activity of JAK proteins can interfere with the signaling of immunomodulatory cytokines and block the constitutive activation of the JAK-STAT pathway that characterizes certain malignancies, including chronic myeloproliferative neoplasms. JAK inhibitors may, therefore, be useful to treat malignancies as well as inflammatory or immune disorders. Currently, the most significant advances have been made in the treatment of myelofibrosis, where these drugs may lead to a remarkable improvement in the control of hyperproliferative manifestations. However, available data suggest that this treatment is not curative of myelofibrosis. In general, JAK2 inhibition induces cytopaenias, with this being considered a class side-effect. By contrast, the extrahaematologic toxicity profile varies significantly among the different JAK inhibitors. At present, there are several clinical trials evaluating the combination of ruxolitinib with other drugs, in order to improve its therapeutic activity as well as reducing haematologic toxicity. PMID:27033437

  20. Dipeptidase-inactivated tACE action in vivo: selective inhibition of sperm-zona pellucida binding in the mouse.

    PubMed

    Deguchi, Eishi; Tani, Taeko; Watanabe, Hitomi; Yamada, Shuichi; Kondoh, Gen

    2007-11-01

    The angiotensin-converting enzyme (ACE) plays a crucial role in male fertilization and is a key regulator of blood pressure. Testicular ACE (tACE), the germinal specific isozyme expressed on different promoters, exclusively carries out the role of ACE in fertility, although the site and mode of action are not well known. To investigate the contribution of tACE in fertilization, we produced transgenic mouse lines carrying a dipeptidase-inactivated mutant. Although the transgenic mice showed normal blood pressure, kidney morphology, and fertility, reduced fertilization was observed after in vitro fertilization (IVF). The sperm-zona pellucida (ZP) binding was exclusively impaired in these lines in a manner similar to that observed in an Ace knockout mouse. The dipeptidase activity was reduced in epididymal ingredients but not in the testis. Furthermore, direct application of mutant protein did not suppress sperm-ZP binding of intact sperm during IVF, implying that the dipeptidase-inactivated mutant affects sperm modification in the epididymis for ZP binding. Our results indicate that the dipeptidase-inactivated tACE acts in vivo, suggesting that tACE contributes to fertilization as a dipeptidase at least in the epididymis.

  1. Does Education Plus Action Lead to Leadership on Climate? Preliminary Results from the ACE Leadership Development Longitudinal Survey Project

    NASA Astrophysics Data System (ADS)

    Anderson, R. K.; Qusba, L.; Lappe, M.; Flora, J. A.

    2014-12-01

    Through education and leadership development, Alliance for Climate Education (ACE) is building a generation of confident and capable youth driving climate solutions now throughout their lives. In 2011-12, a random sample of 2,800 high school students across the country was surveyed before and after seeing the ACE Assembly on climate science and solutions. The survey showed that the ACE Assembly resulted in a 27% increase in climate science knowledge scores, with 59% of students increasing their intentions to take action on climate and a doubling of the number of students talking to parents and peers about climate change. Students were also compared to the Global Warming's Six Americas classification of Americans' views on climate. Following the ACE Assembly, 60% of students were alarmed or concerned about climate change. Building off these results, in 2014 ACE began to assess the results of its leadership development program that follows the ACE Assembly. The goal of this survey project is to measure ACE's long-term impact on students' college and career pathways, civic engagement and climate action. Preliminary results show that a majority of students in ACE's leadership development program are alarmed about global warming and are having conversations about global warming. A majority of these students also feel confident in their ability to lead a climate-related campaign in their school and community. These students will continue to be surveyed through 2015.

  2. Validating the ACE Model for Evaluating Student Performance Using a Teaching-Learning Process Based on Computational Modeling Systems

    ERIC Educational Resources Information Center

    Louzada, Alexandre Neves; Elia, Marcos da Fonseca; Sampaio, Fábio Ferrentini; Vidal, Andre Luiz Pestana

    2014-01-01

    The aim of this work is to adapt and test, in a Brazilian public school, the ACE model proposed by Borkulo for evaluating student performance as a teaching-learning process based on computational modeling systems. The ACE model is based on different types of reasoning involving three dimensions. In addition to adapting the model and introducing…

  3. Egg ovotransferrin‐derived ACE inhibitory peptide IRW increases ACE2 but decreases proinflammatory genes expression in mesenteric artery of spontaneously hypertensive rats

    PubMed Central

    Majumder, Kaustav; Liang, Guanxiang; Chen, Yanhong; Guan, LeLuo; Davidge, Sandra T.

    2015-01-01

    Scope Egg ovotransferrin‐derived angiotensin converting enzyme (ACE) inhibitory peptide IRW was previously shown to reduce blood pressure in spontaneously hypertensive rats through reduced vascular inflammation and increased nitric oxide‐mediated vasorelaxation. The main objective of the present study was to investigate the molecular mechanism of this peptide through transcriptome analysis by RNAseq technique. Methods and results Total RNA was extracted from kidney and mesenteric arteries; the RNAseq libraries (from untreated and IRW‐treated groups) were constructed and subjected to sequence using HiSeq 2000 system (Illumina) system. A total of 12 764 and 13 352 genes were detected in kidney and mesenteric arteries, respectively. The differentially expressed (DE) genes between untreated and IRW‐treated groups were identified and the functional analysis through ingenuity pathway analysis revealed a greater role of DE genes identified from mesenteric arteries than that of kidney in modulating various cardiovascular functions. Subsequent qPCR analysis further confirmed that IRW significantly increased the expression of ACE‐2, ABCB‐1, IRF‐8, and CDH‐1 while significantly decreased the expression ICAM‐1 and VCAM‐1 in mesenteric arteries. Conclusion Our research showed for the first time that ACE inhibitory peptide IRW could contribute to its antihypertensive activity through increased ACE2 and decreased proinflammatory genes expression. PMID:26016560

  4. Long Term Missions at the Sun-Earth Libration Point L1: ACE, SOHO, and WIND

    NASA Technical Reports Server (NTRS)

    Roberts, Craig E.

    2011-01-01

    Three heliophysics missions -- the Advanced Composition Explorer (ACE), Solar Heliospheric Observatory (SOHO), and the Global Geoscience WIND -- have been orbiting the Sun-Earth interior libration point L1 continuously since 1997, 1996, and 2004, respectively. ACE and WIND (both NASA missions) and SOHO (an ESA-NASA joint mission) are all operated from the NASA Goddard Space Flight Center (GSFC). While ACE and SOHO have been dedicated libration point orbiters since their launches, WIND has had also a remarkable 10-year career flying a deep-space, multiple lunar-flyby trajectory prior to 2004. That era featured 36 targeted lunar flybys with excursions to both L1 and L2 before its final insertion in L1 orbit. A figure depicts the orbits of the three spacecraft, showing projections of the orbits onto the orthographic planes of a solar rotating ecliptic frame of reference. The SOHO orbit is a quasi-periodic halo orbit, where the frequencies of the in-plane and out-of-plane motions are practically equal. Such an orbit is seen to repeat itself with a period of approximately 178 days. For ACE and WIND, the frequencies of the in-plane and out-of-plane motions are unequal, giving rise to the characteristic Lissajous motion. ACE's orbit is of moderately small amplitude, whereas WIND's orbit is a large-amplitude Lissajous of dimensions close to those of the SOHO halo orbit. As motion about the collinear points is inherently unstable, stationkeeping maneuvers are necessary to prevent orbital decay and eventual escape from the L1 region. Though the three spacecraft are dissimilar (SOHO is a 3-axis stabilized Sun pointer, WIND is a spin-stabilized ecliptic pole pointer, and ACE is also spin-stabilized with its spin axis maintained between 4 and 20 degrees of the Sun), the stationkeeping technique for the three is fundamentally the same. The technique consists of correcting the energy of the orbit via a delta-V directed parallel or anti-parallel to the Spacecraft-to-Sun line. SOHO

  5. Entacapone, a catechol-O-methyltransferase inhibitor, improves the motor activity and dopamine content of basal ganglia in a rat model of Parkinson's disease induced by Japanese encephalitis virus.

    PubMed

    Hamaue, Naoya; Ogata, Akihiko; Terado, Mutsuko; Tsuchida, Shirou; Yabe, Ichiro; Sasaki, Hidenao; Hirafuji, Masahiko; Togashi, Hiroko; Aoki, Takashi

    2010-01-14

    Levodopa is the main medication used for the treatment of Parkinson's disease. However, dyskinesia and wearing-off appear after the administration of high-dose levodopa for a long period. To combat the dyskinesia and wearing-off, levodopa is used together with a dopamine (DA) receptor agonist, and the amount of levodopa is decreased. We have reported the monoamine oxidase (MAO)-B inhibitor selegiline to be effective for treating motor dysfunction in Parkinson's disease model rats. We analyzed the improvement in motor functions and catecholamine contents in various brain regions induced by a combination of the catechol-O-methyltransferase (COMT) inhibitor entacapone and a levodopa/dopadecarboxylase inhibitor (DDCI) in Japanese encephalitis virus (JEV) induced Parkinson's disease model rats. Entacapone (10 mg/kg) was administered via a single oral administration with levodopa/DDCI (10 mg/kg). The motor functions of the JEV model rats were significantly worsened, compared with those of the healthy control rats. The motor functions in the Parkinson's disease model rats were significantly recovered to the same levels as the healthy control rats by the combined administration of entacapone and levodopa/DDCI. A significant improvement in motor function was not demonstrated in the case of the administration of levodopa/DDCI alone. The striatal DA concentrations in the model rat brains were significantly increased by using levodopa/DDCI together with entacapone. Motor function was recovered by raising the striatum DA density in the model rats. Thus, COMT inhibitors are useful for decreasing the amount of levodopa administered to Parkinson's disease patients.

  6. Finding the perfect spot for fluorine: improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold.

    PubMed

    Lou, Yan; Sweeney, Zachary K; Kuglstatter, Andreas; Davis, Dana; Goldstein, David M; Han, Xiaochun; Hong, Junbae; Kocer, Buelent; Kondru, Rama K; Litman, Renee; McIntosh, Joel; Sarma, Keshab; Suh, Judy; Taygerly, Joshua; Owens, Timothy D

    2015-01-15

    A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.

  7. A Trypsin Inhibitor from Tamarind Reduces Food Intake and Improves Inflammatory Status in Rats with Metabolic Syndrome Regardless of Weight Loss

    PubMed Central

    Carvalho, Fabiana M. C.; Lima, Vanessa C. O.; Costa, Izael S.; Medeiros, Amanda F.; Serquiz, Alexandre C.; Lima, Maíra C. J. S.; Serquiz, Raphael P.; Maciel, Bruna L. L.; Uchôa, Adriana F.; Santos, Elizeu A.; Morais, Ana H. A.

    2016-01-01

    Trypsin inhibitors are studied in a variety of models for their anti-obesity and anti-inflammatory bioactive properties. Our group has previously demonstrated the satietogenic effect of tamarind seed trypsin inhibitors (TTI) in eutrophic mouse models and anti-inflammatory effects of other trypsin inhibitors. In this study, we evaluated TTI effect upon satiety, biochemical and inflammatory parameters in an experimental model of metabolic syndrome (MetS). Three groups of n = 5 male Wistar rats with obesity-based MetS received for 10 days one of the following: (1) Cafeteria diet; (2) Cafeteria diet + TTI (25 mg/kg); and (3) Standard diet. TTI reduced food intake in animals with MetS. Nevertheless, weight gain was not different between studied groups. Dyslipidemia parameters were not different with the use of TTI, only the group receiving standard diet showed lower very low density lipoprotein (VLDL) and triglycerides (TG) (Kruskal–Wallis, p < 0.05). Interleukin-6 (IL-6) production did not differ between groups. Interestingly, tumor necrosis factor-alpha (TNF-α) was lower in animals receiving TTI. Our results corroborate the satietogenic effect of TTI in a MetS model. Furthermore, we showed that TTI added to a cafeteria diet may decrease inflammation regardless of weight loss. This puts TTI as a candidate for studies to test its effectiveness as an adjuvant in MetS treatment. PMID:27690087

  8. Recombinant Expression and Characterization of Human and Murine ACE2: Species-Specific Activation of the Alternative Renin-Angiotensin-System