Gastrin-releasing peptide receptor (GRPr) promotes EMT, growth, and invasion in canine prostate cancer.

PubMed

Elshafae, Said M; Hassan, Bardes B; Supsavhad, Wachiraphan; Dirksen, Wessel P; Camiener, Rachael Y; Ding, Haiming; Tweedle, Michael F; Rosol, Thomas J

2016-06-01

The gastrin-releasing peptide receptor (GRPr) is upregulated in early and late-stage human prostate cancer (PCa) and other solid tumors of the mammary gland, lung, head and neck, colon, uterus, ovary, and kidney. However, little is known about its role in prostate cancer. This study examined the effects of a heterologous GRPr agonist, bombesin (BBN), on growth, motility, morphology, gene expression, and tumor phenotype of an osteoblastic canine prostate cancer cell line (Ace-1) in vitro and in vivo. The Ace-1 cells were stably transfected with the human GRPr and tumor cells were grown in vitro and as subcutaneous and intratibial tumors in nude mice. The effect of BBN was measured on cell proliferation, cell migration, tumor growth (using bioluminescence), tumor cell morphology, bone tumor phenotype, and epithelial-mesenchymal transition (EMT) and metastasis gene expression (quantitative RT-PCR). GRPr mRNA expression was measured in primary canine prostate cancers and normal prostate glands. Bombesin (BBN) increased tumor cell proliferation and migration in vitro and tumor growth and invasion in vivo. BBN upregulated epithelial-to-mesenchymal transition (EMT) markers (TWIST, SNAIL, and SLUG mRNA) and downregulated epithelial markers (E-cadherin and β-catenin mRNA), and modified tumor cell morphology to a spindle cell phenotype. Blockade of GRPr upregulated E-cadherin and downregulated VIMENTIN and SNAIL mRNA. BBN altered the in vivo tumor phenotype in bone from an osteoblastic to osteolytic phenotype. Primary canine prostate cancers had increased GRPr mRNA expression compared to normal prostates. These data demonstrated that the GRPr is important in prostate cancer growth and progression and targeting GRPr may be a promising strategy for treatment of prostate cancer. Prostate 76:796-809, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Solid-Phase Nucleic Acid Sequence-Based Amplification and Length-Scale Effects during RNA Amplification.

PubMed

Ma, Youlong; Teng, Feiyue; Libera, Matthew

2018-06-05

Solid-phase oligonucleotide amplification is of interest because of possible applications to next-generation sequencing, multiplexed microarray-based detection, and cell-free synthetic biology. Its efficiency is, however, less than that of traditional liquid-phase amplification involving unconstrained primers and enzymes, and understanding how to optimize the solid-phase amplification process remains challenging. Here, we demonstrate the concept of solid-phase nucleic acid sequence-based amplification (SP-NASBA) and use it to study the effect of tethering density on amplification efficiency. SP-NASBA involves two enzymes, avian myeloblastosis virus reverse transcriptase (AMV-RT) and RNase H, to convert tethered forward and reverse primers into tethered double-stranded DNA (ds-DNA) bridges from which RNA - amplicons can be generated by a third enzyme, T7 RNA polymerase. We create microgels on silicon surfaces using electron-beam patterning of thin-film blends of hydroxyl-terminated and biotin-terminated poly(ethylene glycol) (PEG-OH, PEG-B). The tethering density is linearly related to the PEG-B concentration, and biotinylated primers and molecular beacon detection probes are tethered to streptavidin-activated microgels. While SP-NASBA is very efficient at low tethering densities, the efficiency decreases dramatically with increasing tethering density due to three effects: (a) a reduced hybridization efficiency of tethered molecular beacon detection probes; (b) a decrease in T7 RNA polymerase efficiency; (c) inhibition of T7 RNA polymerase activity by AMV-RT.

Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors

PubMed Central

Wang, Lei; de Kloet, Annette D.; Pati, Dipanwita; Hiller, Helmut; Smith, Justin A.; Pioquinto, David J.; Ludin, Jacob A.; Oh, S. Paul; Katovich, Michael J.; Frazier, Charles J.; Raizada, Mohan K.; Krause, Eric G.

2016-01-01

Over-activation of brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme (ACE2) inhibits RAS activity by converting angiotensin II, the effector peptide of RAS, to angiotensin-(1-7), which activates Mas receptors (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ~62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the BLA. PMID:26767952

Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies.

PubMed

Raftopoulos, Haralambos; Laadem, Abderrahmane; Hesketh, Paul J; Goldschmidt, Jerome; Gabrail, Nashat; Osborne, Cynthia; Ali, Muhammad; Sherman, Matthew L; Wang, Ding; Glaspy, John A; Puccio-Pick, Marie; Zou, Jun; Crawford, Jeffrey

2016-04-01

Sotatercept may represent a novel approach to the treatment of chemotherapy-induced anemia (CIA). We report the results from two phase 2 randomized studies examining the use of sotatercept for the treatment of CIA in patients with metastatic cancer. In study A011-08, patients with metastatic breast cancer were randomized to 2:2:2:1 to receive sotatercept 0.1, 0.3, or 0.5 mg/kg, or placebo, respectively, every 28 days. In study ACE-011-NSCL-001, patients with solid tumors treated with platinum-based chemotherapy received sotatercept 15 or 30 mg every 42 days. The primary endpoint for both studies was hematopoietic response, defined as a hemoglobin (Hb) increase of ≥1 g/dL from baseline. Both studies were terminated early due to slow patient accrual. Among patients treated with sotatercept in the A011-08 and ACE-011-NSCL-001 studies, more patients achieved a mean Hb increase of ≥1 g/dL in the combined sotatercept 0.3 mg/kg and 15 mg (66.7 %) group and sotatercept 0.5 mg/kg and 30 mg (38.9 %) group versus the sotatercept 0.1 mg/kg (0 %) group. No patients achieved a mean Hb increase of ≥1 g/dL in the placebo group. The incidence of treatment-related adverse events (AEs) was low in both studies, and treatment discontinuations due to AEs were uncommon. Although both studies were terminated early, these results indicate that sotatercept is active and has an acceptable safety profile in the treatment of CIA.

Effect of long-term treatment with urocortin on the activity of somatic angiotensin-converting enzyme in spontaneously hypertensive rats.

PubMed

Yang, Cui; Liu, Xiuxia; Li, Shengnan

2010-02-01

Our previous acute study on urocortin (Ucn) demonstrated that Ucn altered serum and tissue angiotensin-converting enzyme (ACE) activity in rats. Therefore, the present investigation was designed to explore the effect of long-term treatment with Ucn on somatic ACE (sACE) and other components of the renin-angiotensin system (RAS). After 8 weeks of intravenous administration of Ucn in spontaneously hypertensive rats (SHR), serum and tissue sACE, angiotensin II (Ang II), nitric oxide (NO), Ang-(1-7), and tissue chymase activities were evaluated. RT-PCR analysis was performed to determine the quantity of tissue sACE mRNA. Serum sACE activity was reduced by Ucn, although tissue sACE activity and tissue sACE mRNA were elevated. Chymase activity was observed to be enhanced by Ucn, whereas the ACE inhibitor enalapril failed to influence chymase. Serum and tissue Ang II activity was reduced, but NO and Ang-(1-7) production was increased in a concentration-dependent manner after Ucn treatment. Meanwhile, a significant decrease of the systolic blood pressure (SBP) was observed after the long-term Ucn administration, and there was a significant positive correlation (r2 = 0.6993) between serum ACE activity and SBP. Pretreatment with the corticotropin-releasing factor (CRF) blocker astressin and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway blocker PD98059 abolished these effects of Ucn. Our findings further support the hypothesis that the changes of sACE activity and the production of other RAS components may play roles in the vasodilatory property of Ucn via the activation of the ERK1/2 pathway.

The Impact of DNA Topology and Guide Length on Target Selection by a Cytosine-Specific Cas9.

PubMed

Tsui, Tsz Kin Martin; Hand, Travis H; Duboy, Emily C; Li, Hong

2017-06-16

Cas9 is an RNA-guided DNA cleavage enzyme being actively developed for genome editing and gene regulation. To be cleaved by Cas9, a double stranded DNA, or the protospacer, must be complementary to the guide region, typically 20-nucleotides in length, of the Cas9-bound guide RNA, and adjacent to a short Cas9-specific element called Protospacer Adjacent Motif (PAM). Understanding the correct juxtaposition of the protospacer- and PAM-interaction with Cas9 will enable development of versatile and safe Cas9-based technology. We report identification and biochemical characterization of Cas9 from Acidothermus cellulolyticus (AceCas9). AceCas9 depends on a 5'-NNNCC-3' PAM and is more efficient in cleaving negative supercoils than relaxed DNA. Kinetic as well as in vivo activity assays reveal that AceCas9 achieves optimal activity when combined with a guide RNA containing a 24-nucleotide complementarity region. The cytosine-specific, DNA topology-sensitive, and extended guide-dependent properties of AceCas9 may be explored for specific genome editing applications.

Angiotensin-converting enzyme 2 is subject to post-transcriptional regulation by miR-421.

PubMed

Lambert, Daniel W; Lambert, Louise A; Clarke, Nicola E; Hooper, Nigel M; Porter, Karen E; Turner, Anthony J

2014-08-01

ACE2 (angiotensin converting enzyme 2) plays a critical role in the local tissue RAS (renin-angiotensin system) by hydrolysing the potent hypertensive and mitogenic peptide AngII (angiotensin II). Changes in the levels of ACE2 have been observed in a number of pathologies, including cardiovascular disease, but little is known of the mechanisms regulating its expression. In the present study, therefore, the potential role of miRNAs in the regulation of ACE2 expression in primary human cardiac myofibroblasts was examined. Putative miRNA-binding sites were identified in the 3'-UTR of the ACE2 transcript using online prediction algorithms. Two of these, miR-200b and miR-421, were selected for further analysis. A reporter system using the 3'-UTR of ACE2 fused to the coding region of firefly luciferase was used to determine the functionality of the identified binding sites in vitro. This identified miR-421, but not miR-200b, as a potential regulator of ACE2. The ability of miR-421, an miRNA implicated in the development of thrombosis, to down-regulate ACE2 expression was subsequently confirmed by Western blot analysis of both primary cardiac myofibroblasts and transformed cells transfected with a synthetic miR-421 precursor. Real-time PCR analysis of miR-421 revealed widespread expression in human tissues. miR-421 levels in cardiac myofibroblasts showed significant inter-patient variability, in keeping with the variability of ACE2 expression we have observed previously. In conclusion, the present study is the first to demonstrate that ACE2 may be subject to post-transcriptional regulation and reveals a novel potential therapeutic target, miR-421, which could be exploited to modulate ACE2 expression in disease.

Functional and molecular evidence for expression of the renin angiotensin system and ADAM17-mediated ACE2 shedding in COS7 cells

PubMed Central

Grobe, Nadja; Di Fulvio, Mauricio; Kashkari, Nada; Chodavarapu, Harshita; Somineni, Hari K.; Singh, Richa

2015-01-01

The renin angiotensin system (RAS) plays a vital role in the regulation of the cardiovascular and renal functions. COS7 is a robust and easily transfectable cell line derived from the kidney of the African green monkey, Cercopithecus aethiops. The aims of this study were to 1) demonstrate the presence of an endogenous and functional RAS in COS7, and 2) investigate the role of a disintegrin and metalloproteinase-17 (ADAM17) in the ectodomain shedding of angiotensin converting enzyme-2 (ACE2). Reverse transcription coupled to gene-specific polymerase chain reaction demonstrated expression of ACE, ACE2, angiotensin II type 1 receptor (AT1R), and renin at the transcript levels in total RNA cell extracts. Western blot and immunohistochemistry identified ACE (60 kDa), ACE2 (75 kDa), AT1R (43 kDa), renin (41 kDa), and ADAM17 (130 kDa) in COS7. At the functional level, a sensitive and selective mass spectrometric approach detected endogenous renin, ACE, and ACE2 activities. ANG-(1–7) formation (m/z 899) from the natural substrate ANG II (m/z 1,046) was detected in lysates and media. COS7 cells stably expressing shRNA constructs directed against endogenous ADAM17 showed reduced ACE2 shedding into the media. This is the first study demonstrating endogenous expression of the RAS and ADAM17 in the widely used COS7 cell line and its utility to study ectodomain shedding of ACE2 mediated by ADAM17 in vitro. The transfectable nature of this cell line makes it an attractive cell model for studying the molecular, functional, and pharmacological properties of the renal RAS. PMID:25740155

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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

Expression of genes of the cardiac and renal renin-angiotensin systems in preterm piglets: is this system a suitable target for therapeutic intervention?

PubMed

Kim, Eleanor; Eiby, Yvonne; Lumbers, Eugenie; Boyce, Amanda; Gibson, Karen; Lingwood, Barbara

2015-10-01

The newborn circulating, cardiac and renal renin-angiotensin systems (RASs) are essential for blood pressure control, and for cardiac and renal development. If cardiac and renal RASs are immature this may contribute to cardiovascular compromise in preterm infants. This study measured mRNA expression of cardiac and renal RAS components in preterm, glucocorticoid (GC) exposed preterm, and term piglets. Renal and cardiac RAS mRNA levels were measured using real-time polymerase chain reaction (PCR). Genes studied were: (pro)renin receptor, renin, angiotensinogen, angiotensin converting enzyme (ACE), ACE2, angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R). All the genes studied were expressed in the kidney; neither renin nor AT2R mRNA were detected in the heart. There were no gestational changes in (pro)renin receptor, renin, ACE or AT1R mRNA levels. Right ventricular angiotensinogen mRNA levels in females were lower in preterm animals than at term, and GC exposure increased levels in male piglets. Renal angiotensinogen mRNA levels in female term piglets were lower than females from both preterm groups, and lower than male term piglets. Left ventricular ACE2 mRNA expression was lower in GC treated preterm piglets. Renal AT2R mRNA abundance was highest in GC treated preterm piglets, and the AT1R/AT2R ratio was increased at term. Preterm cardiac and renal RAS mRNA levels were similar to term piglets, suggesting that immaturity of these RASs does not contribute to preterm cardiovascular compromise. Since preterm expression of both renal and cardiac angiotensin II-AT1R is similar to term animals, cardiovascular dysfunction in the sick preterm human neonate might be effectively treated by agents acting on their RASs. © The Author(s), 2015.

Regulation of NlE74A on vitellogenin might be mediated by angiotensin converting enzyme through a fecundity-related SNP in the brown planthopper, Nilaparvata lugens.

PubMed

Sun, Zhongxiang; Shi, Qi; Xu, Cuicui; Wang, Rumeng; Wang, Huanhuan; Song, Yuanyuan; Zeng, Rensen

2018-06-19

The major yolk protein precursors (YPP) gene, vitellogenin (Vg), usually considered as a reproductive indicator and molecular marker for evaluating insect fecundity, is controlled by insect hormone (mainly ecdysteroids and juvenile hormone), transcription factors and many other fecundity-related genes. To better understand the underlying molecular regulation mechanisms of the NlVg in the brown planthopper Nilaparvata lugens (N. lugens), the correlation between one early ecdysone response gene E74 and one important fecundity-related gene angiotensin converting enzyme (ACE) on the regulation of Vg gene expression, was investigated. We first showed that the mRNA expression level of NlACE were significantly higher in a high-fecundity population (HFP) than a low-fecundity population (LFP) at different development stages, and knockdown of NlACE expression by RNA interference (RNAi) results in a reduced level of NlVg expression and N. lugens fecundity. Subsequently, we analyzed the promoter of NlACE and found an E74A binding site, which was also differentially expressed in HFP and LFP. Then a gene putatively encoding E74A, namely NlE74A, predominant in the ovary and fat body was cloned and characterized. Furthermore, the developmental profile during female adult and the tissue-specific expression pattern of NlACE and NlE74A were similar to the expression pattern of NlVg gene, implying that both NlACE and NlE74A may be involved in regulating the expression of NlVg. Finally, after injecting the dsRNA of NlE74A, the NlACE expression levels were significantly reduced simultaneously at 24 h and 48 h post-injection, and the NlVg expression level was significant reduced at 24 h post-injection and the downswing was more significant at 48 h post-injection. These results imply that regulation of NlE74A on NlVg transcription might be mediated by NlACE through the E74 binding site at the NlACE promoter region in N. lugens. Copyright © 2018. Published by Elsevier Inc.

Stabilization of Angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid.

PubMed

Wester, Anita; Devocelle, Marc; Tallant, E Ann; Chappell, Mark C; Gallagher, Patricia E; Paradisi, Francesca

2017-10-01

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system, is a promising candidate as a treatment for cancer that reflects its anti-proliferative and anti-angiogenic properties. However, the peptide's therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP 3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer.

Artificial sweeteners--a recently recognized class of emerging environmental contaminants: a review.

PubMed

Lange, Frank T; Scheurer, Marco; Brauch, Heinz-J

2012-07-01

An overview is given of existing trace analytical methods for the determination of seven popular artificial sweeteners [acesulfame (ACE), aspartame, cyclamate (CYC), neotame, neohesperidine dihydrochalcone, saccharin (SAC), and sucralose (SUC)] from aqueous environmental samples. Liquid chromatography-electrospray ionization tandem mass spectrometry and liquid chromatography-electrospray ionization high-resolution mass spectrometry are the methods most widely applied, either directly or after solid-phase extraction. Limits of detection and limits of quantification down to the low nanogram per liter range can be achieved. ACE, CYC, SAC, and SUC were detected in wastewater treatment plants in high microgram per liter concentrations. Per capita loads of individual sweeteners can vary within a wide range depending on their use in different countries. Whereas CYC and SAC are usually degraded by more than 90% during wastewater treatment, ACE and SUC pass through wastewater treatment plants mainly unchanged. This suggests their use as virtually perfect markers for the study of the impact of wastewater on source waters and drinking waters. In finished water of drinking water treatment plants using surface-water-influenced source water, ACE and SUC were detected in concentrations up to 7 and 2.4 μg/L, respectively. ACE was identified as a precursor of oxidation byproducts during ozonation, resulting in an aldehyde intermediate and acetic acid. Although the concentrations of ACE and SUC are among the highest measured for anthropogenic trace pollutants found in surface water, groundwater, and drinking water, the levels are at least three orders of magnitude lower than organoleptic threshold values. However, ecotoxicology studies are scarce and have focused on SUC. Thus, further research is needed both on identification of transformation products and on the ecotoxicological impact of artificial sweeteners and their transformation products.

Determination of DDT and metabolites in surface water and sediment using LLE, SPE, ACE and SE.

PubMed

Sibali, Linda L; Okonkwo, Jonathan O; Zvinowanda, Caliphs

2009-12-01

Surface water and sediment samples collected from Jukskei River in South Africa, were subjected to different extraction techniques, liquid-liquid (LLE), solid-phase extraction (SPE), activated carbon extraction (ACE) and soxhlet extraction (SE) for sediment. The samples were extracted with dichloromethane, cleaned in a silica gel column and the extracts quantified using a Varian 3800 GC-ECD. The percentage recovery test for 2,4'DDT, DDE and DDD and 4,4'DDT, DDE and DDD in water ranged from 80%-96% and 76%-95% (LLE); 56%-76% and 56%-70% (SPE) and 75%-84% (ACE), respectively; while that recoveries for sediment samples varied from 65%-95% for 2,4'DDT, DDE and DDD and 80%-91% for 4,4'DDT, DDE and DDD. The high recoveries exhibited by ACE compared very well with LLE and SE. This was not the case with SPE which exhibited the lowest value of recoveries for both 2,4 and 4,4'DDD, DDE and DDT standard samples. The mean concentrations of DDT and metabolites ranged from nd-1.10 μg/L, nd-0.80 μg/L, nd-1.21 μg/L and 1.92 μg/L for LLE, SPE, ACE and SE, respectively. The total DDT (2,4' and 4,4'-DDT) in water and sediment samples ranged from 1.20-3.25 μg/L and 1.82-5.24 μg/L, respectively. The low concentrations of the DDT metabolites obtained in the present study may suggest a recent contamination of the river by DDT.

Long-term systemic angiotensin II type 1 receptor blockade regulates mRNA expression of dorsomedial medulla renin-angiotensin system components.

PubMed

Gilliam-Davis, Shea; Gallagher, Patricia E; Payne, Valerie S; Kasper, Sherry O; Tommasi, Ellen N; Westwood, Brian M; Robbins, Michael E; Chappell, Mark C; Diz, Debra I

2011-07-14

In Fischer 344 (F344) rats, renin-angiotensin system (RAS) blockade for 1 yr with the angiotensin II type 1 (AT(1)) receptor blocker L-158,809 prevents age-related impairments in metabolic function, similar to transgenic rats with low glial angiotensinogen (Aogen). Brain RAS regulation may contribute to the benefits of long-term systemic AT(1) antagonism. We assessed the mRNA of RAS components in the dorsomedial medulla of F344 rats at 3 (young; n = 8) or 15 mo of age (old; n = 7) and in rats treated from 3 to 15 mo of age with 20 mg/l of the AT(1) receptor antagonist L-158,809 (Old+L; n = 6). Aogen and renin mRNA were lower in the young compared with old group. Angiotensin-converting enzyme (ACE) mRNA was lower in the old and Old+L compared with the young group. ACE2 and neprilysin expression were significantly higher in Old+L compared with young or old rats. AT(1b), AT(2), and Mas receptor mRNA were higher with treatment. Leptin receptor mRNA was lower in the old rats and this was prevented by L-158,809 treatment. Dual-specificity phosphatase 1 (DUSP1) mRNA was highest in the Old+L group. Aggregate correlate summation revealed a positive relationship for Mas receptor mRNA with food intake. The findings provide evidence for regulation of dorsomedial medullary renin and Aogen mRNA during aging. Long-term AT(1) receptor blockade increases the mRNA of the enzymes ACE2 and neprilysin and the MAS receptor, which could potentially shift the balance from ANG II to ANG-(1-7) and prevent age-related declines in the leptin receptor and its signaling pathway.

Carbon nanotube enhanced label-free detection of microRNAs based on hairpin probe triggered solid-phase rolling-circle amplification

NASA Astrophysics Data System (ADS)

Tian, Qianqian; Wang, Ying; Deng, Ruijie; Lin, Lei; Liu, Yang; Li, Jinghong

2014-12-01

The detection of microRNAs (miRNAs) is imperative for gaining a better understanding of the functions of these biomarkers and has great potential for the early diagnosis of human disease. High sensitivity and selectivity for miRNA detection brings new challenges. Herein, an ultrasensitive protocol for electrochemical detection of miRNA is designed through carbon nanotube (CNT) enhanced label-free detection based on hairpin probe triggered solid-phase rolling-circle amplification (RCA). Traditionally, RCA, widely applied for signal enhancement in the construction of a variety of biosensors, has an intrinsic limitation of ultrasensitive detection, as it is difficult to separate the enzymes, templates, and padlock DNAs from the RCA products in the homogeneous solution. We purposely designed a solid-phase RCA strategy, using CNTs as the solid substrate, integrated with a hairpin structured probe to recognize target miRNA. In the presence of miRNA the stem-loop structure will be unfolded, triggering the CNT based RCA process. Due to the efficient blocking effect originating from the polymeric RCA products, the label-free assay of miRNA exhibits an ultrasensitive detection limit of 1.2 fM. Furthermore, the protocol possesses excellent specificity for resolving lung cancer-related let-7 family members which have only one-nucleotide variations. The high sensitivity and selectivity give the method great potential for applications in online diagnostics and in situ detection in long-term development.The detection of microRNAs (miRNAs) is imperative for gaining a better understanding of the functions of these biomarkers and has great potential for the early diagnosis of human disease. High sensitivity and selectivity for miRNA detection brings new challenges. Herein, an ultrasensitive protocol for electrochemical detection of miRNA is designed through carbon nanotube (CNT) enhanced label-free detection based on hairpin probe triggered solid-phase rolling-circle amplification (RCA). Traditionally, RCA, widely applied for signal enhancement in the construction of a variety of biosensors, has an intrinsic limitation of ultrasensitive detection, as it is difficult to separate the enzymes, templates, and padlock DNAs from the RCA products in the homogeneous solution. We purposely designed a solid-phase RCA strategy, using CNTs as the solid substrate, integrated with a hairpin structured probe to recognize target miRNA. In the presence of miRNA the stem-loop structure will be unfolded, triggering the CNT based RCA process. Due to the efficient blocking effect originating from the polymeric RCA products, the label-free assay of miRNA exhibits an ultrasensitive detection limit of 1.2 fM. Furthermore, the protocol possesses excellent specificity for resolving lung cancer-related let-7 family members which have only one-nucleotide variations. The high sensitivity and selectivity give the method great potential for applications in online diagnostics and in situ detection in long-term development. Electronic supplementary information (ESI) available: Preparation of the chemically modified multi-walled carbon nanotubes (CNTs), characterization of the CNTs and modified CNTs, preparation of the circular probe, gel electrophoresis of the RCA products, and DNA probes as noted in the text. See DOI: 10.1039/c4nr05243a

Tissue-specific modulation of angiotensin-converting enzyme (ACE) in hyperthyroidism.

PubMed

Carneiro-Ramos, M S; Silva, V B; Santos, R A S; Barreto-Chaves, M L M

2006-11-01

We have previously demonstrated the interaction between the RAS and thyroid hormones (TH). The present study was designed to determine the role of TH in the local regulation of ACE activity and expression in different tissues. Adult male Wistar rats were randomized into three groups: T4-25 and T4-100 (0.025 and 0.100mg/kg of body weight/day of l-thyroxine for 14 days, respectively) and control. Hemodynamic parameters as well as cardiac and renal hypertrophy were evaluated. ACE activity and mRNA levels were determined by Fluorimetric and Northern blot assays, respectively. Both doses increased SBP and HR, as well as inducing cardiac and renal hypertrophy. Pulmonary and serum ACE levels were comparable among the groups. Both doses promoted increased renal ACE activity and expression but surprisingly ACE was diminished in the heart in both hyperthyroid groups. This change was mediated by a tissue-specific transcription mechanism.

Solid-Phase Synthesis of RNA Analogs Containing Phosphorodithioate Linkages.

PubMed

Yang, Xianbin

2017-09-18

The oligoribonucleotide phosphorodithioate (PS2-RNA) modification uses two sulfur atoms to replace two non-bridging oxygen atoms at an internucleotide phosphorodiester backbone linkage. Like a natural phosphodiester RNA backbone linkage, a PS2-modified backbone linkage is achiral at phosphorus. PS2-RNAs are highly stable to nucleases and several in vitro assays have demonstrated their biological activity. For example, PS2-RNAs silenced mRNA in vitro and bound to protein targets in the form of PS2-aptamers (thioaptamers). Thus, the interest in and promise of PS2-RNAs has drawn attention to synthesizing, isolating, and characterizing these compounds. RNA-thiophosphoramidite monomers are commercially available from AM Biotechnologies and this unit describes an effective methodology for solid-phase synthesis, deprotection, and purification of RNAs having PS2 internucleotide linkages. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

Gestational Protein Restriction Increases Angiotensin II Production in Rat Lung1

PubMed Central

Gao, Haijun; Yallampalli, Uma; Yallampalli, Chandra

2013-01-01

ABSTRACT Gestational protein restriction (PR) alters the renin-angiotensin system in uterine arteries and placentas and elevates plasma levels of angiotensin II in pregnant rats. To date, how PR increases maternal plasma levels of angiotensin II remains unknown. In this study, we hypothesize that the expression and/or the activity of angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 (ACE) in lungs, but not kidneys and blood, largely contribute to elevated plasma angiotensin II levels in pregnant rats subject to gestational PR. Time-scheduled pregnant Sprague-Dawley rats were fed a normal or low-protein diet from Day 3 of pregnancy until euthanized at Day 19 or 22. Expressions of Ace and Ace2 (angiotens in I converting enzyme [peptidyl-dipeptidase A] 2) in lungs and kidneys from pregnant rats by quantitative real-time PCR and Western blotting, and the activities of these proteins in lungs, kidneys, and plasma, were measured. The mRNA levels of Ace and Ace2 in lungs were elevated by PR at both Days 19 and 22 of pregnancy. The abundance of ACE protein in lungs was increased, but ACE2 protein was decreased, by PR. The activities of ACE, but not ACE2, in lungs were increased by PR. PR did not change expressions of Ace and Ace2, the activities of both ACE and ACE2 in kidneys, and the abundance and activity of plasma ACE. These findings suggest that maternal lungs contribute to the elevated plasma levels of angiotensin II by increasing both the expression and the activity of ACE in response to gestational PR. PMID:23365412

Role of angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis in the hypotensive effect of azilsartan.

PubMed

Iwanami, Jun; Mogi, Masaki; Tsukuda, Kana; Wang, Xiao-Li; Nakaoka, Hirotomo; Ohshima, Kousei; Chisaka, Toshiyuki; Bai, Hui-Yu; Kanno, Harumi; Min, Li-Juan; Horiuchi, Masatsugu

2014-07-01

The possible counteracting effect of angiotensin (Ang)-converting enzyme (ACE)2/Ang-(1-7)/Mas axis against the ACE/Ang II/Ang II type 1 (AT1) receptor axis in blood pressure control has been previously described. We examined the possibility that this pathway might be involved in the anti-hypertensive effect of a newly developed AT1 receptor blocker (ARB), azilsartan, and compared azilsartan's effects with those of another ARB, olmesartan. Transgenic mice carrying the human renin and angiotensinogen genes (hRN/hANG-Tg) were given azilsartan or olmesartan. Systolic and diastolic blood pressure, as determined by radiotelemetry, were significantly higher in hRN/hANG-Tg mice than in wild-type (WT) mice. Treatment with azilsartan or olmesartan (1 or 5 mg kg(-1) per day) significantly decreased systolic and diastolic blood pressure, and the blood pressure-lowering effect of azilsartan was more marked than that of olmesartan. The urinary Na concentration decreased in an age-dependent manner in hRN/hANG-Tg mice. Administration of azilsartan or olmesartan increased urinary Na concentration, and this effect was weaker with olmesartan than with azilsartan. Azilsartan decreased ENaC-α mRNA expression in the kidney and decreased the ratio of heart to body weight. Olmesartan had a similar but less-marked effect. ACE2 mRNA expression was lower in the kidneys and hearts of hRN/hANG-Tg mice than in WT mice. This decrease in ACE2 mRNA expression was attenuated by azilsartan, but not by olmesartan. These results suggest that the hypotensive and anti-hypertrophic effects of azilsartan may involve activation of the ACE2/Ang-(1-7)/Mas axis with AT1 receptor blockade.

Library Screen Identifies Enterococcus faecalis CcpA, the Catabolite Control Protein A, as an Effector of Ace, a Collagen Adhesion Protein Linked to Virulence

PubMed Central

Gao, Peng; Pinkston, Kenneth L.; Bourgogne, Agathe; Cruz, Melissa R.; Garsin, Danielle A.; Murray, Barbara E.

2013-01-01

The Enterococcus faecalis cell wall-anchored protein Ace is an important virulence factor involved in cell adhesion and infection. Expression of Ace on the cell surface is affected by many factors, including stage of growth, culture temperature, and environmental components, such as serum, urine, and collagen. However, the mechanisms that regulate or modulate Ace display are not well understood. With interest in identifying genes associated with Ace expression, we utilized a whole-cell enzyme-linked immunosorbent assay (ELISA)-based screening method to identify mutants from a transposon insertion mutant library which exhibited distinct Ace surface expression profiles. We identified a ccpA insertion mutant which showed significantly decreased levels of Ace surface expression at early growth phase versus those of wild-type OG1RF. Confirmation of the observation was achieved through flow cytometry and complementation analysis. Compared to the wild type, the E. faecalis ccpA mutant had an impaired ability to adhere to collagen when grown to early exponential phase, consistent with the lack of Ace expression in the early growth phase. As a key component of carbon catabolite regulation, CcpA has been previously reported to play a critical role in regulating expression of proteins involved in E. faecalis carbohydrate uptake and utilization. Our discovery is the first to associate CcpA with the production of a major E. faecalis virulence factor, providing new insights into the regulation of E. faecalis pathogenesis. PMID:23974022

KSC-97PC1170

NASA Image and Video Library

1997-07-31

The solid rocket motors of the Delta II rocket which will to be used to launch the Advanced Composition Explorer (ACE) spacecraft are erected at Launch Complex 17A at Cape Canaveral Air Station. Scheduled for launch on Aug. 25, ACE will study low-energy particles of solar origin and high-energy galactic particles. The ACE observatory will be placed into an orbit almost a million miles (1.5 million kilometers) away from the Earth, about 1/100 the distance from the Earth to the Sun

Sex-dependent effects of antenatal glucocorticoids on insulin sensitivity in adult sheep: role of the adipose tissue renin angiotensin system

PubMed Central

Massmann, G. Angela; Zhang, Jie; Seong, Won Joon; Kim, Minhyoung

2017-01-01

Exposure to glucocorticoids in utero is associated with changes in organ function and structure in the adult. The aims of this study were to characterize the effects of antenatal exposure to glucocorticoids on glucose handling and the role of adipose tissue. Pregnant sheep received betamethasone (Beta, 0.17 mg/kg) or vehicle 24 h apart at 80 days of gestation and allowed to deliver at term. At 9 mo, male and female offspring were fed at either 100% of nutritional allowance (lean) or ad libitum for 3 mo (obese). At 1 yr, they were chronically instrumented under general anesthesia. Glucose tolerance was evaluated using a bolus of glucose (0.25 g/kg). Adipose tissue was harvested after death to determine mRNA expression levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) 1, ACE2, and peroxisome proliferator-activated receptor γ (PPAR-γ). Data are expressed as means ± SE and analyzed by ANOVA. Sex, obesity, and Beta exposure had significant effects on glucose tolerance and mRNA expression. Beta impaired glucose tolerance in lean females but not males. Superimposed obesity worsened the impairment in females and unmasked the defect in males. Beta increased ACE1 mRNA in females and males and AGT in females only (P < 0.05 by three-way ANOVA). Obesity increased AGT in females but had no effect on ACE1 in either males or females. PPAR-γ mRNA exhibited a significant sex (F = 42.8; P < 0.01) and obesity (F = 6.9; P < 0.05) effect and was significantly higher in males (P < 0.01 by three-way ANOVA). We conclude that adipose tissue may play an important role in the sexually dimorphic response to antenatal glucocorticoids. PMID:28356296

Availability and feasibility of structured, routine collection of comorbidity data in a colorectal cancer multi-disciplinary team (MDT) setting.

PubMed

Abukar, A A; Ramsanahie, A; Martin-Lumbard, K; Herrington, E R; Winslow, V; Wong, S; Ahmed, S; Thaha, M A

2018-05-03

Availability of comorbidity assessment at multi-disciplinary team (MDT) discussions is cornerstone in making the MDT process more robust and decisive in optimising treatment and improving quality of survivorship. Comorbidity assessments using tools, such as the ACE-27 questionnaire would aid in optimising the decision-making process at MDTs so that treatment decisions can be made without delay. This study determined the availability of comorbidity data in a CRC MDT and the feasibility of routine comorbidity data collection using the validated ACE-27 questionnaire. Secondary aims determined the optimal time and method of collecting comorbidity data. A retrospective mapping exercise (phase I; 6-months) examined the availability of comorbidity data within the MDT. Phase II prospectively collected comorbidity data using ACE-27 for a 3-month period following a short pilot. In phase I, 73/135 (54%) patients had comorbidity data readily available informing the MDT discussion; 62 patients lacked this information. After a review of the patient records, it was clear that 41 of these 62 also had comorbidities and 21 out of the 135 had ≥ 2 major system disorders. Common referral sources to the MDT were surgical outpatient clinics (42%) and the endoscopy unit (13%). The average lead-time from referral to MDT discussion was 14 days. In phase II, an ACE-27 questionnaire was prospectively administered in 50 patients, mean age 54 years (range 20-84). Male: female ratio 26:24. Average time to administer ACE-27 was 4.8 min (range 1-15). The phase I study confirmed the widely acknowledged view of poor comorbidity data availability within a CRC MDT. Phase II demonstrated the feasibility of routinely collecting comorbidity data using ACE-27.

Angiotensin-converting enzyme inhibition and angiotensin AT1 receptor blockade downregulate angiotensin-converting enzyme expression and attenuate renal injury in streptozotocin-induced diabetic rats.

PubMed

Motawi, Tarek K; El-Maraghy, Shohda A; Senousy, Mahmoud A

2013-07-01

Angiotensin-converting enzyme (ACE) is upregulated in the diabetic kidney and contributes to renal injury. This study investigates the possible beneficial effects of the ACE inhibitor (ACEI), enalapril and the AT1 receptor blocker (ARB), valsartan, on renal ACE expression, renal structure, and function in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were allocated into four groups: control, STZ-diabetic rats, and STZ-diabetic rats treated with either enalapril (10 mg/kg/day) or valsartan (50 mg/kg/day) for 8 weeks. Enalapril and valsartan reduced renal ACE mRNA and protein expression, Na(+) /K(+) -ATPase activity, oxidative stress, and serum transforming growth factor-β1 levels compared to the diabetic group. Both treatments normalized renal nitrate/nitrite levels and ameliorated the observed histopathological changes. In conclusion, ACE downregulation by ACEI and ARB indicates that angiotensin II upregulates ACE through AT1 receptor. Prevention of diabetes-induced changes in ACE expression and Na(+) /K(+) -ATPase activity could be a new explanation of the renoprotective effects of ACEIs and ARBs. © 2013 Wiley Periodicals, Inc.

Additive Construction with Mobile Emplacement (ACME) / Automated Construction of Expeditionary Structures (ACES) Materials Delivery System (MDS)

NASA Technical Reports Server (NTRS)

Mueller, R. P.; Townsend, I. I.; Tamasy, G. J.; Evers, C. J.; Sibille, L. J.; Edmunson, J. E.; Fiske, M. R.; Fikes, J. C.; Case, M.

2018-01-01

The purpose of the Automated Construction of Expeditionary Structures, Phase 3 (ACES 3) project is to incorporate the Liquid Goods Delivery System (LGDS) into the Dry Goods Delivery System (DGDS) structure to create an integrated and automated Materials Delivery System (MDS) for 3D printing structures with ordinary Portland cement (OPC) concrete. ACES 3 is a prototype for 3-D printing barracks for soldiers in forward bases, here on Earth. The LGDS supports ACES 3 by storing liquid materials, mixing recipe batches of liquid materials, and working with the Dry Goods Feed System (DGFS) previously developed for ACES 2, combining the materials that are eventually extruded out of the print nozzle. Automated Construction of Expeditionary Structures, Phase 3 (ACES 3) is a project led by the US Army Corps of Engineers (USACE) and supported by NASA. The equivalent 3D printing system for construction in space is designated Additive Construction with Mobile Emplacement (ACME) by NASA.

Long-term systemic angiotensin II type 1 receptor blockade regulates mRNA expression of dorsomedial medulla renin-angiotensin system components

PubMed Central

Gilliam-Davis, Shea; Gallagher, Patricia E.; Payne, Valerie S.; Kasper, Sherry O.; Tommasi, Ellen N.; Westwood, Brian M.; Robbins, Michael E.; Chappell, Mark C.

2011-01-01

In Fischer 344 (F344) rats, renin-angiotensin system (RAS) blockade for 1 yr with the angiotensin II type 1 (AT1) receptor blocker L-158,809 prevents age-related impairments in metabolic function, similar to transgenic rats with low glial angiotensinogen (Aogen). Brain RAS regulation may contribute to the benefits of long-term systemic AT1 antagonism. We assessed the mRNA of RAS components in the dorsomedial medulla of F344 rats at 3 (young; n = 8) or 15 mo of age (old; n = 7) and in rats treated from 3 to 15 mo of age with 20 mg/l of the AT1 receptor antagonist L-158,809 (Old+L; n = 6). Aogen and renin mRNA were lower in the young compared with old group. Angiotensin-converting enzyme (ACE) mRNA was lower in the old and Old+L compared with the young group. ACE2 and neprilysin expression were significantly higher in Old+L compared with young or old rats. AT1b, AT2, and Mas receptor mRNA were higher with treatment. Leptin receptor mRNA was lower in the old rats and this was prevented by L-158,809 treatment. Dual-specificity phosphatase 1 (DUSP1) mRNA was highest in the Old+L group. Aggregate correlate summation revealed a positive relationship for Mas receptor mRNA with food intake. The findings provide evidence for regulation of dorsomedial medullary renin and Aogen mRNA during aging. Long-term AT1 receptor blockade increases the mRNA of the enzymes ACE2 and neprilysin and the MAS receptor, which could potentially shift the balance from ANG II to ANG-(1–7) and prevent age-related declines in the leptin receptor and its signaling pathway. PMID:21540301

Region-Specific Onset of Handling-Induced Changes in Corticotropin-Releasing Factor and Glucocorticoid Receptor Expression

PubMed Central

Fenoglio, Kristina A.; Brunson, Kristen L.; Avishai-Eliner, Sarit; Chen, Yuncai; Baram, Tallie Z.

2011-01-01

Early-life experience including maternal care profoundly influences hormonal stress responses during adulthood. Daily handling on postnatal day (P) 2–9, eliciting augmented maternal care upon returning pups to their cage, permanently modifies the expression of the stress neuromodulators corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR). We have previously demonstrated reduced hypothalamic CRF expression already at the end of the handling period, followed by enhanced hippocampal GR mRNA levels (by P45). However, the initial site(s) and time of onset of these enduring changes have remained unclear. Therefore, we used semiquantitative in situ hybridization to delineate the spatiotemporal evolution of CRF and GR expression throughout stress-regulatory brain regions in handled (compared with undisturbed) pups. Enhanced CRF mRNA expression was apparent in the amygdaloid central nucleus (ACe) of handled pups already by P6. By P9, the augmented CRF mRNA levels persisted in ACe, accompanied by increased peptide expression in the bed nucleus of the stria terminalis and reduced expression in the paraventricular nucleus. The earliest change in GR consisted of reduced expression in the ACe of handled pups on P9, a time point when hippocampal GR expression was not yet affected. Thus, altered gene expression in ACe, bed nucleus of the stria terminalis as well as paraventricular nucleus may contribute to the molecular cascade by which handling (and increased maternal care) influences the stress response long term. PMID:15044366

Emerging Biodegradation of the Previously Persistent Artificial Sweetener Acesulfame in Biological Wastewater Treatment.

PubMed

Kahl, Stefanie; Kleinsteuber, Sabine; Nivala, Jaime; van Afferden, Manfred; Reemtsma, Thorsten

2018-03-06

The persistence of acesulfame (ACE) in wastewater treatment (and subsequently the aquatic environment) has led to its use as a marker substance for wastewater input into surface water and groundwater. However, ACE degradation of >85% during summer and autumn was observed in nine German wastewater treatment plants (WWTPs). Annual removal performance was more stable in larger plants, enhanced by low biological oxygen demand and impeded by water temperatures below 10 °C. Literature data suggest that the potential to degrade ACE emerged in WWTPs around the year 2010. This development is ongoing, as illustrated by ACE content in the German rivers Elbe and Mulde: Between 2013 and 2016 the ACE mass load decreased by 70-80%. In enrichment cultures with ACE as sole carbon source the carbonaceous fraction of ACE was removed completely, indicating catabolic biotransformation and the inorganic compound sulfamic acid formed in quantitative amounts. Sequencing of bacterial 16S rRNA genes suggests that several species are involved in ACE degradation, with proteobacterial species affiliated to Phyllobacteriaceae, Methylophilaceae, Bradyrhizobiaceae, and Pseudomonas becoming specifically enriched. ACE appears to be the first micropollutant for which the evolution of a catabolic pathway in WWTPs has been witnessed. It can yet only be speculated whether the emergence of ACE removal in WWTPs in different regions of the world is due to independent evolution or to global spreading of genes or adapted microorganisms.

Genetic Deletion of ACE2 Induces Vascular Dysfunction in C57BL/6 Mice: Role of Nitric Oxide Imbalance and Oxidative Stress.

PubMed

Rabelo, Luiza A; Todiras, Mihail; Nunes-Souza, Valéria; Qadri, Fatimunnisa; Szijártó, István András; Gollasch, Maik; Penninger, Josef M; Bader, Michael; Santos, Robson A; Alenina, Natalia

2016-01-01

Accumulating evidence indicates that angiotensin-converting enzyme 2 (ACE2) plays a critical role in cardiovascular homeostasis, and its altered expression is associated with major cardiac and vascular disorders. The aim of this study was to evaluate the regulation of vascular function and assess the vascular redox balance in ACE2-deficient (ACE2-/y) animals. Experiments were performed in 20-22 week-old C57BL/6 and ACE2-/y male mice. Evaluation of endothelium-dependent and -independent relaxation revealed an impairment of in vitro and in vivo vascular function in ACE2-/y mice. Drastic reduction in eNOS expression at both protein and mRNA levels, and a decrease in •NO concentrations were observed in aortas of ACE2-/y mice in comparison to controls. Consistently, these mice presented a lower plasma and urine nitrite concentration, confirming reduced •NO availability in ACE2-deficient animals. Lipid peroxidation was significantly increased and superoxide dismutase activity was decreased in aorta homogenates of ACE2-/y mice, indicating impaired antioxidant capacity. Taken together, our data indicate, that ACE2 regulates vascular function by modulating nitric oxide release and oxidative stress. In conclusion, we elucidate mechanisms by which ACE2 is involved in the maintenance of vascular homeostasis. Furthermore, these findings provide insights into the role of the renin-angiotensin system in both vascular and systemic redox balance.

Six Misconceptions about Accreditation in Higher Education: Lessons from Teacher Education

ERIC Educational Resources Information Center

Murray, Frank B.

2012-01-01

The role of accreditation is to assure that the standards that uniquely define institutions and programs are adhered to so that their increasingly high costs produce solid value. In the fall 2011 issue of "The Presidency," a publication of the American Council on Education (ACE), Terry Hartle, a senior vice-president of ACE, outlined six…

Affinity capillary electrophoresis for studying interactions in life sciences.

PubMed

Olabi, Mais; Stein, Matthias; Wätzig, Hermann

2018-05-10

Affinity capillary electrophoresis (ACE) analyzes noncovalent interactions between ligands and analytes based on changes in their electrophoretic mobility. This technique has been widely used to investigate various biomolecules, mainly proteins, polysaccharides and hormones. ACE is becoming a technique of choice to validate high throughput screening results, since it is very predictively working in realistic and relevant media, e.g. in body fluids. It is highly recommended to incorporate ACE as a powerful analytical tool to properly prepare animal testing and preclinical studies. The interacting molecules can be found free in solution or can be immobilized to a solid support. Thus, ACE is classified in two modes, free solution ACE and immobilized ACE. Every ACE mode has advantages and disadvantages. Each can be used for a variety of applications. This review covers literature of scopus and SciFinder data base in the period from 2016 until beginning 2018, including the keywords "affinity capillary electrophoresis", "immunoaffinity capillary electrophoresis", "immunoassay capillary electrophoresis" and "immunosorbent capillary electrophoresis". More than 200 articles have been found and 112 have been selected and thoroughly discussed. During this period, the data processing and the underlying calculations in mobility shift ACE (ms ACE), frontal analysis ACE (FA ACE) and plug-plug kinetic capillary electrophoresis (ppKCE) as mostly applied free solution techniques have substantially improved. The range of applications in diverse free solution and immobilized ACE techniques has been considerably broadened. Copyright © 2018. Published by Elsevier Inc.

Health Information Technologies-Academic and Commercial Evaluation (HIT-ACE) methodology: description and application to clinical feedback systems.

PubMed

Lyon, Aaron R; Lewis, Cara C; Melvin, Abigail; Boyd, Meredith; Nicodimos, Semret; Liu, Freda F; Jungbluth, Nathaniel

2016-09-22

Health information technologies (HIT) have become nearly ubiquitous in the contemporary healthcare landscape, but information about HIT development, functionality, and implementation readiness is frequently siloed. Theory-driven methods of compiling, evaluating, and integrating information from the academic and commercial sectors are necessary to guide stakeholder decision-making surrounding HIT adoption and to develop pragmatic HIT research agendas. This article presents the Health Information Technologies-Academic and Commercial Evaluation (HIT-ACE) methodology, a structured, theory-driven method for compiling and evaluating information from multiple sectors. As an example demonstration of the methodology, we apply HIT-ACE to mental and behavioral health measurement feedback systems (MFS). MFS are a specific class of HIT that support the implementation of routine outcome monitoring, an evidence-based practice. HIT-ACE is guided by theories and frameworks related to user-centered design and implementation science. The methodology involves four phases: (1) coding academic and commercial materials, (2) developer/purveyor interviews, (3) linking putative implementation mechanisms to hit capabilities, and (4) experimental testing of capabilities and mechanisms. In the current demonstration, phase 1 included a systematic process to identify MFS in mental and behavioral health using academic literature and commercial websites. Using user-centered design, implementation science, and feedback frameworks, the HIT-ACE coding system was developed, piloted, and used to review each identified system for the presence of 38 capabilities and 18 additional characteristics via a consensus coding process. Bibliometic data were also collected to examine the representation of the systems in the scientific literature. As an example, results are presented for the application of HIT-ACE phase 1 to MFS wherein 49 separate MFS were identified, reflecting a diverse array of characteristics and capabilities. Preliminary findings demonstrate the utility of HIT-ACE to represent the scope and diversity of a given class of HIT beyond what can be identified in the academic literature. Phase 2 data collection is expected to confirm and expand the information presented and phases 3 and 4 will provide more nuanced information about the impact of specific HIT capabilities. In all, HIT-ACE is expected to support adoption decisions and additional HIT development and implementation research.

Advanced Collaborative Emissions Study (ACES)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Greenbaum, Daniel; Costantini, Maria; Van Erp, Annemoon

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 enginesmore » 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.« less

A Novel Splice-Site Mutation in Angiotensin I-Converting Enzyme (ACE) Gene, c.3691+1G>A (IVS25+1G>A), Causes a Dramatic Increase in Circulating ACE through Deletion of the Transmembrane Anchor

PubMed Central

Persu, Alexandre; Lambert, Michel; Deinum, Jaap; Cossu, Marta; de Visscher, Nathalie; Irenge, Leonid; Ambroise, Jerôme; Minon, Jean-Marc; Nesterovitch, Andrew B.; Churbanov, Alexander; Popova, Isolda A.; Danilov, Sergei M.; Danser, A. H. Jan; Gala, Jean-Luc

2013-01-01

Background Angiotensin-converting enzyme (ACE) (EC 4.15.1) metabolizes many biologically active peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels are associated with different cardiovascular and respiratory diseases. Methods and Results Two Belgian families with a 8-16-fold increase in blood ACE level were incidentally identified. A novel heterozygous splice site mutation of intron 25 - IVS25+1G>A (c.3691+1G>A) - cosegregating with elevated plasma ACE was identified in both pedigrees. Messenger RNA analysis revealed that the mutation led to the retention of intron 25 and Premature Termination Codon generation. Subjects harboring the mutation were mostly normotensive, had no left ventricular hypertrophy or cardiovascular disease. The levels of renin-angiotensin-aldosterone system components in the mutated cases and wild-type controls were similar, both at baseline and after 50 mg captopril. Compared with non-affected members, quantification of ACE surface expression and shedding using flow cytometry assay of dendritic cells derived from peripheral blood monocytes of affected members, demonstrated a 50% decrease and 3-fold increase, respectively. Together with a dramatic increase in circulating ACE levels, these findings argue in favor of deletion of transmembrane anchor, leading to direct secretion of ACE out of cells. Conclusions We describe a novel mutation of the ACE gene associated with a major familial elevation of circulating ACE, without evidence of activation of the renin-angiotensin system, target organ damage or cardiovascular complications. These data are consistent with the hypothesis that membrane-bound ACE, rather than circulating ACE, is responsible for Angiotensin II generation and its cardiovascular consequences. PMID:23560051

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.

Molecular characterization and transcriptional regulation of the renin-angiotensin system genes in Senegalese sole (Solea senegalensis Kaup, 1858): differential gene regulation by salinity.

PubMed

Armesto, Paula; Cousin, Xavier; Salas-Leiton, Emilio; Asensio, Esther; Manchado, Manuel; Infante, Carlos

2015-06-01

In this work, the complete cDNA sequence encoding angiotensinogen (agt) in the euryhaline flatfish Senegalese sole was obtained. Additionally, putative coding sequences belonging to other renin-angiotensin system (RAS) genes including renin (ren), angiotensin-converting enzyme (ace), angiotensin-converting enzyme 2 (ace2), as well as angiotensin II receptor type I (agtr1) and type II (agtr2), were also identified. In juvenile tissues, agt transcripts were mainly detected in liver, ren in kidney, ace and ace2 in intestine, agtr1 in kidney and brain, and agtr2 in liver and kidney. Expression analysis of the six RAS genes after a salinity shift revealed a clear increase of agt mRNA abundance in liver just after transferring soles to high salinity water (60 ppt) with a peak at 48 h. Moreover, gene expression analysis in gills showed transcriptional regulation of ace and agtr1 at 48 h and agtr2 at 96 h after transferring soles to 60 ppt. Incubation of larvae before mouth opening (until 3 days post hatch; dph) at low salinity (10 ppt) resulted in a coordinated transcriptional up-regulation of RAS genes. Nevertheless, no differences in mRNA abundance between salinities were observed when larvae were cultivated to low salinity after mouth opening. Whole-mount in situ hybridization (WISH) signal for agt and ace in 3 dph larvae incubated at 10 ppt and 35 ppt confirmed that the former gene was mainly expressed in liver whereas the later gene was mainly located in pharynx and posterior gut, without pronounced differences in intensity between salinities. Possible physiological significance of all these results is discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

Anticancer effects on human pancreatic cancer cells of triterpenoids, polysaccharides and 1,3-β-D-glucan derived from the fruiting body of Antrodia camphorata.

PubMed

Lee, Chu-I; Wu, Chih-Chung; Hsieh, Shu-Ling; Lee, Chun-Lin; Chang, Yueh-Ping; Chang, Chih-Chuan; Wang, Yi-Zhen; Wang, Jyh-Jye

2014-12-01

Antrodia camphorata is a fungus native to Taiwan, and it is considered a precious medicinal agent. We analyzed triterpenoids, polysaccharides and 1,3-β-D-glucan, three major effective components in A. camphorata extracts (ACE). ACE exhibited a selective cytotoxic effect on BxPC-3 human pancreatic cancer cells. ACE markedly inhibited the migration ability of BxPC-3 cells. Treatment of BxPC-3 cells with ACE resulted in the increase of cells in the sub-G1 phase and G2/M phase arrest. Apoptosis was confirmed by validating phosphatidylserine externalization, the observation of characteristic chromatin condensation, and nuclear DNA fragmentation. ACE induced apoptosis in BxPC-3 cells through a mitochondria-dependent pathway by triggering an appropriate balance of bax/bcl-2, cytochrome c release, activation of caspase-9 and -3, and poly(ADP-ribose) polymerase cleavage. ACE shows great therapeutic potential due to its cytotoxic effects against BxPC-3 cells which include inhibiting cell migration and inducing mitochondria-mediated apoptosis.

Functional nucleic acid entrapment in sol-gel derived materials.

PubMed

Carrasquilla, Carmen; Brennan, John D

2013-10-01

Functional nucleic acids (FNAs) are single-stranded DNA or RNA molecules, typically generated through in vitro selection, that have the ability to act as receptors for target molecules (aptamers) or perform catalysis of a chemical reaction (deoxyribozymes and ribozymes). Fluorescence-signaling aptamers and deoxyribozymes have recently emerged as promising biological recognition and signaling elements, although little has been done to evaluate their potential for solid-phase assays, particularly with species made of RNA due to their lack of chemical stability and susceptibility to nuclease attack. Herein, we present a detailed overview of the methods utilized for solid-phase immobilization of FNAs using a sol-gel entrapment method that can provide protection from nuclease degradation and impart long-term chemical stability to the FNA reporter systems, while maintaining their signaling capabilities. This article will also provide a brief review of the results of such entrapment studies involving fluorescence-signaling versions of a DNA aptamer, selected RNA-cleaving deoxyribozymes, and two different RNA aptamers in a series of sol-gel derived composites, ranging from highly polar silica to hydrophobic methylsilsesquioxane-based materials. Given the ability to produce sol-gel derived materials in a variety of configurations, particularly as thin film coatings on electrodes, optical fibers, and other devices, this entrapment method should provide a useful platform for numerous solid-phase FNA-based biosensing applications. Copyright © 2013 Elsevier Inc. All rights reserved.

ACE2-EPC-EXs protect ageing ECs against hypoxia/reoxygenation-induced injury through the miR-18a/Nox2/ROS pathway.

PubMed

Zhang, Cheng; Wang, Jinju; Ma, Xiaotang; Wang, Wenjun; Zhao, Bin; Chen, Yanfang; Chen, Can; Bihl, Ji C

2018-03-01

Oxidative stress is one of the mechanisms of ageing-associated vascular dysfunction. Angiotensin-converting enzyme 2 (ACE2) and microRNA (miR)-18a have shown to be down-regulated in ageing cells. Our previous study has shown that ACE2-primed endothelial progenitor cells (ACE2-EPCs) have protective effects on endothelial cells (ECs), which might be due to their released exosomes (EXs). Here, we aimed to investigate whether ACE2-EPC-EXs could attenuate hypoxia/reoxygenation (H/R)-induced injury in ageing ECs through their carried miR-18a. Young and angiotensin II-induced ageing ECs were subjected to H/R and co-cultured with vehicle (medium), EPC-EXs, ACE2-EPCs-EXs, ACE2-EPCs-EXs + DX600 or ACE2-EPCs-EXs with miR-18a deficiency (ACE2-EPCs-EXs anti-miR-18a ). Results showed (1) ageing ECs displayed increased senescence, apoptosis and ROS production, but decreased ACE2 and miR-18a expressions and tube formation ability; (2) under H/R condition, ageing ECs showed higher rate of apoptosis, ROS overproduction and nitric oxide reduction, up-regulation of Nox2, down-regulation of ACE2, miR-18a and eNOS, and compromised tube formation ability; (3) compared with EPC-EXs, ACE2-EPC-EXs had better efficiencies on protecting ECs from H/R-induced changes; (4) The protective effects were less seen in ACE2-EPCs-EXs + DX600 and ACE2-EPCs-EXs anti-miR-18a groups. These data suggest that ACE-EPCs-EXs have better protective effects on H/R injury in ageing ECs which could be through their carried miR-18a and subsequently down-regulating the Nox2/ROS pathway. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Influence of gas-liquid two-phase flow on angiotensin-I converting enzyme inhibitory peptides separation by ultra-filtration.

PubMed

Charoenphun, Narin; Youravong, Wirote

2017-01-01

Membrane fouling is a major problem in ultra-filtration systems and two-phase flow is a promising technique for permeate flux enhancement. The objective of this research was to study the use of an ultra-filtration (UF) system to enrich angiotensin-I converting enzyme (ACE) inhibitory peptides from tilapia protein hydrolysate. To select the most appropriate membrane and operating condition, the effects of membrane molecular weight cut-off (MWCO), transmembrane pressure (TMP) and cross-flow velocity (CFV) on permeate flux and ACE inhibitory peptide separation were studied. Additionally, the gas-liquid two-phase flow technique was applied to investigate its effect on the process capability. The results showed that the highest ACE inhibitory activity was obtained from permeate of the 1 kDa membrane. In terms of TMP and CFV, the permeate flux tended to increase with TMP and CFV. The use of gas-liquid two-phase flow as indicated by shear stress number could reduce membrane fouling and increase the permeate flux up to 42%, depending on shear stress number. Moreover, the use of a shear stress number of 0.039 led to an augmentation in ACE inhibitory activity of permeates. Operating conditions using a shear stress number of 0.039 were recommended for enrichment of ACE inhibitory peptides. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, S.-S.; IGE Therapeutics, Inc., Cellular and Cancer Immunology, 6370 Lusk Boulevard, F109, San Diego, CA 92121; Yang Yongmin

GFP-C{kappa} fusion protein was previously shown selectable on ribosome display platform with solid phase antibodies against GFP determinant [Y.-M. Yang, T.J. Barankiewicz, M. He, M. Taussig, S.-S. Chen, Selection of antigenic markers on a GFP-C{kappa} fusion scaffold with high sensitivity by eukaryotic ribosome display, Biochem. Biophys. Res. Commun. 359 (2007) 251-257]. Herein, we show that members of aptameric peptide library constructed within the site 6 and site 8/9 loops of GFP of the ribosome display construct are selectable upon binding to the solid phase IgE antigen. An input of 1.0 {mu}g of the dual site aptameric GFP library exhibiting amore » diversity of 7.5 x 10{sup 11} was transcribed, translated and incubated with solid phase IgE. RT-PCR products were amplified from mRNA of the aptamer-ribosome-mRNA (ARM) complex captured on the solid phase IgE. Clones of aptameric GFP were prepared from RT-PCR product of ARM complex following repetitive selection. Recombinant aptameric GFP proteins from the selected clones bind IgE coated on the 96-well plate, and the binding was abrogated by incubation with soluble human IgE but not human IgG. Selected aptameric GFP proteins also exhibit binding to three different sources of human IgE (IgE PS, BED, and JW8) but not irrelevant proteins. These observations indicate that appropriately selected aptameric GFP on a solid phase ligand by ribosome display may serve as an affinity reagent for blocking reactivity of a biological ligand.« less

Sex-dependent effects of antenatal glucocorticoids on insulin sensitivity in adult sheep: role of the adipose tissue renin angiotensin system.

PubMed

Massmann, G Angela; Zhang, Jie; Seong, Won Joon; Kim, Minhyoung; Figueroa, Jorge P

2017-06-01

Exposure to glucocorticoids in utero is associated with changes in organ function and structure in the adult. The aims of this study were to characterize the effects of antenatal exposure to glucocorticoids on glucose handling and the role of adipose tissue. Pregnant sheep received betamethasone (Beta, 0.17 mg/kg) or vehicle 24 h apart at 80 days of gestation and allowed to deliver at term. At 9 mo, male and female offspring were fed at either 100% of nutritional allowance (lean) or ad libitum for 3 mo (obese). At 1 yr, they were chronically instrumented under general anesthesia. Glucose tolerance was evaluated using a bolus of glucose (0.25 g/kg). Adipose tissue was harvested after death to determine mRNA expression levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) 1, ACE2, and peroxisome proliferator-activated receptor γ (PPAR-γ). Data are expressed as means ± SE and analyzed by ANOVA. Sex, obesity, and Beta exposure had significant effects on glucose tolerance and mRNA expression. Beta impaired glucose tolerance in lean females but not males. Superimposed obesity worsened the impairment in females and unmasked the defect in males. Beta increased ACE1 mRNA in females and males and AGT in females only ( P < 0.05 by three-way ANOVA). Obesity increased AGT in females but had no effect on ACE1 in either males or females. PPAR-γ mRNA exhibited a significant sex ( F = 42.8; P < 0.01) and obesity ( F = 6.9; P < 0.05) effect and was significantly higher in males ( P < 0.01 by three-way ANOVA). We conclude that adipose tissue may play an important role in the sexually dimorphic response to antenatal glucocorticoids. Copyright © 2017 the American Physiological Society.

Apoptosis of Hepatocellular Carcinoma Cells Induced by Nanoencapsulated Polysaccharides Extracted from Antrodia Camphorata

PubMed Central

Chang, Ke Liang B.; Kong, Zwe-Ling

2015-01-01

Antrodia camphorata is a well-known medicinal mushroom in Taiwan and has been studied for decades, especially with focus on anti-cancer activity. Polysaccharides are the major bioactive compounds reported with anti-cancer activity, but the debates on how they target cells still remain. Research addressing the encapsulation of polysaccharides from A. camphorata extract (ACE) to enhance anti-cancer activity is rare. In this study, ACE polysaccharides were nano-encapsulated in chitosan-silica and silica (expressed as ACE/CS and ACE/S, respectively) to evaluate the apoptosis effect on a hepatoma cell line (Hep G2). The results showed that ACE polysaccharides, ACE/CS and ACE/S all could damage the Hep G2 cell membrane and cause cell death, especially in the ACE/CS group. In apoptosis assays, DNA fragmentation and sub-G1 phase populations were increased, and the mitochondrial membrane potential decreased significantly after treatments. ACE/CS and ACE/S could also increase reactive oxygen species (ROS) generation, induce Fas/APO-1 (apoptosis antigen 1) expression and elevate the proteolytic activities of caspase-3, caspase-8 and caspase-9 in Hep G2 cells. Unsurprisingly, ACE/CS induced a similar apoptosis mechanism at a lower dosage (ACE polysaccharides = 13.2 μg/mL) than those of ACE/S (ACE polysaccharides = 21.2 μg/mL) and ACE polysaccharides (25 μg/mL). Therefore, the encapsulation of ACE polysaccharides by chitosan-silica nanoparticles may provide a viable approach for enhancing anti-tumor efficacy in liver cancer cells. PMID:26327534

Nucleic acid hybridization with RNA immobilized on filter paper.

NASA Technical Reports Server (NTRS)

Saxinger, W. C.; Ponnamperuma, C.; Gillespie, D.

1972-01-01

RNA has been immobilized in a manner suitable for use in molecular hybridization experiments with dissolved RNA or DNA by a nonaqueous solid-phase reaction with carbonyldiimidazole and RNA 'dry coated' on cellulose or, preferably, on previously activated phosphocellulose filters. Immobilization of RNA does not appear to alter its chemical character or cause it to acquire affinity for unspecific RNA or DNA. The versatility and efficiency of this method make it potentially attractive for use in routine analytical or preparative hybridization experiments, among other applications.

Murine recombinant angiotensin-converting enzyme 2 attenuates kidney injury in experimental Alport syndrome.

PubMed

Bae, Eun Hui; Fang, Fei; Williams, Vanessa R; Konvalinka, Ana; Zhou, Xiaohua; Patel, Vaibhav B; Song, Xuewen; John, Rohan; Oudit, Gavin Y; Pei, York; Scholey, James W

2017-06-01

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase in the renin-angiotensin system that catalyzes the breakdown of angiotensin II to angiotensin 1-7. We have reported that ACE2 expression in the kidney is reduced in experimental Alport syndrome but the impact of this finding on disease progression has not been studied. Accordingly, we evaluated effects of murine recombinant ACE2 treatment in Col4a3 knockout mice, a model of Alport syndrome characterized by proteinuria and progressive renal injury. Murine recombinant ACE2 (0.5 mg/kg/day) was administered from four to seven weeks of age via osmotic mini-pump. Pathological changes were attenuated by murine recombinant ACE2 treatment which ameliorated kidney fibrosis as shown by decreased expression of COL1α1 mRNA, less accumulation of extracellular matrix proteins, and inhibition of transforming growth factor-β signaling. Further, increases in proinflammatory cytokine expression, macrophage infiltration, inflammatory signaling pathway activation, and heme oxygenase-1 levels in Col4a3 knockout mice were also reduced by murine recombinant ACE2 treatment. Lastly, murine recombinant ACE2 influenced the turnover of renal ACE2, as it suppressed the expression of tumor necrosis factor-α converting enzyme, a negative regulator of ACE2. Thus, treatment with exogenous ACE2 alters angiotensin peptide metabolism in the kidneys of Col4a3 knockout mice and attenuates the progression of Alport syndrome nephropathy. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

MSCs with ACE II gene affect apoptosis pathway of acute lung injury induced by bleomycin.

PubMed

Zhang, Xiaomiao; Gao, Fengying; Li, Qian; Dong, Zhixia; Sun, Bo; Hou, Lili; Li, Zhuozhe; Liu, Zhenwei

2015-02-01

The aim of this study was to evaluate the effect and related mechanisms of Mesenchymal stem cells (MSCs) and Angiotensin converting enzyme II (ACE II) on acute lung injury (ALI). MSCs were separated from umbilical cord cells, and the changes of phenotype before and after ACE II silence were observed using Flow Cytometer. ALI model was induced by 10 mg/mL bleomycin in 60 Balb/c mice, and the rest 8 mice were regarded as the baseline group. The mice were randomly divided into four groups (n = 15): control, ACE II, stem, and stem + ACE II. The apoptotic index (AI) was calculated using TUNEL, and the detection of protein and mRNA of Bax, Bak and p53, Bcl-2, Grp78, CHOP and Caspase 12 were used by western-blot and RT-PCR, respectively. The umbilical cord cells differentiated into stable MSCs about 14 days, and ACE II transfection reached a peak at the 5th day after transfection. ACE II silence did not affect the phenotype of MSCs. All the proteins and mRNAs expression except Bcl-2 in the stem and stem + ACE II were significantly lower than those in control from 8 h (p < 0.05, p < 0.01), while Bcl-2 exhibited an opposite trend. Stem + ACE II performed a better effect than single stem in most indexes, including AI (p < 0.05, p < 0.01). The co-administration of MSCs and ACE II can significantly suppress apoptosis in ALI mice, and may be an effective clinical treatment for ALI.

76 FR 37136 - Post-Summary Corrections to Entry Summaries Filed in ACE Pursuant to the ESAR IV Test

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-24

... Phased Out for Entry Summaries Filed in ACE The Post-Entry Amendment (PEA) test allows importers to amend... DEPARTMENT OF HOMELAND SECURITY U.S. Customs and Border Protection Post-Summary Corrections to Entry Summaries Filed in ACE Pursuant to the ESAR IV Test AGENCY: U.S. Customs and Border Protection...

Promiscuous interactions and protein disaggregases determine the material state of stress-inducible RNP granules

PubMed Central

Kroschwald, Sonja; Maharana, Shovamayee; Mateju, Daniel; Malinovska, Liliana; Nüske, Elisabeth; Poser, Ina; Richter, Doris; Alberti, Simon

2015-01-01

RNA-protein (RNP) granules have been proposed to assemble by forming solid RNA/protein aggregates or through phase separation into a liquid RNA/protein phase. Which model describes RNP granules in living cells is still unclear. In this study, we analyze P bodies in budding yeast and find that they have liquid-like properties. Surprisingly, yeast stress granules adopt a different material state, which is reminiscent of solid protein aggregates and controlled by protein disaggregases. By using an assay to ectopically nucleate RNP granules, we further establish that RNP granule formation does not depend on amyloid-like aggregation but rather involves many promiscuous interactions. Finally, we show that stress granules have different properties in mammalian cells, where they show liquid-like behavior. Thus, we propose that the material state of RNP granules is flexible and that the solid state of yeast stress granules is an adaptation to extreme environments, made possible by the presence of a powerful disaggregation machine. DOI: http://dx.doi.org/10.7554/eLife.06807.001 PMID:26238190

Analysis of WakeVAS Benefits Using ACES Build 3.2.1

NASA Technical Reports Server (NTRS)

Smith, Jeremy C.

2005-01-01

The FAA and NASA are currently engaged in a Wake Turbulence Research Program to revise wake turbulence separation standards, procedures, and criteria to increase airport capacity while maintaining or increasing safety. The research program is divided into three phases: Phase I near term procedural enhancements; Phase II wind dependent Wake Vortex Advisory System (WakeVAS) Concepts of Operations (ConOps); and Phase III farther term ConOps based on wake prediction and sensing. This report contains an analysis that evaluates the benefits of a closely spaced parallel runway (CSPR) Phase I ConOps, a single runway and CSPR Phase II ConOps and a single runway Phase III ConOps. A series of simulation runs were performed using the Airspace Concepts Evaluation System (ACES) Build 3.21 air traffic simulator to provide an initial assessment of the reduction in delay and cost savings obtained by the use of a WakeVAS at selected U.S. airports. The ACES simulator is being developed by NASA Ames Research Center as part of the Virtual Airspace Modelling and Simulation (VAMS) program.

Meta-analysis of genome wide association studies (GWAS) on the intolerance of Angiotensin converting enzyme inhibitors

PubMed Central

Mahmoudpour, Seyed Hamidreza; Veluchamy, Abirami; Siddiqui, Moneeza Kalhan; Asselbergs, Folkert W.; Souverein, Patrick C.; de Keyser, Catherine E.; Hofman, Albert; Lang, Chim C.; Doney, Alexander SF.; Stricker, Bruno H.; de Boer, Anthonius; Maitland-van der Zee, Anke-Hilse; Palmer, Colin NA.

2016-01-01

Objectives To identify SNPs associated with switching from an ACE-inhibitor to an angiotensin receptor blocker (ARB). Methods Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and the GoDARTS study in Scotland. Cases were intolerant subjects who switched from an ACE-inhibitor to an ARB, controls were subjects who used ACE-inhibitors continuously for at least 2 years and did not switch. GWAS using an additive model was run in these sets and results were meta-analysed using GWAMA. Results 972 cases out of 5 161 ACE-inhibitor starters were identified. 8 SNPs within 4 genes reached the GWAS significance level (P<5×10-8) in the meta-analysis (RBFOX3, GABRG2, SH2B1 and MBOAT1). The strongest associated SNP was located in an intron of RBFOX3, which contains a RNA binding protein (rs2061538: MAF=0.16, OR=1.52[95%CI: 1.32-1.76], p=6.2x10-9). Conclusions These results indicate that genetic variation in abovementioned genes may increase the risk of ACE-inhibitors induced adverse reactions. PMID:28030426

RNA Sequencing Identifies New RNase III Cleavage Sites in Escherichia coli and Reveals Increased Regulation of mRNA

DOE PAGES

Gordon, Gina C.; Cameron, Jeffrey C.; Pfleger, Brian F.

2017-03-28

Ribonucleases facilitate rapid turnover of RNA, providing cells with another mechanism to adjust transcript and protein levels in response to environmental conditions. While many examples have been documented, a comprehensive list of RNase targets is not available. To address this knowledge gap, we compared levels of RNA sequencing coverage of Escherichia coli and a corresponding RNase III mutant to expand the list of known RNase III targets. RNase III is a widespread endoribonuclease that binds and cleaves double-stranded RNA in many critical transcripts. RNase III cleavage at novel sites found in aceEF, proP, tnaC, dctA, pheM, sdhC, yhhQ, glpT, aceK,more » and gluQ accelerated RNA decay, consistent with previously described targets wherein RNase III cleavage initiates rapid degradation of secondary messages by other RNases. In contrast, cleavage at three novel sites in the ahpF, pflB, and yajQ transcripts led to stabilized secondary transcripts. Two other novel sites in hisL and pheM overlapped with transcriptional attenuators that likely serve to ensure turnover of these highly structured RNAs. Many of the new RNase III target sites are located on transcripts encoding metabolic enzymes. For instance, two novel RNase III sites are located within transcripts encoding enzymes near a key metabolic node connecting glycolysis and the tricarboxylic acid (TCA) cycle. Pyruvate dehydrogenase activity was increased in an rnc deletion mutant compared to the wild-type (WT) strain in early stationary phase, confirming the novel link between RNA turnover and regulation of pathway activity. Identification of these novel sites suggests that mRNA turnover may be an underappreciated mode of regulating metabolism. IMPORTANCE: The concerted action and overlapping functions of endoribonucleases, exoribonucleases, and RNA processing enzymes complicate the study of global RNA turnover and recycling of specific transcripts. More information about RNase specificity and activity is needed to make predictions of transcript half-life and to design synthetic transcripts with optimal stability. RNase III does not have a conserved target sequence but instead recognizes RNA secondary structure. Prior to this study, only a few RNase III target sites in E. coli were known, so we used RNA sequencing to provide a more comprehensive list of cleavage sites and to examine the impact of RNase III on transcript degradation. Finally, with this added information on how RNase III participates in transcript regulation and recycling, a more complete picture of RNA turnover can be developed for E. coli. Similar approaches could be used to augment our understanding of RNA turnover in other bacteria.« less

RNA Sequencing Identifies New RNase III Cleavage Sites in Escherichia coli and Reveals Increased Regulation of mRNA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gordon, Gina C.; Cameron, Jeffrey C.; Pfleger, Brian F.

Ribonucleases facilitate rapid turnover of RNA, providing cells with another mechanism to adjust transcript and protein levels in response to environmental conditions. While many examples have been documented, a comprehensive list of RNase targets is not available. To address this knowledge gap, we compared levels of RNA sequencing coverage of Escherichia coli and a corresponding RNase III mutant to expand the list of known RNase III targets. RNase III is a widespread endoribonuclease that binds and cleaves double-stranded RNA in many critical transcripts. RNase III cleavage at novel sites found in aceEF, proP, tnaC, dctA, pheM, sdhC, yhhQ, glpT, aceK,more » and gluQ accelerated RNA decay, consistent with previously described targets wherein RNase III cleavage initiates rapid degradation of secondary messages by other RNases. In contrast, cleavage at three novel sites in the ahpF, pflB, and yajQ transcripts led to stabilized secondary transcripts. Two other novel sites in hisL and pheM overlapped with transcriptional attenuators that likely serve to ensure turnover of these highly structured RNAs. Many of the new RNase III target sites are located on transcripts encoding metabolic enzymes. For instance, two novel RNase III sites are located within transcripts encoding enzymes near a key metabolic node connecting glycolysis and the tricarboxylic acid (TCA) cycle. Pyruvate dehydrogenase activity was increased in an rnc deletion mutant compared to the wild-type (WT) strain in early stationary phase, confirming the novel link between RNA turnover and regulation of pathway activity. Identification of these novel sites suggests that mRNA turnover may be an underappreciated mode of regulating metabolism. IMPORTANCE: The concerted action and overlapping functions of endoribonucleases, exoribonucleases, and RNA processing enzymes complicate the study of global RNA turnover and recycling of specific transcripts. More information about RNase specificity and activity is needed to make predictions of transcript half-life and to design synthetic transcripts with optimal stability. RNase III does not have a conserved target sequence but instead recognizes RNA secondary structure. Prior to this study, only a few RNase III target sites in E. coli were known, so we used RNA sequencing to provide a more comprehensive list of cleavage sites and to examine the impact of RNase III on transcript degradation. Finally, with this added information on how RNase III participates in transcript regulation and recycling, a more complete picture of RNA turnover can be developed for E. coli. Similar approaches could be used to augment our understanding of RNA turnover in other bacteria.« less

Somatic isoform of angiotensin I-converting enzyme in the pathology of testicular germ cell tumors.

PubMed

Franke, F E; Pauls, K; Kerkman, L; Steger, K; Klonisch, T; Metzger, R; Alhenc-Gelas, F; Burkhardt, E; Bergmann, M; Danilov, S M

2000-12-01

Retained fetal expression of angiotensin I-converting enzyme (ACE, CD143) has recently been shown in intratubular germ cell neoplasms (IGCN) and invasive germ cell tumors (GCT), suggesting the somatic isoform (sACE) as a characteristic component of neoplastic germ cells. We analyzed the distribution of sACE in 159 testicular GCT, including 87 IGCN. sACE protein was determined by immunohistochemistry (MAb CG2) on routinely formalin-fixed and paraffin-embedded tissue sections, supplemented by mRNA expression analysis using in situ hybridization. These data were compared with those obtained by germ cell/placental alkaline phosphatases (PIAP; MAbs PL8-F6 and 8A9) employing an uniform score system for the evaluation of immunoreactivity (IRS; possible values from 0 to 12). Expression of sACE and PIAP was found in all 87 analyzed IGCN (IRS > 4, median IRS of 12). Heterogeneous staining patterns were not related to the type of adjacent GCT but correlated with low expression in adjacent seminomas (P =.032 for sACE; P =.005 for PIAP). Both sACE and PIAP often showed a decreased and more heterogeneous but still moderate expression in 91 classic seminomas (median IRS of 8) and were completely absent in tumor cells of spermatocytic seminomas. Despite all similarities, we found sACE and PIAP differently regulated during GCT progression. This was documented by a well-preserved expression of either sACE or PIAP or both in all classic seminomas, low PIAP immunoreactivity in metastasis of seminomas, and completely diverging expression patterns in nonseminomatous GCT. Our findings underline the close molecular relationship between IGCN and seminoma, and suggest sACE as an appropriate marker for seminomatous differentiated tumors. HUM PATHOL 31:1466-1476. Copyright 2000 by W.B. Saunders Company

Leptin regulates ACE activity in mice.

PubMed

Hilzendeger, Aline Mourao; Morais, Rafael Leite; Todiras, Mihail; Plehm, Ralph; da Costa Goncalves, Andrey; Qadri, Fatimunnisa; Araujo, Ronaldo Carvalho; Gross, Volkmar; Nakaie, Clovis Ryuichi; Casarini, Dulce Elena; Carmona, Adriana Karaoglanovic; Bader, Michael; Pesquero, João Bosco

2010-09-01

Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here, we used ob/ob mice, a model lacking leptin, to answer the question whether ACE and leptin could interact to influence blood pressure, thereby linking the renin-angiotensin system and obesity. These mice are obese and diabetic but have normal 24 h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin, and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Chronic infusion of leptin increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion restored ACE activity in leptin-deficient mice. Moreover, the effect of an ACE inhibitor on blood pressure was not changed in ob/+ mice during leptin treatment but increased four times in obese mice. In summary, our findings show that the renin-angiotensin system is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible connection between the renin-angiotensin system and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems, which may play a role in the pathogenesis of obesity, hypertension, and metabolic syndrome.

Static and moving solid/gas interface modeling in a hybrid rocket engine

NASA Astrophysics Data System (ADS)

Mangeot, Alexandre; William-Louis, Mame; Gillard, Philippe

2018-07-01

A numerical model was developed with CFD-ACE software to study the working condition of an oxygen-nitrogen/polyethylene hybrid rocket combustor. As a first approach, a simplified numerical model is presented. It includes a compressible transient gas phase in which a two-step combustion mechanism is implemented coupled to a radiative model. The solid phase from the fuel grain is a semi-opaque material with its degradation process modeled by an Arrhenius type law. Two versions of the model were tested. The first considers the solid/gas interface with a static grid while the second uses grid deformation during the computation to follow the asymmetrical regression. The numerical results are obtained with two different regression kinetics originating from ThermoGravimetry Analysis and test bench results. In each case, the fuel surface temperature is retrieved within a range of 5% error. However, good results are only found using kinetics from the test bench. The regression rate is found within 0.03 mm s-1 and average combustor pressure and its variation over time have the same intensity than the measurements conducted on the test bench. The simulation that uses grid deformation to follow the regression shows a good stability over a 10 s simulated time simulation.

Captopril reduces cardiac inflammatory markers in spontaneously hypertensive rats by inactivation of NF-kB

PubMed Central

2010-01-01

Background Captopril is an angiotensin-converting enzyme (ACE) inhibitor widely used in the treatment of arterial hypertension and cardiovascular diseases. Our objective was to study whether captopril is able to attenuate the cardiac inflammatory process associated with arterial hypertension. Methods Left ventricle mRNA expression and plasma levels of pro-inflammatory (interleukin-1β (IL-1β) and IL-6) and anti-inflammatory (IL-10) cytokines, were measured in spontaneously hypertensive rats (SHR) and their control normotensive, Wistar-Kyoto (WKY) rats, with or without a 12-week treatment with captopril (80 mg/Kg/day; n = six animals per group). To understand the mechanisms involved in the effect of captopril, mRNA expression of ACE, angiotensin II type I receptor (AT1R) and p22phox (a subunit of NADPH oxidase), as well as NF-κB activation and expression, were measured in the left ventricle of these animals. Results In SHR, the observed increases in blood pressures, heart rate, left ventricle relative weight, plasma levels and cardiac mRNA expression of IL-1β and IL-6, as well as the reductions in the plasma levels and in the cardiac mRNA expression of IL-10, were reversed after the treatment with captopril. Moreover, the mRNA expressions of ACE, AT1R and p22phox, which were enhanced in the left ventricle of SHR, were reduced to normal values after captopril treatment. Finally, SHR presented an elevated cardiac mRNA expression and activation of the transcription nuclear factor, NF-κB, accompanied by a reduced expression of its inhibitor, IκB; captopril administration corrected the observed changes in all these parameters. Conclusion These findings show that captopril decreases the inflammation process in the left ventricle of hypertensive rats and suggest that NF-κB-driven inflammatory reactivity might be responsible for this effect through an inactivation of NF-κB-dependent pro-inflammatory factors. PMID:20462420

Dietary sodium deprivation evokes activation of brain regional neurons and down-regulation of angiotensin II type 1 receptor and angiotensin-convertion enzyme mRNA expression.

PubMed

Lu, B; Yang, X J; Chen, K; Yang, D J; Yan, J Q

2009-12-15

Previous studies have indicated that the renin-angiotensin-aldosterone system (RAAS) is implicated in the induction of sodium appetite in rats and that different dietary sodium intakes influence the mRNA expression of central and peripheral RAAS components. To determine whether dietary sodium deprivation activates regional brain neurons related to sodium appetite, and changes their gene expression of RAAS components of rats, the present study examined the c-Fos expression after chronic exposure to low sodium diet, and determined the relationship between plasma and brain angiotensin I (ANG I), angiotensin II (ANG II) and aldosterone (ALD) levels and the sodium ingestive behavior variations, as well as the effects of prolonged dietary sodium deprivation on ANG II type 1 (AT1) and ANG II type 2 (AT2) receptors and angiotensin-convertion enzyme (ACE) mRNA levels in the involved brain regions using the method of real-time polymerase chain reaction (PCR). Results showed that the Fos immunoreactivity (Fos-ir) expression in forebrain areas such as subfornical organ (SFO), paraventricular hypothalamic nuclei (PVN), supraoptic nucleus (SON) and organum vasculosum laminae terminalis (OVLT) all increased significantly and that the levels of ANG I, ANG II and ALD also increased in plasma and forebrain in rats fed with low sodium diet. In contrast, AT1, ACE mRNA in PVN, SON and OVLT decreased significantly in dietary sodium depleted rats, while AT2 mRNA expression did not change in the examined areas. These results suggest that many brain areas are activated by increased levels of plasma and/or brain ANG II and ALD, which underlies the elevated preference for hypertonic salt solution after prolonged exposure to low sodium diet, and that the regional AT1 and ACE mRNA are down-regulated after dietary sodium deprivation, which may be mediated by increased ANG II in plasma and/or brain tissue.

Enalapril protects against myocardial ischemia/reperfusion injury in a swine model of cardiac arrest and resuscitation

PubMed Central

Wang, Guoxing; Zhang, Qian; Yuan, Wei; Wu, Junyuan; Li, Chunsheng

2016-01-01

There is strong evidence to suggest that angiotensin-converting enzyme inhibitors (ACEIs) protect against local myocardial ischemia/reperfusion (I/R) injury. This study was designed to explore whether ACEIs exert cardioprotective effects in a swine model of cardiac arrest (CA) and resuscitation. Male pigs were randomly assigned to three groups: sham-operated group, saline treatment group and enalapril treatment group. Thirty minutes after drug infusion, the animals in the saline and enalapril groups were subjected to ventricular fibrillation (8 min) followed by cardiopulmonary resuscitation (up to 30 min). Cardiac function was monitored, and myocardial tissue and blood were collected for analysis. Enalapril pre-treatment did not improve cardiac function or the 6-h survival rate after CA and resuscitation; however, this intervention ameliorated myocardial ultrastructural damage, reduced the level of plasma cardiac troponin I and decreased myocardial apoptosis. Plasma angiotensin (Ang) II and Ang-(1–7) levels were enhanced in the model of CA and resuscitation. Enalapril reduced the plasma Ang II level at 4 and 6 h after the return of spontaneous circulation whereas enalapril did not affect the plasma Ang-(1–7) level. Enalapril pre-treatment decreased the myocardial mRNA and protein expression of angiotensin-converting enzyme (ACE). Enalapril treatment also reduced the myocardial ACE/ACE2 ratio, both at the mRNA and the protein level. Enalapril pre-treatment did not affect the upregulation of ACE2, Ang II type 1 receptor (AT1R) and MAS after CA and resuscitation. Taken together, these findings suggest that enalapril protects against ischemic injury through the attenuation of the ACE/Ang II/AT1R axis after CA and resuscitation in pigs. These results suggest the potential therapeutic value of ACEIs in patients with CA. PMID:27633002

Separation and Characterization of Angiotensin I Converting Enzyme (ACE) Inhibitory Peptides from Saurida elongata Proteins Hydrolysate by IMAC-Ni2.

PubMed

Sun, Lixia; Wu, Shanguang; Zhou, Liqin; Wang, Feng; Lan, Xiongdiao; Sun, Jianhua; Tong, Zhangfa; Liao, Dankui

2017-02-15

Lizard fish protein hydrolysates (LFPH) were prepared from Lizard fish ( Saurida elongata ) proteins possessing powerful angiotensin I converting enzyme (ACE) inhibitory activity and the fraction (LFPH-I) with high ACE inhibitory activity was obtained through ultrafiltration. The active Fraction (F2) was isolated from LFPH-I using immobilized metal affinity chromatography (IMAC - Ni 2+ ). Analysis of amino acid levels revealed that F2 eluted from IMAC was enriched in Met, His, Tyr, Pro, Ile, and Leu compared to the crude peptide LFPH-I. F2 with the high ACE inhibitory activity (IC 50 of 0.116 mg·mL -1 ) was further separated by a reverse-phase column to yield a novel ACE inhibitory peptide with IC 50 value of 52 μM. The ACE inhibitory peptide was identified as Arg-Tyr-Arg-Pro, RYRP. The present study demonstrated that IMAC may be a useful tool for the separation of ACE inhibitory peptides from protein hydrolysate.

Identification of ACE-inhibitory peptides from Phaseolus vulgaris after in vitro gastrointestinal digestion.

PubMed

Tagliazucchi, Davide; Martini, Serena; Bellesia, Andrea; Conte, Angela

2015-01-01

The objective of this study was to identify the angiotensin I-converting enzyme (ACE)-inhibitory peptides released from thermally treated Phaseolus vulgaris (pinto) whole beans after in vitro gastrointestinal digestion. The degree of hydrolysis increased during digestion reaching a value of 50% at the end of the pancreatic digestion. The <3 kDa fraction of the postpancreatic sample showed high ACE-inhibitory activity (IC50 = 105.6 ± 2.1 μg of peptides/mL). Peptides responsible for the ACE-inhibitory activity were isolated by reverse-phase high-performance liquid chromatography (HPLC). Three fractions, showing the highest inhibitory activity, were selected for tandem mass spectrometry (MS/MS) experiments. Eleven of the identified sequences have previously been described as ACE-inhibitors. Most of the identified bioactive peptides have a hydrophobic amino acid, (iso)leucine or phenylalanine, or proline at the C-terminal position, which is crucial for their ACE-inhibitory activity. The sequence of some peptides allowed us to anticipate the presence of ACE-inhibitory activity.

Exploration of the molecular interactions between angiotensin-I-converting enzyme (ACE) and the inhibitory peptides derived from hazelnut (Corylus heterophylla Fisch.).

PubMed

Liu, Chunlei; Fang, Li; Min, Weihong; Liu, Jingsheng; Li, Hongmei

2018-04-15

The mechanism of action of food-derived angiotensin-I-converting enzyme (ACE) inhibitory peptides has not been completely elucidated. In the present study, ion-exchange chromatography, gel filtration chromatography, reverse phase-high performance liquid chromatography, and liquid chromatography-electrospray ionization-tandem mass (LC-ESI-MS/MS) were employed for purifying and identifying the ACE inhibitory peptides from hazelnut. To understand the mode of action of these peptides, ACE inhibition kinetics, in vitro and in vivo bioavailability assays, active site analysis, and interaction between the inhibitory peptides and ACE were investigated. The results identified novel ACE inhibitory peptides Ala-Val-Lys-Val-Leu (AVKVL), Tyr-Leu-Val-Arg (YLVR), and Thr-Leu-Val-Gly-Arg (TLVGR) with IC 50 values of 73.06, 15.42, and 249.3 μM, respectively. All peptides inhibited the ACE activity via a non-competitive mode. The binding free energies of AVKVL, YLVR, and TLVGR for ACE were -3.46, -6.48, and -7.37 kcal/mol, respectively. The strong inhibition of ACE by YLVR may be attributed to the formation of cation-pi interactions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Overexpression of heterogeneous nuclear ribonucleoprotein F stimulates renal Ace-2 gene expression and prevents TGF-β1-induced kidney injury in a mouse model of diabetes.

PubMed

Lo, Chao-Sheng; Shi, Yixuan; Chang, Shiao-Ying; Abdo, Shaaban; Chenier, Isabelle; Filep, Janos G; Ingelfinger, Julie R; Zhang, Shao-Ling; Chan, John S D

2015-10-01

We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita mouse model of type 1 diabetes. Adult male Akita transgenic (Tg) mice overexpressing specifically hnRNP F in their renal proximal tubular cells (RPTCs) were studied. Non-Akita littermates and Akita mice served as controls. Immortalised rat RPTCs stably transfected with plasmid containing either rat Hnrnpf cDNA or rat Ace-2 gene promoter were also studied. Overexpression of hnRNP F attenuated systemic hypertension, glomerular filtration rate, albumin/creatinine ratio, urinary angiotensinogen (AGT) and angiotensin (Ang) II levels, renal fibrosis and profibrotic gene (Agt, Tgf-β1, TGF-β receptor II [Tgf-βrII]) expression, stimulated anti-profibrotic gene (Ace-2 and Ang 1-7 receptor [MasR]) expression, and normalised urinary Ang 1-7 level in Akita Hnrnpf-Tg mice as compared with Akita mice. In vitro, hnRNP F overexpression stimulated Ace-2 gene promoter activity, mRNA and protein expression, and attenuated Agt, Tgf-β1 and Tgf-βrII gene expression. Furthermore, hnRNP F overexpression prevented TGF-β1 signalling and TGF-β1 inhibition of Ace-2 gene expression. These data demonstrate that hnRNP F stimulates Ace-2 gene transcription, prevents TGF-β1 inhibition of Ace-2 gene transcription and induction of kidney injury in diabetes. HnRNP F may be a potential target for treating hypertension and renal fibrosis in diabetes.

Computer codes for thermal analysis of a solid rocket motor nozzle

NASA Technical Reports Server (NTRS)

Chauhan, Rajinder Singh

1988-01-01

A number of computer codes are available for performing thermal analysis of solid rocket motor nozzles. Aerotherm Chemical Equilibrium (ACE) computer program can be used to perform one-dimensional gas expansion to determine the state of the gas at each location of a nozzle. The ACE outputs can be used as input to a computer program called Momentum/Energy Integral Technique (MEIT) for predicting boundary layer development development, shear, and heating on the surface of the nozzle. The output from MEIT can be used as input to another computer program called Aerotherm Charring Material Thermal Response and Ablation Program (CMA). This program is used to calculate oblation or decomposition response of the nozzle material. A code called Failure Analysis Nonlinear Thermal and Structural Integrated Code (FANTASTIC) is also likely to be used for performing thermal analysis of solid rocket motor nozzles after the program is duly verified. A part of the verification work on FANTASTIC was done by using one and two dimension heat transfer examples with known answers. An attempt was made to prepare input for performing thermal analysis of the CCT nozzle using the FANTASTIC computer code. The CCT nozzle problem will first be solved by using ACE, MEIT, and CMA. The same problem will then be solved using FANTASTIC. These results will then be compared for verification of FANTASTIC.

Purification of angiotensin I-converting enzyme (ACE) inhibitory peptides from casein hydrolysate by IMAC-Ni2.

PubMed

Wu, Shanguang; Feng, Xuezhen; Lu, Yuan; Lu, Yuting; Liu, Saisai; Tian, Yuhong

2017-10-01

Casein proteins were hydrolyzed by papain to identify inhibitory peptides of angiotensin I-converting enzyme (ACE). The hydrolysate was fractionized by immobilized metal affinity chromatography (IMAC-Ni 2+ ). The fraction with high ACE inhibitory activity was enriched and further chromatographed on a reverse-phase column to yield four fractions. Among the fractions, the L4 fraction exhibited the highest ACE inhibitory activity and was identified by sequence analysis as Trp-Tyr-Leu-His-Tyr-Ala (WYLHYA), with IC 50 value of 16.22 ± 0.83 µM in vitro. This peptide was expected to be applied as an ingredient for preventing hypertension and IMAC-Ni 2+ may provide a simple method for purification of ACE inhibitory peptides.

Massively parallel rRNA gene sequencing exacerbates the potential for biased community diversity comparisons due to variable library sizes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gihring, Thomas; Green, Stefan; Schadt, Christopher Warren

2011-01-01

Technologies for massively parallel sequencing are revolutionizing microbial ecology and are vastly increasing the scale of ribosomal RNA (rRNA) gene studies. Although pyrosequencing has increased the breadth and depth of possible rRNA gene sampling, one drawback is that the number of reads obtained per sample is difficult to control. Pyrosequencing libraries typically vary widely in the number of sequences per sample, even within individual studies, and there is a need to revisit the behaviour of richness estimators and diversity indices with variable gene sequence library sizes. Multiple reports and review papers have demonstrated the bias in non-parametric richness estimators (e.g.more » Chao1 and ACE) and diversity indices when using clone libraries. However, we found that biased community comparisons are accumulating in the literature. Here we demonstrate the effects of sample size on Chao1, ACE, CatchAll, Shannon, Chao-Shen and Simpson's estimations specifically using pyrosequencing libraries. The need to equalize the number of reads being compared across libraries is reiterated, and investigators are directed towards available tools for making unbiased diversity comparisons.« less

Isolation of high-quality total RNA from rumen anaerobic bacteria and fungi, and subsequent detection of glycoside hydrolases.

PubMed

Wang, Pan; Qi, Meng; Barboza, Perry; Leigh, Mary Beth; Ungerfeld, Emilio; Selinger, L Brent; McAllister, Tim A; Forster, Robert J

2011-07-01

The rumen is one of the most powerful fibrolytic fermentation systems known. Gene expression analyses, such as reverse transcription PCR (RT-PCR), microarrays, and metatranscriptomics, are techniques that could significantly expand our understanding of this ecosystem. The ability to isolate and stabilize representative RNA samples is critical to obtaining reliable results with these procedures. In this study, we successfully isolated high-quality total RNA from the solid phase of ruminal contents by using an improved RNA extraction method. This method is based on liquid nitrogen grinding of whole ruminal solids without microbial detachment and acid guanidinium - phenol - chloroform extraction combined with column purification. Yields of total RNA were as high as 150 µg per g of fresh ruminal content. The typical large subunit/small subunit rRNA ratio ranged from 1.8 to 2.0 with an RNA integrity number (Agilent Technologies) greater than 8.5. By eliminating the detachment step, the resulting RNA was more representative of the complete ecosystem. Our improved method removed a major barrier limiting analysis of rumen microbial function from a gene expression perspective. The polyA-tailed eukaryotic mRNAs obtained have successfully been applied to next-generation sequencing, and metatranscriptomic analysis of the solid fraction of rumen contents revealed abundant sequences related to rumen fungi.

Surface Instability of Liquid Propellant under Vertical Oscillatory Forcing

NASA Technical Reports Server (NTRS)

Yang, H. Q.; Peugeot, John

2011-01-01

Fluid motion in a fuel tank produced during thrust oscillations can circulate sub-cooled hydrogen near the liquid-vapor interface resulting in increased condensation and ullage pressure collapse. The first objective of this study is to validate the capabilities of a Computational Fluid Dynamics (CFD) tool, CFD-ACE+, in modeling the fundamental interface transition physics occurring at the propellant surface. The second objective is to use the tool to assess the effects of thrust oscillations on surface dynamics. Our technical approach is to first verify the CFD code against known theoretical solutions, and then validate against existing experiments for small scale tanks and a range of transition regimes. A 2D axisymmetric, multi-phase model of gases, liquids, and solids is used to verify that CFD-ACE+ is capable of modeling fluid-structure interaction and system resonance in a typical thrust oscillation environment. Then, the 3D mode is studied with an assumed oscillatory body force to simulate the thrust oscillating effect. The study showed that CFD modeling can capture all of the transition physics from solid body motion to standing surface wave and to droplet ejection from liquid-gas interface. Unlike the analytical solutions established during the 1960 s, CFD modeling is not limited to the small amplitude regime. It can extend solutions to the nonlinear regime to determine the amplitude of surface waves after the onset of instability. The present simulation also demonstrated consistent trends from numerical experiments through variation of physical properties from low viscous fluid to high viscous fluids, and through variation of geometry and input forcing functions. A comparison of surface wave patterns under various forcing frequencies and amplitudes showed good agreement with experimental observations. It is concluded that thrust oscillations can cause droplet formation at the interface, which results in increased surface area and enhanced heat transfer between the liquid and gas phases as the ejected droplets travel well into the warmer gas region.

Graphitized Porous Carbon for Rapid Screening of Angiotensin-Converting Enzyme Inhibitory Peptide GAMVVH from Silkworm Pupa Protein and Molecular Insight into Inhibition Mechanism.

PubMed

Tao, Mengliang; Sun, Huaju; Liu, Long; Luo, Xuan; Lin, Guoyou; Li, Renbo; Zhao, Zhenxia; Zhao, Zhongxing

2017-10-04

A novel hydrophobic hexapeptide with high angiotensin-converting enzyme (ACE) inhibitory activity was screened from silkworm pupa protein (SPP) hydrolysate via graphitized porous carbon and reverse-phase high-performance liquid chromatography methods. Graphitized porous carbon derived from dopamine, possessing high surface area and high graphitic carbon, was used to rapidly screen and enrich hydrophobic peptides from SPP hydrolysate. The ACE inhibition pattern and mechanism of the purified peptide were also systematically studied by the classic Lineweaver-Burk model and by molecular docking/dynamic simulation. The novel hydrophobic hexapeptide was identified as Gly-Ala-Met-Val-Val-His (GAMVVH, IC 50 = 19.39 ± 0.21 μM) with good thermal/antidigestive stabilities. Lineweaver-Burk plots revealed that GAMVVH behaved as a competitive ACE inhibitor. It formed hydrogen bonds with S1 and S2 pockets of ACE and established competitive coordination with Zn(II) of ACE. The synergy of hydrogen bonds with active pockets and Zn(II) coordination efficiently changed the three-dimensional structure of ACE and thus inhibited bioactivity of ACE.

Egg ovotransferrin-derived ACE inhibitory peptide IRW increases ACE2 but decreases proinflammatory genes expression in mesenteric artery of spontaneously hypertensive rats.

PubMed

Majumder, Kaustav; Liang, Guanxiang; Chen, Yanhong; Guan, LeLuo; Davidge, Sandra T; Wu, Jianping

2015-09-01

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. 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. 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. © 2015 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

High-throughput interpretation of gene structure changes in human and nonhuman resequencing data, using ACE

USDA-ARS?s Scientific Manuscript database

We describe a suite of software tools for identifying possible functional changes in gene structure that may result from sequence variants. ACE (“Assessing Changes to Exons”) converts phased genotype calls to a collection of explicit haplotype sequences, maps transcript annotations onto them, detect...

Endothelial function in pigs transgenic for human complement regulating factor.

PubMed

Warnecke, Gregor; Severson, Sandra R; Ugurlu, Mustafa M; Taner, Cemal B; Logan, John S; Diamond, Lisa E; Miller, Virginia M; McGregor, Christopher G A

2002-04-15

Expression of human complement regulating factor (hCRF) in porcine organs prevents hyperacute rejection of these organs after xenotransplantation to nonhuman primates. Experiments were designed to characterize endothelial and smooth muscle function of arteries from pigs transgenic for hCD46. Arterial blood from outbred pigs transgenic for hCD46 expression and nontransgenic animals of the same lineage was analyzed for angiotensin-converting enzyme (ACE), C-type natriuretic peptide (CNP), and nitric oxide. Aortic endothelial cells were prepared for measurement of mRNA or activity for nitric oxide synthase (NOS). Rings cut from femoral and pulmonary arteries were suspended in organ chambers for measurement of isometric tension. CNP was significantly greater, ACE was similar, and nitric oxide was significantly less in plasma from transgenic compared with nontransgenic pigs. Neither mRNA nor activity of NOS differed between the groups. Endothelium-dependent relaxations to bradykinin and acetylcholine but not the calcium ionophore were shifted significantly to the left in femoral and pulmonary arteries from hCD46 transgenic pigs compared with nontransgenic pigs. The ACE-inhibitor captopril augmented relaxations similarly in both groups, but NG-monomethyl-L-arginine (L-NMMA) did not inhibit relaxations in rings from transgenic pigs. Data suggest that expression of hCD46 on endothelium of pigs selectively augments endothelium-dependent relaxations to bradykinin by increased release of endothelium-derived factors other than nitric oxide. There does not seem to be any change in activity of ACE or NOS with expression of the human protein. Increased relaxations to bradykinin may be beneficial in lowering vascular resistance when transgenic organs are used for xenotransplantation.

Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema.

PubMed

Brown, Nancy J; Byiers, Stuart; Carr, David; Maldonado, Mario; Warner, Barbara Ann

2009-09-01

Dipeptidyl peptidase-IV (DPP-IV) inhibitors decrease degradation of the incretins. DPP-IV inhibitors also decrease degradation of peptides, such as substance P, that may be involved in the pathogenesis of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. This study tested the hypothesis that DPP-IV inhibition affects risk of clinical angioedema, by comparing the incidence of angioedema in patients treated with the DPP-IV inhibitor vildagliptin versus those treated with comparator in Phase III randomized clinical trials. Prospectively defined angioedema-related events were adjudicated in a blinded fashion by an internal medicine adjudication committee and expert reviewer. Concurrent ACE inhibitor or angiotensin receptor blocker exposure was ascertained from case report forms. Study drug exposure was ascertained from unblinded data from phase III studies. Odds ratios and 95% confidence intervals comparing angioedema risk in vildagliptin-treated and comparator-treated patients were calculated for the overall population and for patients taking ACE inhibitors or angiotensin receptor blockers, using both an analysis of pooled data and a meta-analysis (Peto method). Overall, there was no association between vildagliptin use and angioedema. Among individuals taking an ACE inhibitor, however, vildagliptin use was associated with an increased risk of angioedema (14 confirmed cases among 2754 vildagliptin users versus 1 case among 1819 comparator users: odds ratio 4.57 [95% confidence interval 1.57 to 13.28]) in the meta-analysis. Vildagliptin use may be associated with increased risk of angioedema among patients taking ACE inhibitors, although absolute risk is small. Physicians confronted with angioedema in a patient taking an ACE inhibitor and DPP-IV inhibitor should consider this possible drug-drug interaction.

Milk-derived peptide Val-Pro-Pro (VPP) inhibits obesity-induced adipose inflammation via an angiotensin-converting enzyme (ACE) dependent cascade.

PubMed

Sawada, Yoko; Sakamoto, Yuri; Toh, Mariko; Ohara, Nozomi; Hatanaka, Yuiko; Naka, Ayano; Kishimoto, Yoshimi; Kondo, Kazuo; Iida, Kaoruko

2015-12-01

This study aimed to examine the effects of Val-Pro-Pro (VPP), a food-derived peptide with an angiotensin-converting enzyme (ACE) inhibitory property, on obesity-linked insulin resistance, and adipose inflammation in vivo and in vitro. C57BL/6J mice were fed high-fat high-sucrose diet and VPP (0.1% in water) for 4 months. For in vitro analysis, coculture of 3T3-L1 adipocytes overexpressing either ACE (3T3-ACE) or green fluorescent protein (3T3-GFP) and RAW264 macrophages was conducted with VPP. In diet-induced obese mice, VPP improved insulin sensitivity, concomitant with a significant decrease in tumor necrosis factor α (TNF-α) and IL-1β expression in adipose tissue, with a tendency (p = 0.06) toward decreased CC chemokine ligand 5 expression. Additionally, VPP administration inhibited macrophage accumulation and activation in fat tissues. In vitro, VPP attenuated TNF-α mRNA induced by ACE overexpression in 3T3-L1 adipocytes. TNF-α and IL-1β expression decreased following VPP treatment of RAW264 macrophage and 3T3-ACE adipocyte cocultures, but not in RAW264-3T3-GFP adipocyte cocultures. Our data suggest that VPP inhibits adipose inflammation in the interaction between adipocytes and macrophages, acting as an ACE inhibitor, thereby improving obesity-related insulin resistance. Thus, ingestion of VPP may be a viable protective and therapeutic strategy for insulin resistance and obesity-associated adipose inflammation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identification of Novel Saccharomyces cerevisiae Proteins with Nuclear Export Activity: Cell Cycle-Regulated Transcription Factor Ace2p Shows Cell Cycle-Independent Nucleocytoplasmic Shuttling

PubMed Central

Jensen, Torben Heick; Neville, Megan; Rain, Jean Christophe; McCarthy, Terri; Legrain, Pierre; Rosbash, Michael

2000-01-01

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-G1-specific genes. We now provide evidence that Ace2p is nuclear not only in late M-early G1 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. PMID:11027275

Production of antioxidant and ACE-inhibitory peptides from Kluyveromyces marxianus protein hydrolysates: Purification and molecular docking.

PubMed

Mirzaei, Mahta; Mirdamadi, Saeed; Ehsani, Mohamad Reza; Aminlari, Mahmoud

2018-04-01

Kluyveromyces marxianus protein hydrolysates were prepared by two different sonicated-enzymatic (trypsin and chymotrypsin) hydrolysis treatments to obtain antioxidant and ACE-inhibitory peptides. Trypsin and chymotrypsin hydrolysates obtained by 5 h, exhibited the highest antioxidant and ACE-inhibitory activities. After fractionation using ultrafiltration and reverse phase high performance liquid chromatography (RP-HPLC) techniques, two new peptides were identified. One fragment (LL-9, MW = 1180 Da) with the amino acid sequence of Leu-Pro-Glu-Ser-Val-His-Leu-Asp-Lys showed significant ACE inhibitory activity (IC 50  = 22.88 μM) while another peptide fragment (VL-9, MW = 1118 Da) with the amino acid sequence of Val-Leu-Ser-Thr-Ser-Phe-Pro-Pro-Lys showed the highest antioxidant and ACE inhibitory properties (IC 50  = 15.20 μM, 5568 μM TE/mg protein). The molecular docking studies revealed that the ACE inhibitory activities of VL-9 is due to interaction with the S2 (His513, His353, Glu281) and S'1 (Glu162) pockets of ACE and LL-9 can fit perfectly into the S1 (Thr345) and S2 (Tyr520, Lys511, Gln281) pockets of ACE. Copyright © 2017. Published by Elsevier B.V.

Effects of acetylate hyperforin on the processing of amyloid precursor protein.

PubMed

Chen, Xiang; Feng, Wenshang; Chen, Qing; Yang, Xiangling; Yang, Depo; Wang, Dongmei; Zhong, Ling

2009-02-20

Hyperforin (HF) is a phloroglucinol compound obtained from St. John's Wort (Hypericum perforatum). Recent studies have shown that Hyperforin can be used to improve psychopathologic symptoms of Alzheimer's disease but the mechanism is not clear. This may be partly due to the difficult in studying Hyperforin, since this chemical is unstable and is sensitive to light, oxygen, and heat. In this study, we explored the effects of acetylate hyperforin (ace-HF), a stable derivative of hyperforin, on the processing of amyloid precursor protein (APP). HEK293 cells transfected with pcDNA3.1APP695sw and SH-SY5Y cells were treated with ace-HF, followed by measuring the levels of APP and sAPPα. Twelve hours of treatment led to an increase in extracellular sAPPα, but APP mRNA and protein levels were unchanged. Further studies with α-secretase and a pan PKC inhibitor, Calphostin C, indicated that ace-HF's effect on extracellular sAPPα was closely related to PKC activities and α-secretase activities. Our findings suggest that ace-HF can modulate α-secretase-mediated APP processing via a PKC signaling pathway.

RNAi of selected candidate genes interrupts growth and development of Helicoverpa armigera.

PubMed

Chikate, Yojana R; Dawkar, Vishal V; Barbole, Ranjit S; Tilak, Priyadarshini V; Gupta, Vidya S; Giri, Ashok P

2016-10-01

Helicoverpa armigera is one of the major crop pests and is less amenable to current pest control approaches. RNA interference (RNAi) is emerging as a potent arsenal for the insect pest control over current methods. Here, we examined the effect on growth and development in H. armigera by targeting various enzymes/proteins such as proteases like trypsins (HaTry2, 3, 4 and 6), chymotrypsin (HaChy4) and cysteine protease like cathepsin (HaCATHL); glutathione S-transferases (HaGST1a, 6 and 8); esterases (HaAce4, HaJHE); catalase (HaCAT); super-oxide-dismutase (HaCu/ZnSOD); fatty acid binding protein (HaFabp) and chitin deacetylase (HaCda5b) through dsRNA approach. Significant downregulation of cognate mRNA expression and reduced activity of trypsin and GST-like enzyme were evident upon feeding candidate dsRNAs to the larvae. Among these, the highest mortality was observed in HaAce4 dsRNA fed larvae followed by HaJHE; HaCAT; HaCuZnSOD; HaFabp and HaTry3 whereas remaining ones showed relatively lower mortality. Furthermore, the dsRNA fed larvae showed significant reduction in the larval mass and abnormalities at the different stages of H. armigera development compared to their control diets. For example, malformed larvae, pupae and moth at a dose of 60μg/day were evident in high number of individual insects fed on dsRNA containing diets. Moreover, the growth and development of insects and moths were retarded in dsRNA fed larvae. These findings might provide potential new candidates for designing effective dsRNA as pesticide in crop protection. Copyright © 2016 Elsevier B.V. All rights reserved.

Ca(2+) -complex stability of GAPAGPLIVPY peptide in gas and aqueous phase, investigated by affinity capillary electrophoresis and molecular dynamics simulations and compared to mass spectrometric results.

PubMed

Nachbar, Markus; El Deeb, Sami; Mozafari, Mona; Alhazmi, Hassan A; Preu, Lutz; Redweik, Sabine; Lehmann, Wolf Dieter; Wätzig, Hermann

2016-03-01

Strong, sequence-specific gas-phase bindings between proline-rich peptides and alkaline earth metal ions in nanoESI-MS experiments were reported by Lehmann et al. (Rapid Commun. Mass Spectrom. 2006, 20, 2404-2410), however its relevance for physiological-like aqueous phase is uncertain. Therefore, the complexes should also be studied in aqueous solution and the relevance of the MS method for binding studies be evaluated. A mobility shift ACE method was used for determining the binding between the small peptide GAPAGPLIVPY and various metal ions in aqueous solution. The findings were compared to the MS results and further explained using computational methods. While the MS data showed a strong alkaline earth ion binding, the ACE results showed nonsignificant binding. The proposed vacuum state complex also decomposed during a molecular dynamic simulation in aqueous solution. This study shows that the formed stable peptide-metal ion adducts in the gas phase by ESI-MS does not imply the existence of analogous adducts in the aqueous phase. Comparing peptide-metal ion interaction under the gaseous MS and aqueous ACE conditions showed huge difference in binding behavior. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Whey-grape juice drink processed by supercritical carbon dioxide technology: Physicochemical characteristics, bioactive compounds and volatile profile.

PubMed

Amaral, Gabriela V; Silva, Eric Keven; Cavalcanti, Rodrigo N; Martins, Carolina P C; Andrade, Luiz Guilherme Z S; Moraes, Jeremias; Alvarenga, Verônica O; Guimarães, Jonas T; Esmerino, Erick A; Freitas, Mônica Q; Silva, Márcia C; Raices, Renata S L; Sant' Ana, Anderson S; Meireles, M Angela A; Cruz, Adriano G

2018-01-15

The effect of supercritical carbon dioxide technology (SCCD, 14, 16, and 18MPa at 35±2°C for 10min) on whey-grape juice drink characteristics was investigated. Physicochemical characterization (pH, titratable acidity, total soluble solids), bioactive compounds (phenolic compounds, anthocyanin, DPPH and ACE activity) and the volatile compounds were performed. Absence of differences were found among treatments for pH, titratable acidity, soluble solids, total anthocyanin and DPPH activity (p-value>0.05). A direct relationship between SCCD pressure and ACE inhibitory activity was observed, with 34.63, 38.75, and 44.31% (14, 16, and 18MPa, respectively). Regards the volatile compounds, it was noted few differences except by the presence of ketones. The findings confirm the SCCD processing as a potential promising technology to the conventional thermal treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Determination of artificial sweeteners in sewage sludge samples using pressurised liquid extraction and liquid chromatography-tandem mass spectrometry.

PubMed

Ordoñez, Edgar Y; Quintana, José Benito; Rodil, Rosario; Cela, Rafael

2013-12-13

An analytical method for the determination of six artificial sweeteners in sewage sludge has been developed. The procedure is based on pressurised liquid extraction (PLE) with water followed by solid-phase extraction (SPE) and subsequent liquid chromatography-tandem mass spectrometry analysis. After optimisation of the different PLE parameters, extraction with aqueous 500mM formate buffer (pH 3.5) at 80°C during a single static cycle of 21min proved to be best conditions. After a subsequent SPE, quantification limits, referred to dry weight (dw) of sewage sludge, ranged from 0.3ng/g for acesulfame (ACE) to 16ng/g for saccharin (SAC) and neohespiridine dihydrochalcone. The trueness, expressed as recovery, ranged between 72% and 105% and the precision, expressed as relative standard deviation, was lower than 16%. Moreover, the method proved its linearity up to the 2μg/g range. Finally, the described method was applied to the determination of the artificial sweeteners in primary and secondary sewage sludge from urban wastewater treatment plants. Four of the six studied artificial sweeteners (ACE, cyclamate, SAC and sucralose) were found in the samples at concentrations ranging from 17 to 628ng/g dw. Copyright © 2013 Elsevier B.V. All rights reserved.

Are ACE Inhibitors and Beta-blockers Dangerous in Patients at Risk for Anaphylaxis?

PubMed

Coop, Christopher A; Schapira, Rebecca S; Freeman, Theodore M

The objective of this article is to review the available studies regarding angiotensin converting enzyme (ACE) inhibitors and beta-blockers and their effect on patients at risk for anaphylaxis. A literature search was conducted in PUBMED to identify peer-reviewed articles using the following keywords: anaphylaxis, ACE inhibitor, beta-blocker, food allergy, radiocontrast media, venom allergy, skin testing, and immunotherapy. Some studies show an increased risk of anaphylaxis in patients who are taking ACE inhibitors and beta-blockers, whereas others studies do not show an increased risk. For venom immunotherapy, there are more data supporting the concomitant use of beta-blockers and ACE inhibitors in the build-up and maintenance phases. Most of the medical literature is limited to case reports and retrospective data. Prospective controlled trials are needed on this important topic. For those patients at risk of anaphylaxis who lack cardiovascular disease, it is recommended to avoid beta-blockers and possibly ACE inhibitors. However, for those patients with cardiovascular disease, beta-blockers and ACE inhibitors have been shown to increase life expectancy. Consideration should be given for the concomitant use of these medications while patients are receiving venom immunotherapy. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.

Production of ACE inhibitory peptides from sweet sorghum grain protein using alcalase: Hydrolysis kinetic, purification and molecular docking study.

PubMed

Wu, Qiongying; Du, Jinjuan; Jia, Junqiang; Kuang, Cong

2016-05-15

In this study, sweet sorghum grain protein (SSGP) was hydrolyzed using alcalase yielding ACE inhibitory peptides. A kinetic model was proposed to describe the enzymolysis process of SSGP. The kinetic parameters, a and b, were determined according to experimental data. It was found that the model was reliable to describe the kinetic behaviour for SSGP hydrolysis by alcalase. After hydrolysis, the SSGP hydrolysate with DH of 19% exhibited the strongest ACE inhibitory activity and the hydrolysate was then used to isolate ACE inhibitory peptides. A novel ACE inhibitory peptide was successfully purified from this hydrolysate by ultrafiltration, ion exchange chromatography, gel filtration chromatography, and reversed-phased high performance liquid chromatography (RP-HPLC). The amino acid sequence of the purified peptide was identified as Thr-Leu-Ser (IC50=102.1 μM). The molecular docking studies revealed that the ACE inhibition of the tripeptide was mainly attributed to its C-terminal Ser, which can effectively interact with the S1 and S2 pockets of ACE. Our studies suggest that the tripeptide from the SSGP hydrolysate can be utilized to develop functional food ingredients or pharmaceuticals for prevention of hypertension. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of acetylate hyperforin on the processing of amyloid precursor protein

PubMed Central

Chen, Xiang; Feng, Wenshang; Chen, Qing; Yang, Xiangling; Yang, Depo; Wang, Dongmei; Zhong, Ling

2009-01-01

Hyperforin (HF) is a phloroglucinol compound obtained from St. John's Wort (Hypericum perforatum). Recent studies have shown that Hyperforin can be used to improve psychopathologic symptoms of Alzheimer's disease but the mechanism is not clear. This may be partly due to the difficult in studying Hyperforin, since this chemical is unstable and is sensitive to light, oxygen, and heat. In this study, we explored the effects of acetylate hyperforin (ace-HF), a stable derivative of hyperforin, on the processing of amyloid precursor protein (APP). HEK293 cells transfected with pcDNA3.1APP695sw and SH-SY5Y cells were treated with ace-HF, followed by measuring the levels of APP and sAPPα. Twelve hours of treatment led to an increase in extracellular sAPPα, but APP mRNA and protein levels were unchanged. Further studies with α-secretase and a pan PKC inhibitor, Calphostin C, indicated that ace-HF's effect on extracellular sAPPα was closely related to PKC activities and α-secretase activities. Our findings suggest that ace-HF can modulate α-secretase-mediated APP processing via a PKC signaling pathway. PMID:21383880

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.

Analysis of Wake VAS Benefits Using ACES Build 3.2.1: VAMS Type 1 Assessment

NASA Technical Reports Server (NTRS)

Smith, Jeremy C.

2005-01-01

The FAA and NASA are currently engaged in a Wake Turbulence Research Program to revise wake turbulence separation standards, procedures, and criteria to increase airport capacity while maintaining or increasing safety. The research program is divided into three phases: Phase I near term procedural enhancements; Phase II wind dependent Wake Vortex Advisory System (WakeVAS) Concepts of Operations (ConOps); and Phase III farther term ConOps based on wake prediction and sensing. The Phase III Wake VAS ConOps is one element of the Virtual Airspace Modelling and Simulation (VAMS) program blended concepts for enhancing the total system wide capacity of the National Airspace System (NAS). This report contains a VAMS Program Type 1 (stand-alone) assessment of the expected capacity benefits of Wake VAS at the 35 FAA Benchmark Airports and determines the consequent reduction in delay using the Airspace Concepts Evaluation System (ACES) Build 3.2.1 simulator.

Locally acting ACE-083 increases muscle volume in healthy volunteers.

PubMed

Glasser, Chad E; Gartner, Michael R; Wilson, Dawn; Miller, Barry; Sherman, Matthew L; Attie, Kenneth M

2018-02-27

ACE-083 is a locally acting follistatin-based therapeutic that binds myostatin and other muscle regulators and has been shown to increase muscle mass and force in neuromuscular disease mouse models. This first-in-human study examined these effects. In this phase 1, randomized, double-blind, placebo-controlled, dose-ranging study in healthy postmenopausal women, ACE-083 (50-200 mg) or placebo was administered unilaterally into rectus femoris (RF) or tibialis anterior (TA) muscles as 1 or 2 doses 3 weeks apart. Fifty-eight postmenopausal women were enrolled, 42 ACE-083 and 16 placebo. No serious adverse events (AE), dose-limiting toxicities, or discontinuations resulting from AEs occurred. Maximum (mean ± SD) increases in RF and TA muscle volume were 14.5% ± 4.5% and 8.9% ± 4.7%, respectively. No significant changes in mean muscle strength were observed. ACE-083 was well tolerated and resulted in significant targeted muscle growth. ACE-083 may have the potential to increase muscle mass in a wide range of neuromuscular disorders. Muscle Nerve, 2018. © 2018 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.

Mixed-bed ion exchange chromatography employing a salt-free pH gradient for improved sensitivity and compatibility in MudPIT.

PubMed

Mommen, Geert P M; Meiring, Hugo D; Heck, Albert J R; de Jong, Ad P J M

2013-07-16

In proteomics, comprehensive analysis of peptides mixtures necessitates multiple dimensions of separation prior to mass spectrometry analysis to reduce sample complexity and increase the dynamic range of analysis. The main goal of this work was to improve the performance of (online) multidimensional protein identification technology (MudPIT) in terms of sensitivity, compatibility and recovery. The method employs weak anion and strong cation mixed-bed ion exchange chromatography (ACE) in the first separation dimension and reversed phase chromatography (RP) in the second separation dimension (Motoyama et.al. Anal. Chem 2007, 79, 3623-34.). We demonstrated that the chromatographic behavior of peptides in ACE chromatography depends on both the WAX/SCX mixing ratio as the ionic strength of the mobile phase system. This property allowed us to replace the conventional salt gradient by a (discontinuous) salt-free, pH gradient. First dimensional separation of peptides was accomplished with mixtures of aqueous formic acid and dimethylsulfoxide with increasing concentrations. The overall performance of this mobile phase system was found comparable to ammonium acetate buffers in application to ACE chromatography, but clearly outperformed strong cation exchange for use in first dimensional peptide separation. The dramatically improved compatibility between (salt-free) ion exchange chromatography and reversed phase chromatography-mass spectrometry allowed us to downscale the dimensions of the RP analytical column down to 25 μm i.d. for an additional 2- to 3-fold improvement in performance compared to current technology. The achieved levels of sensitivity, orthogonality, and compatibility demonstrates the potential of salt-free ACE MudPIT for the ultrasensitive, multidimensional analysis of very modest amounts of sample material.

Potentiation of Paclitaxel-Induced Pain Syndrome in Mice by Angiotensin I Converting Enzyme Inhibition and Involvement of Kinins.

PubMed

Brusco, Indiara; Silva, Cássia Regina; Trevisan, Gabriela; de Campos Velho Gewehr, Camila; Rigo, Flávia Karine; La Rocca Tamiozzo, Lidia; Rossato, Mateus Fortes; Tonello, Raquel; Dalmolin, Gerusa Duarte; de Almeida Cabrini, Daniela; Gomez, Marcus Vinícius; Ferreira, Juliano; Oliveira, Sara Marchesan

2017-12-01

Paclitaxel is a chemotherapeutic agent used to treat solid tumours. However, it causes an acute and neuropathic pain syndrome that limits its use. Among the mechanisms involved in neuropathic pain caused by paclitaxel is activation of kinin receptors. Angiotensin converting enzyme (ACE) inhibitors can enhance kinin receptor signalling. The goal of this study was to evaluate the role of kinins on paclitaxel-associated acute pain syndromes (P-APS) and the effect of ACE inhibition on P-APS and paclitaxel-associated chronic peripheral neuropathy (P-CPN) in mice. Herein, we show that paclitaxel caused mechanical allodynia and spontaneous nociceptive behaviour that was reduced by antagonists of kinin receptors B 1 (DALBk and SSR240612) and B 2 (Hoe140 and FR173657). Moreover, enalapril (an ACE inhibitor) enhanced the mechanical allodynia induced by a low dose of paclitaxel. Likewise, paclitaxel injection inhibited ACE activity and increased the expressions of B 1 and B 2 receptors and bradykinin-related peptides levels in peripheral tissue. Together, our data support the involvement of kinin receptors in the P-APS and suggest kinin receptor antagonists to treat this syndrome. Because hypertension is the most frequent comorbidity affecting cancer patients, treatment of hypertension with ACE inhibitors in patients undergoing paclitaxel chemotherapy should be reviewed, since this could enhance the P-APS and P-CPN.

Abstracts of ARI Research Publications FY 1983

DTIC Science & Technology

1983-10-01

and the relationship between SM usage and the soldier’s ability to perform his or her job skills , as measured by 2 SQT scores. Questionnaire data were...System (ACES) on soldier performance. Four -’ ACES programs were selected for evaluation: Basic Skills Education Program I, Literacy Phase (BSEP I...the prototype system was operated at Fort Carson, CO, the relationships among maintenance workload, efficiency, and skill were studied. As workload

Recent Observations of Clouds and Precipitation by the Airborne Precipitation Radar 2nd Generation in Support of the GPM and ACE Missions

NASA Technical Reports Server (NTRS)

Durden, Stephen L.; Tanelli, Simone; Im, Eastwood

2012-01-01

In this paper we illustrate the unique dataset collected during the Global Precipitation Measurement Cold-season Precipitation Experiment (GCPEx, US/Canada Jan/Feb 2012). We will focus on the significance of these observations for the development of algorithms for GPM and ACE, with particular attention to classification and retrievals of frozen and mixed phase hydrometeors.

Physiological adaptation of Escherichia coli after transfer onto refrigerated ground meat and other solid matrices: a molecular approach.

PubMed

Guernec, Anthony; Robichaud-Rincon, Philippe; Saucier, Linda

2012-10-01

Bacteria on meat are subjected to specific living conditions that differ drastically from typical laboratory procedures in synthetic media. This study was undertaken to determine the behavior of bacteria when transferred from a rich-liquid medium to solid matrices, as is the case during microbial process validation. Escherichia coli cultured in Brain-Heart Infusion (BHI) broth to different growth phases were inoculated in ground beef (GB) and stored at 5°C for 12 days or spread onto BHI agar and cooked meat medium (CMM), and incubated at 37°C for several hours. We monitored cell densities and the expression of σ factors and genes under their control over time. The initial growth phase of the inoculum influenced growth resumption after transfer onto BHI agar and CMM. Whatever the solid matrix, bacteria adapted to their new environment and did not perceive stress immediately after inoculation. During this period, the σ(E) and σ(H) regulons were not activated and rpoD mRNA levels adjusted quickly. The rpoS and gadA mRNA levels did not increase after inoculation on solid surfaces and displayed normal growth-dependent modifications. After transfer onto GB, dnaK and groEL gene expression was affected more by the low temperature than by the composition of a meat environment. Copyright © 2012 Elsevier Ltd. All rights reserved.

ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage.

PubMed

Sato, Teruki; Sato, Chitose; Kadowaki, Ayumi; Watanabe, Hiroyuki; Ho, Lena; Ishida, Junji; Yamaguchi, Tomokazu; Kimura, Akinori; Fukamizu, Akiyoshi; Penninger, Josef M; Reversade, Bruno; Ito, Hiroshi; Imai, Yumiko; Kuba, Keiji

2017-06-01

Elabela/Toddler/Apela (ELA) has been identified as a novel endogenous peptide ligand for APJ/Apelin receptor/Aplnr. ELA plays a crucial role in early cardiac development of zebrafish as well as in maintenance of self-renewal of human embryonic stem cells. Apelin was the first identified APJ ligand, and exerts positive inotropic heart effects and regulates the renin-angiotensin system. The aim of this study was to investigate the biological effects of ELA in the cardiovascular system. Continuous infusion of ELA peptide significantly suppressed pressure overload-induced cardiac hypertrophy, fibrosis and impaired contractility in mice. ELA treatment reduced mRNA expression levels of genes associated with heart failure and fibrosis. The cardioprotective effects of ELA were diminished in APJ knockout mice, indicating that APJ is the key receptor for ELA in the adult heart. Mechanistically, ELA downregulated angiotensin-converting enzyme (ACE) expression in the stressed hearts, whereas it showed little effects on angiotensin-converting enzyme 2 (ACE2) expression, which are distinct from the effects of Apelin. FoxM1 transcription factor, which induces ACE expression in the stressed hearts, was downregulated by ELA but not by Apelin. ELA antagonized angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. The ELA-APJ axis protects from pressure overload-induced heart failure possibly via suppression of ACE expression and pathogenic angiotensin II signalling. The different effects of ELA and Apelin on the expression of ACE and ACE2 implicate fine-tuned mechanisms for a ligand-induced APJ activation and downstream signalling. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

The Transcriptome Analysis and Comparison Explorer--T-ACE: a platform-independent, graphical tool to process large RNAseq datasets of non-model organisms.

PubMed

Philipp, E E R; Kraemer, L; Mountfort, D; Schilhabel, M; Schreiber, S; Rosenstiel, P

2012-03-15

Next generation sequencing (NGS) technologies allow a rapid and cost-effective compilation of large RNA sequence datasets in model and non-model organisms. However, the storage and analysis of transcriptome information from different NGS platforms is still a significant bottleneck, leading to a delay in data dissemination and subsequent biological understanding. Especially database interfaces with transcriptome analysis modules going beyond mere read counts are missing. Here, we present the Transcriptome Analysis and Comparison Explorer (T-ACE), a tool designed for the organization and analysis of large sequence datasets, and especially suited for transcriptome projects of non-model organisms with little or no a priori sequence information. T-ACE offers a TCL-based interface, which accesses a PostgreSQL database via a php-script. Within T-ACE, information belonging to single sequences or contigs, such as annotation or read coverage, is linked to the respective sequence and immediately accessible. Sequences and assigned information can be searched via keyword- or BLAST-search. Additionally, T-ACE provides within and between transcriptome analysis modules on the level of expression, GO terms, KEGG pathways and protein domains. Results are visualized and can be easily exported for external analysis. We developed T-ACE for laboratory environments, which have only a limited amount of bioinformatics support, and for collaborative projects in which different partners work on the same dataset from different locations or platforms (Windows/Linux/MacOS). For laboratories with some experience in bioinformatics and programming, the low complexity of the database structure and open-source code provides a framework that can be customized according to the different needs of the user and transcriptome project.

Loss of Angiotensin-Converting Enzyme 2 Exacerbates Diabetic Retinopathy by Promoting Bone Marrow Dysfunction.

PubMed

Duan, Yaqian; Beli, Eleni; Li Calzi, Sergio; Quigley, Judith L; Miller, Rehae C; Moldovan, Leni; Feng, Dongni; Salazar, Tatiana E; Hazra, Sugata; Al-Sabah, Jude; Chalam, Kakarla V; Le Phuong Trinh, Thao; Meroueh, Marya; Markel, Troy A; Murray, Matthew C; Vyas, Ruchi J; Boulton, Michael E; Parsons-Wingerter, Patricia; Oudit, Gavin Y; Obukhov, Alexander G; Grant, Maria B

2018-05-15

Angiotensin-converting enzyme 2 (ACE2) is the primary enzyme of the vasoprotective axis of the renin angiotensin system (RAS). We tested the hypothesis that loss of ACE2 would exacerbate diabetic retinopathy by promoting bone marrow dysfunction. ACE2 -/y were crossed with Akita mice, a model of type 1 diabetes. When comparing the bone marrow of the ACE2 -/y -Akita mice to that of Akita mice, we observed a reduction of both short-term and long-term repopulating hematopoietic stem cells, a shift of hematopoiesis towards myelopoiesis, and an impairment of lineage - c-kit + hematopoietic stem/progenitor cell (HS/PC) migration and proliferation. Migratory and proliferative dysfunction of these cells was corrected by exposure to angiotensin-1-7 (Ang-1-7), the protective peptide generated by ACE2. Over the duration of diabetes examined, ACE2 deficiency led to progressive reduction in electrical responses assessed by electroretinography and to increases in neural infarcts observed by fundus photography. Compared to Akita mice, ACE2 -/y -Akita at 9-months of diabetes showed an increased number of acellular capillaries indicative of more severe diabetic retinopathy. In diabetic and control human subjects, CD34 + cells, a key bone marrow HS/PC population, were assessed for changes in mRNA levels for MAS, the receptor for Ang-1-7. Levels were highest in CD34 + cells from diabetics without retinopathy. Higher serum Ang-1-7 levels predicted protection from development of retinopathy in diabetics. Treatment with Ang-1-7 or alamandine restored the impaired migration function of CD34 + cells from subjects with retinopathy. These data support that activation of the protective RAS within HS/PCs may represent a therapeutic strategy for prevention of diabetic retinopathy. This article is protected by copyright. All rights reserved. © 2018 AlphaMed Press.

Microbial identification by immunohybridization assay of artificial RNA labels

NASA Technical Reports Server (NTRS)

Kourentzi, Katerina D.; Fox, George E.; Willson, Richard C.

2002-01-01

Ribosomal RNA (rRNA) and engineered stable artificial RNAs (aRNAs) are frequently used to monitor bacteria in complex ecosystems. In this work, we describe a solid-phase immunocapture hybridization assay that can be used with low molecular weight RNA targets. A biotinylated DNA probe is efficiently hybridized in solution with the target RNA, and the DNA-RNA hybrids are captured on streptavidin-coated plates and quantified using a DNA-RNA heteroduplex-specific antibody conjugated to alkaline phosphatase. The assay was shown to be specific for both 5S rRNA and low molecular weight (LMW) artificial RNAs and highly sensitive, allowing detection of as little as 5.2 ng (0.15 pmol) in the case of 5S rRNA. Target RNAs were readily detected even in the presence of excess nontarget RNA. Detection using DNA probes as small as 17 bases targeting a repetitive artificial RNA sequence in an engineered RNA was more efficient than the detection of a unique sequence.

Increased insulin-stimulated expression of arterial angiotensinogen and angiotensin type 1 receptor in patients with type 2 diabetes mellitus and atheroma.

PubMed

Hodroj, Wassim; Legedz, Liliana; Foudi, Nabil; Cerutti, Catherine; Bourdillon, Marie-Claude; Feugier, Patrick; Beylot, Michel; Randon, Jacques; Bricca, Giampiero

2007-03-01

Because inhibition of the renin-angiotensin system (RAS) reduces the onset of type 2 diabetes (T2D) and prevents atherosclerosis, we investigated the expression of RAS in the arterial wall of T2D and nondiabetic (CTR) patients. mRNA and protein levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and AT1 receptor (AT1R) were determined in carotid atheroma plaque, nearby macroscopically intact tissue (MIT), and in vascular smooth muscle cells (VSMCs) before and after insulin stimulation from 21 T2D and 22 CTR patients. AGT and ACE mRNA and their protein levels were 2- to 3-fold higher in atheroma and in MIT of T2D patients. VSMCs from T2D patients had respectively 2.5- and 5-fold higher AGT and AT1R mRNA and protein contents. Insulin induced an increase in AGT and AT1R mRNA with similar ED50. These responses were blocked by PD98059, an inhibitor of MAP-kinase in the two groups whereas wortmannin, an inhibitor of PI3-kinase, partially prevented the response in CTR patients. Phosphorylated ERK1-2 was 4-fold higher in MIT from T2D than from CTR patients. The arterial RAS is upregulated in T2D patients, which can be partly explained by an hyperactivation of the ERK1-2 pathway by insulin.

Two Novel Bioactive Peptides from Antarctic Krill with Dual Angiotensin Converting Enzyme and Dipeptidyl Peptidase IV Inhibitory Activities.

PubMed

Ji, Wei; Zhang, Chaohua; Ji, Hongwu

2017-07-01

Inhibition of dipeptidyl peptidase IV (DPP-IV) and angiotensin converting enzyme (ACE) are considered useful in managing 2 often associated conditions: diabetes and hypertension. In this study, corolase PP was used to hydrolyze Antarctic krill protein. The hydrolysate (AKH) was isolated by ultrafiltration and purified by size-exclusion chromatography, ion exchange chromatography and reversed-phase high-performance liquid chromatography (RP-HPLC) sequentially. The in vitro inhibitory activities of all AKHs and several fractions obtained against ACE and DPP-IV were assessed. Two peptides, purified with dual-strength inhibitory activity against ACE and DPP-IV, were identified by TOF-MS/MS. Results indicated that not all fractions exhibited dual inhibitory activities of ACE and DPP-IV. The purified peptide Lys-Val-Glu-Pro-Leu-Pro had half-maximal inhibitory concentrations (IC 50 ) of 0.93±0.05 and 0.73±0.04 mg/mL against ACE and DPP-IV, respectively. The other peptide Pro-Ala-Leu had IC 50 values of 0.64±0.05 and 0.88±0.03 mg/mL against ACE and DPP-IV, respectively. This study firstly reported the sequences of dual bioactive peptides from Antarctic krill proteins, further provided new insights into the bioactive peptides responsible for the ACE and DPP-IV inhibitory activities from the Antarctic krill protein hydrolysate to manage hypertension and diabetes. © 2017 Institute of Food Technologists®.

Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism.

PubMed

Francis, Andrew J; Resendiz, Marino J E

2017-07-28

Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular methodology for applications in various fields and for different research purposes. The procedure described herein focuses on the synthesis, purification, and characterization of dodecamers of RNA 5'-[CUA CGG AAU CAU]-3' containing zero, one, or two modifications located at the C2'-O-position. The probes are based on 2-thiophenylmethyl groups, incorporated into RNA nucleotides via standard organic synthesis and introduced into the corresponding oligonucleotides via their respective phosphoramidites. This report makes use of phosphoramidite chemistry via the four canonical nucleobases (Uridine (U), Cytosine (C), Guanosine (G), Adenosine (A)), as well as 2-thiophenylmethyl functionalized nucleotides modified at the 2'-O-position; however, the methodology is amenable for a large variety of modifications that have been developed over the years. The oligonucleotides were synthesized on a controlled-pore glass (CPG) support followed by cleavage from the resin and deprotection under standard conditions, i.e., a mixture of ammonia and methylamine (AMA) followed by hydrogen fluoride/triethylamine/N-methylpyrrolidinone. The corresponding oligonucleotides were purified via polyacrylamide electrophoresis (20% denaturing) followed by elution, desalting, and isolation via reversed-phase chromatography (Sep-pak, C18-column). Quantification and structural parameters were assessed via ultraviolet-visible (UV-vis) and circular dichroism (CD) photometric analysis, respectively. This report aims to serve as a resource and guide for beginner and expert researchers interested in embarking in this field. It is expected to serve as a work-in-progress as new technologies and methodologies are developed. The description of the methodologies and techniques within this document correspond to a DNA/RNA synthesizer (refurbished and purchased in 2013) that uses phosphoramidite chemistry.

Validation Of The Airspace Concept Evaluation System Using Real World Data

NASA Technical Reports Server (NTRS)

Zelinski, Shannon

2005-01-01

This paper discusses the process of performing a validation of the Airspace Concept Evaluation System (ACES) using real world historical flight operational data. ACES inputs are generated from select real world data and processed to create a realistic reproduction of a single day of operations within the National Airspace System (NAS). ACES outputs are then compared to real world operational metrics and delay statistics for the reproduced day. Preliminary results indicate that ACES produces delays and airport operational metrics similar to the real world with minor variations of delay by phase of flight. ACES is a nation-wide fast-time simulation tool developed at NASA Ames Research Center. ACES models and simulates the NAS using interacting agents representing center control, terminal flow management, airports, individual flights, and other NAS elements. These agents pass messages between one another similar to real world communications. This distributed agent based system is designed to emulate the highly unpredictable nature of the NAS, making it a suitable tool to evaluate current and envisioned airspace concepts. To ensure that ACES produces the most realistic results, the system must be validated. There is no way to validate future concepts scenarios using real world historical data, but current day scenario validations increase confidence in the validity of future scenario results. Each operational day has unique weather and traffic demand schedules. The more a simulation utilizes the unique characteristic of a specific day, the more realistic the results should be. ACES is able to simulate the full scale demand traffic necessary to perform a validation using real world data. Through direct comparison with the real world, models may continuee to be improved and unusual trends and biases may be filtered out of the system or used to normalize the results of future concept simulations.

Thin layer chromatography-densitometric determination of some non-sedating antihistamines in combination with pseudoephedrine or acetaminophen in synthetic mixtures and in pharmaceutical formulations.

PubMed

El-Kommos, Michael E; El-Gizawy, Samia M; Atia, Noha N; Hosny, Noha M

2014-03-01

The combination of certain non-sedating antihistamines (NSA) such as fexofenadine (FXD), ketotifen (KET) and loratadine (LOR) with pseudoephedrine (PSE) or acetaminophen (ACE) is widely used in the treatment of allergic rhinitis, conjunctivitis and chronic urticaria. A rapid, simple, selective and precise densitometric method was developed and validated for simultaneous estimation of six synthetic binary mixtures and their pharmaceutical dosage forms. The method employed thin layer chromatography aluminum plates precoated with silica gel G 60 F254 as the stationary phase. The mobile phases chosen for development gave compact bands for the mixtures FXD-PSE (I), KET-PSE (II), LOR-PSE (III), FXD-ACE (IV), KET-ACE (V) and LOR-ACE (VI) [Retardation factor (Rf ) values were (0.20, 0.32), (0.69, 0.34), (0.79, 0.13), (0.36, 0.70), (0.51, 0.30) and (0.76, 0.26), respectively]. Spectrodensitometric scanning integration was performed at 217, 218, 218, 233, 272 and 251 nm for the mixtures I-VI, respectively. The linear regression data for the calibration plots showed an excellent linear relationship. The method was validated for precision, accuracy, robustness and recovery. Limits of detection and quantitation were calculated. Statistical analysis proved that the method is reproducible and selective for the simultaneous estimation of these binary mixtures. Copyright © 2013 John Wiley & Sons, Ltd.

Total rRNA-Seq Analysis Gives Insight into Bacterial, Fungal, Protozoal and Archaeal Communities in the Rumen Using an Optimized RNA Isolation Method

PubMed Central

Elekwachi, Chijioke O.; Wang, Zuo; Wu, Xiaofeng; Rabee, Alaa; Forster, Robert J.

2017-01-01

Advances in high throughput, next generation sequencing technologies have allowed an in-depth examination of biological environments and phenomena, and are particularly useful for culture-independent microbial community studies. Recently the use of RNA for metatranscriptomic studies has been used to elucidate the role of active microbes in the environment. Extraction of RNA of appropriate quality is critical in these experiments and TRIzol reagent is often used for maintaining stability of RNA molecules during extraction. However, for studies using rumen content there is no consensus on (1) the amount of rumen digesta to use or (2) the amount of TRIzol reagent to be used in RNA extraction procedures. This study evaluated the effect of using various quantities of ground rumen digesta and of TRIzol reagent on the yield and quality of extracted RNA. It also investigated the possibility of using lower masses of solid-phase rumen digesta and lower amounts of TRIzol reagent than is used currently, for extraction of RNA for metatranscriptomic studies. We found that high quality RNA could be isolated from 2 g of ground rumen digesta sample, whilst using 0.6 g of ground matter for RNA extraction and using 3 mL (a 5:1 TRIzol : extraction mass ratio) of TRIzol reagent. This represents a significant savings in the cost of RNA isolation. These lower masses and volumes were then applied in the RNA-Seq analysis of solid-phase rumen samples obtained from 6 Angus X Hereford beef heifers which had been fed a high forage diet (comprised of barley straw in a forage-to-concentrate ratio of 70:30) for 102 days. A bioinformatics analysis pipeline was developed in-house that generated relative abundance values of archaea, protozoa, fungi and bacteria in the rumen and also allowed the extraction of individual rRNA variable regions that could be analyzed in downstream molecular ecology programs. The average relative abundances of rRNA transcripts of archaea, bacteria, protozoa and fungi in our samples were 1.4 ± 0.06, 44.16 ± 1.55, 35.38 ± 1.64, and 16.37 ± 0.65% respectively. This represents the first study to define the relative active contributions of these populations to the rumen ecosystem and is especially important in defining the role of the anaerobic fungi and protozoa. PMID:28983291

Total rRNA-Seq Analysis Gives Insight into Bacterial, Fungal, Protozoal and Archaeal Communities in the Rumen Using an Optimized RNA Isolation Method.

PubMed

Elekwachi, Chijioke O; Wang, Zuo; Wu, Xiaofeng; Rabee, Alaa; Forster, Robert J

2017-01-01

Advances in high throughput, next generation sequencing technologies have allowed an in-depth examination of biological environments and phenomena, and are particularly useful for culture-independent microbial community studies. Recently the use of RNA for metatranscriptomic studies has been used to elucidate the role of active microbes in the environment. Extraction of RNA of appropriate quality is critical in these experiments and TRIzol reagent is often used for maintaining stability of RNA molecules during extraction. However, for studies using rumen content there is no consensus on (1) the amount of rumen digesta to use or (2) the amount of TRIzol reagent to be used in RNA extraction procedures. This study evaluated the effect of using various quantities of ground rumen digesta and of TRIzol reagent on the yield and quality of extracted RNA. It also investigated the possibility of using lower masses of solid-phase rumen digesta and lower amounts of TRIzol reagent than is used currently, for extraction of RNA for metatranscriptomic studies. We found that high quality RNA could be isolated from 2 g of ground rumen digesta sample, whilst using 0.6 g of ground matter for RNA extraction and using 3 mL (a 5:1 TRIzol : extraction mass ratio) of TRIzol reagent. This represents a significant savings in the cost of RNA isolation. These lower masses and volumes were then applied in the RNA-Seq analysis of solid-phase rumen samples obtained from 6 Angus X Hereford beef heifers which had been fed a high forage diet (comprised of barley straw in a forage-to-concentrate ratio of 70:30) for 102 days. A bioinformatics analysis pipeline was developed in-house that generated relative abundance values of archaea, protozoa, fungi and bacteria in the rumen and also allowed the extraction of individual rRNA variable regions that could be analyzed in downstream molecular ecology programs. The average relative abundances of rRNA transcripts of archaea, bacteria, protozoa and fungi in our samples were 1.4 ± 0.06, 44.16 ± 1.55, 35.38 ± 1.64, and 16.37 ± 0.65% respectively. This represents the first study to define the relative active contributions of these populations to the rumen ecosystem and is especially important in defining the role of the anaerobic fungi and protozoa.

A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations.

PubMed

Duan, Yong; Wu, Chun; Chowdhury, Shibasish; Lee, Mathew C; Xiong, Guoming; Zhang, Wei; Yang, Rong; Cieplak, Piotr; Luo, Ray; Lee, Taisung; Caldwell, James; Wang, Junmei; Kollman, Peter

2003-12-01

Molecular mechanics models have been applied extensively to study the dynamics of proteins and nucleic acids. Here we report the development of a third-generation point-charge all-atom force field for proteins. Following the earlier approach of Cornell et al., the charge set was obtained by fitting to the electrostatic potentials of dipeptides calculated using B3LYP/cc-pVTZ//HF/6-31G** quantum mechanical methods. The main-chain torsion parameters were obtained by fitting to the energy profiles of Ace-Ala-Nme and Ace-Gly-Nme di-peptides calculated using MP2/cc-pVTZ//HF/6-31G** quantum mechanical methods. All other parameters were taken from the existing AMBER data base. The major departure from previous force fields is that all quantum mechanical calculations were done in the condensed phase with continuum solvent models and an effective dielectric constant of epsilon = 4. We anticipate that this force field parameter set will address certain critical short comings of previous force fields in condensed-phase simulations of proteins. Initial tests on peptides demonstrated a high-degree of similarity between the calculated and the statistically measured Ramanchandran maps for both Ace-Gly-Nme and Ace-Ala-Nme di-peptides. Some highlights of our results include (1) well-preserved balance between the extended and helical region distributions, and (2) favorable type-II poly-proline helical region in agreement with recent experiments. Backward compatibility between the new and Cornell et al. charge sets, as judged by overall agreement between dipole moments, allows a smooth transition to the new force field in the area of ligand-binding calculations. Test simulations on a large set of proteins are also discussed. Copyright 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1999-2012, 2003

Identification of Potent ACE Inhibitory Peptides from Wild Almond Proteins.

PubMed

Mirzapour, Mozhgan; Rezaei, Karamatollah; Sentandreu, Miguel Angel

2017-10-01

In this study, the production, fractionation, purification and identification of ACE (angiotensin-I-converting enzyme) inhibitory peptides from wild almond (Amygdalus scoparia) proteins were investigated. Wild almond proteins were hydrolyzed using 5 different enzymes (pepsin, trypsin, chymotrypsin, alcalase and flavourzyme) and assayed for their ACE inhibitory activities. The degree of ACE inhibiting activity obtained after hydrolysis was found to be in the following order: alcalase > chymotrypsin > trypsin/pepsin > flavourzyme. The hydrolysates obtained from alcalase (IC 50 = 0.8 mg/mL) were fractionated by sequential ultrafiltration at 10 and 3 kDa cutoff values and the most active fraction (<3 kDa) was further separated using reversed phase high-performance liquid chromatography (RP-HPLC). Peptide sequence identifications were carried out on highly potential fractions obtained from RP-HPLC by means of liquid chromatography coupled to electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS). Sequencing of ACE inhibitory peptides present in the fraction 26 of RP-HPLC resulted in the identification of 3 peptide sequences (VVNE, VVTR, and VVGVD) not reported previously in the literature. Sequence identification of fractions 40 and 42 from RP-HPLC, which showed the highest ACE inhibitory activities (84.1% and 86.9%, respectively), resulted in the identification of more than 40 potential ACE inhibitory sequences. The results indicate that wild almond protein is a rich source of potential antihypertensive peptides and can be suggested for applications in functional foods and drinks with respect to hindrance and mitigation of hypertension after in vivo assessment. This study has shown the potential of wild almond proteins as good sources for producing ACE-inhibitory active peptides. According to this finding, peptides with higher ACE inhibitory activities could be released during the gastrointestinal digestion and contribute to the health- promoting activities of this natural protein source. © 2017 Institute of Food Technologists®.

Atmospheric Climate Experiment Plus

NASA Astrophysics Data System (ADS)

Lundahl, K.

ACE+ is an atmospheric sounding mission using radio occultation techniques and is a combination of the two Earth Explorer missions ACE and WATS earlier proposed to ESA. ACE was highly rated by ESA in the Call for Earth Explorer Opportunity Missions in 1999 and was prioritised as number three and selected as a "hot-stand-by". A phase A study was carried out during 2000 and 2001. ACE will observe atmospheric parameters using radio occultations from an array of 6 micro-satellites which track the L- band signal of GPS satellites to map the detailed refractivity and thermal structure of the global atmosphere from surface to space. Water vapour and wind in Atmospheric Troposphere and Stratosphere WATS was the response to ESA's Call for Ideas for the next Earth Explorer Core Missions in 2001. WATS combines ACE GPS atmospheric occultations and LEO-LEO cross-link occultations. Cross-links strongly enhance the capability of measuring humidity relative to the ACE mission. The Earth Science Advisory Committée at ESA noted that the LEO-GNSS occultation technique is already well established through several missions in recent years and could not recommend WATS for a Phase A study as an Earth Explorer Core Mission. The ESAC was, however, deeply impressed by the LEO-LEO component of the WATS proposal and would regard it as regrettable if this science would be lost and encourages the ACE/WATS team to explore other means to achieve its scientific goal. ACE+ is therefore the response to ESA's 2nd Call for Earth Explorer Opportunity Missions in 2001 and will contribute in a significant manner to ESA's Living Planet Programme. ACE+ will considerably advance our knowledge about atmosphere physics and climate change processes. The mission will demonstrate a highly innovative approach using radio occultations for globally measuring profiles of humidity and temperature throughout the atmosphere and stratosphere. A constellation of 4 small satellites, tracking L-band GPS/GALILEO signals and X/K-band LEO-LEO cross-link signals, will be launched in 2 counter-rotating orbits with 2 satellites in each at 650 and 850 km respectively. Several aspects drive the spacecraft design. The GRAS+ and CALL+ instruments have a relatively high power consumption. The pointing and stability requirements call for a fully capable 3-axis attitude control system. Satellite characteristics include a mass of 130 kg, and available power of 80 W. The bus is based on the SMART-1 satellite from Swedish Space Corporation. In order to meet the cost envelope of the Earth Explorer Opportunity Missions the spacecraft should be a simple and robust design and makes use of the latest, but proven, technical developments as CAN-bus, GaAs solar cells and Li-Ion batteries. Low cost launch with a mix of START-1 and Rockot is also foreseen and could take place in 2006-2007. This paper describes mission characteristics and technical solutions for ACE+ .

The use of solid supports to generate nucleic acid carriers.

PubMed

Unciti-Broceta, Asier; Díaz-Mochón, Juan José; Sánchez-Martín, Rosario M; Bradley, Mark

2012-07-17

Nucleic acids are the foundation stone of all cellular processes. Consequently, the use of DNA or RNA to treat genetic and acquired disorders (so called gene therapy) offers enormous potential benefits. The restitution of defective genes or the suppression of malignant genes could target a range of diseases, including cancers, inherited diseases (cystic fibrosis, muscular dystrophy, etc.), and viral infections. However, this strategy has a major barrier: the size and charge of nucleic acids largely restricts their transit into eukaryotic cells. Potential strategies to solve this problem include the use of a variety of natural and synthetic nucleic acid carriers. Driven by the aim and ambition of translating this promising therapeutic approach into the clinic, researchers have been actively developing advanced delivery systems for nucleic acids for more than 20 years. A decade ago we began our investigations of solid-phase techniques to construct families of novel nucleic acid carriers for transfection. We envisaged that the solid-phase synthesis of polycationic dendrimers and derivatized polyamimes would offer distinct advantages over solution phase techniques. Notably in solid phase synthesis we could take advantage of mass action and streamlined purification procedures, while simplifying the handling of compounds with high polarities and plurality of functional groups. Parallel synthesis methods would also allow rapid access to libraries of compounds with improved purities and yields over comparable solution methodologies and facilitate the development of structure activity relationships. We also twisted the concept of the solid-phase support on its head: we devised miniaturized solid supports that provided an innovative cell delivery vehicle in their own right, carrying covalently conjugated cargos (biomolecules) into cells. In this Account, we summarize the main outcomes of this series of chemically related projects.

Progress in standoff surface contaminant detector platform

NASA Astrophysics Data System (ADS)

Dupuis, Julia R.; Giblin, Jay; Dixon, John; Hensley, Joel; Mansur, David; Marinelli, William J.

2017-05-01

Progress towards the development of a longwave infrared quantum cascade laser (QLC) based standoff surface contaminant detection platform is presented. The detection platform utilizes reflectance spectroscopy with application to optically thick and thin materials including solid and liquid phase chemical warfare agents, toxic industrial chemicals and materials, and explosives. The platform employs an ensemble of broadband QCLs with a spectrally selective detector to interrogate target surfaces at 10s of m standoff. A version of the Adaptive Cosine Estimator (ACE) featuring class based screening is used for detection and discrimination in high clutter environments. Detection limits approaching 0.1 μg/cm2 are projected through speckle reduction methods enabling detector noise limited performance. The design, build, and validation of a breadboard version of the QCL-based surface contaminant detector are discussed. Functional test results specific to the QCL illuminator are presented with specific emphasis on speckle reduction.

Differential recognition of ACE inhibitors in Xenopus laevis oocytes expressing rat PEPT1 and PEPT2.

PubMed

Zhu, T; Chen, X Z; Steel, A; Hediger, M A; Smith, D E

2000-05-01

To examine the mechanism of inhibition of glycylsarcosine (GlySar) transport by quinapril and enalapril, and whether or not angiotensin converting enzyme (ACE) inhibitors are transported by PEPT2 as well as by PEPT1. Xenopus laevis oocytes were cRNA-injected with rat PEPT1 or PEPT2 and the transport kinetics of radiolabeled GlySar were studied in the absence and presence of quinapril and enalapril. The two-microelectrode voltage-clamp technique was also performed to probe the electrogenic uptake of captopril, quinapril and enalapril. Kinetic analyses demonstrated that quinapril inhibited the uptake of GlySar in a noncompetitive manner in Xenopus oocytes injected with PEPT1 or PEPT2 (Ki = 0.8 or 0.4 mM, respectively). In contrast, a competitive interaction was observed between GlySar and enalapril (Ki = 10.8 mM for PEPT1 or 4.3 mM for PEPT2). Most significantly, captopril and enalapril, but not quinapril, induced inwardly-directed currents in both PEPT1- and PEPT2-expressed oocytes. These results are unique in providing direct evidence for the substrate recognition and transport of some ACE inhibitors by the high- and low-affinity oligopeptide transporters. Our findings point to differences between PEPT1 and PEPT2 in their affinity to, rather than in their specificity for, ACE inhibitors.

The use of carrier RNA to enhance DNA extraction from microfluidic-based silica monoliths.

PubMed

Shaw, Kirsty J; Thain, Lauren; Docker, Peter T; Dyer, Charlotte E; Greenman, John; Greenway, Gillian M; Haswell, Stephen J

2009-10-12

DNA extraction was carried out on silica-based monoliths within a microfluidic device. Solid-phase DNA extraction methodology was applied in which the DNA binds to silica in the presence of a chaotropic salt, such as guanidine hydrochloride, and is eluted in a low ionic strength solution, such as water. The addition of poly-A carrier RNA to the chaotropic salt solution resulted in a marked increase in the effective amount of DNA that could be recovered (25ng) compared to the absence of RNA (5ng) using the silica-based monolith. These findings confirm that techniques utilising nucleic acid carrier molecules can enhance DNA extraction methodologies in microfluidic applications.

Selection of antigenic markers on a GFP-C{kappa} fusion scaffold with high sensitivity by eukaryotic ribosome display

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang Yongmin; IgE Therapeutics, Inc., San Diego, CA 92121-2233; Barankiewicz, Teresa J.

2007-07-27

Ribosome display is a cell-free system permitting gene selection through the physical association of genetic material (mRNA) and its phenotypic (protein) product. While often used to select single-chain antibodies from large libraries by panning against immobilized antigens, we have adapted ribosome display for use in the 'reverse' format in order to select high affinity antigenic determinants against solid-phase antibody. To create an antigenic scaffold, DNA encoding green fluorescent protein (GFP) was fused to a light chain constant domain (C{kappa}) with stop codon deleted, and with 5' signals (T7 promoter, Kozak) enabling coupled transcription/translation in a eukaryotic cell-free system. Epitopes onmore » either GFP (5') or C{kappa} (3') were selected by anti-GFP or anti-C{kappa} antibodies, respectively, coupled to magnetic beads. After selection, mRNA was amplified directly from protein-ribosome-mRNA (PRM) complexes by in situ PCR followed by internal amplification and reassembly PCR. As little as 10 fg of the 1 kb DNA construct, i.e. approximately 7500 molecules, could be recovered following a single round of interaction with solid-phase anti-GFP antibody. This platform is highly specific and sensitive for the antigen-antibody interaction and may permit selection and reshaping of high affinity antigenic variants of scaffold proteins.« less

The synthesis of 2-(5-(3-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenol using sodium impregnated on activated chicken eggshells catalyst

NASA Astrophysics Data System (ADS)

Mardiana, L.; Bakri, R.; Septiarti, A.; Ardiansah, B.

2017-04-01

The novel compound of 2-(5-(3-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenol as a pyrazoline derivative has been synthesized by two-steps reaction using sodium impregnated on activated chicken eggshells (Na-ACE) catalyst. Na-ACE was primarily prepared by a simple wet impregnation of NaOH solution on activated chicken eggshells solid support. The Na-ACE catalyst produced was characterized using FTIR spectrophotometer, XRD and SEM then applied in pyrazoline synthesis. First, chalcone was prepared from the reaction of 2-hydroxyacetophenone and 3-methoxybenzaldehyde by base-catalyzed aldol condensation. This product was subsequently reacted with hydrazine hydrate to give corresponding pyrazoline. The structure elucidation of the compound using FTIR, UV-Vis, LC-ESI-MS and 1H-NMR indicated the desired product has been successfully synthesized. Furthermore, the potential antioxidant activities of chalcone and pyrazoline have also been studied in-vitro using DPPH radical scavenging method. The results revealed that pyrazoline has a greater antioxidant activity than chalcone.

The artificial sweetener acesulfame potassium affects the gut microbiome and body weight gain in CD-1 mice.

PubMed

Bian, Xiaoming; Chi, Liang; Gao, Bei; Tu, Pengcheng; Ru, Hongyu; Lu, Kun

2017-01-01

Artificial sweeteners have been widely used in the modern diet, and their observed effects on human health have been inconsistent, with both beneficial and adverse outcomes reported. Obesity and type 2 diabetes have dramatically increased in the U.S. and other countries over the last two decades. Numerous studies have indicated an important role of the gut microbiome in body weight control and glucose metabolism and regulation. Interestingly, the artificial sweetener saccharin could alter gut microbiota and induce glucose intolerance, raising questions about the contribution of artificial sweeteners to the global epidemic of obesity and diabetes. Acesulfame-potassium (Ace-K), a FDA-approved artificial sweetener, is commonly used, but its toxicity data reported to date are considered inadequate. In particular, the functional impact of Ace-K on the gut microbiome is largely unknown. In this study, we explored the effects of Ace-K on the gut microbiome and the changes in fecal metabolic profiles using 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics. We found that Ace-K consumption perturbed the gut microbiome of CD-1 mice after a 4-week treatment. The observed body weight gain, shifts in the gut bacterial community composition, enrichment of functional bacterial genes related to energy metabolism, and fecal metabolomic changes were highly gender-specific, with differential effects observed for males and females. In particular, ace-K increased body weight gain of male but not female mice. Collectively, our results may provide a novel understanding of the interaction between artificial sweeteners and the gut microbiome, as well as the potential role of this interaction in the development of obesity and the associated chronic inflammation.

The artificial sweetener acesulfame potassium affects the gut microbiome and body weight gain in CD-1 mice

PubMed Central

Bian, Xiaoming; Chi, Liang; Gao, Bei; Tu, Pengcheng; Ru, Hongyu

2017-01-01

Artificial sweeteners have been widely used in the modern diet, and their observed effects on human health have been inconsistent, with both beneficial and adverse outcomes reported. Obesity and type 2 diabetes have dramatically increased in the U.S. and other countries over the last two decades. Numerous studies have indicated an important role of the gut microbiome in body weight control and glucose metabolism and regulation. Interestingly, the artificial sweetener saccharin could alter gut microbiota and induce glucose intolerance, raising questions about the contribution of artificial sweeteners to the global epidemic of obesity and diabetes. Acesulfame-potassium (Ace-K), a FDA-approved artificial sweetener, is commonly used, but its toxicity data reported to date are considered inadequate. In particular, the functional impact of Ace-K on the gut microbiome is largely unknown. In this study, we explored the effects of Ace-K on the gut microbiome and the changes in fecal metabolic profiles using 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics. We found that Ace-K consumption perturbed the gut microbiome of CD-1 mice after a 4-week treatment. The observed body weight gain, shifts in the gut bacterial community composition, enrichment of functional bacterial genes related to energy metabolism, and fecal metabolomic changes were highly gender-specific, with differential effects observed for males and females. In particular, ace-K increased body weight gain of male but not female mice. Collectively, our results may provide a novel understanding of the interaction between artificial sweeteners and the gut microbiome, as well as the potential role of this interaction in the development of obesity and the associated chronic inflammation. PMID:28594855

Rapid and Sensitive Quantification of Vibrio cholerae and Vibrio mimicus Cells in Water Samples by Use of Catalyzed Reporter Deposition Fluorescence In Situ Hybridization Combined with Solid-Phase Cytometry

PubMed Central

Schauer, Sonja; Sommer, Regina; Farnleitner, Andreas H.

2012-01-01

A new protocol for rapid, specific, and sensitive cell-based quantification of Vibrio cholerae/Vibrio mimicus in water samples was developed. The protocol is based on catalyzed reporter deposition fluorescence in situ hybridization (CARD-FISH) in combination with solid-phase cytometry. For pure cultures, we were able to quantify down to 6 V. cholerae cells on one membrane with a relative precision of 39% and down to 12 cells with a relative precision of 17% after hybridization with the horseradish peroxidase (HRP)-labeled probe Vchomim1276 (specific for V. cholerae and V. mimicus) and signal amplification. The corresponding position of the probe on the 16S rRNA is highly accessible even when labeled with HRP. For the first time, we were also able to successfully quantify V. cholerae/V. mimicus via solid-phase cytometry in extremely turbid environmental water samples collected in Austria. Cell numbers ranged from 4.5 × 101 cells ml−1 in the large saline lake Neusiedler See to 5.6 × 104 cells ml−1 in an extremely turbid shallow soda lake situated nearby. We therefore suggest CARD-FISH in combination with solid-phase cytometry as a powerful tool to quantify V. cholerae/V. mimicus in ecological studies as well as for risk assessment and monitoring programs. PMID:22885749

One-pot preparation of mRNA/cDNA display by a novel and versatile puromycin-linker DNA.

PubMed

Mochizuki, Yuki; Biyani, Manish; Tsuji-Ueno, Sachika; Suzuki, Miho; Nishigaki, Koichi; Husimi, Yuzuru; Nemoto, Naoto

2011-09-12

A rapid, easy, and robust preparation method for mRNA/cDNA display using a newly designed puromycin-linker DNA is presented. The new linker is structurally simple, easy to synthesize, and cost-effective for use in "in vitro peptide and protein selection". An introduction of RNase T1 nuclease site to the new linker facilitates the easy recovery of mRNA/cDNA displayed protein by an improvement of the efficiency of ligating the linker to mRNAs and efficient release of mRNA/cDNA displayed protein from the solid-phase (magnetic bead). For application demonstration, affinity selections were successfully performed. Furthermore, we introduced a "one-pot" preparation protocol to perform mRNA display easy. Unlike conventional approaches that require tedious and downstream multistep process including purification, this protocol will make the mRNA/cDNA display methods more practical and convenient and also facilitate the development of next-generation, high-throughput mRNA/cDNA display systems amenable to automation.

New potentially antihypertensive peptides liberated in milk during fermentation with selected lactic acid bacteria and kombucha cultures.

PubMed

Elkhtab, Ebrahim; El-Alfy, Mohamed; Shenana, Mohamed; Mohamed, Abdelaty; Yousef, Ahmed E

2017-12-01

Compounds with the ability to inhibit angiotensin-converting enzyme (ACE) are used medically to treat human hypertension. The presence of such compounds naturally in food is potentially useful for treating the disease state. The goal of this study was to screen lactic acid bacteria, including species commonly used as dairy starter cultures, for the ability to produce new potent ACE-inhibiting peptides during milk fermentation. Strains of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus delbrueckii ssp. bulgaricus, Lactobacillus helveticus, Lactobacillus paracasei, Lactococcus lactis, Leuconostoc mesenteroides, and Pediococcus acidilactici were tested in this study. Additionally, a symbiotic consortium of yeast and bacteria, used commercially to produce kombucha tea, was tested. Commercially sterile milk was inoculated with lactic acid bacteria strains and kombucha culture and incubated at 37°C for up to 72 h, and the liberation of ACE-inhibiting compounds during fermentation was monitored. Fermented milk was centrifuged and the supernatant (crude extract) was subjected to ultrafiltration using 3- and 10-kDa cut-off filters. Crude and ultrafiltered extracts were tested for ACE-inhibitory activity. The 10-kDa filtrate resulting from L. casei ATCC 7469 and kombucha culture fermentations (72 h) showed the highest ACE-inhibitory activity. Two-step purification of these filtrates was done using HPLC equipped with a reverse-phase column. Analysis of HPLC-purified fractions by liquid chromatography-mass spectrometry/mass spectrometry identified several new peptides with potent ACE-inhibitory activities. Some of these peptides were synthesized, and their ACE-inhibitory activities were confirmed. Use of organisms producing these unique peptides in food fermentations could contribute positively to human health. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Adverse Childhood Experiences and Prescribed Psychotropic Medications in Adults

PubMed Central

Anda, Robert F.; Brown, David W.; Felitti, Vincent J.; Bremner, J. Douglas; Dube, Shanta R.; Giles, Wayne H.

2011-01-01

Background Prescription drugs are one of the fastest growing healthcare costs in the United States. However, the long-term influence of child abuse and related traumatic stressors on prescriptions for psychotropic medications in adults has not been described. This study assessed the relationship of eight adverse childhood experiences (ACEs) to rates of prescriptions for psychotropic medications throughout adulthood. These ACEs included: abuse (emotional, physical, or sexual), witnessing domestic violence, growing up with substance abusing, mentally ill, or criminal household members, and parental separation/ divorce. Methods Data about ACEs were collected between 1995 and 1997 from adult health maintenance organization patients; prescription data were available from 1997 to 2004. The number of ACEs (ACE Score: maximum 8) was used as a measure of cumulative traumatic stress during childhood. The relationship of the score to rates of prescribed psychotropic drugs was prospectively assessed among 15,033 adult patients eligible for the follow-up phase of the study (mean follow-up: 6.1 years). Data were analyzed in 2006. Multivariate models were adjusted for age, race, gender, and education. Results Prescription rates increased yearly during the follow-up and in a graded fashion as the ACE Score increased (p for trend <0.001). After adjusting compared with persons with an ACE Score of 0, persons with a score of equal to or more than 5 had a nearly threefold increase in rates of psychotropic prescriptions. Graded relationships were observed between the score and prescription rates for antidepressant, anxiolytic, antipsychotic, and mood-stabilizing/bipolar medications; rates for persons with a score of equal to or more than 5 for these classes of drugs increased 3-, 2-, 10-, and 17-fold, respectively. Conclusions The strong relationship of the ACE Score to increased utilization of psychotropic medications underscores the contribution of childhood experience to the burden of adult mental illness. Moreover, the huge economic costs associated with the use of psychotropic medications provide additional incentive to address the high prevalence and consequences of childhood traumatic stressors. PMID:17478264

An attractive way of egg white protein by-product use for producing of novel anti-hypertensive peptides.

PubMed

Pokora, M; Zambrowicz, A; Dąbrowska, A; Eckert, E; Setner, B; Szołtysik, M; Szewczuk, Z; Zabłocka, A; Polanowski, A; Trziszka, T; Chrzanowska, J

2014-05-15

The aim of this study was to (i) examine how enzymatic hydrolysis with a non-commercially available proteinase of fig-leaf gourd fruit (Cucurbita ficifolia) increased the use value of egg white protein preparations, generated as byproducts in the industrial process of lysozyme and cystatin isolation from egg white, and (ii) evaluate the inhibition of angiotensin I-converting enzyme (ACE) by the obtained hydrolysates. Purification procedures including membrane filtration, gel filtration chromatography and reversed-phase high-performance liquid chromatography (RP-HPLC) led to the production of several peptide fractions. Two novel ovalbumin-derived tetrapeptides: SWVE (f 148-151) and DILN (f 86-89) with ACE inhibitory activity were obtained. Study of their inhibitory kinetics revealed a non-competitive binding mode, with an IC50 value against ACE of 33.88 and 73.44 μg for SWVE and DILN, respectively. Synthetic peptides which were designed on the basis of peptide SWVE were examined. A tripeptide sequence of SWV revealed the strongest ACE-inhibitory activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Obtaining Reliable Predictions of Terrestrial Energy Coupling From Real-Time Solar Wind Measurements

NASA Technical Reports Server (NTRS)

Weimer, Daniel R.

2002-01-01

Measurements of the interplanetary magnetic field (IMF) from the ACE (Advanced Composition Explorer), Wind, IMP-8 (Interplanetary Monitoring Platform), and Geotail spacecraft have revealed that the IMF variations are contained in phase planes that are tilted with respect to the propagation direction, resulting in continuously variable changes in propagation times between spacecraft, and therefore, to the Earth. Techniques for using 'minimum variance analysis' have been developed in order to be able to measure the phase front tilt angles, and better predict the actual propagation times from the L1 orbit to the Earth, using only the real-time IMF measurements from one spacecraft. The use of empirical models with the IMF measurements at L1 from ACE (or future satellites) for predicting 'space weather' effects has also been demonstrated.

Novel angiotensin I-converting enzyme inhibitory peptides produced in fermented milk by specific wild Lactococcus lactis strains.

PubMed

Rodríguez-Figueroa, J C; González-Córdova, A F; Torres-Llanez, M J; Garcia, H S; Vallejo-Cordoba, B

2012-10-01

The ability of specific wild Lactococcus lactis strains to hydrolyze milk proteins to release angiotensin I-converting enzyme (ACE) inhibitory peptides was evaluated. The peptide profiles were obtained from the <3 kDa water-soluble extract and subsequently fractionated by reversed-phase HPLC. The fractions with the lowest half-maximal inhibitory concentration estimated values (peptide concentration necessary to inhibit ACE activity by 50%) were Lc. lactis NRRL B-50571 fraction (F)1 (0.034 ± 0.002 μg/mL; mean ± SD) and Lc. lactis NRRL B-50572B F 0005 (0.041 ± 0.003 μg/mL; mean ± SD). All peptide fractions were analyzed by reversed-phase HPLC tandem mass spectrometry. Twenty-one novel peptide sequences associated with ACE inhibitory (ACEI) activity were identified. Several novel ACEI peptides presented peptides encrypted with proven hypotensive activity. In conclusion, specific wild Lc. lactis strains were able to hydrolyze milk proteins to generate potent ACEI peptides. However, further studies are necessary to find out the relationship between Lc. lactis strain proteolytic systems and their ability to biogenerate hypotensive peptides. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Maternal Dexamethasone Treatment Alters Tissue and Circulating Components of the Renin-Angiotensin System in the Pregnant Ewe and Fetus

PubMed Central

Jellyman, Juanita K.; De Blasio, Miles J.; Johnson, Emma; Giussani, Dino A.; Broughton Pipkin, Fiona; Fowden, Abigail L.

2015-01-01

Antenatal synthetic glucocorticoids promote fetal maturation in pregnant women at risk of preterm delivery and their mechanism of action may involve other endocrine systems. This study investigated the effect of maternal dexamethasone treatment, at clinically relevant doses, on components of the renin-angiotensin system (RAS) in the pregnant ewe and fetus. From 125 days of gestation (term, 145 ± 2 d), 10 ewes carrying single fetuses of mixed sex (3 female, 7 male) were injected twice im, at 10–11 pm, with dexamethasone (2 × 12 mg, n = 5) or saline (n = 5) at 24-hour intervals. At 10 hours after the second injection, maternal dexamethasone treatment increased angiotensin-converting enzyme (ACE) mRNA levels in the fetal lungs, kidneys, and heart and ACE concentration in the circulation and lungs, but not kidneys, of the fetuses. Fetal cardiac mRNA abundance of angiotensin II (AII) type 2 receptor decreased after maternal dexamethasone treatment. Between the two groups of fetuses, there were no significant differences in plasma angiotensinogen or renin concentrations; in transcript levels of renal renin, or AII type 1 or 2 receptors in the lungs and kidneys; or in pulmonary, renal or cardiac protein content of the AII receptors. In the pregnant ewes, dexamethasone administration increased pulmonary ACE and plasma angiotensinogen, and decreased plasma renin, concentrations. Some of the effects of dexamethasone treatment on the maternal and fetal RAS were associated with altered insulin and thyroid hormone activity. Changes in the local and circulating RAS induced by dexamethasone exposure in utero may contribute to the maturational and tissue-specific actions of antenatal glucocorticoid treatment. PMID:26039155

The Effects of Angiotensin II and Angiotensin-(1–7) in the Rostral Ventrolateral Medulla of Rats on Stress-Induced Hypertension

PubMed Central

Du, Dongshu; Chen, Jun; Liu, Min; Zhu, Minxia; Jing, Haojia; Fang, Jie; Shen, Linlin; Zhu, Danian; Yu, Jerry; Wang, Jin

2013-01-01

We have shown that angiotensin II (Ang II) and angiotensin-(1–7) [Ang-(1–7)] increased arterial blood pressure (BP) via glutamate release when microinjected into the rostral ventrolateral medulla (RVLM) in normotensive rats (control). In the present study, we tested the hypothesis that Ang II and Ang-(1–7) in the RVLM are differentially activated in stress-induced hypertension (SIH) by comparing the effects of microinjection of Ang II, Ang-(1–7), and their receptor antagonists on BP and amino acid release in SIH and control rats. We found that Ang II had greater pressor effect, and more excitatory (glutamate) and less inhibitory (taurine and γ-aminobutyric acid) amino acid release in SIH than in control animals. Losartan, a selective AT1 receptor (AT1R) antagonist, decreased mean BP in SIH but not in control rats. PD123319, a selective AT2 receptor (AT2R) antagonist, increased mean BP in control but not in SIH rats. However, Ang-(1–7) and its selective Mas receptor antagonist Ang779 evoked similar effects on BP and amino acid release in both SIH and control rats. Furthermore, we found that in the RVLM, AT1R, ACE protein expression (western blot) and ACE mRNA (real-time PCR) were significantly higher, whereas AT2R protein, ACE2 mRNA and protein expression were significantly lower in SIH than in control rats. Mas receptor expression was similar in the two groups. The results support our hypothesis and demonstrate that upregulation of Ang II by AT1R, not Ang-(1–7), system in the RVLM causes hypertension in SIH rats by increasing excitatory and suppressing inhibitory amino acid release. PMID:23967142

Purification and characterization of angiotensin I converting enzyme inhibition peptides from sandworm Sipunculus nudus

NASA Astrophysics Data System (ADS)

Sun, Xueping; Wang, Man; Liu, Buming; Sun, Zhenliang

2017-10-01

Three angiotensin I converting enzyme (ACE) inhibition peptides were isolated from sandworm Sipunculus nudus protein hydrolysate prepared using protamex. Consecutive purification methods, including size exclusion chromatography and reverse-phase high performance liquid chromatography (RP-HPLC), were used to isolate the ACE inhibition peptides. The amino acid sequences of the peptides were identified as Ile-Asn-Asp, Val-Glu-Pro-Gly and Leu-Ala-Asp-Glu-Phe. The IC50 values of the purified peptides for ACE inhibition activity were 34.72 μmol L-1, 20.55 μmol L-1 and 22.77 μmol L-1, respectively. These results suggested that S. nudus proteins contain specific peptides that can be released by enzymatic hydrolysis. This study may provide an experimental basis for further systematic research, rational development and clinical utilization of sandworm resources.

Isolation and identification of a new intracellular antimicrobial peptide produced by Paenibacillus alvei AN5.

PubMed

Alkotaini, Bassam; Anuar, Nurina; Kadhum, Abdul Amir Hassan; Sani, Asmahani Azira Abdu

2014-04-01

A wild-type, Gram-positive, rod-shaped, endospore-forming and motile bacteria has been isolated from palm oil mill sludge in Malaysia. Molecular identification using 16S rRNA gene sequence analysis indicated that the bacteria belonged to genus Paenibacillus. With 97 % similarity to P. alvei (AUG6), the isolate was designated as P. alvei AN5. An antimicrobial compound was extracted from P. alvei AN5-pelleted cells using 95 % methanol and was then lyophilized. Precipitates were re-suspended in phosphate buffered saline (PBS), producing an antimicrobial crude extract (ACE). The ACE showed antimicrobial activity against Salmonella enteritidis ATCC 13076, Escherichia coli ATCC 29522, Bacillus cereus ATCC 14579 and Lactobacillus plantarum ATCC 8014. By using SP-Sepharose cation exchange chromatography, Sephadex G-25 gel filtration and Tricine SDS-PAGE, the ACE was purified, which produced a ~2-kDa active band. SDS-PAGE and infrared (IR) spectroscopy indicated the proteinaceous nature of the antimicrobial compound in the ACE, and liquid chromatography electrospray ionization mass spectroscopy and de novo sequencing using an automatic, Q-TOF premier system detected a peptide with the amino acid sequence F-C-K-S-L-P-L-P-L-S-V-K (1,330.7789 Da). This novel peptide was designated as AN5-2. The antimicrobial peptide exhibited stability from pH 3 to 12 and maintained its activity after being heated to 90 °C. It also remained active after incubation with denaturants (urea, SDS and EDTA).

Correlations between gene expression highlight a different activation of ACE/TLR4/PTGS2 signaling in symptomatic and asymptomatic plaques in atherosclerotic patients.

PubMed

Ferronato, Silvia; Scuro, Alberto; Gomez-Lira, Macarena; Mazzucco, Sara; Olivato, Silvia; Turco, Alberto; Elisa, Orlandi; Malerba, Giovanni; Romanelli, Maria Grazia

2018-06-19

Inflammation has a key role and translates the effects of many known risk factors for the disease in atherosclerotic vulnerable plaques. Aiming to look into the elements that induce the development of either a vulnerable or stable atherosclerotic plaque, and considering that inflammation has a central role in the progression of lesions, we analyzed the expression of genes involved in the ACE/TLR4/PTGS2 signaling in carotid plaques of symptomatic and asymptomatic patients. Patients with internal carotid artery stenosis undergoing carotid endarterectomy at Verona University Hospital were included in this study. A total of 71 patients was considered for gene expression analysis (29 atherothrombotic stroke patients and 42 asymptomatic patients). Total RNA was extracted from the excised plaques and expression of PTGS2, ACE, TLR4, PTGER4, PTGER3, EPRAP and ACSL4 genes was analyzed by real-time PCR. The correlation between the pair of genes was studied by Spearman coefficient. From the analyzed genes, we did not observe any individual difference in gene expression but the network of co-expressed genes suggests a different activation of pathways in the two groups of plaques.

Rapid screening and identification of ACE inhibitors in snake venoms using at-line nanofractionation LC-MS.

PubMed

Mladic, Marija; de Waal, Tessa; Burggraaff, Lindsey; Slagboom, Julien; Somsen, Govert W; Niessen, Wilfried M A; Manjunatha Kini, R; Kool, Jeroen

2017-10-01

This study presents an analytical method for the screening of snake venoms for inhibitors of the angiotensin-converting enzyme (ACE) and a strategy for their rapid identification. The method is based on an at-line nanofractionation approach, which combines liquid chromatography (LC), mass spectrometry (MS), and pharmacology in one platform. After initial LC separation of a crude venom, a post-column flow split is introduced enabling parallel MS identification and high-resolution fractionation onto 384-well plates. The plates are subsequently freeze-dried and used in a fluorescence-based ACE activity assay to determine the ability of the nanofractions to inhibit ACE activity. Once the bioactive wells are identified, the parallel MS data reveals the masses corresponding to the activities found. Narrowing down of possible bioactive candidates is provided by comparison of bioactivity profiles after reversed-phase liquid chromatography (RPLC) and after hydrophilic interaction chromatography (HILIC) of a crude venom. Additional nanoLC-MS/MS analysis is performed on the content of the bioactive nanofractions to determine peptide sequences. The method described was optimized, evaluated, and successfully applied for screening of 30 snake venoms for the presence of ACE inhibitors. As a result, two new bioactive peptides were identified: pELWPRPHVPP in Crotalus viridis viridis venom with IC 50  = 1.1 μM and pEWPPWPPRPPIPP in Cerastes cerastes cerastes venom with IC 50  = 3.5 μM. The identified peptides possess a high sequence similarity to other bradykinin-potentiating peptides (BPPs), which are known ACE inhibitors found in snake venoms.

Effect of all-trans retinoic acid treatment on prohibitin and renin-angiotensin-aldosterone system expression in hypoxia-induced renal tubular epithelial cell injury.

PubMed

Zhou, Tian-Biao; Ou, Chao; Rong, Liang; Drummen, Gregor P C

2014-09-01

All-trans retinoic acid (ATRA) exerts various effects on physiological processes such as cell growth, differentiation, apoptosis and inflammation. Prohibitins (PHB), including prohibitin 1 (PHB1) and prohibitin 2 (PHB2), are evolutionary conserved and pleiotropic proteins implicated in various cellular functions, including proliferation, tumor suppression, apoptosis, transcription, and mitochondrial protein folding. The renin-angiotensin-aldosterone system plays a pivotal role in the regulation of blood pressure and volume homeostasis. All these factors and systems have been implicated in renal interstitial fibrosis. Therefore, the objective of this study was to investigate the effect of ATRA treatment on the renin-angiotensin-aldosterone system and expression of prohibitins to further understand its role in the processes leading to renal interstitial fibrosis. The hypoxic and oxidative stress conditions in obstructive renal disease were simulated in a hypoxia/reoxygenation model with renal tubular epithelial cells (RTEC) as a model system. Subsequently, the effect of ATRA on mRNA and protein expression levels was determined and correlations were established between factors involved in the renin-angiotensin-aldosterone system, the prohibitins, cellular redox status, renal interstitial fibrosis and ATRA treatment. Correlation analysis showed that both PHB1 and PHB2 protein levels were negatively correlated with angiotensin I, ACE1, angiotensin II, TGF-β1, Col-IV, FN, ROS, and MDA (PHB1: r = -0.792, -0.834, -0.805, -0.795, -0.778, -0.798, -0.751, -0.682; PHB2: r = -0.872, -0.799, -0.838, -0.773, -0.769, -0.841, -0.794, -0.826; each p < 0.05), but positively correlated with ACE2, SOD, and GSH (PHB1: r = 0.796, 0.879, 0.824; PHB2: r = 0.785, 0.914, 0.849; each p < 0.05). ACE1 was positively correlated with angiotensin I, angiotensin II, TGF-β1, Col-IV, FN, ROS, and MDA, and negatively correlated with ACE2, SOD, and GSH (each p < 0.05). ACE2 was negatively correlated with ACE1, angiotensin I, angiotensin II, TGF-β1, Col-IV, FN, ROS, and MDA, and positively correlated with SOD and GSH (each p < 0.05). The results suggest that ATRA acts as a positive regulator of PHB1, PHB2 and ACE2, and as a negative regulator of ACE1, angiotensin I, and angiotensin II in a RTEC model system under hypoxia/reoxygenation conditions. © The Author(s) 2014.

Incorporating contact angles in the surface tension force with the ACES interface curvature scheme

NASA Astrophysics Data System (ADS)

Owkes, Mark

2017-11-01

In simulations of gas-liquid flows interacting with solid boundaries, the contact line dynamics effect the interface motion and flow field through the surface tension force. The surface tension force is directly proportional to the interface curvature and the problem of accurately imposing a contact angle must be incorporated into the interface curvature calculation. Many commonly used algorithms to compute interface curvatures (e.g., height function method) require extrapolating the interface, with defined contact angle, into the solid to allow for the calculation of a curvature near a wall. Extrapolating can be an ill-posed problem, especially in three-dimensions or when multiple contact lines are near each other. We have developed an accurate methodology to compute interface curvatures that allows for contact angles to be easily incorporated while avoiding extrapolation and the associated challenges. The method, known as Adjustable Curvature Evaluation Scale (ACES), leverages a least squares fit of a polynomial to points computed on the volume-of-fluid (VOF) representation of the gas-liquid interface. The method is tested by simulating canonical test cases and then applied to simulate the injection and motion of water droplets in a channel (relevant to PEM fuel cells).

Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin- and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa.

PubMed

Ojeda, Deyanira; Jiménez-Ferrer, Enrique; Zamilpa, Alejandro; Herrera-Arellano, Armando; Tortoriello, Jaime; Alvarez, Laura

2010-01-08

The beverages of Hibiscus sabdariffa calyces are widely used in Mexico as diuretic, for treating gastrointestinal disorders, liver diseases, fever, hypercholesterolemia and hypertension. Different works have demonstrated that Hibiscus sabdariffa extracts reduce blood pressure in humans, and recently, we demonstrated that this effect is due to angiotensin converting enzyme (ACE) inhibitor activity. The aim of the current study was to isolate and characterizer the constituents responsible of the ACE activity of the aqueous extract of Hibiscus sabdariffa. Bioassay-guided fractionation of the aqueous extract of dried calyces of Hibiscus sabdariffa using preparative reversed-phase HPLC, and the in vitro ACE Inhibition assay, as biological monitor model, were used for the isolation. The isolated compounds were characterized by spectroscopic methods. The anthocyanins delphinidin-3-O-sambubioside (1) and cyanidin-3-O-sambubioside (2) were isolated by bioassay-guided purification. These compounds showed IC(50) values (84.5 and 68.4 microg/mL, respectively), which are similar to those obtained by related flavonoid glycosides. Kinetic determinations suggested that these compounds inhibit the enzyme activity by competing with the substrate for the active site. The competitive ACE inhibitor activity of the anthocyanins 1 and 2 is reported for the first time. This activity is in good agreement with the folk medicinal use of Hibiscus sabdariffa calyces as antihypertensive. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Endogenous angiotensinergic system in neurons of rat and human trigeminal ganglia

PubMed Central

Imboden, Hans; Patil, Jaspal; Nussberger, Juerg; Nicoud, Françoise; Hess, Benno; Ahmed, Nermin; Schaffner, Thomas; Wellner, Maren; Müller, Dominik; Inagami, Tadashi; Senbonmatsu, Takaaki; Pavel, Jaroslav; Saavedra, Juan M.

2009-01-01

To clarify the role of Angiotensin II (Ang II) in the sensory system and especially in the trigeminal ganglia, we studied the expression of angiotensinogen (Ang-N)-, renin-, angiotensin converting enzyme (ACE)- and cathepsin D-mRNA, and the presence of Ang II and substance P in the rat and human trigeminal ganglia. The rat trigeminal ganglia expressed substantial amounts of Ang-N- and ACE mRNA as determined by quantitative real time PCR. Renin mRNA was untraceable in rat samples. Cathepsin D was detected in the rat trigeminal ganglia indicating the possibility of existence of pathways alternative to renin for Ang I formation. In situ hybridization in rat trigeminal ganglia revealed expression of Ang-N mRNA in the cytoplasm of numerous neurons. By using immunocytochemistry, a number of neurons and their processes in both the rat and human trigeminal ganglia were stained for Ang II. Post in situ hybridization immunocytochemistry reveals that in the rat trigeminal ganglia some, but not all Ang-N mRNA-positive neurons marked for Ang II. In some neurons Substance P was found colocalized with Ang II. Angiotensins from rat trigeminal ganglia were quantitated by radioimmunoassay with and without prior separation by high performance liquid chromatography. Immunoreactive angiotensin II (ir-Ang II) was consistently present and the sum of true Ang II (1-8) octapeptide and its specifically measured metabolites were found to account for it. Radioimmunological and immunocytochemical evidence of ir-Ang II in neuronal tissue is compatible with Ang II as a neurotransmitter. In conclusion, these results suggest that Ang II could be produced locally in the neurons of rat trigeminal ganglia. The localization and colocalization of neuronal Ang II with Substance P in the trigeminal ganglia neurons may be the basis for a participation and function of Ang II in the regulation of nociception and migraine pathology. PMID:19323983

Model Estimated GCR Particle Flux Variation - Assessment with CRIS Data

NASA Astrophysics Data System (ADS)

Saganti, Premkumar

We present model calculated particle flux as a function of time during the current solar cycle along with the comparisons from the ACE/CRIS data and the Mars/MARIE data. In our model calculations we make use of the NASA's HZETRN (High Z and Energy Transport) code along with the nuclear fragmentation cross sections that are described by the quantum multiple scattering (QMSFRG) model. The time dependant variation of the GCR environment is derived making use of the solar modulation potential, phi. For the past ten years, Advanced Composition Explorer (ACE) has been in orbit at the Sun- Earth libration point (L1). Data from the Cosmic Ray Isotope Spectrometer (CRIS) instrument onboard the ACE spacecraft has been available from 1997 through the present time. Our model calculated particle flux showed high degree of correlation during the earlier phase of the current solar cycle (2003) in the lower Z region within 15

Developing an Evaluation Tool for Assessing Clinical Ethics Consultation Skills in Simulation Based Education: The ACES Project.

PubMed

Wasson, Katherine; Parsi, Kayhan; McCarthy, Michael; Siddall, Viva Jo; Kuczewski, Mark

2016-06-01

The American Society for Bioethics and Humanities has created a quality attestation (QA) process for clinical ethics consultants; the pilot phase of reviewing portfolios has begun. One aspect of the QA process which is particularly challenging is assessing the interpersonal skills of individual clinical ethics consultants. We propose that using case simulation to evaluate clinical ethics consultants is an approach that can meet this need provided clear standards for assessment are identified. To this end, we developed the Assessing Clinical Ethics Skills (ACES) tool, which identifies and specifies specific behaviors that a clinical ethics consultant should demonstrate in an ethics case simulation. The aim is for the clinical ethics consultant or student to use a videotaped case simulation, along with the ACES tool scored by a trained rater, to demonstrate their competence as part of their QA portfolio. The development and piloting of the tool is described.

ACES: Space shuttle flight software analysis expert system

NASA Technical Reports Server (NTRS)

Satterwhite, R. Scott

1990-01-01

The Analysis Criteria Evaluation System (ACES) is a knowledge based expert system that automates the final certification of the Space Shuttle onboard flight software. Guidance, navigation and control of the Space Shuttle through all its flight phases are accomplished by a complex onboard flight software system. This software is reconfigured for each flight to allow thousands of mission-specific parameters to be introduced and must therefore be thoroughly certified prior to each flight. This certification is performed in ground simulations by executing the software in the flight computers. Flight trajectories from liftoff to landing, including abort scenarios, are simulated and the results are stored for analysis. The current methodology of performing this analysis is repetitive and requires many man-hours. The ultimate goals of ACES are to capture the knowledge of the current experts and improve the quality and reduce the manpower required to certify the Space Shuttle onboard flight software.

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.

CCR5 RNA Pseudoknots: Residue and Site-Specific Labeling correlate Internal Motions with microRNA Binding.

PubMed

Chen, Bin; Longhini, Andrew P; Nußbaumer, Felix; Kreutz, Christoph; Dinman, Jonathan D; Dayie, T Kwaku

2018-04-11

Conformational dynamics of RNA molecules play a critical role in governing their biological functions. Measurements of RNA dynamic behavior sheds important light on sites that interact with their binding partners or cellular stimulators. However, such measurements using solution-state NMR are difficult for large RNA molecules (>70 nt; nt=nucleotides) owing to severe spectral overlap, homonuclear 13 C scalar couplings, and line broadening. Herein, a strategic combination of solid-phase synthesis, site-specific isotopic labeled phosphoramidites, and enzymatic ligation is introduced. This approach allowed the position-specific insertion of isotopic probes into a 96 nt CCR5 RNA fragment. Accurate measurements of functional dynamics using the Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion (RD) experiments enabled extraction of the exchange rates and populations of this RNA. NMR chemical shift perturbation analysis of the RNA/microRNA-1224 complex indicated that A90-C1' of the pseudoknot exhibits similar changes in chemical shift observed in the excited state. This work demonstrates the general applicability of a NMR-labeling strategy to probe functional RNA structural dynamics. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Import Manipulate Plot RELAP5/MOD3 Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, K. R.

1999-10-05

XMGR5 was derived from an XY plotting tool called ACE/gr, which is copyrighted by Paul J. Turner and in the public domain. The interactive version of ACE/GR is xmgr, and includes a graphical interface to the X-windows system. Enhancements to xmgr have been developed which import, manipualate, and plot data from RELAP/MOD3, MELCOR, FRAPCON, and SINDA codes, and NRC databank files. capabilities, include two-phase property table lookup functions, an equation interpreter, arithmetic library functions, and units conversion. Plot titles, labels, legends, and narrative can be displayed using Latin or Cyrillic alphabets.

Improvement to Airport Throughput Using Intelligent Arrival Scheduling and an Expanded Planning Horizon

NASA Technical Reports Server (NTRS)

Glaab, Patricia C.

2012-01-01

The first phase of this study investigated the amount of time a flight can be delayed or expedited within the Terminal Airspace using only speed changes. The Arrival Capacity Calculator analysis tool was used to predict the time adjustment envelope for standard descent arrivals and then for CDA arrivals. Results ranged from 0.77 to 5.38 minutes. STAR routes were configured for the ACES simulation, and a validation of the ACC results was conducted comparing the maximum predicted time adjustments to those seen in ACES. The final phase investigated full runway-to-runway trajectories using ACES. The radial distance used by the arrival scheduler was incrementally increased from 50 to 150 nautical miles (nmi). The increased Planning Horizon radii allowed the arrival scheduler to arrange, path stretch, and speed-adjust flights to more fully load the arrival stream. The average throughput for the high volume portion of the day increased from 30 aircraft per runway for the 50 nmi radius to 40 aircraft per runway for the 150 nmi radius for a traffic set representative of high volume 2018. The recommended radius for the arrival scheduler s Planning Horizon was found to be 130 nmi, which allowed more than 95% loading of the arrival stream.

Daughter-Specific Transcription Factors Regulate Cell Size Control in Budding Yeast

PubMed Central

Di Talia, Stefano; Wang, Hongyin; Skotheim, Jan M.; Rosebrock, Adam P.; Futcher, Bruce; Cross, Frederick R.

2009-01-01

In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle. PMID:19841732

Casein Fermentate of Lactobacillus animalis DPC6134 Contains a Range of Novel Propeptide Angiotensin-Converting Enzyme Inhibitors▿

PubMed Central

Hayes, M.; Stanton, C.; Slattery, H.; O'Sullivan, O.; Hill, C.; Fitzgerald, G. F.; Ross, R. P.

2007-01-01

This work evaluated the angiotensin-converting-enzyme (ACE)-inhibitory activities of a bovine sodium caseinate fermentate generated using the proteolytic capabilities of the porcine small intestinal isolate Lactobacillus animalis DPC6134 (NCIMB deposit 41355). The crude 10-kDa L. animalis DPC6134 fermentate exhibited ACE-inhibitory activity of 85.51% (±15%) and had a 50% inhibitory concentration (IC50) of 0.8 mg protein/ml compared to captopril, which had an IC50 value of 0.005 mg/ml. Fractionation of the crude L. animalis DPC6134 fermentate by membrane filtration and reversed-phase high-performance liquid chromatography (HPLC) generated three bioactive fractions from a total of 72 fractions. Fractions 10, 19, and 43 displayed ACE-inhibitory activity percentages of 67.53 (±15), 83.71 (±19), and 42.36 (±11), respectively, where ACE inhibition was determined with 80 μl of the fractions with protein concentrations of 0.5 mg/ml. HPLC and mass spectrometry analysis identified 25 distinct peptide sequences derived from α-, β-, and κ-caseins. In silico predictions, based on the C-terminal tetrapeptide sequences, suggested that peptide NIPPLTQTPVVVPPFIQ, corresponding to β-casein f(73-89); peptide IGSENSEKTTMP, corresponding to αs1-casein f(201212); peptide SQSKVLPVPQ, corresponding to β-casein f(166-175); peptide MPFPKYPVEP, corresponding to β-casein f(124133); and peptide EPVLGPVRGPFP, corresponding to β-casein f(210-221), contained ACE-inhibitory activities. These peptides were chosen for chemical synthesis to confirm the ACE-inhibitory activity of the fractions. Chemically synthesized peptides displayed IC50 values in the range of 92 μM to 790 μM. Additionally, a simulated gastrointestinal digestion confirmed that the ACE-inhibitory 10-kDa L. animalis DPC6134 fermentation was resistant to a cocktail of digestive enzymes found in the gastrointestinal tract. PMID:17483275

The benefit of angiotensin AT1 receptor blockers for early treatment of hypertensive patients.

PubMed

Trimarco, Bruno; Santoro, Ciro; Pepe, Marco; Galderisi, Maurizio

2017-12-01

ESC guidelines for management of arterial hypertension allow one to choose among five classes of antihypertensive drugs indiscriminately. They are based on the principle that in the management of hypertensive patients, it is fundamental to reduce blood pressure (BP), independently of the utilized drug. However, it has been demonstrated that the renin-angiotensin system (RAS) plays a relevant role in the hypertensive-derived development and progression of organ damage. Thus, antihypertensive drugs interfering with the RAS should be preferred in preventing and reducing target organ damage. The availability of two classes of drugs, ACE-inhibitors and angiotensin AT1 receptor blockers (ARBs), both interfering with the RAS, makes the choice between them difficult. Both pharmacological strategies offer an effective BP control, and a substantial improvement of prognosis in different associated pathologies. Regarding cardiovascular prevention, ACE-inhibitors have an extensive scientific literature regarding utility in high-risk patients. Nevertheless, there is evidence to support the concept that in the early phases of organ tissue damage, the RAS is activated, but the ACE pathway producing angiotensin II is not always employed. Accordingly, ACE-inhibitors appear to be less effective, whereas ARBs have a greater beneficial action in the initial stages of atherosclerotic disease. Moreover, patients undergoing ARBs therapy show a substantially lower risk of therapy discontinuation when compared to those treated with ACE-inhibitors, because of a better tolerability. In conclusion, ACE-inhibitors should be used in patients who have already developed organ damage, but tolerate this drug well, while ARBs should be the first choice in naïve hypertensive patients without organ damage or at the initial stages of disease.

Effects of angiotensin-converting enzyme inhibition on transient ischemia: the Quinapril Anti-Ischemia and Symptoms of Angina Reduction (QUASAR) trial.

PubMed

Pepine, Carl J; Rouleau, Jean-Lucien; Annis, Karen; Ducharme, Anique; Ma, Patrick; Lenis, Jacques; Davies, Richard; Thadani, Udho; Chaitman, Bernard; Haber, Harry E; Freedman, S Ben; Pressler, Milton L; Pitt, Bertram

2003-12-17

We sought to determine whether angiotensin-converting enzyme inhibition (ACE-I) (i.e., quinapril) prevents transient ischemia (exertional and spontaneous) in patients with coronary artery disease (CAD). It is known that ACE-I reduces the risk of death, myocardial infarction (MI), and other CAD-related outcomes in high-risk patients. Numerous studies have confirmed that ACE-I improves coronary flow and endothelial function. Whether ACE-I also decreases transient ischemia is unclear, because no studies have been adequately designed or sufficiently powered to evaluate this issue. Using a randomized, double-blinded, placebo-controlled, multicenter design, we enrolled 336 CAD patients with stable angina. None had uncontrolled hypertension, left ventricular (LV) dysfunction, or recent MI, and all developed electrocardiographic (ECG) evidence of ischemia during exercise. They were randomly assigned to one of two groups: 40 mg/day quinapril (n = 177) or placebo (n = 159) for 8 weeks. Patients then entered an additional eight-week treatment phase to examine the full dose range. Those assigned to 40 mg quinapril continued that dose and those assigned to placebo were titrated to 80 mg/day. Treadmill testing, the Seattle Angina Questionnaire, and ambulatory ECG monitoring were used to assess responses at baseline and at 8 and 16 weeks. The groups did not differ significantly at entry or in terms of indexes assessing myocardial ischemia at 8 or 16 weeks of treatment. In this low-risk population, ACE-I was not associated with serious adverse events. Our findings suggest short-term ACE-I in CAD patients without hypertension, LV dysfunction, or acute MI is not associated with significant effects on transient ischemia.

RNA and DNA interactions with zwitterionic and charged lipid membranes - a DSC and QCM-D study.

PubMed

Michanek, Agnes; Kristen, Nora; Höök, Fredrik; Nylander, Tommy; Sparr, Emma

2010-04-01

The aim of the present study is to establish under which conditions tRNA associates with phospholipid bilayers, and to explore how this interaction influences the lipid bilayer. For this purpose we have studied the association of tRNA or DNA of different sizes and degrees of base pairing with a set of model membrane systems with varying charge densities, composed of zwitterionic phosphatidylcholines (PC) in mixtures with anionic phosphatidylserine (PS) or cationic dioctadecyl-dimethyl-ammoniumbromide (DODAB), and with fluid or solid acyl-chains (oleoyl, myristoyl and palmitoyl). To prove and quantify the attractive interaction between tRNA and model-lipid membrane we used quartz crystal microbalance with dissipation (QCM-D) monitoring to study the tRNA adsorption to deposit phospholipid bilayers from solutions containing monovalent (Na(+)) or divalent (Ca(2+)) cations. The influence of the adsorbed polynucleic acids on the lipid phase transitions and lipid segregation was studied by means of differential scanning calorimetry (DSC). The basic findings are: i) tRNA adsorbs to zwitterionic liquid-crystalline and gel-phase phospholipid bilayers. The interaction is weak and reversible, and cannot be explained only on the basis of electrostatic attraction. ii) The adsorbed amount of tRNA is higher for liquid-crystalline bilayers compared to gel-phase bilayers, while the presence of divalent cations show no significant effect on the tRNA adsorption. iii) The adsorption of tRNA can lead to segregation in the mixed 1,2-dimyristoyl-sn-glycerol-3-phosphatidylcholine (DMPC)-1,2-dimyristoyl-sn-glycero-3-phosphatidylserine (DMPS) and DMPC-DODAB bilayers, where tRNA is likely excluded from the anionic DMPS-rich domains in the first system, and associated with the cationic DODAB-rich domains in the second system. iv) The addition of shorter polynucleic acids influence the chain melting transition and induce segregation in a mixed DMPC-DMPS system, while larger polynucleic acids do not influence the melting transition in these system. The results in this study on tRNA-phospholipid interactions can have implications for understanding its biological function in, e.g., the cell nuclei, as well as in applications in biotechnology and medicine. Copyright 2010 Elsevier B.V. All rights reserved.

Nicotine-Like Effects of the Neonicotinoid Insecticides Acetamiprid and Imidacloprid on Cerebellar Neurons from Neonatal Rats

PubMed Central

Kimura-Kuroda, Junko; Komuta, Yukari; Kuroda, Yoichiro; Hayashi, Masaharu; Kawano, Hitoshi

2012-01-01

Background Acetamiprid (ACE) and imidacloprid (IMI) belong to a new, widely used class of pesticide, the neonicotinoids. With similar chemical structures to nicotine, neonicotinoids also share agonist activity at nicotinic acetylcholine receptors (nAChRs). Although their toxicities against insects are well established, their precise effects on mammalian nAChRs remain to be elucidated. Because of the importance of nAChRs for mammalian brain function, especially brain development, detailed investigation of the neonicotinoids is needed to protect the health of human children. We aimed to determine the effects of neonicotinoids on the nAChRs of developing mammalian neurons and compare their effects with nicotine, a neurotoxin of brain development. Methodology/Principal Findings Primary cultures of cerebellar neurons from neonatal rats allow for examinations of the developmental neurotoxicity of chemicals because the various stages of neurodevelopment—including proliferation, migration, differentiation, and morphological and functional maturation—can be observed in vitro. Using these cultures, an excitatory Ca2+-influx assay was employed as an indicator of neural physiological activity. Significant excitatory Ca2+ influxes were evoked by ACE, IMI, and nicotine at concentrations greater than 1 µM in small neurons in cerebellar cultures that expressed the mRNA of the α3, α4, and α7 nAChR subunits. The firing patterns, proportion of excited neurons, and peak excitatory Ca2+ influxes induced by ACE and IMI showed differences from those induced by nicotine. However, ACE and IMI had greater effects on mammalian neurons than those previously reported in binding assay studies. Furthermore, the effects of the neonicotinoids were significantly inhibited by the nAChR antagonists mecamylamine, α-bungarotoxin, and dihydro-β-erythroidine. Conclusions/Significance This study is the first to show that ACE, IMI, and nicotine exert similar excitatory effects on mammalian nAChRs at concentrations greater than 1 µM. Therefore, the neonicotinoids may adversely affect human health, especially the developing brain. PMID:22393406

Toll-Like Receptor and Accessory Molecule mRNA Expression in Humans and Mice as Well as in Murine Autoimmunity, Transient Inflammation, and Progressive Fibrosis

PubMed Central

Ramaiah, Santhosh Kumar Vankayala; Günthner, Roman; Lech, Maciej; Anders, Hans-Joachim

2013-01-01

The cell type-, organ-, and species-specific expression of the Toll-like receptors (TLRs) are well described, but little is known about the respective expression profiles of their accessory molecules. We therefore determined the mRNA expression levels of LBP, MD2, CD36, CD14, granulin, HMGB1, LL37, GRP94, UNC93b1, TRIL, PRAT4A, AP3B1, AEP and the respective TLRs in human and mouse solid organs. Humans and mice displayed significant differences between their respective mRNA expression patterns of these factors. In addition, the expression profiles in transient tissue inflammation upon renal ischemia-reperfusion injury, in spleens and kidneys from mice with lupus-like systemic autoimmunity, and in progressive tissue fibrosis upon unilateral ureteral obstruction were studied. Several TLR co-factors were specifically regulated during the different phases of these disease entities, suggesting a functional involvement in the disease process. Thus, the organ- and species-specific expression patterns need to be considered in the design and interpretation of studies related to TLR-mediated innate immunity, which seems to be involved in the tissue injury phase, in the phase of tissue regeneration, and in progressive tissue remodelling. PMID:23803655

Aceneuramic Acid Extended Release Administration Maintains Upper Limb Muscle Strength in a 48-week Study of Subjects with GNE Myopathy: Results from a Phase 2, Randomized, Controlled Study.

PubMed

Argov, Zohar; Caraco, Yoseph; Lau, Heather; Pestronk, Alan; Shieh, Perry B; Skrinar, Alison; Koutsoukos, Tony; Ahmed, Ruhi; Martinisi, Julia; Kakkis, Emil

2016-03-03

GNE Myopathy (GNEM) is a progressive adult-onset myopathy likely caused by deficiency of sialic acid (SA) biosynthesis. Evaluate the safety and efficacy of SA (delivered by aceneuramic acid extended-release [Ace-ER]) as treatment for GNEM. A Phase 2, randomized, double-blind, placebo-controlled study evaluating Ace-ER 3 g/day or 6 g/day versus placebo was conducted in GNEM subjects (n = 47). After the first 24 weeks, placebo subjects crossed over to 3 g/day or 6 g/day for 24 additional weeks (dose pre-assigned during initial randomization). Assessments included serum SA, muscle strength by dynamometry, functional assessments, clinician- and patient-reported outcomes, and safety. Dose-dependent increases in serum SA levels were observed. Supplementation with Ace-ER resulted in maintenance of muscle strength in an upper extremity composite (UEC) score at 6 g/day compared with placebo at Week 24 (LS mean difference +2.33 kg, p = 0.040), and larger in a pre-specified subgroup able to walk ≥200 m at Screening (+3.10 kg, p = 0.040). After cross-over, a combined 6 g/day group showed significantly better UEC strength than a combined 3 g/day group (+3.46 kg, p = 0.0031). A similar dose-dependent response was demonstrated within the lower extremity composite score, but was not significant (+1.06 kg, p = 0.61). The GNEM-Functional Activity Scale demonstrated a trend improvement in UE function and mobility in a combined 6 g/day group compared with a combined 3 g/day group. Patients receiving Ace-ER tablets had predominantly mild-to-moderate AEs and no serious adverse events. This is the first clinical study to provide evidence that supplementation with SA delivered by Ace-ER may stabilize muscle strength in individuals with GNEM and initiating treatment earlier in the disease course may lead to better outcomes.

Aceneuramic Acid Extended Release Administration Maintains Upper Limb Muscle Strength in a 48-week Study of Subjects with GNE Myopathy: Results from a Phase 2, Randomized, Controlled Study

PubMed Central

Argov, Zohar; Caraco, Yoseph; Lau, Heather; Pestronk, Alan; Shieh, Perry B.; Skrinar, Alison; Koutsoukos, Tony; Ahmed, Ruhi; Martinisi, Julia; Kakkis, Emil

2016-01-01

Background: GNE Myopathy (GNEM) is a progressive adult-onset myopathy likely caused by deficiency of sialic acid (SA) biosynthesis. Objective: Evaluate the safety and efficacy of SA (delivered by aceneuramic acid extended-release [Ace-ER]) as treatment for GNEM. Methods: A Phase 2, randomized, double-blind, placebo-controlled study evaluating Ace-ER 3 g/day or 6 g/day versus placebo was conducted in GNEM subjects (n = 47). After the first 24 weeks, placebo subjects crossed over to 3 g/day or 6 g/day for 24 additional weeks (dose pre-assigned during initial randomization). Assessments included serum SA, muscle strength by dynamometry, functional assessments, clinician- and patient-reported outcomes, and safety. Results: Dose-dependent increases in serum SA levels were observed. Supplementation with Ace-ER resulted in maintenance of muscle strength in an upper extremity composite (UEC) score at 6 g/day compared with placebo at Week 24 (LS mean difference +2.33 kg, p = 0.040), and larger in a pre-specified subgroup able to walk ≥200 m at Screening (+3.10 kg, p = 0.040). After cross-over, a combined 6 g/day group showed significantly better UEC strength than a combined 3 g/day group (+3.46 kg, p = 0.0031). A similar dose-dependent response was demonstrated within the lower extremity composite score, but was not significant (+1.06 kg, p = 0.61). The GNEM-Functional Activity Scale demonstrated a trend improvement in UE function and mobility in a combined 6 g/day group compared with a combined 3 g/day group. Patients receiving Ace-ER tablets had predominantly mild-to-moderate AEs and no serious adverse events. Conclusions: This is the first clinical study to provide evidence that supplementation with SA delivered by Ace-ER may stabilize muscle strength in individuals with GNEM and initiating treatment earlier in the disease course may lead to better outcomes. PMID:27854209

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

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

PubMed

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

2016-10-13

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.

Distribution of Dechlorinating Bacteria between the Aqueous and Solid Phases

NASA Astrophysics Data System (ADS)

Cápiro, N. L.; Hatt, J. K.; Wang, Y.; Loeffler, F. E.; Pennell, K. D.

2010-12-01

Microbial monitoring of aquifers relies on nucleic acid biomarker analysis, which is typically performed with biomass recovered from groundwater samples; however, it is unclear what fraction of the target population(s) is associated with groundwater (i.e., planktonic cells) or is attached to solid phases (i.e., biofilms). Understanding how the titer of target organism(s) in groundwater correlates with the true cell titers of the target organism in the aquifer (i.e., planktonic plus attached cells) is critical for a meaningful interpretation of the data, the prediction of bioremediation performance, and the implementation of site management strategies. To evaluate the distribution of active cells between resident solid phase and the aqueous phase, one-dimensional columns were packed under water-saturated conditions with Bio-Dechlor INOCULUM, a PCE-to ethene-dechlorinating bacterial consortium containing both multiple Dehalococcoides (Dhc) strains and Geobacter lovleyi strain SZ (GeoSZ). The columns were packed with two distinct solid matrices: a low organic content sandy Federal Fine Ottawa soil or Appling soil with higher organic matter content. Influent reduced mineral salts medium supplied at a groundwater pore-water velocity of 0.3 m/day contained both 10 mM lactate as electron donor and 0.33 mM PCE as electron acceptor. Routine collection of biomass from column side ports and effluent samples measured the titers of target cells in the aqueous phase and determined when steady state conditions had been reached. A second set of column experiments evaluated delivery and filtration effects by the solid matrix (i.e., Federal Fine Ottawa sand versus Appling soil) under the same conditions except that electron donor or acceptor were omitted (no growth conditions). Quantitative real-time PCR (qPCR) analysis using Dhc and GeoSZ 16S rRNA gene-targeted primer and probe sets determined the planktonic cell counts, and destructive sampling of the columns allowed measurement of the total cell titer (i.e., attached plus planktonic cells). The results indicate that within the higher organic matter Appling soil, the fraction of target cells associated with the solid phase was nearly 2-orders of magnitude higher compared to the fraction attached to the aqueous phase. In the sandy soil, differences were approximately 1-order of magnitude. Ongoing efforts use dynamic light scattering and electrophoretic mobility measurements over a range of ionic strengths and pH values to shed light on the parameters that control microbial attachment behavior. Knowledge of factors that affect microbial distribution between aqueous and solid phases is essential for interpreting qPCR data obtained from site groundwater where biological remedies are implemented.

A Heterogeneous Multiprocessor Graphics System Using Processor-Enhanced Memories

DTIC Science & Technology

1989-02-01

frames per second, font generation directly from conic spline descriptions, and rapid calculation of radiosity form factors. The hardware consists of...generality for rendering curved surfaces, volume data, objects dcscri id with Constructive Solid Geometry, for rendering scenes using the radiosity ...f.aces and for computing a spherical radiosity lighting model (see Section 7.6). Custom Memory Chips \\ 208 bits x 128 pixels - Renderer Board ix p o a

High-intensity interval training has beneficial effects on cardiac remodeling through local renin-angiotensin system modulation in mice fed high-fat or high-fructose diets.

PubMed

de Oliveira Sá, Guilherme; Dos Santos Neves, Vívian; de Oliveira Fraga, Shyrlei R; Souza-Mello, Vanessa; Barbosa-da-Silva, Sandra

2017-11-15

HIIT (high-intensity interval training) has the potential to reduce cardiometabolic risk factors, but the effects on cardiac remodeling and local RAS (renin-angiotensin system) in mice fed high-fat or high-fructose diets still need to be fully addressed. Sixty male C57BL/6 mice (12weeks old) were randomly divided into three groups, control (C), High-fat (HF), or High-fructose diet (HRU) and were monitored for eight weeks before being submitted to the HIIT. Each group was randomly assigned to 2 subgroups, one subgroup was started on a 12-week HIIT protocol (T=trained group), while the other subgroup remained non-exercised (NT=not-trained group). HIIT reduced BM and systolic blood pressure in high-fat groups, while enhanced insulin sensitivity after high-fat or high-fructose intake. Moreover, HIIT reduced left ventricular hypertrophy in HF-T and HFRU-T. Notably, HIIT modulated key factors in the local left ventricular renin-angiotensin-system (RAS): reduced protein expression of renin, ACE (Angiotensin-converting enzyme), and (Angiotensin type 2 receptor) AT2R in HF-T and HFRU-T groups but reduced (Angiotensin type 1 receptor) AT1R protein expression only in the high-fat trained group. HIIT modulated ACE2/Ang (1-7)/Mas receptor axis. ACE2 mRNA gene expression was enhanced in HF-T and HFRU-T groups, complying with elevated Mas (Mas proto-oncogene, G protein-coupled receptor) receptor mRNA gene expression after HIIT. This study shows the effectiveness of HIIT sessions in producing improvements in insulin sensitivity and mitigating LV hypertrophy, though hypertension was controlled only in the high-fat-fed submitted to HIIT protocol. Local RAS system in the heart mediates these findings and receptor MAS seems to play a pivotal role when it comes to the amelioration of cardiac structural and functional remodeling due to HIIT. Copyright © 2017 Elsevier Inc. All rights reserved.

[Diagnostic process and management of schizophrenia in Spain: the ACEE project].

PubMed

Baca Baldomero, E; Leal Cercós, C; Varela, C; Riesgo, Y; Roca, M

2006-01-01

Although schizophrenia has a great impact on the health care, social and family levels, there is little epidemiological information on patients with schizophrenia, its diagnosis and treatment in Spain. The ACEE (Abordaje Clínico de la Esquizofrenia en España; Clinical Approach to Schizophrenia in Spain) study was designed with the primary objective of defining the management of schizophrenia in Spain from the perspective of current clinical practice. ACEE is a descriptive cross-sectional multicenter observational study with data collected in the setting of current clinical practice by means of a specifically designed questionnaire. A total of 1,937 patients have been studied (83% pertaining to the public sector and 17% to private one). Most subjects had paranoid schizophrenia in the stabilization phase, and did not work because of their illness. Most (96%) were receiving antipsychotic treatment and 55% also received some non-drug treatment. Negative symptoms were more frequent than positive symptoms (88% versus 63%). Significant differences were observed for type of patients and diagnostic procedures involved between the public and private health care sectors. The ACEE study shows that schizophrenic patients attending Spanish psychiatric centers are mainly single, non-working males who are living in their family setting. Treatment basically consists of antipsychotics combined with other drugs, and few complementary examinations are performed.

ACE phenotyping in human heart.

PubMed

Tikhomirova, Victoria E; Kost, Olga A; Kryukova, Olga V; Golukhova, Elena Z; Bulaeva, Naida I; Zholbaeva, Aigerim Z; Bokeria, Leo A; Garcia, Joe G N; Danilov, Sergei M

2017-01-01

Angiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, is expressed as a type-1 membrane glycoprotein on the surface of different cells, including endothelial cells of the heart. We hypothesized that the local conformation and, therefore, the properties of heart ACE could differ from lung ACE due to different microenvironment in these organs. We performed ACE phenotyping (ACE levels, conformation and kinetic characteristics) in the human heart and compared it with that in the lung. ACE activity in heart tissues was 10-15 lower than that in lung. Various ACE effectors, LMW endogenous ACE inhibitors and HMW ACE-binding partners, were shown to be present in both heart and lung tissues. "Conformational fingerprint" of heart ACE (i.e., the pattern of 17 mAbs binding to different epitopes on the ACE surface) significantly differed from that of lung ACE, which reflects differences in the local conformations of these ACEs, likely controlled by different ACE glycosylation in these organs. Substrate specificity and pH-optima of the heart and lung ACEs also differed. Moreover, even within heart the apparent ACE activities, the local ACE conformations, and the content of ACE inhibitors differ in atria and ventricles. Significant differences in the local conformations and kinetic properties of heart and lung ACEs demonstrate tissue specificity of ACE and provide a structural base for the development of mAbs able to distinguish heart and lung ACEs as a potential blood test for predicting atrial fibrillation risk.

The utility of tumor-specifically internalizing peptides for targeted siRNA delivery into human solid tumors.

PubMed

Un, Frank; Zhou, Bingsen; Yen, Yun

2012-11-01

Ribonucleotide reductase composed of the hRRM1 and hRRM2 subunits catalyzes the conversion of ribonucleotides to their corresponding deoxy forms for DNA replication. Anti-hRRM2 siRNA degrades hRRM2's mRNA and suppresses tumorigenesis. A Phase I clinical trial demonstrated its therapy potential. HN-1 represents a tumor-specifically internalizing peptide for targeted-drug delivery into human head and neck squamous cell carcinoma. Internalization of peptide was monitored by fluorescence microscopy. The peptide-siRNA conjugate was chemically synthesized. The hRRM2 expression was monitored by western blot analysis. HN-1(TYR) (HN-1 with two N-terminally added tyrosines) was internalized by human head and neck or breast cancer cells. Anti-hRRM2 siRNA(R) (resistant to RNase degradation) was conjugated to HN-1(TYR) without compromising their properties. The treatment with HN-1(TYR)-anti-hRRM2 siRNA(R) partly suppressed the endogenously expressed hRRM2 in human breast cancer cells. Our results establish the utility of tumor-specifically internalizing peptides for targeted siRNA delivery into human cancer cells.

ACE phenotyping in human heart

PubMed Central

Tikhomirova, Victoria E.; Kost, Olga A.; Kryukova, Olga V.; Golukhova, Elena Z.; Bulaeva, Naida I.; Zholbaeva, Aigerim Z.; Bokeria, Leo A.; Garcia, Joe G. N.

2017-01-01

Aims Angiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, is expressed as a type-1 membrane glycoprotein on the surface of different cells, including endothelial cells of the heart. We hypothesized that the local conformation and, therefore, the properties of heart ACE could differ from lung ACE due to different microenvironment in these organs. Methods and results We performed ACE phenotyping (ACE levels, conformation and kinetic characteristics) in the human heart and compared it with that in the lung. ACE activity in heart tissues was 10–15 lower than that in lung. Various ACE effectors, LMW endogenous ACE inhibitors and HMW ACE-binding partners, were shown to be present in both heart and lung tissues. “Conformational fingerprint” of heart ACE (i.e., the pattern of 17 mAbs binding to different epitopes on the ACE surface) significantly differed from that of lung ACE, which reflects differences in the local conformations of these ACEs, likely controlled by different ACE glycosylation in these organs. Substrate specificity and pH-optima of the heart and lung ACEs also differed. Moreover, even within heart the apparent ACE activities, the local ACE conformations, and the content of ACE inhibitors differ in atria and ventricles. Conclusions Significant differences in the local conformations and kinetic properties of heart and lung ACEs demonstrate tissue specificity of ACE and provide a structural base for the development of mAbs able to distinguish heart and lung ACEs as a potential blood test for predicting atrial fibrillation risk. PMID:28771512

An Angiotensin I-Converting Enzyme Mutation (Y465D) Causes a Dramatic Increase in Blood ACE via Accelerated ACE Shedding

PubMed Central

Gordon, Kerry; Nesterovitch, Andrew B.; Lünsdorf, Heinrich; Chen, Zhenlong; Castellon, Maricela; Popova, Isolda A.; Kalinin, Sergey; Mendonca, Emma; Petukhov, Pavel A.; Schwartz, David E.

2011-01-01

Background Angiotensin I-converting enzyme (ACE) metabolizes a range of peptidic substrates and plays a key role in blood pressure regulation and vascular remodeling. Thus, elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases. Previously, a striking familial elevation in blood ACE was explained by mutations in the ACE juxtamembrane region that enhanced the cleavage-secretion process. Recently, we found a family whose affected members had a 6-fold increase in blood ACE and a Tyr465Asp (Y465D) substitution, distal to the stalk region, in the N domain of ACE. Methodology/Principal Findings HEK and CHO cells expressing mutant (Tyr465Asp) ACE demonstrate a 3- and 8-fold increase, respectively, in the rate of ACE shedding compared to wild-type ACE. Conformational fingerprinting of mutant ACE demonstrated dramatic changes in ACE conformation in several different epitopes of ACE. Cell ELISA carried out on CHO-ACE cells also demonstrated significant changes in local ACE conformation, particularly proximal to the stalk region. However, the cleavage site of the mutant ACE - between Arg1203 and Ser1204 - was the same as that of WT ACE. The Y465D substitution is localized in the interface of the N-domain dimer (from the crystal structure) and abolishes a hydrogen bond between Tyr465 in one monomer and Asp462 in another. Conclusions/Significance The Y465D substitution results in dramatic increase in the rate of ACE shedding and is associated with significant local conformational changes in ACE. These changes could result in increased ACE dimerization and accessibility of the stalk region or the entire sACE, thus increasing the rate of cleavage by the putative ACE secretase (sheddase). PMID:21998728

Water Vapor Permeability of the Advanced Crew Escape Suit

NASA Technical Reports Server (NTRS)

Bue, Grant; Kuznetz, Larry; Gillis, David; Jones, Jeffery; Daniel, Brian; Gernhardt, Michael; Hamilton, Douglas

2009-01-01

Crew Exploration Vehicle (CEV) crewmembers are expected to return to earth wearing a suit similar to the current Advanced Crew Escape Suit (ACES). To ensure optimum cognitive performance, suited crewmembers must maintain their core body temperature within acceptable limits. There are currently several options for thermal maintenance in the post-landing phase. These include the current baseline, which uses an ammonia boiler, purge flow using oxygen in the suit, accessing sea water for liquid cooling garment (LCG) cooling and/or relying on the evaporative cooling capacity of the suit. These options vary significantly in mass, power, engineering and safety factors, with relying on the evaporative cooling capacity of the suit being the least difficult to implement. Data from previous studies indicates that the evaporative cooling capacity of the ACES was much higher than previously expected, but subsequent tests were performed for longer duration and higher metabolic rates to better define the water vapor permeability of the ACES. In these tests five subjects completed a series of tests performing low to moderate level exercise in order to control for a target metabolic rate while wearing the ACES in an environmentally controlled thermal chamber. Four different metabolic profiles at a constant temperature of 95 F and relative humidity of 50% were evaluated. These tests showed subjects were able to reject about twice as much heat in the permeable ACES as they were in an impermeable suit that had less thermal insulation. All of the heat rejection differential is attributed to the increased evaporation capability through the Gortex bladder of the suit.

High-salt diets during pregnancy affected fetal and offspring renal renin-angiotensin system.

PubMed

Mao, Caiping; Liu, Rong; Bo, Le; Chen, Ningjing; Li, Shigang; Xia, Shuixiu; Chen, Jie; Li, Dawei; Zhang, Lubo; Xu, Zhice

2013-07-01

Intrauterine environments are related to fetal renal development and postnatal health. Influence of salty diets during pregnancy on renal functions and renin-angiotensin system (RAS) was determined in the ovine fetuses and offspring. Pregnant ewes were fed high-salt diet (HSD) or normal-salt diet (NSD) for 2 months during middle-to-late gestation. Fetal renal functions, plasma hormones, and mRNA and protein expressions of the key elements of renal RAS were measured in the fetuses and offspring. Fetal renal excretion of sodium was increased while urine volume decreased in the HSD group. Fetal blood urea nitrogen was increased, while kidney weight:body weight ratio decreased in the HSD group. The altered ratio was also observed in the offspring aged 15 and 90 days. Maternal and fetal plasma antidiuretic hormone was elevated without changes in plasma renin activity and Ang I levels, while plasma Ang II was decreased. The key elements of local renal RAS, including angiotensinogen, angiotensin converting enzyme (ACE), ACE2, AT1, and AT2 receptor expression in both mRNA and protein, except renin, were altered following maternal high salt intake. The results suggest that high intake of salt during pregnancy affected fetal renal development associated with an altered expression of the renal key elements of RAS, some alterations of fetal origins remained after birth as possible risks in developing renal or cardiovascular diseases.

Effect of liposomes on the rate of alkaline hydrolysis of indomethacin and acemetacin.

PubMed

Matos, C; Chaimovich, H; Lima, J L; Cuccovia, I M; Reis, S

2001-03-01

The anti-inflammatory, analgesic, and antipyretic drugs indomethacin (INDO) and acemetacin (ACE), extensively used for the treatment of diseases of degenerative or inflammatory character, exhibit marked gastric irritant action, have low water solubility at neutral pH, and decompose in alkali. Alternative formulations are being investigated to obtain products with lower toxicity and higher stability. Here we examine the effect of liposome charge on the rate of alkaline decomposition of INDO and ACE using micelles as reference. Binding of ACE and INDO to zwitterionic hexadecylphosphocholine (HDPC) micelles and phosphatidylcholine (PC) liposomes was analyzed using a two-phase separation model to quantify the effect of these aggregates on the rate of alkaline degradation. The substrate association constants to HDPC micelles were 1335 and 2192 M(-1) for INDO and ACE, respectively, whereas the corresponding values for PC vesicles were 612 and 3050 M(-1). The difference was attributed to the additional hydrophobicity of ACE. The inhibitory effect of HDPC micelles and PC vesicles was quantified by calculating the ratio between the rate constants in water (k(w)) and in the aggregate (k(m)). The values of the k(w)/k(m) ratios for INDO and ACE in HDPC micelles were, respectively, 80 and 42, and in PC liposomes these ratios were 21 and 3.7, respectively. Positively charged micelles of hexadecyltrimethylammonium chloride (CTAC) and vesicles containing varying proportions of dioctadecyldimethylammonium chloride (DODAC) and PC increase the rate of INDO and ACE alkaline decomposition. Vesicle effects were very sensitive to the DODAC/PC ratio, with rates increasing with the proportion of DODAC. The data were analyzed quantitatively using a pseudophase model with explicit consideration of ion exchange. The calculated second-order rate constants in micelles and vesicles were lower than that in water. The charge density in the liposome necessary to increase the entrapment efficiency and decrease drug decomposition can be modulated, by judicious choice of pH and ionic strength. These manipulations can lead to more stable formulation with increased efficiency in drug entrapment and controlled effects on drug stability.

DNA - peptide polyelectrolyte complexes: Phase control by hybridization

NASA Astrophysics Data System (ADS)

Vieregg, Jeffrey; Lueckheide, Michael; Marciel, Amanda; Leon, Lorraine; Tirrell, Matthew

DNA is one of the most highly-charged molecules known, and interacts strongly with charged molecules in the cell. Condensation of long double-stranded DNA is one of the classic problems of biophysics, but the polyelectrolyte behavior of short and/or single-stranded nucleic acids has attracted far less study despite its importance for both biological and engineered systems. We report here studies of DNA oligonucleotides complexed with cationic peptides and polyamines. As seen previously for longer sequences, double-stranded oligonucleotides form solid precipitates, but single-stranded oligonucleotides instead undergo liquid-liquid phase separation to form coacervate droplets. Complexed oligonucleotides remain competent for hybridization, and display sequence-dependent environmental response. We observe similar behavior for RNA oligonucleotides, and methylphosphonate substitution of the DNA backbone indicates that nucleic acid charge density controls whether liquid or solid complexes are formed. Liquid-liquid phase separations of this type have been implicated in formation of membraneless organelles in vivo, and have been suggested as protocells in early life scenarios; oligonucleotides offer an excellent method to probe the physics controlling these phenomena.

Tissue-specific expression of transgenic secreted ACE in vasculature can restore normal kidney functions, but not blood pressure, of Ace-/- mice.

PubMed

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

2014-01-01

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

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

PubMed Central

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

2014-01-01

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

Single-domain angiotensin I converting enzyme (kininase II): characterization and properties.

PubMed

Deddish, P A; Wang, L X; Jackman, H L; Michel, B; Wang, J; Skidgel, R A; Erdös, E G

1996-12-01

Somatic angiotensin I converting enzyme (ACE; kininase II) has two active sites, in two (N and C) domains. We studied the active centers with separate N-domain ACE (N-ACE), testicular C-domain ACE (germinal ACE) and, as control, renal somatic ACE. Germinal ACE cleaved the nonapeptide bradykinin about two times faster than N-ACE in 20 mM Cl-. Bradykinin1-7 was hydrolyzed further to bradykinin1-5 by N-ACE four times faster in the absence of Cl-, but at 300 mM Cl- the C-domain hydrolyzed it twice as fast. The hematopoietic system regulatory peptide acetyl-Ser-Asp-Lys-Pro was split to two dipeptides by N-ACE, depending on the chloride concentration, 8 to 24 times faster than by germinal ACE; at 100 mM Cl-, the Kcat with N-ACE was eight times higher. One millimolar 1-fluoro-2,4-dinitrobenzene inhibited germinal ACE 96% but it inhibited N-ACE by only 31%. [3H]Ramiprilat was displaced by other unlabeled ACE inhibitors to establish their relative affinities. Captopril had the lowest IC50 (0.5 nM) with N-ACE and the highest IC50 (8.3 nM) with the germinal ACE. The IC50 values of ramiprilat and quinaprilat were about the same with both active sites. The association and dissociation constants of [3H]ramiprilat indicated faster association with and faster dissociation from N-ACE than from germinal ACE. After exposure to alkali or moderate heat, somatic ACE was cleaved by plasmin and kallikrein, releasing N-ACE and apparently inactivating the C-domain. These studies affirm the differences in the activity, stability and inhibition of the two active sites of ACE.

Zinc finger X-chromosomal protein (ZFX) promotes solid agar colony growth of osteosarcoma cells.

PubMed

Jiang, Rui; Wang, Jin-cheng; Sun, Mei; Zhang, Xing-yi; Wu, Han

2012-01-01

Zinc finger X-chromosomal protein (ZFX) is a member of the zinc finger family of proteins. The importance of ZFX in several cancer types, including prostate cancer, laryngeal squamous cell carcinoma, and glioma, has been addressed. However, the role of ZFX in human osteosarcoma remains unknown. Here we investigated the phenotype of ZFX knockdown on cell proliferation and in vitro tumorigenesis using lentivirus-mediated loss-of-function strategy. The results demonstrated that the proliferation and colony formation ability of human osteosarcoma Saos-2 and MG63 cells was impaired by ZFX small interfering RNA (siRNA)-expressing lentivirus. Moreover, loss of ZFX led to G0/G1 phase cell cycle arrest and a significant increase of cells in the sub-G1 fraction, indicating that ZFX functions as an oncogene in the malignant proliferation process in osteosarcoma. Furthermore, ZFX siRNA may have an antitumorigenic effect on osteosarcoma cells. Our findings hold important significance for RNA interference-mediated cancer gene therapy for human osteosarcoma.

Mycobacterial RNA isolation optimized for non-coding RNA: high fidelity isolation of 5S rRNA from Mycobacterium bovis BCG reveals novel post-transcriptional processing and a complete spectrum of modified ribonucleosides.

PubMed

Hia, Fabian; Chionh, Yok Hian; Pang, Yan Ling Joy; DeMott, Michael S; McBee, Megan E; Dedon, Peter C

2015-03-11

A major challenge in the study of mycobacterial RNA biology is the lack of a comprehensive RNA isolation method that overcomes the unusual cell wall to faithfully yield the full spectrum of non-coding RNA (ncRNA) species. Here, we describe a simple and robust procedure optimized for the isolation of total ncRNA, including 5S, 16S and 23S ribosomal RNA (rRNA) and tRNA, from mycobacteria, using Mycobacterium bovis BCG to illustrate the method. Based on a combination of mechanical disruption and liquid and solid-phase technologies, the method produces all major species of ncRNA in high yield and with high integrity, enabling direct chemical and sequence analysis of the ncRNA species. The reproducibility of the method with BCG was evident in bioanalyzer electrophoretic analysis of isolated RNA, which revealed quantitatively significant differences in the ncRNA profiles of exponentially growing and non-replicating hypoxic bacilli. The method also overcame an historical inconsistency in 5S rRNA isolation, with direct sequencing revealing a novel post-transcriptional processing of 5S rRNA to its functional form and with chemical analysis revealing seven post-transcriptional ribonucleoside modifications in the 5S rRNA. This optimized RNA isolation procedure thus provides a means to more rigorously explore the biology of ncRNA species in mycobacteria. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

How to Tackle the Challenge of siRNA Delivery with Sequence-Defined Oligoamino Amides.

PubMed

Reinhard, Sören; Wagner, Ernst

2017-01-01

RNA interference (RNAi) as a mechanism of gene regulation provides exciting opportunities for medical applications. Synthetic small interfering RNA (siRNA) triggers the knockdown of complementary mRNA sequences in a catalytic fashion and has to be delivered into the cytosol of the targeted cells. The design of adequate carrier systems to overcome multiple extracellular and intracellular roadblocks within the delivery process has utmost importance. Cationic polymers form polyplexes through electrostatic interaction with negatively charged nucleic acids and present a promising class of carriers. Issues of polycations regarding toxicity, heterogeneity, and polydispersity can be overcome by solid-phase-assisted synthesis of sequence-defined cationic oligomers. These medium-sized highly versatile nucleic acid carriers display low cytotoxicity and can be modified and tailored in multiple ways to meet specific requirements of nucleic acid binding, polyplex size, shielding, targeting, and intracellular release of the cargo. In this way, sequence-defined cationic oligomers can mimic the dynamic and bioresponsive behavior of viruses. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Efficacy of a Novel Class of RNA Interference Therapeutic Agents

PubMed Central

Matsumoto, Takahiro; D'Alessandro-Gabazza, Corina N.; Gil-Bernabe, Paloma; Boveda-Ruiz, Daniel; Naito, Masahiro; Kobayashi, Tetsu; Toda, Masaaki; Mizutani, Takayuki; Taguchi, Osamu; Morser, John; Eguchi, Yutaka; Kuroda, Masahiko; Ochiya, Takahiro; Hayashi, Hirotake; Gabazza, Esteban C.; Ohgi, Tadaaki

2012-01-01

RNA interference (RNAi) is being widely used in functional gene research and is an important tool for drug discovery. However, canonical double-stranded short interfering RNAs are unstable and induce undesirable adverse effects, and thus there is no currently RNAi-based therapy in the clinic. We have developed a novel class of RNAi agents, and evaluated their effectiveness in vitro and in mouse models of acute lung injury (ALI) and pulmonary fibrosis. The novel class of RNAi agents (nkRNA®, PnkRNA™) were synthesized on solid phase as single-stranded RNAs that, following synthesis, self-anneal into a unique helical structure containing a central stem and two loops. They are resistant to degradation and suppress their target genes. nkRNA and PnkRNA directed against TGF-β1mRNA ameliorate outcomes and induce no off-target effects in three animal models of lung disease. The results of this study support the pathological relevance of TGF-β1 in lung diseases, and suggest the potential usefulness of these novel RNAi agents for therapeutic application. PMID:22916145

Heavy Ion Flux Comparison of MARIE and ACE/CRIS Instruments

NASA Technical Reports Server (NTRS)

Lee, K. T.; Andersen, V.; Atwell, W.; Cleghorn, T.; Cucinotta, F.; Pinsky, L.; Saganti, P.; Turner, R.; Zeitlin, C.

2003-01-01

The charged particle spectrum for nuclei from protons to neon, (charge Z=10) has been observed during the cruise phase and in orbit around Mars by the MARIE charge particle spectrometer aboard the Odyssey spacecraft. The cruise data was taken between April 23, 2001 and August 11, 2001. The Mars orbit data was taken from March 5, 2002 through December 2002. Both the cruise data set and the orbital data set are compared with the simultaneous observations made by the CRIS instrument aboard the ACE space-craft, located at L1. Any detectable differences between the two spacecraft data sets could lead to the understanding of the radial dependence of solar modulation.

Polymorphism of angiotensin-converting enzyme gene in sarcoidosis.

PubMed

Arbustini, E; Grasso, M; Leo, G; Tinelli, C; Fasani, R; Diegoli, M; Banchieri, N; Cipriani, A; Gorrini, M; Semenzato, G; Luisetti, M

1996-02-01

Sarcoidosis is the disease in which increased levels of serum Angiotensin-converting enzyme (sACE) are most often detected. It has recently been shown that the deletion (D) or the insertion (I) of a 250bp-DNA fragment in the ACE gene accounts for three main ACE genotypes (i.e., II, ID, and DD) and for 47% of total phenotypic variance in sACE level. The aim of our work was to investigate whether or not patients with sarcoidosis have an increased incidence of those ACE genotypes coding for highest sACE levels and to investigate whether or not sACE level in sarcoidosis is related to ACE genotypes. We studied 61 unrelated patients with sarcoidosis (test group) and 80 unrelated healthy control subjects (control group). The ACE I and D alleles were detected with polymerase chain reaction on genomic DNA. In the control group we found an ACE genotype distribution that agreed with the Hardy-Weinberg proportion. The ACE genotype distribution was not significantly different in the test group. There was no correlation between ACE genotype and roentgenologic stage of sarcoidosis. Plotting the sACE level in the control group against ACE genotype, we found a trend of increasing mean sACE value according to the order II < ID < DD. The same trend for ACE genotype was found in the test group, in which it also paralleled the trend of sACE values plotted against roentgenologic stage, according to the order Stage I < Stage II < Stage III. We conclude that in sarcoidosis the ACE genotype distribution is not altered. The trends for increasing sACE values in sarcoidosis according to both ACE genotype and roentgenologic stage would suggest that both mechanisms play a role in determining sACE level.

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

PubMed Central

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

2016-01-01

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

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.

Renal tubular ACE-mediated tubular injury is the major contributor to microalbuminuria in early diabetic nephropathy.

PubMed

Eriguchi, Masahiro; Lin, Mercury; Yamashita, Michifumi; Zhao, Tuantuan V; Khan, Zakir; Bernstein, Ellen A; Gurley, Susan B; Gonzalez-Villalobos, Romer A; Bernstein, Kenneth E; Giani, Jorge F

2018-04-01

Diabetic nephropathy is a major cause of end-stage renal disease in developed countries. While angiotensin-converting enzyme (ACE) inhibitors are used to treat diabetic nephropathy, how intrarenal ACE contributes to diabetic renal injury is uncertain. Here, two mouse models with different patterns of renal ACE expression were studied to determine the specific contribution of tubular vs. glomerular ACE to early diabetic nephropathy: it-ACE mice, which make endothelial ACE but lack ACE expression by renal tubular epithelium, and ACE 3/9 mice, which lack endothelial ACE and only express renal ACE in tubular epithelial cells. The absence of endothelial ACE normalized the glomerular filtration rate and endothelial injury in diabetic ACE 3/9 mice. However, these mice developed tubular injury and albuminuria and displayed low renal levels of megalin that were similar to those observed in diabetic wild-type mice. In diabetic it-ACE mice, despite hyperfiltration, the absence of renal tubular ACE greatly reduced tubulointerstitial injury and albuminuria and increased renal megalin expression compared with diabetic wild-type and diabetic ACE 3/9 mice. These findings demonstrate that endothelial ACE is a central regulator of the glomerular filtration rate while tubular ACE is a key player in the development of tubular injury and albuminuria. These data suggest that tubular injury, rather than hyperfiltration, is the main cause of microalbuminuria in early diabetic nephropathy.

Discovery of Anti-Hypertensive Oligopeptides from Adlay Based on In Silico Proteolysis and Virtual Screening

PubMed Central

Qiao, Liansheng; Li, Bin; Chen, Yankun; Li, Lingling; Chen, Xi; Wang, Lingzhi; Lu, Fang; Luo, Ganggang; Li, Gongyu; Zhang, Yanling

2016-01-01

Adlay (Coix larchryma-jobi L.) was the commonly used Traditional Chinese Medicine (TCM) with high content of seed storage protein. The hydrolyzed bioactive oligopeptides of adlay have been proven to be anti-hypertensive effective components. However, the structures and anti-hypertensive mechanism of bioactive oligopeptides from adlay were not clear. To discover the definite anti-hypertensive oligopeptides from adlay, in silico proteolysis and virtual screening were implemented to obtain potential oligopeptides, which were further identified by biochemistry assay and molecular dynamics simulation. In this paper, ten sequences of adlay prolamins were collected and in silico hydrolyzed to construct the oligopeptide library with 134 oligopeptides. This library was reverse screened by anti-hypertensive pharmacophore database, which was constructed by our research team and contained ten anti-hypertensive targets. Angiotensin-I converting enzyme (ACE) was identified as the main potential target for the anti-hypertensive activity of adlay oligopeptides. Three crystal structures of ACE were utilized for docking studies and 19 oligopeptides were finally identified with potential ACE inhibitory activity. According to mapping features and evaluation indexes of pharmacophore and docking, three oligopeptides were selected for biochemistry assay. An oligopeptide sequence, NPATY (IC50 = 61.88 ± 2.77 µM), was identified as the ACE inhibitor by reverse-phase high performance liquid chromatography (RP-HPLC) assay. Molecular dynamics simulation of NPATY was further utilized to analyze interactive bonds and key residues. ALA354 was identified as a key residue of ACE inhibitors. Hydrophobic effect of VAL518 and electrostatic effects of HIS383, HIS387, HIS513 and Zn2+ were also regarded as playing a key role in inhibiting ACE activities. This study provides a research strategy to explore the pharmacological mechanism of Traditional Chinese Medicine (TCM) proteins based on in silico proteolysis and virtual screening, which could be beneficial to reveal the pharmacological action of TCM proteins and provide new lead compounds for peptides-based drug design. PMID:27983650

Nonenzymatic microorganism identification based on ribosomal RNA

NASA Astrophysics Data System (ADS)

Ives, Jeffrey T.; Pierini, Alicia M.; Stokes, Jeffrey A.; Wahlund, Thomas M.; Read, Betsy; Bechtel, James H.; Bronk, Burt V.

1999-11-01

Effective defense against biological warfare (BW) agents requires rapid, fieldable and accurate systems. For micro- organisms like bacteria and viruses, ribosomal RNA (rRNA) provides a valuable target with multiple advantages of species specificity and intrinsic target amplification. Vegetative and spore forms of bacteria contain approximately 104 copies of rRNA. Direct detection of rRNA copies can eliminate some of the interference and preparation difficulties involved in enzymatic amplification methods. In order to apply the advantages of rRNA to BW defense, we are developing a fieldable system based on 16S rRNA, physical disruption of the micro-organism, solid phase hybridization, and fluorescence detection. Our goals include species-specific identification, complete operation from raw sample to identification in 15 minutes or less, and compact, fieldable instrumentation. Initial work on this project has investigated the lysis and hybridization steps, the species-specificity of oligonucleotides probes, and the development of a novel electromagnetic method to physically disrupt the micro- organisms. Target bacteria have been Escherichia coli (E. coli) and Bacillus subtilis (B. subtilis). Continuing work includes further development of methods to rapidly disrupt the micro-organisms and release the rRNA, improved integration and processing, and extension to bacterial and mammalian viruses like MS2 and vesicular stomatitis virus.

Understanding of evaluation capacity building in practice: a case study of a national medical education organization.

PubMed

Sarti, Aimee J; Sutherland, Stephanie; Landriault, Angele; DesRosier, Kirk; Brien, Susan; Cardinal, Pierre

2017-01-01

Evaluation capacity building (ECB) is a topic of great interest to many organizations as they face increasing demands for accountability and evidence-based practices. ECB is about building the knowledge, skills, and attitudes of organizational members, the sustainability of rigorous evaluative practices, and providing the resources and motivations to engage in ongoing evaluative work. There exists a solid foundation of theoretical research on ECB, however, understanding what ECB looks like in practice is relatively thin. Our purpose was to investigate what ECB looks like firsthand within a national medical educational organization. The context for this study was the Acute Critical Events Simulation (ACES) organization in Canada, which has successfully evolved into a national educational program, driven by physicians. We conducted an exploratory qualitative study to better understand and describe ECB in practice. In doing so, interviews were conducted with program leaders and instructors so as to gain a richer understanding of evaluative processes and practices. A total of 21 individuals participated in the semistructured interviews. Themes from our qualitative data analysis included the following: evaluation knowledge, skills, and attitudes, use of evaluation findings, shared evaluation beliefs and commitment, evaluation frameworks and processes, and resources dedicated to evaluation. The national ACES organization was a useful case study to explore ECB in practice. The ECB literature provided a solid foundation to understand the purpose and nuances of ECB. This study added to the paucity of studies focused on examining ECB in practice. The most important lesson learned was that the organization must have leadership who are intrinsically motivated to employ and use evaluation data to drive ongoing improvements within the organization. Leaders who are intrinsically motivated will employ risk taking when evaluation practices and processes may be somewhat unfamiliar. Creating and maintaining a culture of data use and ongoing inquiry have enabled national ACES to achieve a sustainable evaluation practice.

The "Speedy" Synthesis of Atom-Specific (15)N Imino/Amido-Labeled RNA.

PubMed

Neuner, Sandro; Santner, Tobias; Kreutz, Christoph; Micura, Ronald

2015-08-10

Although numerous reports on the synthesis of atom-specific (15)N-labeled nucleosides exist, fast and facile access to the corresponding phosphoramidites for RNA solid-phase synthesis is still lacking. This situation represents a severe bottleneck for NMR spectroscopic investigations on functional RNAs. Here, we present optimized procedures to speed up the synthesis of (15)N(1) adenosine and (15)N(1) guanosine amidites, which are the much needed counterparts of the more straightforward-to-achieve (15)N(3) uridine and (15)N(3) cytidine amidites in order to tap full potential of (1)H/(15)N/(15)N-COSY experiments for directly monitoring individual Watson-Crick base pairs in RNA. Demonstrated for two preQ1 riboswitch systems, we exemplify a versatile concept for individual base-pair labeling in the analysis of conformationally flexible RNAs when competing structures and conformational dynamics are encountered. © 2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

The “Speedy” Synthesis of Atom-Specific 15N Imino/Amido-Labeled RNA

PubMed Central

Kreutz, Christoph; Micura, Ronald

2016-01-01

Although numerous reports on the synthesis of atom-specific 15N-labeled nucleosides exist, fast and facile access to the corresponding phosphoramidites for RNA solid-phase synthesis is still lacking. This situation represents a severe bottleneck for NMR spectroscopic investigations on functional RNAs. Here, we present optimized procedures to speed up the synthesis of 15N(1) adenosine and 15N(1) guanosine amidites, which are the much needed counterparts of the more straightforward-to-achieve 15N(3) uridine and 15N(3) cytidine amidites in order to tap full potential of 1H/15N/15N-COSY experiments for directly monitoring individual Watson–Crick base pairs in RNA. Demonstrated for two preQ1 riboswitch systems, we exemplify a versatile concept for individual base-pair labeling in the analysis of conformationally flexible RNAs when competing structures and conformational dynamics are encountered. PMID:26237536

ACE Phenotyping as a Guide Toward Personalized Therapy With ACE Inhibitors.

PubMed

Danilov, Sergei M; Tovsky, Stan I; Schwartz, David E; Dull, Randal O

2017-07-01

Angiotensin-converting enzyme (ACE) inhibitors (ACEI) are widely used in the management of cardiovascular diseases but with significant interindividual variability in the patient's response. To investigate whether interindividual variability in the response to ACE inhibitors is explained by the "ACE phenotype"-for example, variability in plasma ACE concentration, activity, and conformation and/or the degree of ACE inhibition in each individual. The ACE phenotype was determined in plasma of 14 patients with hypertension treated chronically for 4 weeks with 40 mg enalapril (E) or 20 mg E + 16 mg candesartan (EC) and in 20 patients with hypertension treated acutely with a single dose (20 mg) of E with or without pretreatment with hydrochlorothiazide. The ACE phenotyping included (1) plasma ACE concentration; (2) ACE activity (with 2 substrates: Hip-His-Leu and Z-Phe-His-Leu and calculation of their ratio); (3) detection of ACE inhibitors in patient's blood (indicator of patient compliance) and the degree of ACE inhibition (ie, adherence); and (4) ACE conformation. Enalapril reduced systolic and diastolic blood pressure in most patients; however, 20% of patients were considered nonresponders. Chronic treatment results in 40% increase in serum ACE concentrations, with the exception of 1 patient. There was a trend toward better response to ACEI among patients who had a higher plasma ACE concentration. Due to the fact that "20% of patients do not respond to ACEI by blood pressure drop," the initial blood ACE level could not be a predictor of blood pressure reduction in an individual patient. However, ACE phenotyping provides important information about conformational and kinetic changes in ACE of individual patients, and this could be a reason for resistance to ACE inhibitors in some nonresponders.

Imbalanced plasma ACE and ACE2 level in the uremic patients with cardiovascular diseases and its change during a single hemodialysis session.

PubMed

Yang, Chung-Wei; Lu, Li-Che; Chang, Chia-Chu; Cho, Ching-Chang; Hsieh, Wen-Yeh; Tsai, Chin-Hung; Lin, Yi-Chang; Lin, Chih-Sheng

2017-11-01

The renin-angiotensin system (RAS) has significant influences on heart and renal disease progression. Angiotensin converting enzyme (ACE) and angiotensin converting enzyme II (ACE2) are major peptidases of RAS components and play counteracting functions through angiotensin II (Ang II)/ATIR and angiotensin-(1-7) (Ang-(1-7))/Mas axis, respectively. There were 360 uremic patients on regular hemodialysis (HD) treatment (inclusive of 119 HD patients with cardiovascular diseases (CVD) and 241 HD patients without CVD and 50 healthy subjects were enrolled in this study. Plasma ACE, ACE2, Ang II and Ang-(1-7) levels of the HD patients were determined. We compared pre-HD levels of plasma ACE, ACE2, Ang II and Ang-(1-7) in the HD patients with and without CVD to those of the controls. The HD patients, particularly those with CVD, showed a significant increase in the levels of ACE and Ang II, whereas ACE2 and Ang-(1-7) levels were lower than those in the healthy controls. Therefore, imbalanced ACE/ACE2 was observed in the HD patients with CVD. In the course of a single HD session, the plasma ACE, ACE/ACE2 and Ang II levels in the HD patients with CVD were increased from pre-HD to post-HD. On the contrary, ACE2 levels were decreased after the HD session. These changes were not detected in the HD patients without CVD. Pathogenically imbalanced circulating ACE/ACE2 was detected in the HD patients, particularly those with CVD. HD session could increase ACE/Ang II/AT1R axis and decrease ACE2/Ang-(1-7)/Mas axis activity in the circulation of HD patients with CVD.

Relationship of angiotensin I-converting enzyme (ACE) and bradykinin B2 receptor (BDKRB2) polymorphism with diabetic nephropathy.

PubMed

Zou, Honghong; Wu, Guoqing; Lv, Jinlei; Xu, Gaosi

2017-06-01

To determine whether ACE 2 I/D and BDKRB2 3 +9/-9 polymorphism causatively affect diabetic nephropathy progression RESULTS: STZ-induced metabolic disorder, as well as inflammatory responses, was significantly aggravated in ACE II-B2R 4 +9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp diabetic mice but not ACE II-B2R-9bp, indicating the genetic susceptibility of ACE DD or B2R+9bp to diabetic nephropathy. Furthermore, ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp rather than ACE II-B2R-9bp, worsened renal performance and enhanced pathological alterations induced by STZ. Markedly elevated monocyte chemoattractant protein-1(MCP-1), podocin, osteopontin (OPN), transforming growth factor-β1 (TGF-β1), and reduced nephrin, podocin were also detected both in diabetic mice and podocytes under hyperglycemic conditions in response to ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp, versus ACE II-B2R-9bp. In addition, high glucose-induced mitochondrial oxidative stress and cell apoptosis were observably increased in response to ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp but not ACE II-B2R-9bp. We provide first evidence indicating the causation between ACE DD or B2R+9bp genotype and the increased risk for diabetic nephropathy, broadening our horizon about the role of genetic modulators in this disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Sex dimorphism in ANGII-mediated crosstalk between ACE2 and ACE in diabetic nephropathy.

PubMed

Clotet-Freixas, Sergi; Soler, Maria Jose; Palau, Vanesa; Anguiano, Lidia; Gimeno, Javier; Konvalinka, Ana; Pascual, Julio; Riera, Marta

2018-06-08

Angiotensin-converting enzyme (ACE) and ACE2 play a critical role in the renin-angiotensin system (RAS) by altering angiotensin II (ANGII) levels, thus governing its deleterious effects. Both enzymes are altered by sex and diabetes, and play an important role in the development of diabetic nephropathy (DN). Importantly, previous evidence in diabetic and ACE2-deficient (ACE2KO) males suggest a sex-dependent crosstalk between renal ACE and ACE2. In the present work, we aimed to study the sex-specific susceptibility to diabetes and direct infusion of ANGII in kidney disease progression, with a special focus on its link to ACE2 and ACE. In our mouse model, ANGII promoted hypertension, albuminuria, reduced glomerular filtration, and glomerular histological alterations. ANGII adverse effects were accentuated by diabetes and ACE2 deficiency, in a sex-dependent fashion: ACE2 deficiency accentuated ANGII-induced hypertension, albuminuria, and glomerular hypertrophy in diabetic females, whereas in diabetic males exacerbated ANGII-mediated glomerular hypertrophy, mesangial expansion, and podocyte loss. At the molecular level, ANGII downregulated renal ACE gene and enzymatic activity levels, as well as renin gene expression in ACE2KO mice. Interestingly, male sex and diabetes accentuated this effect. Here we show sex dimorphism in the severity of diabetes- and ANGII-related renal lesions, and demonstrate that ACE2- and ACE-related compensatory mechanisms are sex-specific. Supporting our previous findings, the modulation and ANGII-mediated crosstalk between ACE2 and ACE in DN progression was more evident in males. This work increases the understanding of the sex-specific role of ACE2 and ACE in DN, reinforcing the necessity of more personalized treatments targeting RAS.

Regulation of the aceI multidrug efflux pump gene in Acinetobacter baumannii.

PubMed

Liu, Qi; Hassan, Karl A; Ashwood, Heather E; Gamage, Hasinika K A H; Li, Liping; Mabbutt, Bridget C; Paulsen, Ian T

2018-06-01

To investigate the function of AceR, a putative transcriptional regulator of the chlorhexidine efflux pump gene aceI in Acinetobacter baumannii. Chlorhexidine susceptibility and chlorhexidine induction of aceI gene expression were determined by MIC and quantitative real-time PCR, respectively, in A. baumannii WT and ΔaceR mutant strains. Recombinant AceR was prepared as both a full-length protein and as a truncated protein, AceR (86-299), i.e. AceRt, which has the DNA-binding domain deleted. The binding interaction of the purified AceR protein and its putative operator region was investigated by electrophoretic mobility shift assays and DNase I footprinting assays. The binding of AceRt with its putative ligand chlorhexidine was examined using surface plasmon resonance and tryptophan fluorescence quenching assays. MIC determination assays indicated that the ΔaceI and ΔaceR mutant strains both showed lower resistance to chlorhexidine than the parental strain. Chlorhexidine-induced expression of aceI was abolished in a ΔaceR background. Electrophoretic mobility shift assays and DNase I footprinting assays demonstrated chlorhexidine-stimulated binding of AceR with two sites upstream of the putative aceI promoter. Surface plasmon resonance and tryptophan fluorescence quenching assays suggested that the purified ligand-binding domain of the AceR protein was able to bind with chlorhexidine with high affinity. This study provides strong evidence that AceR is an activator of aceI gene expression when challenged with chlorhexidine. This study is the first characterization, to our knowledge, of a regulator controlling expression of a PACE family multidrug efflux pump.

Tissue Specificity of Human Angiotensin I-Converting Enzyme

PubMed Central

Kryukova, Olga V.; Tikhomirova, Victoria E.; Golukhova, Elena Z.; Evdokimov, Valery V.; Kalantarov, Gavreel F.; Trakht, Ilya N.; Schwartz, David E.; Dull, Randal O.; Gusakov, Alexander V.; Uporov, Igor V.; Kost, Olga A.; Danilov, Sergei M.

2015-01-01

Background Angiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, as well as in reproductive functions, is expressed as a type-1 membrane glycoprotein on the surface of endothelial and epithelial cells. ACE also presents as a soluble form in biological fluids, among which seminal fluid being the richest in ACE content - 50-fold more than that in blood. Methods/Principal Findings We performed conformational fingerprinting of lung and seminal fluid ACEs using a set of monoclonal antibodies (mAbs) to 17 epitopes of human ACE and determined the effects of potential ACE-binding partners on mAbs binding to these two different ACEs. Patterns of mAbs binding to ACEs from lung and from seminal fluid dramatically differed, which reflects difference in the local conformations of these ACEs, likely due to different patterns of ACE glycosylation in the lung endothelial cells and epithelial cells of epididymis/prostate (source of seminal fluid ACE), confirmed by mass-spectrometry of ACEs tryptic digests. Conclusions Dramatic differences in the local conformations of seminal fluid and lung ACEs, as well as the effects of ACE-binding partners on mAbs binding to these ACEs, suggest different regulation of ACE functions and shedding from epithelial cells in epididymis and prostate and endothelial cells of lung capillaries. The differences in local conformation of ACE could be the base for the generation of mAbs distingushing tissue-specific ACEs. PMID:26600189

Gender difference of serum angiotensin-converting enzyme (ACE) activity in DD genotype of ACE insertion/deletion polymorphism in elderly Chinese.

PubMed

Zhang, Ya-Feng; Cheng, Qiong; Tang, Nelson L S; Chu, Tanya T W; Tomlinson, Brian; Liu, Fan; Kwok, Timothy C Y

2014-12-01

In this study we investigated the gender difference of serum angiotensin-converting enzyme (ACE) activity in a population of Hong Kong-dwelling elderly Chinese. A total of 1767 (843 male, 924 female) Hong Kong-dwelling elderly Chinese were recruited. ACE I/D genotypes were identified by polymerase chain reaction amplification and serum ACE activity was determined using a commercially available kinetic kit. ACE I/D genotype distribution was compared by chi-square test, the correlation between ACE I/D polymorphism and serum ACE activity was analysed by ANOVA test and gender difference of serum ACE activity of different genotypes was compared by independent sample t-test. No statistically significant difference of genotype distribution between male and female subjects was found. Serum ACE activity was significantly correlated with ACE genotype. Overall, there was no gender difference of serum ACE activity; however, when sub-grouping the subjects by ACE I/D genotype, male subjects with DD genotype had higher serum ACE activity than female subjects with DD genotype. No significant gender difference of genotype distribution was found in elderly Chinese. Serum ACE activity was significantly correlated with ACE I/D polymorphism in elderly Chinese. Male subjects with DD genotype had higher serum ACE activity than female subjects with DD genotype. © The Author(s) 2013.

ACE as a Mechanosensor to Shear Stress Influences the Control of Its Own Regulation via Phosphorylation of Cytoplasmic Ser1270

PubMed Central

Barauna, Valerio Garrone; Campos, Luciene Cristina Gastalho; Miyakawa, Ayumi Aurea; Krieger, Jose Eduardo

2011-01-01

Objectives We tested whether angiotensin converting enzyme (ACE) and phosphorylation of Ser1270 are involved in shear-stress (SS)-induced downregulation of the enzyme. Methods and Results Western blotting analysis showed that SS (18 h, 15 dyn/cm2) decreases ACE expression and phosphorylation as well as p-JNK inhibition in human primary endothelial cells (EC). CHO cells expressing wild-type ACE (wt-ACE) also displayed SS-induced decrease in ACE and p-JNK. Moreover, SS decreased ACE promoter activity in wt-ACE, but had no effect in wild type CHO or CHO expressing ACE without either the extra- or the intracellular domains, and decreased less in CHO expressing a mutated ACE at Ser1270 compared to wt-ACE (13 vs. 40%, respectively). The JNK inhibitor (SP600125, 18 h), in absence of SS, also decreased ACE promoter activity in wt-ACE. Finally, SS-induced inhibition of ACE expression and phosphorylation in EC was counteracted by simultaneous exposure to an ACE inhibitor. Conclusions ACE displays a key role on its own downregulation in response to SS. This response requires both the extra- and the intracellular domains and ACE Ser1270, consistent with the idea that the extracellular domain behaves as a mechanosensor while the cytoplasmic domain elicits the downstream intracellular signaling by phosphorylation on Ser1270. PMID:21901117

In vitro angiotensin I converting enzyme inhibition by a peptide isolated from Chiropsalmus quadrigatus Haeckel (box jellyfish) venom hydrolysate.

PubMed

So, Pamela Berilyn T; Rubio, Peter; Lirio, Stephen; Macabeo, Allan Patrick; Huang, Hsi-Ya; Corpuz, Mary Jho-Anne T; Villaflores, Oliver B

2016-09-01

The anti-angiotensin I converting enzyme activity of box jellyfish, Chiropsalmus quadrigatus Haeckel venom hydrolysate was studied. The venom extract was obtained by centrifugation and ultrasonication. Protein concentration of 12.99 μg/mL was determined using Bradford assay. The pepsin and papain hydrolysate was tested for its toxicity by Limit test following the OECD Guideline 425 using 5 female Sprague-Dawley rats. Results showed that the hydrolysate is nontoxic with an LD50 above 2000 mg/kg. In vitro angiotensin I converting enzyme (ACE) inhibitory activity was determined using ACE kit-WST. Isolation of ACE inhibitory peptides using column chromatography with SP-Sephadex G-25 yielded 8 pooled fractions with fraction 3 (86.5%) exhibiting the highest activity. This was followed by reverse phase - high performance liquid chromatography (RP-HPLC) with an octadecyl silica column (Inertsil ODS-3) using methanol:water 15:85 at a flow rate of 1.0 mL/min. Among the 13 fractions separated with the RP-HPLC, fraction 3.5 exhibited the highest ACE inhibitory activity (84.1%). The peptide sequence ACPGPNPGRP (IC50 2.03 μM) from fraction 3.5 was identified using Matrix-assisted laser desorption/ionization with time-of-flight tandem mass spectroscopy analysis (MALDI-TOF/MS). Copyright © 2016 Elsevier Ltd. All rights reserved.

The N domain of somatic angiotensin-converting enzyme negatively regulates ectodomain shedding and catalytic activity.

PubMed

Woodman, Zenda L; Schwager, Sylva L U; Redelinghuys, Pierre; Carmona, Adriana K; Ehlers, Mario R W; Sturrock, Edward D

2005-08-01

sACE (somatic angiotensin-converting enzyme) consists of two homologous, N and C domains, whereas the testis isoenzyme [tACE (testis ACE)] consists of a single C domain. Both isoenzymes are shed from the cell surface by a sheddase activity, although sACE is shed much less efficiently than tACE. We hypothesize that the N domain of sACE plays a regulatory role, by occluding a recognition motif on the C domain required for ectodomain shedding and by influencing the catalytic efficiency. To test this, we constructed two mutants: CNdom-ACE and CCdom-ACE. CNdom-ACE was shed less efficiently than sACE, whereas CCdom-ACE was shed as efficiently as tACE. Notably, cleavage occurred both within the stalk and the interdomain bridge in both mutants, suggesting that a sheddase recognition motif resides within the C domain and is capable of directly cleaving at both positions. Analysis of the catalytic properties of the mutants and comparison with sACE and tACE revealed that the k(cat) for sACE and CNdom-ACE was less than or equal to the sum of the kcat values for tACE and the N-domain, suggesting negative co-operativity, whereas the kcat value for the CCdom-ACE suggested positive co-operativity between the two domains. Taken together, the results provide support for (i) the existence of a sheddase recognition motif in the C domain and (ii) molecular flexibility of the N and C domains in sACE, resulting in occlusion of the C-domain recognition motif by the N domain as well as close contact of the two domains during hydrolysis of peptide substrates.

The N domain of somatic angiotensin-converting enzyme negatively regulates ectodomain shedding and catalytic activity

PubMed Central

Woodman, Zenda L.; Schwager, Sylva L. U.; Redelinghuys, Pierre; Carmona, Adriana K.; Ehlers, Mario R. W.; Sturrock, Edward D.

2005-01-01

sACE (somatic angiotensin-converting enzyme) consists of two homologous, N and C domains, whereas the testis isoenzyme [tACE (testis ACE)] consists of a single C domain. Both isoenzymes are shed from the cell surface by a sheddase activity, although sACE is shed much less efficiently than tACE. We hypothesize that the N domain of sACE plays a regulatory role, by occluding a recognition motif on the C domain required for ectodomain shedding and by influencing the catalytic efficiency. To test this, we constructed two mutants: CNdom-ACE and CCdom-ACE. CNdom-ACE was shed less efficiently than sACE, whereas CCdom-ACE was shed as efficiently as tACE. Notably, cleavage occurred both within the stalk and the interdomain bridge in both mutants, suggesting that a sheddase recognition motif resides within the C domain and is capable of directly cleaving at both positions. Analysis of the catalytic properties of the mutants and comparison with sACE and tACE revealed that the kcat for sACE and CNdom-ACE was less than or equal to the sum of the kcat values for tACE and the N-domain, suggesting negative co-operativity, whereas the kcat value for the CCdom-ACE suggested positive co-operativity between the two domains. Taken together, the results provide support for (i) the existence of a sheddase recognition motif in the C domain and (ii) molecular flexibility of the N and C domains in sACE, resulting in occlusion of the C-domain recognition motif by the N domain as well as close contact of the two domains during hydrolysis of peptide substrates. PMID:15813703

Conformational Changes of Blood ACE in Chronic Uremia

PubMed Central

Petrov, Maxim N.; Shilo, Valery Y.; Tarasov, Alexandr V.; Schwartz, David E.; Garcia, Joe G. N.; Kost, Olga A.; Danilov, Sergei M.

2012-01-01

Background The pattern of binding of monoclonal antibodies (mAbs) to 16 epitopes on human angiotensin I-converting enzyme (ACE) comprise a conformational ACE fingerprint and is a sensitive marker of subtle protein conformational changes. Hypothesis Toxic substances in the blood of patients with uremia due to End Stage Renal Disease (ESRD) can induce local conformational changes in the ACE protein globule and alter the efficacy of ACE inhibitors. Methodology/Principal Findings The recognition of ACE by 16 mAbs to the epitopes on the N and C domains of ACE was estimated using an immune-capture enzymatic plate precipitation assay. The precipitation pattern of blood ACE by a set of mAbs was substantially influenced by the presence of ACE inhibitors with the most dramatic local conformational change noted in the N-domain region recognized by mAb 1G12. The “short” ACE inhibitor enalaprilat (tripeptide analog) and “long” inhibitor teprotide (nonapeptide) produced strikingly different mAb 1G12 binding with enalaprilat strongly increasing mAb 1G12 binding and teprotide decreasing binding. Reduction in S-S bonds via glutathione and dithiothreitol treatment increased 1G12 binding to blood ACE in a manner comparable to enalaprilat. Some patients with uremia due to ESRD exhibited significantly increased mAb 1G12 binding to blood ACE and increased ACE activity towards angiotensin I accompanied by reduced ACE inhibition by inhibitory mAbs and ACE inhibitors. Conclusions/Significance The estimation of relative mAb 1G12 binding to blood ACE detects a subpopulation of ESRD patients with conformationally changed ACE, which activity is less suppressible by ACE inhibitors. This parameter may potentially serve as a biomarker for those patients who may need higher concentrations of ACE inhibitors upon anti-hypertensive therapy. PMID:23166630

Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE

PubMed Central

Rella, Monika; Elliot, Joann L; Revett, Timothy J; Lanfear, Jerry; Phelan, Anne; Jackson, Richard M; Turner, Anthony J; Hooper, Nigel M

2007-01-01

Background Mammalian angiotensin converting enzyme (ACE) plays a key role in blood pressure regulation. Although multiple ACE-like proteins exist in non-mammalian organisms, to date only one other ACE homologue, ACE2, has been identified in mammals. Results Here we report the identification and characterisation of the gene encoding a third homologue of ACE, termed ACE3, in several mammalian genomes. The ACE3 gene is located on the same chromosome downstream of the ACE gene. Multiple sequence alignment and molecular modelling have been employed to characterise the predicted ACE3 protein. In mouse, rat, cow and dog, the predicted protein has mutations in some of the critical residues involved in catalysis, including the catalytic Glu in the HEXXH zinc binding motif which is Gln, and ESTs or reverse-transcription PCR indicate that the gene is expressed. In humans, the predicted ACE3 protein has an intact HEXXH motif, but there are other deletions and insertions in the gene and no ESTs have been identified. Conclusion In the genomes of several mammalian species there is a gene that encodes a novel, single domain ACE-like protein, ACE3. In mouse, rat, cow and dog ACE3, the catalytic Glu is replaced by Gln in the putative zinc binding motif, indicating that in these species ACE3 would lack catalytic activity as a zinc metalloprotease. In humans, no evidence was found that the ACE3 gene is expressed and the presence of deletions and insertions in the sequence indicate that ACE3 is a pseudogene. PMID:17597519

Safety and Efficacy of the ACE-Inhibitor Ramipril in Alport Syndrome: The Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III EARLY PRO-TECT Alport Trial in Pediatric Patients.

PubMed

Gross, Oliver; Friede, Tim; Hilgers, Reinhard; Görlitz, Anke; Gavénis, Karsten; Ahmed, Raees; Dürr, Ulrike

2012-01-01

Introduction. Retrospective observational data show that ACE-inhibitor therapy delays renal failure and improves life expectancy in Alport patients with proteinuria. The EARLY PRO-TECT Alport trial assesses the safety and efficacy of early therapy onset with ramipril in pediatric Alport patients. Methods and analysis. This double-blind, randomized, placebo-controlled, multicenter phase III trial (NCT01485978; EudraCT-number 2010-024300-10) includes 120 pediatric patients aged 24 months to 18 years with early stages of Alport syndrome (isolated hematuria or microalbuminuria). From March 2012, up to 80 patients will be randomized 1:1 to ramipril or placebo. In the event of disease progression during 3-year treatment, patients are unblinded and ramipril is initiated, if applicable. Approximately 40 patients receive open-label ramipril contributing to the safety database. Primary end-points are "time to progression to next disease level" and "incidence of adverse drug events before disease progression." Treatment effect estimates from the randomized comparison and Alport registry data will be combined in supportive analyses to maximize evidence. Conclusion. Without this trial, ACE inhibitors may become standard off-label treatment in Alport syndrome without satisfactory evidence base. The results are expected to be of relevance for therapy of all pediatric patients with kidney disease, and the trial protocol might serve as a model for other rare pediatric glomerulopathies.

Hydronephrosis alters cardiac ACE2 and Mas receptor expression in mice.

PubMed

Zhang, Yanling; Ma, Lulu; Wu, Junyan; Chen, Tingting

2015-06-01

Hydronephrosis is characterized by substantial loss of tubules and affects renin secretion in the kidney. However, whether alterations of angiotensin-converting enzyme (ACE), ACE2 and Mas receptor in the heart are observed in hydronephrosis is unknown. Thus, we assessed these components in hydronephrotic mice treated with AT1 receptor blockade and ACE inhibitor. Hydronephrosis was induced by left ureteral ligation in Balb/C mice except sham-operated animals. The levels of cardiac ACE, ACE2 and Mas receptor were measured after treatment of losartan or enalapril. Hydronephrosis led to an increase of ACE level and a decrease of ACE2 and Mas receptor in the heart. Losartan decreased cardiac ACE level, but ACE2 and Mas receptor levels significantly increased in hydronephrotic mice (p < 0.01). Enalapril increased ACE2 levels (p < 0.01), but did not affect Mas receptor in the heart. Plasma renin activity (PRA) and Ang II decreased in hydronephrotic mice, but significantly increased after treatment with losartan or enalapril. Hydronephrosis increased cardiac ACE and suppressed ACE2 and Mas receptor levels. AT1 blockade caused sustained activation of cardiac ACE2 and Mas receptor, but ACE inhibitor had the limitation of such activation of Mas receptor in hydronephrotic animals. © The Author(s) 2015.

[Diabetic nephropathy: current diagnostics and treatment].

PubMed

Werth, S; Lehnert, H; Steinhoff, J

2015-05-01

Diabetic kidney disease is a leading cause of renal failure in Germany. Albuminuria is an early diagnostic indicator of renal damage in diabetes and, aside from renal failure, a major risk factor of cardiovascular disease. An early diagnosis of diabetic kidney disease is of great importance to reduce associated cardiovascular mortality; glycemic control should aim for HbA1c levels of < 7 %. Guidelines on blood pressure differ, but it should generally be reduced to < 140/90 mmHg; stricter limits should be applied if albuminuria is present. ACE inhibitors (ACE-I) or angiotensin receptor blockers (ARB) should be preferred for blood pressure control. A combination of ACE-Is and ARBs or a renin-inhibitor therapy does not improve cardiovascular outcome, instead it increases the rate of adverse events, e.g., hyperkalemia or renal failure. Lipid control, usually with statins, should be started at an early phase of renal failure. Vitamin D receptor activation and uric acid reduction might play a future role in the treatment of diabetic kidney disease. Pharmacological modification of inflammatory signaling appears to be promising but is not yet of clinical relevance.

National Dam Inspection Program. Laurel Run Dam. NDI ID Number PA-00380. DER ID Number 35-6, Pennsylvania Gas and Water Company. Susquehanna River Basin, Laurel Run, Lackawanna County, Pennsylvania Phase I Inspection Report,

DTIC Science & Technology

1980-04-01

Supply. g. Design and Construction History. Laurel Run Dam was constructed in 1594 by Martin Cawley, a contractor from Archbald. The construction was...1T6Ace joly PHASE I INSPECTION REPORT -4 NATIONAL DAM INSPECTION PROGRAM Lime LAUREL RUN DAM PENNSYLVANIA GAS AND WATER COMPANY RESERVOIR AREA

Single molecule tracking of Ace1p in Saccharomyces cerevisiae defines a characteristic residence time for non-specific interactions of transcription factors with chromatin

PubMed Central

Ball, David A.; Mehta, Gunjan D.; Salomon-Kent, Ronit; Mazza, Davide; Morisaki, Tatsuya; Mueller, Florian; McNally, James G.; Karpova, Tatiana S.

2016-01-01

In vivo single molecule tracking has recently developed into a powerful technique for measuring and understanding the transient interactions of transcription factors (TF) with their chromatin response elements. However, this method still lacks a solid foundation for distinguishing between specific and non-specific interactions. To address this issue, we took advantage of the power of molecular genetics of yeast. Yeast TF Ace1p has only five specific sites in the genome and thus serves as a benchmark to distinguish specific from non-specific binding. Here, we show that the estimated residence time of the short-residence molecules is essentially the same for Hht1p, Ace1p and Hsf1p, equaling 0.12–0.32 s. These three DNA-binding proteins are very different in their structure, function and intracellular concentration. This suggests that (i) short-residence molecules are bound to DNA non-specifically, and (ii) that non-specific binding shares common characteristics between vastly different DNA-bound proteins and thus may have a common underlying mechanism. We develop new and robust procedure for evaluation of adverse effects of labeling, and new quantitative analysis procedures that significantly improve residence time measurements by accounting for fluorophore blinking. Our results provide a framework for the reliable performance and analysis of single molecule TF experiments in yeast. PMID:27566148

N-domain angiotensin-I converting enzyme is expressed in immortalized mesangial, proximal tubule and collecting duct cells.

PubMed

Mei Wang, Pamella Huey; Andrade, Maria Claudina; Quinto, Beata Marie Redublo; Di Marco, Giovana; Mortara, Renato Arruda; Vio, Carlos P; Casarini, Dulce Elena

2015-01-01

Somatic ACE (sACE) is found in glomerulus, proximal tubule and excreted in urine. We hypothesized that N-domain ACE can also be found at these sites. ACE profile was analyzed in mesangial (IMC), proximal (LLC-PK1), distal tubule (MDCK) and collecting duct (IMCD) cells. Cell lysate and culture medium were submitted to gel filtration chromatography, which separated two peaks with ACE activity from cells and medium, except from distal tubule. The first had a high molecular weight and the second, a lower one (65 kDa; N-domain ACE). We focused on N-domain ACE purification and characterization from LLC-PK1. Total LLC-PK1 N-domain ACE purification was achieved by ion-exchange chromatography, which presented only one peak with ACE activity, denominated ACE(int2A). ACE(int2A) activity was influenced by pH, NaCl and temperature. The purified enzyme was inhibited by Captopril and hydrolyzed AngI, Ang1-7 and AcSDKP. Its ability to hydrolyze AcSDKP characterized it as an N-domain ACE. ACE(int2A) also presented high amino acid sequence homology with the N-terminal part of sACE from mouse, rat, human and rabbit. The presence of secreted and intracellular N-domain ACE and sACE in IMC, LLC-PK1 and IMCD cells confirmed our studies along the nephron. We identified, purified and characterized N-domain ACE from LLC-PK1. Copyright © 2014 Elsevier B.V. All rights reserved.

Solid-Phase Synthesis of Difficult Purine-Rich PNAs through Selective Hmb Incorporation: Application to the Total Synthesis of Cell Penetrating Peptide-PNAs

PubMed Central

Tailhades, Julien; Takizawa, Hotake; Gait, Michael J.; Wellings, Don A.; Wade, John D.; Aoki, Yoshitsugu; Shabanpoor, Fazel

2017-01-01

Antisense oligonucleotide (ASO)-based drug development is gaining significant momentum following the recent FDA approval of Eteplirsen (an ASO based on phosphorodiamidate morpholino) and Spinraza (2′-O-methoxyethyl-phosphorothioate) in late 2016. Their attractiveness is mainly due to the backbone modifications which have improved the in vivo characteristics of oligonucleotide drugs. Another class of ASO, based on peptide nucleic acid (PNA) chemistry, is also gaining popularity as a platform for development of gene-specific therapy for various disorders. However, the chemical synthesis of long PNAs, which are more target-specific, remains an ongoing challenge. Most of the reported methodology for the solid-phase synthesis of PNA suffer from poor coupling efficiency which limits production to short PNA sequences of less than 15 residues. Here, we have studied the effect of backbone modifications with Hmb (2-hydroxy-4-methoxybenzyl) and Dmb (2,4-dimethoxybenzyl) to ameliorate difficult couplings and reduce “on-resin” aggregation. We firstly synthesized a library of PNA dimers incorporating either Hmb or Dmb and identified that Hmb is superior to Dmb in terms of its ease of removal. Subsequently, we used Hmb backbone modification to synthesize a 22-mer purine-rich PNA, targeting dystrophin RNA splicing, which could not be synthesized by standard coupling methodology. Hmb backbone modification allowed this difficult PNA to be synthesized as well as to be continued to include a cell-penetrating peptide on the same solid support. This approach provides a novel and straightforward strategy for facile solid-phase synthesis of difficult purine-rich PNA sequences. PMID:29094037

Solid-Phase Synthesis of Difficult Purine-Rich PNAs through Selective Hmb Incorporation: Application to the Total Synthesis of Cell Penetrating Peptide-PNAs.

PubMed

Tailhades, Julien; Takizawa, Hotake; Gait, Michael J; Wellings, Don A; Wade, John D; Aoki, Yoshitsugu; Shabanpoor, Fazel

2017-01-01

Antisense oligonucleotide (ASO)-based drug development is gaining significant momentum following the recent FDA approval of Eteplirsen (an ASO based on phosphorodiamidate morpholino) and Spinraza (2'- O -methoxyethyl-phosphorothioate) in late 2016. Their attractiveness is mainly due to the backbone modifications which have improved the in vivo characteristics of oligonucleotide drugs. Another class of ASO, based on peptide nucleic acid (PNA) chemistry, is also gaining popularity as a platform for development of gene-specific therapy for various disorders. However, the chemical synthesis of long PNAs, which are more target-specific, remains an ongoing challenge. Most of the reported methodology for the solid-phase synthesis of PNA suffer from poor coupling efficiency which limits production to short PNA sequences of less than 15 residues. Here, we have studied the effect of backbone modifications with Hmb (2-hydroxy-4-methoxybenzyl) and Dmb (2,4-dimethoxybenzyl) to ameliorate difficult couplings and reduce "on-resin" aggregation. We firstly synthesized a library of PNA dimers incorporating either Hmb or Dmb and identified that Hmb is superior to Dmb in terms of its ease of removal. Subsequently, we used Hmb backbone modification to synthesize a 22-mer purine-rich PNA, targeting dystrophin RNA splicing, which could not be synthesized by standard coupling methodology. Hmb backbone modification allowed this difficult PNA to be synthesized as well as to be continued to include a cell-penetrating peptide on the same solid support. This approach provides a novel and straightforward strategy for facile solid-phase synthesis of difficult purine-rich PNA sequences.

Solid-phase synthesis of difficult purine-rich PNAs through selective Hmb incorporation: Application to the total synthesis of cell penetrating peptide-PNAs

NASA Astrophysics Data System (ADS)

Tailhades, Julien; Takizawa, Hotake; Gait, Michael J.; Wellings, Don A.; Wade, John D.; Aoki, Yoshitsugu; Shabanpoor, Fazel

2017-10-01

Antisense oligonucleotide (ASO)-based drug development is gaining significant momentum following the recent FDA approval of Eteplirsen (an ASO based on phosphorodiamidate morpholino) and Spinraza (2’-O-methoxyethyl-phosphorothioate) in late 2016. Their attractiveness is mainly due to the backbone modifications which have improved the in vivo characteristics of oligonucleotide drugs. Another class of ASO, based on peptide nucleic acid (PNA) chemistry, is also gaining popularity as a platform for development of gene-specific therapy for various disorders. However, the chemical synthesis of long PNAs, which are more target-specific, remains an ongoing challenge. Most of the reported methodology for the solid-phase synthesis of PNA suffer from poor coupling efficiency which limits production to short PNA sequences of less than 15 residues. Here we have studied the effect of backbone modifications with Hmb (2-hydroxy-4-methoxybenzyl) and Dmb (2,4-dimethoxybenzyl) to ameliorate difficult couplings and reduce “on-resin” aggregation. We firstly synthesized a library of PNA dimers incorporating either Hmb or Dmb and identified that Hmb is superior to Dmb in terms of its ease of removal. Subsequently, we used Hmb backbone modification to synthesize a 22-mer purine-rich PNA, targeting dystrophin RNA splicing, which could not be synthesized by standard coupling methodology. Hmb backbone modification allowed this difficult PNA to be synthesized as well as to be continued to include a cell-penetrating peptide on the same solid support. This approach provides a novel and straightforward strategy for facile solid-phase synthesis of difficult purine-rich PNA sequences.

[Effect of altitude chronic hypoxia on liver enzymes and its correlation with ACE/ACE2 in yak and migrated cattle].

PubMed

Liu, Feng-yun; Hu, Lin; Li, Yu-xian; Liu, Shi-ming; Tang, Yong-ping; Qi, Sheng-gui; Yang, Lei; Wu, Tian-yi

2015-05-01

To investigate the difference of liver enzyme levels and its correlation with serum ACE/ACE2 among yak and cattle on Qinghai-Tibetan plateau, and to further explore the biochemical mechanism of their liver of altitude adaptation. The serum samples of yak were collected at 3,000 m, 3,500 m, 4,000 m and 4,300 m respectively, meanwhile the serum samples of migrated cattle on plateau (2,500 m) and lowland cattle (1,300 m) were also collected. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholinesterase (CHE), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), serum lipase (LPS), angiotensin converting enzyme(ACE), angiotensin converting enzyme-2 (ACE2) in serum were measured by using fully automatic blood biochemcal analyzer. We analysed the differences of the above enzymes and its correlation with ACE/ACE2. We used one way analysis of variance (ANOVA). The levels of ALT in 4,000 m group and 4,300 m group of yak increased significantly compared with other groups, there were no statistically significant differences in AST, CHE, GGT, ACE/ACE2 levels of yaks at different altitudes. As compared to lowland cattle, the serum levels of AST and CHE were increased, the level of LPS and ACE was decreased significantly, respectively, and especially, the ratio of ACE/ACE2 of migranted cattle reduced nearly two times. The levels of LPS were significantly correlated to the ratio of ACE/ACE2 in yak (r = 0.357, P < 0.01), and a high correlation between ALP and ACE/ACE2 in lowland cattle( r = 0.418, P < 0.05), But the biggest contribution rate of the ratio of ACE/ACE2 was only 17.5% for the changes of the levels of liver enzyme. The results indicated that with the altitude increased did not significantly influence the changes of liver enzymes' activities in mountainous yaks but not in cattle. However, all above these changes weren't actually correlated to the ratio of ACE/ACE2.

ACE phenotyping in Gaucher disease.

PubMed

Danilov, Sergei M; Tikhomirova, Victoria E; Metzger, Roman; Naperova, Irina A; Bukina, Tatiana M; Goker-Alpan, Ozlem; Tayebi, Nahid; Gayfullin, Nurshat M; Schwartz, David E; Samokhodskaya, Larisa M; Kost, Olga A; Sidransky, Ellen

2018-04-01

Gaucher disease is characterized by the activation of splenic and hepatic macrophages, accompanied by dramatically increased levels of angiotensin-converting enzyme (ACE). To evaluate the source of the elevated blood ACE, we performed complete ACE phenotyping using blood, spleen and liver samples from patients with Gaucher disease and controls. ACE phenotyping included 1) immunohistochemical staining for ACE; 2) measuring ACE activity with two substrates (HHL and ZPHL); 3) calculating the ratio of the rates of substrate hydrolysis (ZPHL/HHL ratio); 4) assessing the conformational fingerprint of ACE by evaluating the pattern of binding of monoclonal antibodies to 16 different ACE epitopes. We show that in patients with Gaucher disease, the dramatically increased levels of ACE originate from activated splenic and/or hepatic macrophages (Gaucher cells), and that both its conformational fingerprint and kinetic characteristics (ZPHL/HHL ratio) differ from controls and from patients with sarcoid granulomas. Furthermore, normal spleen was found to produce high levels of endogenous ACE inhibitors and a novel, tightly-bound 10-30 kDa ACE effector which is deficient in Gaucher spleen. The conformation of ACE is tissue-specific. In Gaucher disease, ACE produced by activated splenic macrophages differs from that in hepatic macrophages, as well as from macrophages and dendritic cells in sarcoid granulomas. The observed differences are likely due to altered ACE glycosylation or sialylation in these diseased organs. The conformational differences in ACE may serve as a specific biomarker for Gaucher disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Adverse Outcome Pathways (AOPs) in Human Systems Biology: Gas-Phase Probes for Assessing In Vitro Enzyme System Perturbations

EPA Science Inventory

The Air, Climate, and Energy (ACE) and Chemical Safety for Sustainability (CSS) programs at the U.S. EnvironmentalProtection Agency (EPA) encompass broad-based research that includes assessment of the health and environmentalimpacts of anthropogenic and manufactured chemicals. On...

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

PubMed Central

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

2017-01-01

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

The relationship between angiotensin-converting enzyme (ACE) insertion (I) / deletion (D) polymorphism, serum ACE activity and bone mineral density (BMD) in older Chinese.

PubMed

Zhang, Ya-Feng; Wang, Hong; Cheng, Qiong; Qin, Ling; Tang, Nelson Ls; Leung, Ping-Chong; Kwok, Timothy Cy

2017-01-01

In this study, we set out to investigate the relationship between angiotensin-converting enzyme ( ACE) I/D polymorphism, serum ACE activity and bone mineral density (BMD) in older Chinese. A standardized, structured, face-to-face interview was performed to collect demographic information. BMD was measured using dual-energy X-ray absorptiometry (DXA). I/D genotypes of ACE were determined by polymerase chain reaction (PCR) amplification. Serum ACE activity was determined photometrically by a commercially available kinetic kit. Multiple linear regression analysis was used to examine the relationship between ACE I/D polymorphism, serum ACE activity and BMD. A total of 1567 males and 1760 females were selected for analyzing the relationship between ACE I/D polymorphism and BMD. There was no significant difference in spine BMD, total hip BMD and femur neck BMD among different ACE I/D genotypes both in males and females. A total of 1699 males and 1739 females were selected for analyzing the relationship between serum ACE activity and BMD. There was also no significant difference in spine BMD, total hip BMD and femur neck BMD among different serum ACE activity groups both in males and females. There was no relationship between ACE I/D polymorphism, serum ACE activity and BMD in older Chinese.

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

PubMed

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

2017-03-05

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

Innovative Delivery of siRNA to Solid Tumors by Super Carbonate Apatite

PubMed Central

Wu, Xin; Yamamoto, Hirofumi; Nakanishi, Hiroyuki; Yamamoto, Yuki; Inoue, Akira; Tei, Mitsuyoshi; Hirose, Hajime; Uemura, Mamoru; Nishimura, Junichi; Hata, Taishi; Takemasa, Ichiro; Mizushima, Tsunekazu; Hossain, Sharif; Akaike, Toshihiro; Matsuura, Nariaki; Doki, Yuichiro; Mori, Masaki

2015-01-01

RNA interference (RNAi) technology is currently being tested in clinical trials for a limited number of diseases. However, systemic delivery of small interfering RNA (siRNA) to solid tumors has not yet been achieved in clinics. Here, we introduce an in vivo pH-sensitive delivery system for siRNA using super carbonate apatite (sCA) nanoparticles, which is the smallest class of nanocarrier. These carriers consist simply of inorganic ions and accumulate specifically in tumors, yet they cause no serious adverse events in mice and monkeys. Intravenously administered sCA-siRNA abundantly accumulated in the cytoplasm of tumor cells at 4 h, indicating quick achievement of endosomal escape. sCA-survivin-siRNA induced apoptosis in HT29 tumors and significantly inhibited in vivo tumor growth of HCT116, to a greater extent than two other in vivo delivery reagents. With innovative in vivo delivery efficiency, sCA could be a useful nanoparticle for the therapy of solid tumors. PMID:25738937

Innovative delivery of siRNA to solid tumors by super carbonate apatite.

PubMed

Wu, Xin; Yamamoto, Hirofumi; Nakanishi, Hiroyuki; Yamamoto, Yuki; Inoue, Akira; Tei, Mitsuyoshi; Hirose, Hajime; Uemura, Mamoru; Nishimura, Junichi; Hata, Taishi; Takemasa, Ichiro; Mizushima, Tsunekazu; Hossain, Sharif; Akaike, Toshihiro; Matsuura, Nariaki; Doki, Yuichiro; Mori, Masaki

2015-01-01

RNA interference (RNAi) technology is currently being tested in clinical trials for a limited number of diseases. However, systemic delivery of small interfering RNA (siRNA) to solid tumors has not yet been achieved in clinics. Here, we introduce an in vivo pH-sensitive delivery system for siRNA using super carbonate apatite (sCA) nanoparticles, which is the smallest class of nanocarrier. These carriers consist simply of inorganic ions and accumulate specifically in tumors, yet they cause no serious adverse events in mice and monkeys. Intravenously administered sCA-siRNA abundantly accumulated in the cytoplasm of tumor cells at 4 h, indicating quick achievement of endosomal escape. sCA-survivin-siRNA induced apoptosis in HT29 tumors and significantly inhibited in vivo tumor growth of HCT116, to a greater extent than two other in vivo delivery reagents. With innovative in vivo delivery efficiency, sCA could be a useful nanoparticle for the therapy of solid tumors.

Angiotensin-converting enzyme activity in Cavalier King Charles Spaniels with an ACE gene polymorphism and myxomatous mitral valve disease.

PubMed

Meurs, Kathryn M; Olsen, Lisbeth H; Reimann, Maria J; Keene, Bruce W; Atkins, Clarke E; Adin, Darcy; Aona, Brent; Condit, Julia; DeFrancesco, Teresa; Reina-Doreste, Yamir; Stern, Joshua A; Tou, Sandra; Ward, Jessica; Woodruff, Kathleen

2018-02-01

Myxomatous mitral valve disease (MMVD) is the most common heart disease in the dog. It is particularly common in the Cavalier King Charles Spaniel (CKCS) breed and affected dogs are frequently managed with angiotensin-converting enzyme inhibitors (ACE-I). We have previously identified a canine ACE gene polymorphism associated with a decrease in angiotensin-converting enzyme (ACE) activity. The aim of this study was to evaluate for the prevalence of the ACE polymorphism in CKCS with mitral valve disease and to determine whether the presence of the polymorphism is associated with alterations in ACE activity at different stages of cardiac disease. Seventy-three dogs with a diagnosis of mitral valve disease were evaluated and a blood sample was drawn for ACE polymorphism genotyping and ACE activity measurement. Forty-three dogs were homozygous for the ACE polymorphism; five were heterozygous and 25 were homozygous wild type. The mean age and the median severity of disease were not different for dogs with the polymorphism and dogs with the wild-type sequence. The median baseline ACE activity was significantly lower for the ACE polymorphism (27.0 U/l) than the wild-type sequence dogs (31.0 U/l) (P=0.02). Dogs with more severe disease and the ACE polymorphism had significantly lower levels of ACE activity than dogs with the wild-type sequence (P=0.03). The CKCS appears to have a high prevalence of the ACE variant. Dogs with the ACE variant had lower levels of ACE activity even in more advanced mitral valve disease than dogs without the variant. The clinical significance of this finding and its impact on the need for ACE-I in dogs with the polymorphism and heart disease deserves further study.

Bridging Computational Genetics and Vectorcardiography: A Robust Platform for the Early Detection of Heart Disease

NASA Astrophysics Data System (ADS)

Sridhar, S.

2017-12-01

By 2030, it is predicted that over 14 million people will die of heart disease annually, many of whom will discover their risk when it is too late to seek effective treatment or pursue lifestyle changes. In this research study, I sought to design a robust computational platform to gauge a patient's risk for cardiac diseases (CDs) based on demographics, genotype, and cardiac action potentials through machine learning, statistical analysis, and vectorcardiography. By analyzing previously published data, I discovered that certain polymorphisms in the ACE and MTHFR genes contribute significantly to CD risk. The deletion allele of the ACE insertion/deletion polymorphism increases ACE serum levels, promoting CD phenotypes. A point mutation in the MTHFR gene curbs the metabolism of folic acid, giving rise to CD phenotypes. I analyzed over 9000 British Medical Journal and American Heart Association patients to determine the CD risk associated with each ACE and MTHFR genotype. In the vectorcardiography phase of my study, I investigated trends in the maximal vectors of the QRS loop of the cardiac wave. Using a database with both normal and diseased vectorcardiographic action potentials, I plotted the maximal vectors on a 3D RAS coordinate plane to analyze their magnitude and direction. From the ACE datasets, I discovered that female patients over 45 and of Indian descent with two ACE deletion alleles exhibited the highest CD risk. Using this spectrum, I successfully constructed a neural network with an accuracy score of 0.867 that predicts CD risk based on ACE genotype, gender, region, and age. Investigation of the MTHFR genome showed that those with a homozygous mutated gene had a significantly higher CD risk. In my vectorcardiography study, I found that healthy QRS vectors pointed predominantly to the right-anterior region of the coordinate plane and exhibited short, consistent magnitudes. On the other hand, diseased vectors pointed to the left-posterior region and exhibited large, varying magnitudes. Since these vectors exhibited a stark dichotomy in orientation, I designed an SVM classifier that was able to distinguish between normal and diseased vectorcardiographs with an F1 score of 0.965. Overall, my neural network and SVM classifiers have the potential to enhance clinical CD diagnosis in developing nations.

America's Children and the Environment

MedlinePlus

... Labs and Research Centers America's Children and the Environment (ACE) Contact Us Share ACE presents key information ... of updates to ACE . America's Children and the Environment (ACE) America's Children and the Environment (ACE) is ...

Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitor-Based Treatment on Cardiovascular Outcomes in Hypertensive Blacks versus Whites

PubMed Central

Ogedegbe, Gbenga; Shah, Nirav R.; Phillips, Christopher; Goldfeld, Keith; Roy, Jason; Guo, Yu; Gyamfi, Joyce; Torgersen, Christopher; Capponi, Louis; Bangalore, Sripal

2015-01-01

BACKGROUND Clinical trial evidence suggests poorer outcomes in blacks compared to whites when treated with angiotensin-converting enzyme (ACE) inhibitor-based regimen, but this has not been evaluated in clinical practice. OBJECTIVES We evaluated the comparative effectiveness of an ACE inhibitor-based regimen on a composite outcome of all-cause mortality, stroke, and acute myocardial infarction (AMI) in hypertensive blacks compared to whites. METHODS We conducted a retrospective cohort study of 434,646 patients in a municipal health care system. Four exposure groups (Black-ACE, Black-NoACE, White-ACE, White-NoACE) were created based on race and treatment exposure (ACE or NoACE). Risk of the composite outcome and its components was compared across treatment groups and race using weighted Cox proportional hazard models. RESULTS Our analysis included 59,316 new users of ACE inhibitors, 47% of whom were black. Baseline characteristics were comparable for all groups after inverse probability weighting adjustment. For the composite outcome, the race treatment interaction was significant (p = 0.04); ACE use in blacks was associated with poorer cardiovascular outcomes (ACE vs. NoACE: 8.69% vs. 7.74%; p = 0.05) but not in whites (6.40% vs. 6.74%; p = 0.37). Similarly, the Black-ACE group had higher rates of AMI (0.46% vs. 0.26%; p = 0.04), stroke (2.43% vs. 1.93%; p = 0.05) and chronic heart failure (3.75% vs. 2.25%; p < 0.0001) than the Black-NoACE group. However, the Black-ACE group was no more likely to develop adverse effects than the White-ACE group. CONCLUSIONS ACE inhibitor-based therapy was associated with poorer cardiovascular outcomes in hypertensive blacks but not in whites. These findings confirm clinical trial evidence that hypertensive blacks have poorer outcomes than whites when treated with an ACE inhibitor-based regimen. PMID:26361152

ACE insertion/deletion (I/D) polymorphism and diabetic nephropathy.

PubMed

Rahimi, Zohreh

2012-10-01

Angiotensin converting enzyme (ACE) gene encodes ACE, a key component of renin angiotensin system (RAS), plays an important role in blood pressure homeostasis by generating the vasoconstrictor peptide angiotensin II. Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. The presence of ACE insertion/deletion (I/D) polymorphism affects the plasma level of ACE. ACE DD genotype is associated with the highest systemic and renal ACE levels compared with the lowest ACE activity in carriers of II genotype. In this review focus has been performed on the study of ACE I/D polymorphism in various populations and its influence on the risk of onset and progression of diabetic nephropathy. Also, association between ACE I/D polymorphism and response to ACE inhibitor and angiotensin II receptor antagonists will be reviewed. Further, synergistic effect of this polymorphism and variants of some genes on the risk of development of diabetic nephropathy will be discussed.

Silencing of BCR/ABL Chimeric Gene in Human Chronic Myelogenous Leukemia Cell Line K562 by siRNA-Nuclear Export Signal Peptide Conjugates.

PubMed

Shinkai, Yasuhiro; Kashihara, Shinichi; Minematsu, Go; Fujii, Hirofumi; Naemura, Madoka; Kotake, Yojiro; Morita, Yasutaka; Ohnuki, Koichiro; Fokina, Alesya A; Stetsenko, Dmitry A; Filichev, Vyacheslav V; Fujii, Masayuki

2017-06-01

Herein we described the synthesis of siRNA-NES (nuclear export signal) peptide conjugates by solid phase fragment coupling and the application of them to silencing of bcr/abl chimeric gene in human chronic myelogenous leukemia cell line K562. Two types of siRNA-NES conjugates were prepared, and both sense strands at 5' ends were covalently linked to a NES peptide derived from TFIIIA and HIV-1 REV, respectively. Significant enhancement of silencing efficiency was observed for both of them. siRNA-TFIIIA NES conjugate suppressed the expression of BCR/ABL gene to 8.3% at 200 nM and 11.6% at 50 nM, and siRNA-HIV-1REV NES conjugate suppressed to 4.0% at 200 nM and 6.3% at 50 nM, whereas native siRNA suppressed to 36.3% at 200 nM and 30.2% at 50 nM. We could also show complex of siRNA-NES conjugate and designed amphiphilic peptide peptideβ7 could be taken up into cells with no cytotoxicity and showed excellent silencing efficiency. We believe that the complex siRNA-NES conjugate and peptideβ7 is a promising candidate for in vivo use and therapeutic applications.

Proteome analysis of Lactobacillus helveticus H9 during growth in skim milk.

PubMed

Chen, Y F; Zhao, W J; Wu, R N; Sun, Z H; Zhang, W Y; Wang, J C; Bilige, M; Zhang, H P

2014-12-01

Lactobacillus helveticus H9 was isolated from traditionally fermented yak milk in Tibet (China) with the ability to produce the antihypertensive peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) during milk fermentation. To understand the changes in the protein expression of L. helveticus H9, proteome analysis was performed at 3 different growth stages, lag phase (pH 6.1), log phase (pH 5.1), and stationary phase (pH 4.5) using 2-dimensional electrophoresis (2-DE). Further analysis showed that 257 differential protein spots were found and 214 protein spots were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS). The cellular functions of the differentially expressed proteins were complex. Interestingly, the proteolytic system-related proteins aminopeptidase N (PepN), aminopeptidase E (PepE), endopeptidase O2 (PepO2), and oligopeptide transport system permease protein (OppC) were observed only on the maps of pH 5.1 and pH 4.5, which was consistent with the presence of angiotensin I-converting enzyme (ACE)-inhibitory peptides VPP and IPP during these 2 growth stages (log phase and stationary phase). These results, combined with a previous study of gene expression of the proteolytic system, led us to conclude that the Opp transport system, pepE, and pepO2 are likely related to the production of ACE-inhibitory peptides. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Investigation into the Mechanism of Homo- and Heterodimerization of Angiotensin-Converting Enzyme.

PubMed

Abrie, J Albert; Moolman, Wessel J A; Cozier, Gyles E; Schwager, Sylva L; Acharya, K Ravi; Sturrock, Edward D

2018-04-01

Angiotensin-converting enzyme (ACE) plays a central role in the renin-angiotensin system (RAS), which is primarily responsible for blood pressure homeostasis. Studies have shown that ACE inhibitors yield cardiovascular benefits that cannot be entirely attributed to the inhibition of ACE catalytic activity. It is possible that these benefits are due to interactions between ACE and RAS receptors that mediate the protective arm of the RAS, such as angiotensin II receptor type 2 (AT 2 R) and the receptor MAS. Therefore, in this study, we investigated the molecular interactions of ACE, including ACE homodimerization and heterodimerization with AT 2 R and MAS, respectively. Molecular interactions were assessed by fluorescence resonance energy transfer and bimolecular fluorescence complementation in human embryonic kidney 293 cells and Chinese hamster ovary-K1 cells transfected with vectors encoding fluorophore-tagged proteins. The specificity of dimerization was verified by competition experiments using untagged proteins. These techniques were used to study several potential requirements for the germinal isoform of angiotensin-converting enzyme expressed in the testes (tACE) dimerization as well as the effect of ACE inhibitors on both somatic isoforms of angiotensin-converting enzyme expressed in the testes (sACE) and tACE dimerization. We demonstrated constitutive homodimerization of sACE and of both of its domains separately, as well as heterodimerization of both sACE and tACE with AT 2 R, but not MAS. In addition, we investigated both soluble sACE and the sACE N domain using size-exclusion chromatography-coupled small-angle X-ray scattering and we observed dimers in solution for both forms of the enzyme. Our results suggest that ACE homo- and heterodimerization does occur under physiologic conditions. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Profiles of childhood adversities in pathological gamblers - A latent class analysis.

PubMed

Lotzin, Annett; Ulas, Mehmet; Buth, Sven; Milin, Sascha; Kalke, Jens; Schäfer, Ingo

2018-06-01

Despite of high rates of adverse childhood experiences (ACEs) in pathological gamblers, researchers have rarely studied which types of ACEs often co-occur and how these profiles of ACEs are related to current psychopathology. We aimed to identify profiles of ACEs in pathological gamblers and examined how these profiles were related to gambling-related characteristics and current general psychopathology. In 329 current or lifetime pathological gamblers, diagnosed with the Composite Diagnostic Interview for DSM-IV, 10 types of ACEs were measured using the Adverse Childhood Experiences Questionnaire. Global psychopathology was assessed using the Symptom Checklist SCL-27. ACE profiles were identified using latent class analysis. Differences between ACE profiles in gambling-related characteristics and global psychopathology were analyzed using MANOVA. We found that four out of five gamblers (n=257, 78.1%) reported at least one ACE. Four distinct ACE profiles were identified: 'Low ACE', 'High ACE', 'Physical and emotional abuse', and 'Neglect'. The number of the fulfilled pathological gambling criteria and the severity of current global psychopathology differed between the ACE profiles: Gamblers with a 'High ACE' profile fulfilled more pathological gambling criteria and showed a more severe current psychopathology than gamblers of the 'Low ACE' profile. Gamblers with a 'Physical and emotional abuse' or an 'Emotion neglect' profile showed an intermediate severity of psychopathology. Our findings indicate that four different ACE profiles can be distinguished in pathological gamblers that differed in their gambling-related characteristics and current psychopathology. Systematic assessment of profiles of ACEs in pathological gamblers may inform about the severity of current global psychopathology that might be important to be addressed in addition to gambling-specific treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

Surface vimentin is critical for the cell entry of SARS-CoV.

PubMed

Yu, Yvonne Ting-Chun; Chien, Ssu-Chia; Chen, I-Yin; Lai, Chia-Tsen; Tsay, Yeou-Guang; Chang, Shin C; Chang, Ming-Fu

2016-01-22

Severe acute respiratory syndrome coronavirus (SARS-CoV) caused a global panic due to its high morbidity and mortality during 2002 and 2003. Soon after the deadly disease outbreak, the angiotensin-converting enzyme 2 (ACE2) was identified as a functional cellular receptor in vitro and in vivo for SARS-CoV spike protein. However, ACE2 solely is not sufficient to allow host cells to become susceptible to SARS-CoV infection, and other host factors may be involved in SARS-CoV spike protein-ACE2 complex. A host intracellular filamentous cytoskeletal protein vimentin was identified by immunoprecipitation and LC-MS/MS analysis following chemical cross-linking on Vero E6 cells that were pre-incubated with the SARS-CoV spike protein. Moreover, flow cytometry data demonstrated an increase of the cell surface vimentin level by 16.5 % after SARS-CoV permissive Vero E6 cells were treated with SARS-CoV virus-like particles (VLPs). A direct interaction between SARS-CoV spike protein and host surface vimentin was further confirmed by far-Western blotting. In addition, antibody neutralization assay and shRNA knockdown experiments indicated a vital role of vimentin in cell binding and uptake of SARS-CoV VLPs and the viral spike protein. A direct interaction between vimentin and SARS-CoV spike protein during viral entry was observed. Vimentin is a putative anti-viral drug target for preventing/reducing the susceptibility to SARS-CoV infection.

High maternal sodium intake alters sex-specific renal renin-angiotensin system components in newborn Wistar offspring.

PubMed

Maia, D R R; Lopes, K L; Heimann, J C; Furukawa, L N S

2016-01-28

This study aimed to evaluate the systemic and renal renin-angiotensin-aldosterone system (RAAS) at birth in male and female offspring and in mothers fed a high sodium diet (HSD) before and during gestation. Female Wistar rats were fed a HSD (8.0% NaCl) or a normal sodium diet (1.3% NaCl) from 8 weeks of age until delivery of their first litter. Maternal body weight, tail blood pressure, and food and water intake were evaluated. The litter sizes were assessed, and the body and kidney weights of the offspring were measured. Both mothers and offspring were euthanized immediately following the birth of the pups to evaluate plasma renin activity (PRA), renal renin content (RRC), renal angiotensin-converting enzyme (ACE) activity, renal angiotensin (Ang) II content, serum aldosterone (ALDO) levels, and renal cortical and medullary renin messenger RNA expression. In mothers in the HSD group, water intake and kidney mass were higher, whereas renal ACE activity, Ang II, PRA, ALDO and RRC were decreased. In the offspring of HSD-fed dams, the body and kidney mass were lower in both genders, renal ACE activity was lower in females and renal Ang II was lower in males. PRA, RRC, renin gene expression and ALDO levels did not differ between the groups of offspring. The data presented herein showed that a maternal HSD during pregnancy induces low birth weight and a sex-specific response in the RAAS in offspring.

Dynamic Response of a Magnetized Plasma to AN External Source: Application to Space and Solid State Plasmas

NASA Astrophysics Data System (ADS)

Zhou, Huai-Bei

This dissertation examines the dynamic response of a magnetoplasma to an external time-dependent current source. To achieve this goal a new method which combines analytic and numerical techniques to study the dynamic response of a 3-D magnetoplasma to a time-dependent current source imposed across the magnetic field was developed. The set of the cold electron and/or ion plasma equations and Maxwell's equations are first solved analytically in (k, omega)^ace; inverse Laplace and 3 -D complex Fast Fourier Transform (FFT) techniques are subsequently used to numerically transform the radiation fields and plasma currents from the (k, omega) ^ace to the (r, t) space. The dynamic responses of the electron plasma and of the compensated two-component plasma to external current sources are studied separately. The results show that the electron plasma responds to a time -varying current source imposed across the magnetic field by exciting whistler/helicon waves and forming of an expanding local current loop, induced by field aligned plasma currents. The current loop consists of two anti-parallel field-aligned current channels concentrated at the ends of the imposed current and a cross-field current region connecting these channels. The latter is driven by an electron Hall drift. A compensated two-component plasma responds to the same current source as following: (a) For slow time scales tau > Omega_sp{i}{-1} , it generates Alfven waves and forms a non-local current loop in which the ion polarization currents dominate the cross-field current; (b) For fast time scales tau < Omega_sp{i}{-1} , the dynamic response of the compensated two-component plasma is the same as that of the electron plasma. The characteristics of the current closure region are determined by the background plasma density, the magnetic field and the time scale of the current source. This study has applications to a diverse range of space and solid state plasma problems. These problems include current closure in emf inducing tethered satellite systems (TSS), generation of ELF/VLF waves by ionospheric heating, current closure and quasineutrality in thin magnetopause transitions, and short electromagnetic pulse generation in solid state plasmas. The cross-field current in TSS builds up on a time scale corresponding to the whistler waves and results in local current closure. Amplitude modulated HF ionospheric heating generates ELF/VLF waves by forming a horizontal magnetic dipole. The dipole is formed by the current closure in the modified region. For thin transition the time-dependent cross-field polarization field at the magnetopause could be neutralized by the formation of field aligned current loops that close by a cross-field electron Hall current. A moving current source in a solid state plasma results in microwave emission if the speed of the source exceeds the local phase velocity of the helicon or Alfven waves. Detailed analysis of the above problems is presented in the thesis.

5-Fluoro pyrimidines: labels to probe DNA and RNA secondary structures by 1D 19F NMR spectroscopy

PubMed Central

Puffer, Barbara; Kreutz, Christoph; Rieder, Ulrike; Ebert, Marc-Olivier; Konrat, Robert; Micura, Ronald

2009-01-01

19F NMR spectroscopy has proved to be a valuable tool to monitor functionally important conformational transitions of nucleic acids. Here, we present a systematic investigation on the application of 5-fluoro pyrimidines to probe DNA and RNA secondary structures. Oligonucleotides with the propensity to adapt secondary structure equilibria were chosen as model systems and analyzed by 1D 19F and 1H NMR spectroscopy. A comparison with the unmodified analogs revealed that the equilibrium characteristics of the bistable DNA and RNA oligonucleotides were hardly affected upon fluorine substitution at C5 of pyrimidines. This observation was in accordance with UV spectroscopic melting experiments which demonstrated that single 5-fluoro substitutions in double helices lead to comparable thermodynamic stabilities. Thus, 5-fluoro pyrimidine labeling of DNA and RNA can be reliably applied for NMR based nucleic acid secondary structure evaluation. Furthermore, we developed a facile synthetic route towards 5-fluoro cytidine phosphoramidites that enables their convenient site-specific incorporation into oligonucleotides by solid-phase synthesis. PMID:19843610

5-Fluoro pyrimidines: labels to probe DNA and RNA secondary structures by 1D 19F NMR spectroscopy.

PubMed

Puffer, Barbara; Kreutz, Christoph; Rieder, Ulrike; Ebert, Marc-Olivier; Konrat, Robert; Micura, Ronald

2009-12-01

(19)F NMR spectroscopy has proved to be a valuable tool to monitor functionally important conformational transitions of nucleic acids. Here, we present a systematic investigation on the application of 5-fluoro pyrimidines to probe DNA and RNA secondary structures. Oligonucleotides with the propensity to adapt secondary structure equilibria were chosen as model systems and analyzed by 1D (19)F and (1)H NMR spectroscopy. A comparison with the unmodified analogs revealed that the equilibrium characteristics of the bistable DNA and RNA oligonucleotides were hardly affected upon fluorine substitution at C5 of pyrimidines. This observation was in accordance with UV spectroscopic melting experiments which demonstrated that single 5-fluoro substitutions in double helices lead to comparable thermodynamic stabilities. Thus, 5-fluoro pyrimidine labeling of DNA and RNA can be reliably applied for NMR based nucleic acid secondary structure evaluation. Furthermore, we developed a facile synthetic route towards 5-fluoro cytidine phosphoramidites that enables their convenient site-specific incorporation into oligonucleotides by solid-phase synthesis.

Incorporation of isotopic, fluorescent, and heavy-atom-modified nucleotides into RNAs by position-selective labeling of RNA.

PubMed

Liu, Yu; Holmstrom, Erik; Yu, Ping; Tan, Kemin; Zuo, Xiaobing; Nesbitt, David J; Sousa, Rui; Stagno, Jason R; Wang, Yun-Xing

2018-05-01

Site-specific incorporation of labeled nucleotides is an extremely useful synthetic tool for many structural studies (e.g., NMR, electron paramagnetic resonance (EPR), fluorescence resonance energy transfer (FRET), and X-ray crystallography) of RNA. However, specific-position-labeled RNAs >60 nt are not commercially available on a milligram scale. Position-selective labeling of RNA (PLOR) has been applied to prepare large RNAs labeled at desired positions, and all the required reagents are commercially available. Here, we present a step-by-step protocol for the solid-liquid hybrid phase method PLOR to synthesize 71-nt RNA samples with three different modification applications, containing (i) a 13 C 15 N-labeled segment; (ii) discrete residues modified with Cy3, Cy5, or biotin; or (iii) two iodo-U residues. The flexible procedure enables a wide range of downstream biophysical analyses using precisely localized functionalized nucleotides. All three RNAs were obtained in <2 d, excluding time for preparing reagents and optimizing experimental conditions. With optimization, the protocol can be applied to other RNAs with various labeling schemes, such as ligation of segmentally labeled fragments.

A Novel Angiotensin I-Converting Enzyme Mutation (S333W) Impairs N-Domain Enzymatic Cleavage of the Anti-Fibrotic Peptide, AcSDKP

PubMed Central

Danilov, Sergei M.; Wade, Michael S.; Schwager, Sylva L.; Douglas, Ross G.; Nesterovitch, Andrew B.; Popova, Isolda A.; Hogarth, Kyle D.; Bhardwaj, Nakul; Schwartz, David E.; Sturrock, Edward D.; Garcia, Joe G. N.

2014-01-01

Background Angiotensin I-converting enzyme (ACE) has two functional N- and C-domain active centers that display differences in the metabolism of biologically-active peptides including the hemoregulatory tetrapeptide, Ac-SDKP, hydrolysed preferentially by the N domain active center. Elevated Ac-SDKP concentrations are associated with reduced tissue fibrosis. Results We identified a patient of African descent exhibiting unusual blood ACE kinetics with reduced relative hydrolysis of two synthetic ACE substrates (ZPHL/HHL ratio) suggestive of the ACE N domain center inactivation. Inhibition of blood ACE activity by anti-catalytic mAbs and ACE inhibitors and conformational fingerprint of blood ACE suggested overall conformational changes in the ACE molecule and sequencing identified Ser333Trp substitution in the N domain of ACE. In silico analysis demonstrated S333W localized in the S1 pocket of the active site of the N domain with the bulky Trp adversely affecting binding of ACE substrates due to steric hindrance. Expression of mutant ACE (S333W) in CHO cells confirmed altered kinetic properties of mutant ACE and conformational changes in the N domain. Further, the S333W mutant displayed decreased ability (5-fold) to cleave the physiological substrate AcSDKP compared to wild-type ACE. Conclusions and Significance A novel Ser333Trp ACE mutation results in dramatic changes in ACE kinetic properties and lowered clearance of Ac-SDKP. Individuals with this mutation (likely with significantly increased levels of the hemoregulatory tetrapeptide in blood and tissues), may confer protection against fibrosis. PMID:24505347

Up-Regulation of Angiotensin-Converting Enzyme (ACE) Enhances Cell Proliferation and Predicts Poor Prognosis in Laryngeal Cancer.

PubMed

Han, Chao-Dong; Ge, Wen-Sheng

2016-11-01

BACKGROUND The angiotensin-converting enzyme (ACE, CD143) gene plays a crucial role in the pathology of many cancers. Previous studies mostly focused on the gene polymorphism, but the other functions of ACE have rarely been reported. The purpose of this study was to investigate the expression of ACE and its biological function, as well as its prognostic value, in laryngeal cancer. MATERIAL AND METHODS The expression of ACE was detected by quantitative real-time polymerase chain reaction (qRT-PCR) analysis in 106 patients with laryngeal cancer and 85 healthy people. Then the cell proliferation was estimated after the cell lines Hep-2 were transfected with pGL3-ACE and empty vector, respectively. In addition, the relationship between ACE expression and clinicopathologic characteristics was analyzed. Finally, Kaplan-Meier analysis was used to evaluate the overall survival of patients with different ACE expression, while Cox regression analysis was conducted to reveal the prognostic value of ACE in laryngeal cancer. RESULTS Our results demonstrate that ACE is over-expressed in laryngeal cancer and thus promotes cell proliferation. The up-regulation of ACE was significantly influenced by tumor stage and lymph node metastasis. Patients with high ACE expression had a shorter overall survival compared with those with low ACE expression according to Kaplan-Meier analysis. The ACE gene was also found to be an important factor in the prognosis of laryngeal cancer. CONCLUSIONS Our study shows that the ACE gene was up-regulated, which promoted the cell proliferation, and it could be an independent prognostic marker in laryngeal cancer.

Expression and evolutionary analyses of three acetylcholinesterase genes (Mi-ace-1, Mi-ace-2, Mi-ace-3) in the root-knot nematode Meloidogyne incognita.

PubMed

Cui, Ruqiang; Zhang, Lei; Chen, Yuyan; Huang, Wenkun; Fan, Chengming; Wu, Qingsong; Peng, Deliang; da Silva, Washington; Sun, Xiaotang

2017-05-01

The full cDNA of Mi-ace-3 encoding an acetylcholinesterase (AChE) in Meloidogyne incognita was cloned and characterized. Mi-ace-3 had an open reading frame of 1875 bp encoding 624 amino acid residues. Key residues essential to AChE structure and function were conserved. The deduced Mi-ACE-3 protein sequence had 72% amino acid similarity with that of Ditylenchus destructor Dd-AChE-3. Phylogenetic analyses using 41 AChEs from 24 species showed that Mi-ACE-3 formed a cluster with 4 other nematode AChEs. Our results revealed that the Mi-ace-3 cloned in this study, which is orthologous to Caenorhabditis elegans AChE, belongs to the nematode ACE-3/4 subgroup. There was a significant reduction in the number of galls in transgenic tobacco roots when Mi-ace-1, Mi-ace-2, and Mi-ace-3 were knocked down simultaneously, whereas little or no effect were observed when only one or two of these genes were knocked down. This is an indication that the functions of these three genes are redundant. Copyright © 2017. Published by Elsevier Inc.

Renal tubular angiotensin converting enzyme is responsible for nitro-L-arginine methyl ester (L-NAME)-induced salt sensitivity

PubMed Central

Giani, Jorge F.; Eriguchi, Masahiro; Bernstein, Ellen A.; Katsumata, Makoto; Shen, Xiao Z.; Li, Liang; McDonough, Alicia A.; Fuchs, Sebastien; Bernstein, Kenneth E.; Gonzalez-Villalobos, Romer A.

2017-01-01

Renal parenchymal injury predisposes to salt-sensitive hypertension, but how this occurs is not known. Here we tested whether renal tubular angiotensin converting enzyme (ACE), the main site of kidney ACE expression, is central to the development of salt sensitivity in this setting. Two mouse models were used: it-ACE mice in which ACE expression is selectively eliminated from renal tubular epithelial cells; and ACE 3/9 mice, a compound heterozygous mouse model that makes ACE only in renal tubular epithelium from the ACE 9 allele, and in liver hepatocytes from the ACE 3 allele. Salt sensitivity was induced using a post L-NAME salt challenge. While both wild-type and ACE 3/9 mice developed arterial hypertension following three weeks of high salt administration, it-ACE mice remained normotensive with low levels of renal angiotensin II. These mice displayed increased sodium excretion, lower sodium accumulation, and an exaggerated reduction in distal sodium transporters. Thus, in mice with renal injury induced by L-NAME pretreatment, renal tubular epithelial ACE, and not ACE expression by renal endothelium, lung, brain, or plasma, is essential for renal angiotensin II accumulation and salt-sensitive hypertension. PMID:27988209

The Positively Charged Hyperbranched Polymers with Tunable Fluorescence and the Cell Imaging Application.

PubMed

Ma, Hengchang; Qin, Yanfang; Yang, Zenming; Yang, Manyi; Ma, Yucheng; Yin, Pei; Yang, Yuan; Wang, Tao; Lei, Ziqiang; Yao, Xiaoqiang

2018-04-25

Fluorescence-tunable materials are becoming increasingly attractive for their potential application in optics, electronics, and biomedical technology. Herein, a multi-color molecular pixel system is realized using simple copolymerization method. Bleeding both of complementary colors from blue and yellow fluorescence segments, reproduced a serious multicolor fluorescence materials. Interestingly, the emission colors of the polymers can be fine-tuned in solid state, solution phase, and in hydrogel state. More importantly, the positive fluorescent polymers exhibited cell-membrane permeable ability, and were found to accumulate on the cell nucleus, exhibiting remarkable selectivity to give bright fluorescence. The DNA/RNA selectivity experiments in vitro and in vivo verified that [tris(4-(pyridin-4-yl)phenyl)amine]-[1,8-dibromooctane] (TPPA-DBO) has prominent selectivity to DNA over RNA inside cells.

Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease.

PubMed

Wang, Wang; Patel, Vaibhav B; Parajuli, Nirmal; Fan, Dong; Basu, Ratnadeep; Wang, Zuocheng; Ramprasath, Tharmarajan; Kassiri, Zamaneh; Penninger, Josef M; Oudit, Gavin Y

2014-08-01

Angiotensin-converting enzyme 2 (ACE2) metabolizes Ang II into Ang 1-7 thereby negatively regulating the renin-angiotensin system. However, heart disease in humans and in animal models is associated with only a partial loss of ACE2. ACE2 is an X-linked gene; and as such, we tested the clinical relevance of a partial loss of ACE2 by using female ACE2(+/+) (wildtype) and ACE2(+/-) (heterozygote) mice. Pressure overload in ACE2(+/-) mice resulted in greater LV dilation and worsening systolic and diastolic dysfunction. These changes were associated with increased myocardial fibrosis, hypertrophy, and upregulation of pathological gene expression. In response to Ang II infusion, there was increased NADPH oxidase activity and myocardial fibrosis resulting in the worsening of Ang II-induced diastolic dysfunction with a preserved systolic function. Ang II-mediated cellular effects in cultured adult ACE2(+/-) cardiomyocytes and cardiofibroblasts were exacerbated. Ang II-mediated pathological signaling worsened in ACE2(+/-) hearts characterized by an increase in the phosphorylation of ERK1/2 and JNK1/2 and STAT-3 pathways. The ACE2(+/-) mice showed an exacerbated pressor response with increased vascular fibrosis and stiffness. Vascular superoxide and nitrotyrosine levels were increased in ACE2(+/-) vessels consistent with increased vascular oxidative stress. These changes occurred with increased renal fibrosis and superoxide production. Partial heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease secondary to pressure overload and Ang II infusion. Heart disease in humans with idiopathic dilated cardiomyopathy is associated with a partial loss of ACE2. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to pressure overload-induced heart disease. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to Ang II-induced heart and vascular diseases. Partial loss of ACE2 is sufficient to enhance the susceptibility to heart disease.

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

PubMed

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

2008-12-01

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

Angiotensin I-converting-enzyme-inhibitory and antibacterial peptides from Lactobacillus helveticus PR4 proteinase-hydrolyzed caseins of milk from six species.

PubMed

Minervini, F; Algaron, F; Rizzello, C G; Fox, P F; Monnet, V; Gobbetti, M

2003-09-01

Sodium caseinates prepared from bovine, sheep, goat, pig, buffalo or human milk were hydrolyzed by a partially purified proteinase of Lactobacillus helveticus PR4. Peptides in each hydrolysate were fractionated by reversed-phase fast-protein liquid chromatography. The fractions which showed the highest angiotensin I-converting-enzyme (ACE)-inhibitory or antibacterial activity were sequenced by mass spectrum and Edman degradation analyses. Various ACE-inhibitory peptides were found in the hydrolysates: the bovine alpha(S1)-casein (alpha(S1)-CN) 24-47 fragment (f24-47), f169-193, and beta-CN f58-76; ovine alpha(S1)-CN f1-6 and alpha(S2)-CN f182-185 and f186-188; caprine beta-CN f58-65 and alpha(S2)-CN f182-187; buffalo beta-CN f58-66; and a mixture of three tripeptides originating from human beta-CN. A mixture of peptides with a C-terminal sequence, Pro-Gly-Pro, was found in the most active fraction of the pig sodium caseinate hydrolysate. The highest ACE-inhibitory activity of some peptides corresponded to the concentration of the ACE inhibitor (S)-N-(1-[ethoxycarbonyl]-3-phenylpropyl)-ala-pro maleate (enalapril) of 49.253 micro g/ml (100 micro mol/liter). Several of the above sequences had features in common with other ACE-inhibitory peptides reported in the literature. The 50% inhibitory concentration (IC(50)) of some of the crude peptide fractions was very low (16 to 100 micro g/ml). Some identified peptides were chemically synthesized, and the ACE-inhibitory activity and IC(50)s were confirmed. An antibacterial peptide corresponding to beta-CN f184-210 was identified in human sodium caseinate hydrolysate. It showed a very large spectrum of inhibition against gram-positive and -negative bacteria, including species of potential clinical interest, such as Enterococcus faecium, Bacillus megaterium, Escherichia coli, Listeria innocua, Salmonella spp., Yersinia enterocolitica, and Staphylococcus aureus. The MIC for E. coli F19 was ca. 50 micro g/ml. Once generated, the bioactive peptides were resistant to further degradation by proteinase of L. helveticus PR4 or by trypsin and chymotrypsin.

N-Domain Isoform of Angiotensin I Converting Enzyme as a Marker of Hypertension: Populational Study

PubMed Central

Maluf-Meiken, Leila C. V.; Fernandes, Fernanda B.; Aragão, Danielle S.; Ronchi, Fernanda A.; Andrade, Maria C. C.; Franco, Maria C.; Febba, Andreia C. S.; Plavnik, Frida L.; Krieger, José E.; Mill, Jose G.; Sesso, Ricardo C. C.; Casarini, Dulce E.

2012-01-01

The aim of this paper was to investigate the presence of the urinary 90 kDa N-domain ACE in a cohort of the population from Vitoria, Brazil, to verify its association with essential hypertension since this isoform could be a possible genetic marker of hypertension. Anthropometric, clinical, and laboratory parameters of the individuals were evaluated (n = 1150) and the blood pressure (BP) was measured. The study population was divided according to ACE isoforms in urine as follows: ACE 65/90/190, presence of three ACE isoforms (n = 795), ACE 90+ (65/90) (n = 186), and ACE 90− (65/190) (n = 169) based on the presence (+) or absence (−) of the 90 kDa ACE isoform. The anthropometric parameters, lipid profile, serum levels of uric acid, glucose, and the systolic and diastolic BP were significantly greater in the ACE 90+ compared with the ACE 90− and ACE 65/90/190 individuals. We found that 98% of individuals from the ACE 90+ group and 38% from the ACE 65/90/190 group had hypertension, compared to only 1% hypertensive individuals in the ACE 90− group. There is a high presence of the 90 kDa N-domain ACE isoform (85%) in the studied population. The percentile of normotensive subjects with three isoforms was 62%. Our findings could contribute to the development of new efficient strategy to prevent and treat hypertension to avoid the development of cardiovascular disease. PMID:22666552

Angiotensin-I-converting enzyme and its relatives

PubMed Central

Riordan, James F

2003-01-01

Angiotensin-I-converting enzyme (ACE) is a monomeric, membrane-bound, zinc- and chloride-dependent peptidyl dipeptidase that catalyzes the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, by removing a carboxy-terminal dipeptide. ACE has long been known to be a key part of the renin angiotensin system that regulates blood pressure, and ACE inhibitors are important for the treatment of hypertension. There are two forms of the enzyme in humans, the ubiquitous somatic ACE and the sperm-specific germinal ACE, both encoded by the same gene through transcription from alternative promoters. Somatic ACE has two tandem active sites with distinct catalytic properties, whereas germinal ACE, the function of which is largely unknown, has just a single active site. Recently, an ACE homolog, ACE2, has been identified in humans that differs from ACE in being a carboxypeptidase that preferentially removes carboxy-terminal hydrophobic or basic amino acids; it appears to be important in cardiac function. ACE homologs (also known as members of the M2 gluzincin family) have been found in a wide variety of species, even in those that neither have a cardiovascular system nor synthesize angiotensin. X-ray structures of a truncated, deglycosylated form of germinal ACE and a related enzyme from Drosophila have been reported, and these show that the active site is deep within a central cavity. Structure-based drug design targeting the individual active sites of somatic ACE may lead to a new generation of ACE inhibitors, with fewer side-effects than currently available inhibitors. PMID:12914653

78 FR 44142 - Modification of Two National Customs Automation Program (NCAP) Tests Concerning Automated...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-23

... efforts are accomplished through phased releases of ACE component functionality designed to introduce new... designed to evaluate planned components of the NCAP. This test is authorized pursuant to Sec. 101.9(b) of... import meat, poultry, or egg products or ``Samples for Laboratory Examination, Research, Evaluative...

ACE I/D genotype-related increase in ACE plasma activity is a better predictor for schizophrenia diagnosis than the genotype alone.

PubMed

Gadelha, Ary; Yonamine, Camila M; Ota, Vanessa K; Oliveira, Vitor; Sato, João Ricardo; Belangero, Sintia I; Bressan, Rodrigo A; Hayashi, Mirian A F

2015-05-01

Angiotensin-I converting enzyme (ACE) is a key component of the renin-angiotensin system (RAS). Although the several contradictory data, ACE has been associated with schizophrenia (SCZ) pathophysiology. Here the ACE activity of SCZ patients and healthy controls (HCs), and its possible correlations with the ACE polymorphism genotype and symptomatic dimensions, was investigated. ACE activity of 86 SCZ patients and 100 HCs paired by age, gender and educational level was measured, using the FRET peptide substrate and the specific inhibitor lisinopril. The ACE insertion/deletion (I/D) genotypes were assessed by the restriction fragment length polymorphism (RFLP) technique. Significantly higher ACE activity was observed in SCZ patients compared to HCs (t=-5.09; p<0.001). The area under the receiver operating characteristic (ROC) curve was 0.701. Mean ACE activity levels were higher for the D-allele carriers (F=5.570; p=0.005), but no significant difference was found among SCZ patients and HCs for genotypes frequencies (Chi-squared=2.08; df=2; p=0.35). Interestingly, we found that the difference between the measured ACE activity for each SCZ patient and the expected average mean value for each respective genotype group (for control subjects) was a better predictor of SCZ than the ACE dichotomized values (high/low) or ACE I/D. Our results suggest that higher levels of ACE activity are associated with SCZ with stronger impact when the genetic background of each individual is considered. This may explain the heterogeneity of the results on ACE previously reported. Copyright © 2015 Elsevier B.V. All rights reserved.

Somatic ACE regulates self-renewal of mouse spermatogonial stem cells via the MAPK signaling pathway.

PubMed

Gao, Tingting; Zhao, Xin; Liu, Chenchen; Shao, Binbin; Zhang, Xi; Li, Kai; Cai, Jinyang; Wang, Su; Huang, Xiaoyan

2018-05-24

Spermatogonial stem cell (SSC) self-renewal is an indispensable part of spermatogenesis. Angiotensin I-converting enzyme (ACE) is a zinc dipeptidyl carboxypeptidase that plays a critical role in regulation of the renin-angiotensin system. Here, we used RT-PCR and Western blot analysis to confirm that somatic ACE (sACE) but not testicular ACE (tACE) is highly expressed in mouse testis before postpartum day 7 and in cultured SSCs. Our results revealed that sACE is located on the membrane of SSCs. Treating cultured SSCs with the ACE competitive inhibitor captopril was found to inhibit sACE activity, and significantly reduced the proliferation rate of SSCs. Microarray analysis identified 651 genes with significant differential expression. KEGG pathway analysis showed that these differentially expressed genes are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway and cell cycle. sACE was found to play an important role in SSC self-renewal via the regulation of MAPK-dependent cell proliferation.

Angiotensin converting enzyme immobilized on magnetic beads as a tool for ligand fishing.

PubMed

de Almeida, Fernando G; Vanzolini, Kenia L; Cass, Quezia B

2017-01-05

Angiotensin converting enzyme (ACE) presents an important role in blood pressure regulation, since that converts angiotensin I to the vasoconstrictor angiotensin II. Some commercially available ACE inhibitors are captopril, lisinopril and enalapril; due to their side effects, naturally occurring inhibitors have been prospected. In order to endorse this research field we have developed a new tool for ACE ligand screening. To this end, ACE was extracted from bovine lung, purified and chemically immobilized in modified ferrite magnetic beads (ACE-MBs). The ACE-MBs have shown a Michaelian kinetic behavior towards hippuryl-histidyl-leucine. Moreover, as proof of concept, the ACE-MBs was inhibited by lisinopril with a half maximal inhibitory concentration (IC 50 ) of 10nM. At the fishing assay, ACE-MBs were able not only to fish out the reference inhibitor, but also one peptide from a pool of tryptic digested BSA. In conclusion, ACE-MBs emerge as new straightforward tool for ACE kinetics determination, inhibition and binder screening. Copyright © 2016 Elsevier B.V. All rights reserved.

Serine proteases as candidates for proteolytic processing of angiotensin-I converting enzyme.

PubMed

Aragão, Danielle S; de Andrade, Maria Claudina C; Ebihara, Fabiana; Watanabe, Ingrid K M; Magalhães, Dayane C B P; Juliano, Maria Aparecida; Hirata, Izaura Yoshico; Casarini, Dulce Elena

2015-01-01

Somatic angiotensin-I converting enzyme (sACE) is a broadly distributed peptidase which plays a role in blood pressure and electrolyte homeostasis by the conversion of angiotensin I into angiotensin II. N-domain isoforms (nACE) with 65 and 90 kDa have been described in body fluids, tissues and mesangial cells (MC), and a 90 kDa nACE has been described only in spontaneously hypertensive rats. The aim of this study was to investigate the existence of proteolytic enzymes that may act in the hydrolysis of sACE generating nACEs in MC. After the confirmation of the presence of ACE sheddases in Immortalized MC (IMC), we purified and characterized these enzymes using fluorogenic substrates specifically designed for ACE sheddases. Purified enzyme identified as a serine protease by N-terminal sequence was able to generate nACE. In the present study, we described for the first time the presence of ACE sheddases in IMC, identified as serine proteases able to hydrolyze sACE in vitro. Further investigations are necessary to elucidate the mechanisms responsible for the expression and regulation of ACE sheddases in MC and their roles in the generation of nACEs, especially the 90 kDa form possibly related to hypertension. Copyright © 2014 Elsevier B.V. All rights reserved.

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

PubMed Central

Ong, Frank S.; Blackwell, Wendell-Lamar B.; Shah, Kandarp H.; Giani, Jorge F.; Gonzalez-Villalobos, Romer A.; Shen, Xiao Z.; Fuchs, Sebastien

2013-01-01

Angiotensin-converting enzyme (ACE) is a zinc-dependent peptidase responsible for converting angiotensin I into the vasoconstrictor angiotensin II. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates. Because of this, ACE and its peptide substrates and products affect many physiologic processes, including blood pressure control, hematopoiesis, reproduction, renal development, renal function, and the immune response. The defining feature of ACE is that it is composed of two homologous and independently catalytic domains, the result of an ancient gene duplication, and ACE-like genes are widely distributed in nature. The two ACE catalytic domains contribute to the wide substrate diversity of ACE and, by extension, the physiologic impact of the enzyme. Several studies suggest that the two catalytic domains have different biologic functions. Recently, the X-ray crystal structure of ACE has elucidated some of the structural differences between the two ACE domains. This is important now that ACE domain-specific inhibitors have been synthesized and characterized. Once widely available, these reagents will undoubtedly be powerful tools for probing the physiologic actions of each ACE domain. In turn, this knowledge should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors. PMID:23257181

Unpacking the impact of adverse childhood experiences on adult mental health.

PubMed

Merrick, Melissa T; Ports, Katie A; Ford, Derek C; Afifi, Tracie O; Gershoff, Elizabeth T; Grogan-Kaylor, Andrew

2017-07-01

Exposure to childhood adversity has an impact on adult mental health, increasing the risk for depression and suicide. Associations between Adverse Childhood Experiences (ACEs) and several adult mental and behavioral health outcomes are well documented in the literature, establishing the need for prevention. The current study analyzes the relationship between an expanded ACE score that includes being spanked as a child and adult mental health outcomes by examining each ACE separately to determine the contribution of each ACE. Data were drawn from Wave II of the CDC-Kaiser ACE Study, consisting of 7465 adult members of Kaiser Permanente in southern California. Dichotomous variables corresponding to each of the 11 ACE categories were created, with ACE score ranging from 0 to 11 corresponding to the total number of ACEs experienced. Multiple logistic regression modeling was used to examine the relationship between ACEs and adult mental health outcomes adjusting for sociodemographic covariates. Results indicated a graded dose-response relationship between the expanded ACE score and the likelihood of moderate to heavy drinking, drug use, depressed affect, and suicide attempts in adulthood. In the adjusted models, being spanked as a child was significantly associated with all self-reported mental health outcomes. Over 80% of the sample reported exposure to at least one ACE, signifying the potential to capture experiences not previously considered by traditional ACE indices. The findings highlight the importance of examining both cumulative ACE scores and individual ACEs on adult health outcomes to better understand key risk and protective factors for future prevention efforts. Copyright © 2017. Published by Elsevier Ltd.

Acetylcholinesterase genes within the Diptera: takeover and loss in true flies

PubMed Central

Huchard, Elise; Martinez, Michel; Alout, Haoues; Douzery, Emmanuel J.P; Lutfalla, Georges; Berthomieu, Arnaud; Berticat, Claire; Raymond, Michel; Weill, Mylène

2006-01-01

It has recently been reported that the synaptic acetylcholinesterase (AChE) in mosquitoes is encoded by the ace-1 gene, distinct and divergent from the ace-2 gene, which performs this function in Drosophila. This is an unprecedented situation within the Diptera order because both ace genes derive from an old duplication and are present in most insects and arthropods. Nevertheless, Drosophila possesses only the ace-2 gene. Thus, a secondary loss occurred during the evolution of Diptera, implying a vital function switch from one gene (ace-1) to the other (ace-2). We sampled 78 species, representing 50 families (27% of the Dipteran families) spread over all major subdivisions of the Diptera, and looked for ace-1 and ace-2 by systematic PCR screening to determine which taxonomic groups within the Diptera have this gene change. We show that this loss probably extends to all true flies (or Cyclorrhapha), a large monophyletic group of the Diptera. We also show that ace-2 plays a non-detectable role in the synaptic AChE in a lower Diptera species, suggesting that it has non-synaptic functions. A relative molecular evolution rate test showed that the intensity of purifying selection on ace-2 sequences is constant across the Diptera, irrespective of the presence or absence of ace-1, confirming the evolutionary importance of non-synaptic functions for this gene. We discuss the evolutionary scenarios for the takeover of ace-2 and the loss of ace-1, taking into account our limited knowledge of non-synaptic functions of ace genes and some specific adaptations of true flies. PMID:17002944

Zebrafish aussicht mutant embryos exhibit widespread overexpression of ace (fgf8) and coincident defects in CNS development.

PubMed

Heisenberg, C P; Brennan, C; Wilson, S W

1999-05-01

During the development of the zebrafish nervous system both noi, a zebrafish pax2 homolog, and ace, a zebrafish fgf8 homolog, are required for development of the midbrain and cerebellum. Here we describe a dominant mutation, aussicht (aus), in which the expression of noi and ace is upregulated. In aus mutant embryos, ace is upregulated at many sites in the embryo, while noi expression is only upregulated in regions of the forebrain and midbrain which also express ace. Subsequent to the alterations in noi and ace expression, aus mutants exhibit defects in the differentiation of the forebrain, midbrain and eyes. Within the forebrain, the formation of the anterior and postoptic commissures is delayed and the expression of markers within the pretectal area is reduced. Within the midbrain, En and wnt1 expression is expanded. In heterozygous aus embryos, there is ectopic outgrowth of neural retina in the temporal half of the eyes, whereas in putative homozygous aus embryos, the ventral retina is reduced and the pigmented retinal epithelium is expanded towards the midline. The observation that aus mutant embryos exhibit widespread upregulation of ace raised the possibility that aus might represent an allele of the ace gene itself. However, by crossing carriers for both aus and ace, we were able to generate homozygous ace mutant embryos that also exhibited the aus phenotype. This indicated that aus is not tightly linked to ace and is unlikely to be a mutation directly affecting the ace locus. However, increased Ace activity may underly many aspects of the aus phenotype and we show that the upregulation of noi in the forebrain of aus mutants is partially dependent upon functional Ace activity. Conversely, increased ace expression in the forebrain of aus mutants is not dependent upon functional Noi activity. We conclude that aus represents a mutation involving a locus normally required for the regulation of ace expression during embryogenesis.

Association of Urinary N-Domain Angiotensin I-Converting Enzyme with Plasma Inflammatory Markers and Endothelial Function

PubMed Central

Fernandes, Fernanda B; Plavnik, Frida L; Teixeira, Andressa MS; Christofalo, Dejaldo MJ; Ajzen, Sergio A; Higa, Elisa MS; Ronchi, Fernanda A; Sesso, Ricardo CC; Casarini, Dulce E

2008-01-01

The aim of this study was to investigate the association between urinary 90 kDa N-domain Angiotensin I-converting enzyme (ACE) form with C-reactive protein (CRP) and homocysteine plasma levels (Hcy), urinary nitric oxide (NOu), and endothelial function (EF) in normotensive subjects. Forty healthy subjects were evaluated through brachial Doppler US to test the response to reactive hyperemia and a panel of blood tests to determine CRP and Hcy levels, NOu, and urinary ACE. They were divided into groups according to the presence (ACE90+) or absence (ACE90–) of the 90 kDa ACE, the presence (FH+) or absence (FH–) of family history of hypertension, and the presence or absence of these two variables FH+/ACE90+ and FH–/ACE90–. We found an impaired endothelial dilatation in subjects who presented the 90 kDa N-domain ACE as follows: 11.4% ± 5.3% in ACE90+ compared with 17.6% ± 7.1% in ACE90– group and 12.4% ± 5.6% in FH+/ACE90+ compared with 17.7% ± 6.2% in FH–/ACE90– group, P < 0.05. Hcy and CRP levels were statistically significantly lower in FH+/ACE90+ than in FH–/ACE90– group, as follows: 10.0 ± 2.3 μM compared with 12.7 ± 1.5 μM, and 1.3 ± 1.8 mg/L compared with 3.6 ± 2.0 mg/L, respectively. A correlation between flow-mediated dilatation (FMD) and CRP, Hcy, and NOu levels was not found. Our study suggests a reduction in the basal NO production confirmed by NOu analysis in subjects with the 90 kDa N-domain ACE isoform alone or associated with a family history of hypertension. Our data suggest that the presence of the 90 kDa N-domain ACE itself may have a negative impact on flow-mediated dilatation stimulated by reactive hyperemia. PMID:18475311

New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) III: Endogenous Inhibition of Angiotensin Converting Enzyme (ACE) Provides Protection against Cardiovascular Diseases

PubMed Central

Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Édes, István; Papp, Zoltán; Tóth, Attila

2014-01-01

ACE inhibitor drugs decrease mortality by up to one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors. Here we investigated the clinical significance of this potential endogenous ACE inhibition. ACE concentration and activity was measured in patient's serum samples (n = 151). ACE concentration was found to be in a wide range (47–288 ng/mL). ACE activity decreased with the increasing concentration of the serum albumin (HSA): ACE activity was 56±1 U/L in the presence of 2.4±0.3 mg/mL HSA, compared to 39±1 U/L in the presence of 12±1 mg/mL HSA (values are mean±SEM). Effects of the differences in ACE concentration were suppressed in human sera: patients with ACE DD genotype exhibited a 64% higher serum ACE concentration (range, 74–288 ng/mL, median, 155.2 ng/mL, n = 52) compared to patients with II genotype (range, 47–194 ng/mL, median, 94.5 ng/mL, n = 28) while the difference in ACE activities was only 32% (range, 27.3–59.8 U/L, median, 43.11 U/L, and range 15.6–55.4 U/L, median, 32.74 U/L, respectively) in the presence of 12±1 mg/mL HSA. No correlations were found between serum ACE concentration (or genotype) and cardiovascular diseases, in accordance with the proposed suppressed physiological ACE activities by HSA (concentration in the sera of these patients: 48.5±0.5 mg/mL) or other endogenous inhibitors. Main implications are that (1) physiological ACE activity can be stabilized at a low level by endogenous ACE inhibitors, such as HSA; (2) angiotensin II elimination may have a significant role in angiotensin II related pathologies. PMID:24690767

Angiotensin I-converting enzyme Gln1069Arg mutation impairs trafficking to the cell surface resulting in selective denaturation of the C-domain.

PubMed

Danilov, Sergei M; Kalinin, Sergey; Chen, Zhenlong; Vinokour, Elena I; Nesterovitch, Andrew B; Schwartz, David E; Gribouval, Olivier; Gubler, Marie-Claire; Minshall, Richard D

2010-05-03

Angiotensin-converting enzyme (ACE; Kininase II; CD143) hydrolyzes small peptides such as angiotensin I, bradykinin, substance P, LH-RH and several others and thus plays a key role in blood pressure regulation and vascular remodeling. Complete absence of ACE in humans leads to renal tubular dysgenesis (RTD), a severe disorder of renal tubule development characterized by persistent fetal anuria and perinatal death. Patient with RTD in Lisbon, Portugal, maintained by peritoneal dialysis since birth, was found to have a homozygous substitution of Arg for Glu at position 1069 in the C-terminal domain of ACE (Q1069R) resulting in absence of plasma ACE activity; both parents and a brother who are heterozygous carriers of this mutation had exactly half-normal plasma ACE activity compared to healthy individuals. We hypothesized that the Q1069R substitution impaired ACE trafficking to the cell surface and led to accumulation of catalytically inactive ACE in the cell cytoplasm. CHO cells expressing wild-type (WT) vs. Q1069R-ACE demonstrated the mutant accumulates intracellularly and also that it is significantly degraded by intracellular proteases. Q1069R-ACE retained catalytic and immunological characteristics of WT-ACE N domain whereas it had 10-20% of the nativity of the WT-ACE C domain. A combination of chemical (sodium butyrate) or pharmacological (ACE inhibitor) chaperones with proteasome inhibitors (MG 132 or bortezomib) significantly restored trafficking of Q1069R-ACE to the cell surface and increased ACE activity in the cell culture media 4-fold. Homozygous Q1069R substitution results in an ACE trafficking and processing defect which can be rescued, at least in cell culture, by a combination of chaperones and proteasome inhibitors. Further studies are required to determine whether similar treatment of individuals with this ACE mutation would provide therapeutic benefits such as concentration of primary urine.

RNA-Seq of Bacillus licheniformis: active regulatory RNA features expressed within a productive fermentation.

PubMed

Wiegand, Sandra; Dietrich, Sascha; Hertel, Robert; Bongaerts, Johannes; Evers, Stefan; Volland, Sonja; Daniel, Rolf; Liesegang, Heiko

2013-10-01

The production of enzymes by an industrial strain requires a complex adaption of the bacterial metabolism to the conditions within the fermenter. Regulatory events within the process result in a dynamic change of the transcriptional activity of the genome. This complex network of genes is orchestrated by proteins as well as regulatory RNA elements. Here we present an RNA-Seq based study considering selected phases of an industry-oriented fermentation of Bacillus licheniformis. A detailed analysis of 20 strand-specific RNA-Seq datasets revealed a multitude of transcriptionally active genomic regions. 3314 RNA features encoded by such active loci have been identified and sorted into ten functional classes. The identified sequences include the expected RNA features like housekeeping sRNAs, metabolic riboswitches and RNA switches well known from studies on Bacillus subtilis as well as a multitude of completely new candidates for regulatory RNAs. An unexpectedly high number of 855 RNA features are encoded antisense to annotated protein and RNA genes, in addition to 461 independently transcribed small RNAs. These antisense transcripts contain molecules with a remarkable size range variation from 38 to 6348 base pairs in length. The genome of the type strain B. licheniformis DSM13 was completely reannotated using data obtained from RNA-Seq analyses and from public databases. The hereby generated data-sets represent a solid amount of knowledge on the dynamic transcriptional activities during the investigated fermentation stages. The identified regulatory elements enable research on the understanding and the optimization of crucial metabolic activities during a productive fermentation of Bacillus licheniformis strains.

RNA isolation from mammalian cells using porous polymer monoliths: an approach for high-throughput automation.

PubMed

Chatterjee, Anirban; Mirer, Paul L; Zaldivar Santamaria, Elvira; Klapperich, Catherine; Sharon, Andre; Sauer-Budge, Alexis F

2010-06-01

The life science and healthcare communities have been redefining the importance of ribonucleic acid (RNA) through the study of small molecule RNA (in RNAi/siRNA technologies), micro RNA (in cancer research and stem cell research), and mRNA (gene expression analysis for biologic drug targets). Research in this field increasingly requires efficient and high-throughput isolation techniques for RNA. Currently, several commercial kits are available for isolating RNA from cells. Although the quality and quantity of RNA yielded from these kits is sufficiently good for many purposes, limitations exist in terms of extraction efficiency from small cell populations and the ability to automate the extraction process. Traditionally, automating a process decreases the cost and personnel time while simultaneously increasing the throughput and reproducibility. As the RNA field matures, new methods for automating its extraction, especially from low cell numbers and in high throughput, are needed to achieve these improvements. The technology presented in this article is a step toward this goal. The method is based on a solid-phase extraction technology using a porous polymer monolith (PPM). A novel cell lysis approach and a larger binding surface throughout the PPM extraction column ensure a high yield from small starting samples, increasing sensitivity and reducing indirect costs in cell culture and sample storage. The method ensures a fast and simple procedure for RNA isolation from eukaryotic cells, with a high yield both in terms of quality and quantity. The technique is amenable to automation and streamlined workflow integration, with possible miniaturization of the sample handling process making it suitable for high-throughput applications.

Structural Sizing of a Horizontal Take-Off Launch Vehicle with an Air Collection and Enrichment System

NASA Technical Reports Server (NTRS)

McCurdy, David R.; Roche, Joseph M.

2004-01-01

In support of NASA's Next Generation Launch Technology (NGLT) program, the Andrews Gryphon booster was studied. The Andrews Gryphon concept is a horizontal lift-off, two-stage-to-orbit, reusable launch vehicle that uses an air collection and enrichment system (ACES). The purpose of the ACES is to collect atmospheric oxygen during a subsonic flight loiter phase and cool it to cryogenic temperature, ultimately resulting in a reduced initial take-off weight To study the performance and size of an air-collection based booster, an initial airplane like shape was established as a baseline and modeled in a vehicle sizing code. The code, SIZER, contains a general series of volume, surface area, and fuel fraction relationships that tie engine and ACES performance with propellant requirements and volumetric constraints in order to establish vehicle closure for the given mission. A key element of system level weight optimization is the use of the SIZER program that provides rapid convergence and a great deal of flexibility for different tank architectures and material suites in order to study their impact on gross lift-off weight. This paper discusses important elements of the sizing code architecture followed by highlights of the baseline booster study.

Presence of angiotensin converting enzyme isoforms in larval lepidoptera (Spodoptera littoralis).

PubMed

Lemeire, E; Van Camp, J; Smagghe, G

2007-01-01

In this research the presence of angiotensin converting enzyme (ACE) in larvae of the lepidopteran Spodoptera littoralis was evaluated. Making use of the substrate Abz-FRK-(Dnp)P-OH and the specific inhibitor captopril at 10 microM, ACE activity was determined in a fluorescence assay for intact larvae, hemolymph, head, midgut and dorsal tissue. In dorsal tissue and hemolymph, ACE activity was highest. These data are consistent with a possible role for ACE in contractions of the dorsal vessel and metabolism of circulating peptide hormones in the hemolymph. After the presence of ACE was confirmed, a sequential procedure of anion exchange and size exclusion chromatography was applied to purify ACE from whole wandering larvae (last stage). With this procedure, three different ACE pools were collected that cleaved the fluorogenic substrate Abz-FRK-(Dnp)P-OH. Activity could be inhibited by a final concentration of 2.5 microM captopril. In addition, two out of three samples eluted at different salt concentration and thus ACE 1, 2 and 3 represent at least two different ACE isoforms. These data reveal that ACE is present in S. littoralis and that at least two out of three isolated ACE forms are truly isoforms.

ACE insertion/deletion polymorphism and submaximal exercise hemodynamics in postmenopausal women.

PubMed

Hagberg, James M; McCole, Steve D; Brown, Michael D; Ferrell, Robert E; Wilund, Kenneth R; Huberty, Andrea; Douglass, Larry W; Moore, Geoffrey E

2002-03-01

We sought to determine whether the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism is associated with submaximal exercise cardiovascular hemodynamics. Postmenopausal healthy women (20 sedentary, 20 physically active, 22 endurance athletes) had cardiac output (acetylene rebreathing) measured during 40, 60, and 80% VO(2 max) exercise. The interaction of ACE genotype and habitual physical activity (PA) level was significantly associated with submaximal exercise systolic blood pressure, with only sedentary women exhibiting differences among genotypes. No significant effects of ACE genotype or its interaction with PA levels was observed for submaximal exercise diastolic blood pressure. ACE genotype was significantly associated with submaximal exercise heart rate (HR) with ACE II having approximately 10 beats/min higher HR than ACE ID/DD genotype women. ACE genotype did not interact significantly with habitual PA level to associate with submaximal exercise HR. ACE genotype was not independently, but was interactively with habitual PA levels, associated with differences in submaximal exercise cardiac output and stroke volume. For cardiac output, ACE II genotype women athletes had ~25% greater cardiac output than ACE DD genotype women athletes, whereas for stroke volume genotype-dependent differences were observed in both the physically active and athletic women. ACE genotype was not significantly associated, either independently or interactively with habitual PA levels, with submaximal exercise total peripheral resistance or arteriovenous O(2) difference. Thus the common ACE locus polymorphic variation is associated with many submaximal exercise cardiovascular hemodynamic responses.

How long will I have my ACE? The natural history of the antegrade continence enema stoma in idiopathic constipation.

PubMed

Khoo, A Kate; Askouni, Evita; Basson, Sonia; Ng, Jessica; Cleeve, Stewart

2017-11-01

We aim to determine the natural history of the ACE in idiopathic constipation and factors predictive of closure. A retrospective case-note review of all patients undergo ACE formation for idiopathic constipation Jan 2003-Mar 2016. Kaplan-Meier analysis was used to determine ACE survival and Cox's proportional hazard models to examine potential predictors of closure. 29/84 (35%) ACEs were closed: 21/84 due to success and 8/84 due to failure. Median age of closure was 15.5 years (3.5-23.6). Median ACE survival was 77.0 months (95% CI 58.0-96.0). An ACE survival curve was derived from which we estimate that 5-year post-ACE, one-third of patients can expect to have had their ACE closed. Younger age at ACE was predictive of earlier closure (p = 0.023) and closure for success (p < 0.001). Neither patient sex (p = 0.546) nor presence of psychological comorbidities (p = 0.769) predicted likelihood of closure. Incontinence 6-week post-ACE was also associated with increased likelihood of closure (p = 0.042). The ACE survival curve estimates the proportion of patients with idiopathic constipation who can expect closure (either due to success or failure) at certain timepoints. This may be useful for patient counseling. Younger age at ACE was associated with earlier closure (for success).

Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE - a molecular basis for domain selectivity.

PubMed

Cozier, Gyles E; Schwager, Sylva L; Sharma, Rajni K; Chibale, Kelly; Sturrock, Edward D; Acharya, K Ravi

2018-04-01

Angiotensin-1-converting enzyme (ACE) is a zinc metallopeptidase that consists of two homologous catalytic domains (known as nACE and cACE) with different substrate specificities. Based on kinetic studies it was previously reported that sampatrilat, a tight-binding inhibitor of ACE, K i = 13.8 nm and 171.9 nm for cACE and nACE respectively [Sharma et al., Journal of Chemical Information and Modeling (2016), 56, 2486-2494], was 12.4-fold more selective for cACE. In addition, samAsp, in which an aspartate group replaces the sampatrilat lysine, was found to be a nonspecific and lower micromolar affinity inhibitor. Here, we report a detailed three-dimensional structural analysis of sampatrilat and samAsp binding to ACE using high-resolution crystal structures elucidated by X-ray crystallography, which provides a molecular basis for differences in inhibitor affinity and selectivity for nACE and cACE. The structures show that the specificity of sampatrilat can be explained by increased hydrophobic interactions and a H-bond from Glu403 of cACE with the lysine side chain of sampatrilat that are not observed in nACE. In addition, the structures clearly show a significantly greater number of hydrophilic and hydrophobic interactions with sampatrilat compared to samAsp in both cACE and nACE consistent with the difference in affinities. Our findings provide new experimental insights into ligand binding at the active site pockets that are important for the design of highly specific domain selective inhibitors of ACE. The atomic coordinates and structure factors for N- and C-domains of ACE bound to sampatrilat and sampatrilat-Asp complexes (6F9V, 6F9R, 6F9T and 6F9U respectively) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/). © 2018 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

[Conformational Fingerprinting Using Monoclonal Antibodies
(on the Example of Angiotensin I-Converting Enzyme-ACE)].

PubMed

Danilov, S M

2017-01-01

During the past 30 years my laboratory has generated 40+ monoclonal antibodies (mAbs) directed to structural and conformational epitopes on human ACE as well as ACE from rats, mice and other species. These mAbs were successfully used for detection and quantification of ACE by ELISA, Western blotting, flow cytometry and immunohistochemistry. In all these applications mainly single mAbs were used. We hypothesized that we can obtain a completely new kind of information about ACE structure and function if we use the whole set of mAbs directed to different epitopes on the ACE molecule. When we finished epitope mapping of all mAbs to ACE (and especially, those recognizing conformational epitopes), we realized that we had obtained a new tool to study ACE. First, we demonstrated that binding of some mAbs is very sensitive to local conformational changes on the ACE surface-due to local denaturation, inactivation, ACE inhibitor or mAbs binding or due to diseases. Second, we were able to detect, localize and characterize several human ACE mutations. And, finally, we established a new concept - conformational fingerprinting of ACE using mAbs that in turn allowed us to obtain evidence for tissue specificity of ACE, which has promising scientific and diagnostic perspectives. The initial goal for the generation of mAbs to ACE 30 years ago was obtaining mAbs to organ-specific endothelial cells, which could be used for organ-specific drug delivery. Our systematic work on characterization of mAbs to numerous epitopes on ACE during these years has lead not only to the generation of the most effective mAbs for specific drug/gene delivery into the lung capillaries, but also to the establishment of the concept of conformational fingerprinting of ACE, which in turn gives a theoretical base for the generation of mAbs, specific for ACE from different organs. We believe that this concept could be applicable for any glycoprotein against which there is a set of mAbs to different epitopes.

Lest we forget: comparing retrospective and prospective assessments of adverse childhood experiences in the prediction of adult health.

PubMed

Reuben, Aaron; Moffitt, Terrie E; Caspi, Avshalom; Belsky, Daniel W; Harrington, Honalee; Schroeder, Felix; Hogan, Sean; Ramrakha, Sandhya; Poulton, Richie; Danese, Andrea

2016-10-01

Adverse childhood experiences (ACEs; e.g. abuse, neglect, and parental loss) have been associated with increased risk for later-life disease and dysfunction using adults' retrospective self-reports of ACEs. Research should test whether associations between ACEs and health outcomes are the same for prospective and retrospective ACE measures. We estimated agreement between ACEs prospectively recorded throughout childhood (by Study staff at Study member ages 3, 5, 7, 9, 11, 13, and 15) and retrospectively recalled in adulthood (by Study members when they reached age 38), in the population-representative Dunedin cohort (N = 1,037). We related both retrospective and prospective ACE measures to physical, mental, cognitive, and social health at midlife measured through both objective (e.g. biomarkers and neuropsychological tests) and subjective (e.g. self-reported) means. Dunedin and U.S. Centers for Disease Control ACE distributions were similar. Retrospective and prospective measures of adversity showed moderate agreement (r = .47, p < .001; weighted Kappa = .31, 95% CI: .27-.35). Both associated with all midlife outcomes. As compared to prospective ACEs, retrospective ACEs showed stronger associations with life outcomes that were subjectively assessed, and weaker associations with life outcomes that were objectively assessed. Recalled ACEs and poor subjective outcomes were correlated regardless of whether prospectively recorded ACEs were evident. Individuals who recalled more ACEs than had been prospectively recorded were more neurotic than average, and individuals who recalled fewer ACEs than recorded were more agreeable. Prospective ACE records confirm associations between childhood adversity and negative life outcomes found previously using retrospective ACE reports. However, more agreeable and neurotic dispositions may, respectively, bias retrospective ACE measures toward underestimating the impact of adversity on objectively measured life outcomes and overestimating the impact of adversity on self-reported outcomes. Associations between personality factors and the propensity to recall adversity were extremely modest and warrant further investigation. Risk predictions based on retrospective ACE reports should utilize objective outcome measures. Where objective outcome measurements are difficult to obtain, correction factors may be warranted. © 2016 Association for Child and Adolescent Mental Health.

Lest we forget: Comparing retrospective and prospective assessments of adverse childhood experiences in the prediction of adult health

PubMed Central

Reuben, Aaron; Moffitt, Terrie E.; Caspi, Avshalom; Belsky, Daniel W.; Harrington, Honalee; Schroeder, Felix; Hogan, Sean; Ramrakha, Sandhya; Poulton, Richie; Danese, Andrea

2017-01-01

Background Adverse childhood experiences (ACEs; e.g., abuse, neglect, parental loss, etc.) have been associated with increased risk for later-life disease and dysfunction using adults’ retrospective self-reports of ACEs. Research should test whether associations between ACEs and health outcomes are the same for prospective and retrospective ACE measures. Methods We estimated agreement between ACEs prospectively-recorded throughout childhood (by Study staff at Study member ages 3, 5, 7, 9, 11, 13, and 15) and retrospectively-recalled in adulthood (by Study members when they reached age 38), in the population-representative Dunedin cohort (N=1,037). We related both retrospective and prospective ACE measures to physical, mental, cognitive, and social health at midlife measured through both objective (e.g., biomarkers and neuropsychological tests) and subjective (e.g., self-reported) means. Results Dunedin and CDC ACE distributions were similar. Retrospective and prospective measures of adversity showed moderate agreement (r=.47, p<.001; weighted Kappa = .31, 95% CI: .27–.35). Both associated with all midlife outcomes. As compared to prospective ACEs, retrospective ACEs showed stronger associations with life outcomes that were subjectively assessed, and weaker associations with life outcomes that were objectively assessed. Recalled ACEs and poor subjective outcomes were correlated regardless of whether prospectively-recorded ACEs were evident. Individuals who recalled more ACEs than had been prospectively recorded were more neurotic than average, and individuals who recalled fewer ACEs than recorded were more agreeable. Conclusions Prospective ACE records confirm associations between childhood adversity and negative life outcomes found previously using retrospective ACE reports. However, more agreeable and neurotic dispositions may respectively bias retrospective ACE measures toward underestimating the impact of adversity on objectively-measured life outcomes and overestimating the impact of adversity on self-reported outcomes. Associations between personality factors and the propensity to recall adversity were extremely modest and warrant further investigation. Risk predictions based on retrospective ACE reports should utilize objective outcome measures. Where objective outcome measurements are difficult to obtain, correction factors may be warranted. PMID:27647050

Adverse Childhood Experiences and Health in Adulthood in a Rural Population-Based Sample

PubMed Central

Iniguez, Kristen C.; Stankowski, Rachel V.

2016-01-01

Background Adverse childhood experiences (ACEs), including emotional abuse, substance abuse in the household, separation or divorce, physical abuse, violence between adults, mental illness in the household, sexual abuse, or incarceration of a household member, have the potential to profoundly impact health and well-being in adulthood. To assess whether previously reported relationships between ACEs and health outcomes withstand validation, we conducted a community-based ACE study with the unique capacity to link self-reported ACEs and other survey results to validated health data in an electronic medical record (EMR). Methods Information regarding ACEs and health outcomes was captured from 2013–2014 via a telephone survey of residents of the predominantly rural northern and central regions of Wisconsin and electronic abstraction of EMR data. ACE score was calculated by counting each exposure as one point. We examined the relationship between ACE score, type, and self-reported and validated health outcomes. Results A total of 800 participants completed the telephone survey. Overall, 62% reported at least one ACE and 15% reported experiencing four or more. All self-reported measures of poor health were associated with increased ACE score. EMR data were positively correlated with ACE score for increased body mass index and diagnoses of depression, anxiety, and asthma. In contrast, diagnoses of hypertension, hypercholesterolemia, myocardial infarction, and skin and other cancers were inversely related to ACE score. Emotional abuse was the most common ACE reported followed by substance abuse in the household. ACEs tended to cluster so that people who reported at least one ACE were likely to have experienced multiple ACEs. There was no clear correlation between abuse type (e.g., direct abuse vs. household dysfunction) and health outcomes. Conclusions In the first community-based study to link self-reported ACEs to comprehensive health measures documented in the medical record, we observed previously reported associations between childhood adversity and poor outcomes in adulthood, but also noted an inverse relationship between ACE score and certain medical diagnoses. Potential explanations for this finding warrant further investigation. PMID:27503793

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 achieves this using thrusters oriented in line with the solar direction. WIND achieves the delta-V via pulsing radial thrusters when aligned with the Sun. ACE uses axial thrusters to apply delta-V with a component that is 94% or more aligned with the ACE-Sun line. Sunward thrust adds energy to the orbit preventing decay back toward Earth. Thrust directed anti-Sunward takes energy out of the L1 orbit, thereby preventing escape from the Earth-Moon system into independent heliocentric orbit. Libration point orbit stationkeeping delta-V costs grow exponentially with time elapsed from the last maneuver performed. The doubling time constant is approximately 16 days. For the sake of fuel conservation, and for limiting the absolute magnitude of propulsion performance errors, stationkeeping maneuvers should be performed before the delta-V grows too large; for our purposes 'too large' is considered to be greater than 0.5 m/sec. In practice, the typical interval between burns for this trio is about three months, and the typical delta-V is much smaller than 0.5 m/sec. Typical annual stationkeeping costs have been around 1.0 m/sec for ACE and WIND, and much less than that for SOHO. All three spacecraft have ample fuel remaining; barring contingencies all three could, in principle, be maintained at L1 for decades to come. This paper will review the L1 orbits and the mission history of ACE, WIND, and SOHO, and describe the stationkeeping techniques and orbit maneuver experience. The Lissajous phase control that was practiced for ACE during the period from 1999 to 2001 will also be briefly discussed. The final section will consider the future of these ongoing missions.

LC-MS/MS analysis of metformin, saxagliptin and 5-hydroxy saxagliptin in human plasma and its pharmacokinetic study with a fixed-dose formulation in healthy Indian subjects.

PubMed

Shah, Priyanka A; Shah, Jaivik V; Sanyal, Mallika; Shrivastav, Pranav S

2017-03-01

A specific and rapid liquid chromatography-tandem mass spectrometry method is proposed for the simultaneous determination of metformin (MET), saxagliptin (SAXA) and its active metabolite, 5-hydroxy saxagliptin (5-OH SAXA) in human plasma. Sample preparation was accomplished from 50 μL plasma sample by solid-phase extraction using sodium dodecyl sulfate as an ion-pair reagent. Reversed-phase chromatographic resolution of analytes was possible within 3.5 min on ACE 5CN (150 × 4.6 mm, 5 μm) column using acetonitrile and10.0 mm ammonium formate buffer, pH 5.0 (80:20, v/v) as the mobile phase. Triple quadrupole mass spectrometric detection was performed using electrospray ionization in the positive ionization mode. The calibration curves showed good linearity (r 2  ≥ 0.9992) over the established concentration range with limit of quantification of 1.50, 0.10 and 0.20 ng/mL for MET, SAXA and 5-OH SAXA respectively. The extraction recoveries obtained from spiked plasma samples were highly consistent for MET (75.12-77.84%), SAXA (85.90-87.84%) and 5-OH SAXA (80.32-82.69%) across quality controls. The validated method was successfully applied to a bioequivalence study with a fixed-dose formulation consisting of 5 mg SAXA and 500 mg MET in 18 healthy subjects. The reproducibility of the assay was demonstrated by reanalysis of 87 incurred samples. Copyright © 2016 John Wiley & Sons, Ltd.

Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn; Zhang, Dong-Mei; Yu, Xiao-Jing

The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiacmore » atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE attenuates ANG II-induced hypertension and cardiac hypertrophy. • PVN inhibition of ACE attenuates ANG II-induced imbalance of PVN neurotransmitters. • PVN inhibition of ACE attenuates ANG II-induced imbalance of cytokines in the PVN. • PVN blockade of AT1-R attenuates ANG II-induced imbalance of cytokines in the PVN.« less

Phosphoryl Guanidines: A New Type of Nucleic Acid Analogues

PubMed Central

Kupryushkin, M. S.; Pyshnyi, D. V.; Stetsenko, D. A.

2014-01-01

A new type of nucleic acid analogues with a phosphoryl guanidine group is described. Oxidation of polymer-supported dinucleoside 2-cyanoethyl phosphite by iodine in the presence of 1,1,3,3-tetramethyl guanidine yields a dinucleotide with an internucleoside tetramethyl phosphoryl guanidine (Tmg) group as the main product. The Tmg group is stable under conditions of solid-phase DNA synthesis and subsequent cleavage and deprotection with ammonia. Oligonucleotides with one or more Tmg groups bind their complementary DNA or RNA with affinity similar to that of natural oligodeoxyribonucleotides. PMID:25558402

New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) I: Endogenous Angiotensin Converting Enzyme (ACE) Inhibition

PubMed Central

Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Édes, István; Papp, Zoltán; Tóth, Attila

2014-01-01

Angiotensin-converting enzyme (ACE) inhibitors represent the fifth most often prescribed drugs. ACE inhibitors decrease 5-year mortality by approximately one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors, which endogenous inhibitory effects are much less characterized than that for the clinically administered ACE inhibitors. Here we aimed to investigate this endogenous ACE inhibition in human sera. It was hypothesized that ACE activity is masked by an endogenous inhibitor, which dissociates from the ACE when its concentration decreases upon dilution. ACE activity was measured by FAPGG hydrolysis first. The specific (dilution corrected) enzyme activities significantly increased by dilution of human serum samples (23.2±0.7 U/L at 4-fold dilution, 51.4±0.3 U/L at 32-fold dilution, n = 3, p = 0.001), suggesting the presence of an endogenous inhibitor. In accordance, specific enzyme activities did not changed by dilution when purified renal ACE was used, where no endogenous inhibitor was present (655±145 U/L, 605±42 U/L, n = 3, p = 0.715, respectively). FAPGG conversion strongly correlated with angiotensin I conversion suggesting that this feature is not related to the artificial substrate. Serum samples were ultra-filtered to separate ACE (MW: 180 kDa) and the hypothesized inhibitor. Filtering through 50 kDa filters was without effect, while filtering through 100 kDa filters eliminated the inhibiting factor (ACE activity after <100 kDa filtering: 56.4±2.4 U/L, n = 4, control: 26.4±0.7 U/L, n = 4, p<0.001). Lineweaver-Burk plot indicated non-competitive inhibition of ACE by this endogenous factor. The endogenous inhibitor had higher potency on the C-terminal active site than N-terminal active site of ACE. Finally, this endogenous ACE inhibition was also present in mouse, donkey, goat, bovine sera besides men (increasing of specific ACE activity from 4-fold to 32-fold dilution: 2.8-fold, 1.7-fold, 1.5-fold, 1.8-fold, 2.6-fold, respectively). We report here the existence of an evolutionary conserved mechanism suppressing circulating ACE activity, in vivo, similarly to ACE inhibitory drugs. PMID:24691160

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

Associations Between Adverse Childhood Experiences and ADHD Diagnosis and Severity.

PubMed

Brown, Nicole M; Brown, Suzette N; Briggs, Rahil D; Germán, Miguelina; Belamarich, Peter F; Oyeku, Suzette O

Although identifying adverse childhood experiences (ACEs) among children with behavioral disorders is an important step in providing targeted therapy and support, little is known about the burden of ACEs among children with attention deficit-hyperactivity disorder (ADHD). We described the prevalence of ACEs in children with and without ADHD, and examined associations between ACE type, ACE score, and ADHD diagnosis and severity. Using the 2011 to 2012 National Survey of Children's Health, we identified children aged 4 to 17 years whose parents indicated presence and severity of ADHD, and their child's exposure to 9 ACEs. Multivariate logistic regression was used to estimate associations between ACEs, ACE score, and parent-reported ADHD and ADHD severity, adjusted for sociodemographic characteristics. In our sample (N = 76,227, representing 58,029,495 children), children with ADHD had a higher prevalence of each ACE compared with children without ADHD. Children who experienced socioeconomic hardship (adjusted odds ratio [aOR], 1.39; 95% confidence interval [CI], 1.21-1.59), divorce (aOR, 1.34; 95% CI, 1.16-1.55), familial mental illness (aOR, 1.55; 95% CI, 1.26-1.90), neighborhood violence (aOR, 1.47; 95% CI, 1.23-1.75), and incarceration (aOR, 1.39; 95% CI, 1.12-1.72) were more likely to have ADHD. A graded relationship was observed between ACE score and ADHD. Children with ACE scores of 2, 3, and ≥4 were significantly more likely to have moderate to severe ADHD. Children with ADHD have higher ACE exposure compared with children without ADHD. There was a significant association between ACE score, ADHD, and moderate to severe ADHD. Efforts to improve ADHD assessment and management should consider routinely evaluating for ACEs. Copyright © 2016 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

The ACE2 gene: its potential as a functional candidate for cardiovascular disease.

PubMed

Burrell, Louise M; Harrap, Stephen B; Velkoska, Elena; Patel, Sheila K

2013-01-01

The RAS (renin-angiotensin system) plays an important role in the pathophysiology of CVD (cardiovascular disease), and RAS blockade is an important therapeutic strategy in the management of CVD. A new counterbalancing arm of the RAS is now known to exist in which ACE (angiotensin-converting enzyme) 2 degrades Ang (angiotensin) II, the main effector of the classic RAS, and generates Ang-(1-7). Altered ACE2 expression is associated with cardiac and vascular disease in experimental models of CVD, and ACE2 is increased in failing human hearts and atherosclerotic vessels. In man, circulating ACE2 activity increases with coronary heart disease, as well as heart failure, and a large proportion of the variation in plasma ACE2 levels has been attributed to hereditary factors. The ACE2 gene maps to chromosome Xp22 and this paper reviews the evidence associating ACE2 gene variation with CVD and considers clues to potential functional ACE2 variants that may alter gene expression or transcriptional activity. Studies to date have investigated ACE2 gene associations in hypertension, left ventricular hypertrophy and coronary artery disease, but the results have been inconsistent. The discrepancies may reflect the sample size of the studies, the gender or ethnicity of subjects, the cardiovascular phenotype or the ACE2 SNP investigated. The frequent observation of apparent sex-dependence might be of special importance, if confirmed. As yet, there are no studies to concurrently assess ACE2 gene polymorphisms and circulating ACE2 activity. Large-scale carefully conducted clinical studies are urgently needed to clarify more precisely the potential role of ACE2 in the CVD continuum.

Gonadectomy prevents the increase in blood pressure and glomerular injury in angiotensin-converting enzyme 2 knockout diabetic male mice. Effects on renin-angiotensin system.

PubMed

Clotet, Sergi; Soler, María José; Rebull, Marta; Gimeno, Javier; Gurley, Susan B; Pascual, Julio; Riera, Marta

2016-09-01

Angiotensin-converting enzyme 2 (ACE2) deletion worsens kidney injury, and its amplification ameliorates diabetic nephropathy. Male sex increases the incidence, prevalence, and progression of chronic kidney disease in our environment. Here, we studied the effect of ACE2 deficiency and gonadectomy (GDX) on diabetic nephropathy and its relationship with fibrosis, protein kinase B (Akt) activation, and the expression of several components of the renin-angiotensin system (RAS).Mice were injected with streptozotocin to induce diabetes and followed for 19 weeks. Physiological and renal parameters were studied in wild-type and ACE2 knockout (ACE2KO) male mice with and without GDX. Diabetic ACE2KO showed increased blood pressure (BP), glomerular injury, and renal fibrosis compared with diabetic wild-type. Gonadectomized diabetic ACE2KO presented a decrease in BP. In the absence of ACE2, GDX attenuated albuminuria and renal lesions, such as mesangial matrix expansion and podocyte loss. Both, α-smooth muscle actin accumulation and collagen deposition were significantly decreased in renal cortex of gonadectomized diabetic ACE2KO but not diabetic wild-type mice. GDX also reduced circulating ACE activity in ACE2KO mice. Loss of ACE2 modified the effect of GDX on cortical gene expression of RAS in diabetic mice. Akt phosphorylation in renal cortex was increased by diabetes and loss of ACE2 and decreased by GDX in control and diabetic ACE2KO but not in wild-type mice. Our results suggest that GDX may exert a protective effect within the kidney under pathological conditions of diabetes and ACE2 deficiency. This renoprotection may be ascribed to different mechanisms such as decrease in BP, modulation of RAS, and downregulation of Akt-related pathways.

Angiotensin I-converting enzyme insertion/deletion polymorphism and adrenergic response to exercise in hypertensive patients.

PubMed

Jalil, Jorge E; Córdova, Samuel; Ocaranza, Marí a; Schumacher, Erwin; Braun, Sandra; Chamorro, Gastón; Fardella, Carlos; Lavandero, Sergio

2002-08-01

The insertion/deletion ACE polymorphism (ACE I/D) regulates different levels of circulating and tissue ACE activities, which may induce diverse adrenergic responses to physiological stimuli. The aim of this study was to evaluate the influence of the ACE I/D polymorphism on the adrenergic response to isotonic exercise in middle-aged hypertensive patients. Submaximal exercise (on a treadmill, using the Naughton protocol at 75% of maximal heart rate) was performed in 34 patients homozygous for the ACE I/D polymorphism (ACE II and ACE DD) with untreated essential hypertension (II = 19, DD = 15). Plasma venous adrenaline and noradrenaline were measured at rest and at submaximal exercise. Plasma ACE activity was significantly higher in the hypertensive patients carrying the ACE DD genotype compared with the ACE II group. Left atrium size, as well as LV dimensions, mass, and function, were similar in both groups. Total exercise time, baseline and 75% maximal heart rate (MHR) and blood pressure were similar in both groups. Baseline plasma adrenaline and noradrenaline levels were similar in both groups and increased significantly (p<0.05) by ca. 300% at submaximal exercise without differences between groups. The presence of the D allele on the ACE gene in middle-aged hypertensive patients determines higher circulating ACE activity but not increased sympathetic activity in response to submaximal exercise.

Ancylostoma ceylanicum Excretory-Secretory Protein 2 Adopts a Netrin-Like Fold and Defines a Novel Family of Nematode Proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

K Kucera; L Harrison; M Cappello

2011-12-31

Hookworms are human parasites that have devastating effects on global health, particularly in underdeveloped countries. Ancylostoma ceylanicum infects humans and animals, making it a useful model organism to study disease pathogenesis. A. ceylanicum excretory-secretory protein 2 (AceES-2), a highly immunoreactive molecule secreted by adult worms at the site of intestinal attachment, is partially protective when administered as a mucosal vaccine against hookworm anemia. The crystal structure of AceES-2 determined at 1.75 {angstrom} resolution shows that it adopts a netrin-like fold similar to that found in tissue inhibitors of matrix metalloproteases (TIMPs) and in complement factors C3 and C5. However, recombinantmore » AceES-2 does not significantly inhibit the 10 most abundant human matrix metalloproteases or complement-mediated cell lysis. The presence of a highly acidic surface on AceES-2 suggests that it may function as a cytokine decoy receptor. Several small nematode proteins that have been annotated as TIMPs or netrin-domain-containing proteins display sequence homology in structurally important regions of AceES-2's netrin-likefold. Together, our results suggest that AceES-2 defines a novel family of nematode netrin-like proteins, which may function to modulate the host immune response to hookworm and other parasites.« less

Digestive enzyme expression and epithelial structure of small intestine in neonatal rats after 16 days spaceflight

NASA Astrophysics Data System (ADS)

Miyake, M.; Yamasaki, M.; Hazama, A.; Ijiri, K.; Shimizu, T.

It is important to assure whether digestive system can develop normally in neonates during spaceflight. Because the small intestine changes its function and structure drastically around weaning known as redifferentiation. Lactase expression declines and sucrase increases in small intestine for digestion of solid food before weaning. In this paper, we compared this enzyme transition and structural development of small intestine in neonatal rats after spaceflight. To find digestive genes differentially expressed in fight rats, DNA membrane macroarray was also used. Eight-day old rats were loaded to Space Shuttle Columbia, and housed in the animal facility for 16 days in space (STS-90, Neurolab mission). Two control groups (AGC; asynchronous ground control and VIV; vivarium) against flight group (FLT) were prepared. There was no difference in structure (crypt depth) and cell differentiation of epithelium between FLT and AGC by immunohistochemical analysis. We found that the amount of sucrase mRNA compared to lactase was decreased in FLT by RT-PCR. It reflected the enzyme transition was inhibited. Increase of 5 genes (APO A-I, APO A-IV, ACE, aFABP and aminopeptidase M) and decrease of carboxypeptidase-D were detected in FLT using macroarray. We think nutrition differences (less nourishment and late weaning) during spaceflight may cause inhibition of enzyme transition at least partly. The weightlessness might contribute to the inhibition through behavioral change.

High-Throughput and Rapid Screening of Novel ACE Inhibitory Peptides from Sericin Source and Inhibition Mechanism by Using in Silico and in Vitro Prescriptions.

PubMed

Sun, Huaju; Chang, Qing; Liu, Long; Chai, Kungang; Lin, Guangyan; Huo, Qingling; Zhao, Zhenxia; Zhao, Zhongxing

2017-11-22

Several novel peptides with high ACE-I inhibitory activity were successfully screened from sericin hydrolysate (SH) by coupling in silico and in vitro approaches for the first time. Most screening processes for ACE-I inhibitory peptides were achieved through high-throughput in silico simulation followed by in vitro verification. QSAR model based predicted results indicated that the ACE-I inhibitory activity of these SH peptides and six chosen peptides exhibited moderate high ACE-I inhibitory activities (log IC 50 values: 1.63-2.34). Moreover, two tripeptides among the chosen six peptides were selected for ACE-I inhibition mechanism analysis which based on Lineweaver-Burk plots indicated that they behave as competitive ACE-I inhibitors. The C-terminal residues of short-chain peptides that contain more H-bond acceptor groups could easily form hydrogen bonds with ACE-I and have higher ACE-I inhibitory activity. Overall, sericin protein as a strong ACE-I inhibition source could be deemed a promising agent for antihypertension applications.

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.

Using whole mount in situ hybridization to link molecular and organismal biology.

PubMed

Jacobs, Nicole L; Albertson, R Craig; Wiles, Jason R

2011-03-31

Whole mount in situ hybridization (WISH) is a common technique in molecular biology laboratories used to study gene expression through the localization of specific mRNA transcripts within whole mount specimen. This technique (adapted from Albertson and Yelick, 2005) was used in an upper level undergraduate Comparative Vertebrate Biology laboratory classroom at Syracuse University. The first two thirds of the Comparative Vertebrate Biology lab course gave students the opportunity to study the embryology and gross anatomy of several organisms representing various chordate taxa primarily via traditional dissections and the use of models. The final portion of the course involved an innovative approach to teaching anatomy through observation of vertebrate development employing molecular techniques in which WISH was performed on zebrafish embryos. A heterozygous fibroblast growth factor 8 a (fgf8a) mutant line, ace, was used. Due to Mendelian inheritance, ace intercrosses produced wild type, heterozygous, and homozygous ace/fgf8a mutants in a 1:2:1 ratio. RNA probes with known expression patterns in the midline and in developing anatomical structures such as the heart, somites, tailbud, myotome, and brain were used. WISH was performed using zebrafish at the 13 somite and prim-6 stages, with students performing the staining reaction in class. The study of zebrafish embryos at different stages of development gave students the ability to observe how these anatomical structures changed over ontogeny. In addition, some ace/fgf8a mutants displayed improper heart looping, and defects in somite and brain development. The students in this lab observed the normal development of various organ systems using both external anatomy as well as gene expression patterns. They also identified and described embryos displaying improper anatomical development and gene expression (i.e., putative mutants). For instructors at institutions that do not already own the necessary equipment or where funds for lab and curricular innovation are limited, the financial cost of the reagents and apparatus may be a factor to consider, as will the time and effort required on the part of the instructor regardless of the setting. Nevertheless, we contend that the use of WISH in this type of classroom laboratory setting can provide an important link between developmental genetics and anatomy. As technology advances and the ability to study organismal development at the molecular level becomes easier, cheaper, and increasingly popular, many evolutionary biologists, ecologists, and physiologists are turning to research strategies in the field of molecular biology. Using WISH in a Comparative Vertebrate Biology laboratory classroom is one example of how molecules and anatomy can converge within a single course. This gives upper level college students the opportunity to practice modern biological research techniques, leading to a more diversified education and the promotion of future interdisciplinary scientific research.

Methods to Assess Adverse Childhood Experiences of Children and Families: Toward Approaches to Promote Child Well-being in Policy and Practice.

PubMed

Bethell, Christina D; Carle, Adam; Hudziak, James; Gombojav, Narangerel; Powers, Kathleen; Wade, Roy; Braveman, Paula

Advances in human development sciences point to tremendous possibilities to promote healthy child development and well-being across life by proactively supporting safe, stable and nurturing family relationships (SSNRs), teaching resilience, and intervening early to promote healing the trauma and stress associated with disruptions in SSNRs. Assessing potential disruptions in SSNRs, such as adverse childhood experiences (ACEs), can contribute to assessing risk for trauma and chronic and toxic stress. Asking about ACEs can help with efforts to prevent and attenuate negative impacts on child development and both child and family well-being. Many methods to assess ACEs exist but have not been compared. The National Survey of Children's Health (NSCH) now measures ACEs for children, but requires further assessment and validation. We identified and compared methods to assess ACEs among children and families, evaluated the acceptability and validity of the new NSCH-ACEs measure, and identified implications for assessing ACEs in research and practice. Of 14 ACEs assessment methods identified, 5 have been used in clinical settings (vs public health assessment or research) and all but 1 require self or parent report (3 allow child report). Across methods, 6 to 20 constructs are assessed, 4 of which are common to all: parental incarceration, domestic violence, household mental illness/suicide, household alcohol or substance abuse. Common additional content includes assessing exposure to neighborhood violence, bullying, discrimination, or parental death. All methods use a numeric, cumulative risk scoring methodology. The NSCH-ACEs measure was acceptable to respondents as evidenced by few missing values and no reduction in response rate attributable to asking about children's ACEs. The 9 ACEs assessed in the NSCH co-occur, with most children with 1 ACE having additional ACEs. This measure showed efficiency and confirmatory factor analysis as well as latent class analysis supported a cumulative risk scoring method. Formative as well as reflective measurement models further support cumulative risk scoring and provide evidence of predictive validity of the NSCH-ACEs. Common effects of ACEs across household income groups confirm information distinct from economic status is provided and suggest use of population-wide versus high-risk approaches to assessing ACEs. Although important variations exist, available ACEs measurement methods are similar and show consistent associations with poorer health outcomes in absence of protective factors and resilience. All methods reviewed appear to coincide with broader goals to facilitate health education, promote health and, where needed, to mitigate the trauma, chronic stress, and behavioral and emotional sequelae that can arise with exposure to ACEs. Assessing ACEs appears acceptable to individuals and families when conducted in population-based and clinical research contexts. Although research to date and neurobiological findings compel early identification and health education about ACEs in clinical settings, further research to guide use in pediatric practice is required, especially as it relates to distinguishing ACEs assessment from identifying current family psychosocial risks and child abuse. The reflective as well as formative psychometric analyses conducted in this study confirm use of cumulative risk scoring for the NSCH-ACEs measure. Even if children have not been exposed to ACEs, assessing ACEs has value as an educational tool for engaging and educating families and children about the importance of SSNRs and how to recognize and manage stress and learn resilience. Copyright © 2017 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

Reanalyzing Inferred High Energy Ionic Charge States for Solar Energetic Particle Events with ACE and STEREO

NASA Astrophysics Data System (ADS)

Labrador, A. W.; Sollitt, L. S.; Cohen, C.; Cummings, A. C.; Leske, R. A.; Mason, G. M.; Mewaldt, R. A.; Stone, E. C.; von Rosenvinge, T. T.; Wiedenbeck, M. E.

2017-12-01

We have estimated mean high-energy ionic charge states of solar energetic particles (SEPs) using the Sollitt et al. (2008) method. The method applies to abundant elements (e.g. N, O, Ne, Mg, Si, and Fe) in SEP events at the energy ranges covered by the STEREO/LET instrument (e.g. 2.7-70 MeV/nuc for Fe) and the ACE/SIS instrument (e.g. 11-168 MeV/nuc for Fe). The method starts by fitting SEP time-intensity profiles during the decay phase of a given, large SEP event in order to obtain energy-dependent decay times. The mean charge state for each element is estimated from the relationship between the energy dependence of its decay times to that for selected calibration references. For simultaneous estimates among multiple elements, we assume a common rigidity dependence across all elements. Earlier calculations by Sollitt et al. incorporated helium time intensity profile fits with an assumed charge state of 2. Subsequent analysis dropped helium as a reference element, for simplicity, but we have recently reincorporated He for calibration, from either STEREO/LET or ACE/SIS data, combined with C as an additional reference element with an assumed mean charge state of 5.9. For this presentation, we will present validation of the reanalysis using data from the 8 March 2012 SEP event in ACE data and the 28 September 2012 event in STEREO data. We will also introduce additional low-energy He from publicly available ACE/ULEIS and STEREO/SIT data, which should further constrain the charge state calibration. Better charge state calibration could yield more robust convergence to physical solutions for SEP events for which this method has not previously yielded results. Therefore, we will also present analysis for additional SEP events from 2005 to 2017, and we will investigate conditions for which this method yields or does not yield charge states.

Angiotensin converting enzyme over expression in myelocytes enhances the immune response

PubMed Central

Bernstein, Kenneth E.; Gonzalez-Villalobos, Romer A.; Giani, Jorge F.; Shah, Kandarp; Bernstein, Ellen; Janjulia, Tea; Koronyo, Yosef; Shi, Peng D.; Koronyo-Hamaoui, Maya; Fuchs, Sebastien; Shen, Xiao Z.

2015-01-01

Angiotensin converting enzyme (ACE) plays an important role in blood pressure control. ACE also has effects on renal function, reproduction, hematopoiesis and several aspects of the immune response. ACE 10/10 mice over express ACE in monocytic cells; macrophages from ACE 10/10 mice demonstrate increased polarization towards a proinflammatory phenotype. As a result, ACE 10/10 mice have a highly effective immune response following challenge with either melanoma, bacterial infection or Alzheimer’s disease. The ACE 10/10 mice suggest that enhanced monocytic function greatly contributes to the ability of the immune response to defend against a wide variety of antigenic and non-antigenic challenges. PMID:24633750

Just Out of Reach: On the Reliability of the Action-Sentence Compatibility Effect

PubMed Central

Papesh, Megan H.

2015-01-01

The action-sentence compatibility effect (ACE; Glenberg & Kaschak, 2002), a hallmark finding in Embodied Cognition, implicates the motor system in language comprehension. In the ACE, people process sentences implying movement toward or away from themselves, responding with actions toward or away from their bodies. These processes interact, implying a linkage between linguistic and motor systems. From a theoretical perspective, the ACE has been extremely influential, being widely-cited evidence in favor of embodied cognition. The present study began as an attempt to extend the ACE in a new direction, but eventually became a series of attempts to simply replicate the effect. Across eight experiments, I tested whether the ACE extends to a novel mouse-tracking method and/or is susceptible to higher-order cognitive influences. In three experiments, attempts were made to “disembody” the ACE by presenting participants' names on the computer screen (as in Markman & Brendl, 2005). In each experiment, the ACE could not be disembodied, because the ACE did not occur. In further experiments, the ACE was not observed in reading times, regardless of response mode (mouse movements versus button-presses) or stimuli, including those from the original research. Similarly, no ACE was observed in physical movement times. Bayes Factor analyses of the current experiments, and the previous ACE literature, suggest that the evidence for the ACE is generally weak: Many studies considered as positive evidence actually support the null hypothesis, and very few published results offer strong evidence for the ACE. Implications for the embodiment hypothesis are discussed. PMID:26595844

Angiotensin Converting Enzyme Regulates Cell Proliferation and Migration

PubMed Central

Carvalho, Clarissa Coelho; Florentino, Rodrigo Machado; França, Andressa; Matias, Eveline; Guimarães, Paola Bianchi; Batista, Carolina; Freire, Valder; Carmona, Adriana Karaoglanovic; Pesquero, João Bosco; de Paula, Ana Maria; Foureaux, Giselle; Leite, Maria de Fatima

2016-01-01

Background The angiotensin-I converting enzyme (ACE) plays a central role in the renin-angiotensin system, acting by converting the hormone angiotensin-I to the active peptide angiotensin-II (Ang-II). More recently, ACE was shown to act as a receptor for Ang-II, and its expression level was demonstrated to be higher in melanoma cells compared to their normal counterparts. However, the function that ACE plays as an Ang-II receptor in melanoma cells has not been defined yet. Aim Therefore, our aim was to examine the role of ACE in tumor cell proliferation and migration. Results We found that upon binding to ACE, Ang-II internalizes with a faster onset compared to the binding of Ang-II to its classical AT1 receptor. We also found that the complex Ang-II/ACE translocates to the nucleus, through a clathrin-mediated process, triggering a transient nuclear Ca2+ signal. In silico studies revealed a possible interaction site between ACE and phospholipase C (PLC), and experimental results in CHO cells, demonstrated that the β3 isoform of PLC is the one involved in the Ca2+ signals induced by Ang-II/ACE interaction. Further studies in melanoma cells (TM-5) showed that Ang-II induced cell proliferation through ACE activation, an event that could be inhibited either by ACE inhibitor (Lisinopril) or by the silencing of ACE. In addition, we found that stimulation of ACE by Ang-II caused the melanoma cells to migrate, at least in part due to decreased vinculin expression, a focal adhesion structural protein. Conclusion ACE activation regulates melanoma cell proliferation and migration. PMID:27992423

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.

Brain ACE2 shedding contributes to the development of neurogenic hypertension

PubMed Central

Chhabra, Kavaljit H.; Lazartigues, Eric

2015-01-01

Rationale Over-activity of the brain Renin Angiotensin System (RAS) is a major contributor to neurogenic hypertension. While over-expression of Angiotensin-Converting Enzyme type 2 (ACE2) has been shown to be beneficial in reducing hypertension by transforming Angiotensin (Ang)-II into Ang-(1-7), several groups have reported decreased brain ACE2 expression and activity during the development of hypertension. Objective We hypothesized that ADAM17-mediated ACE2 shedding results in decreased membrane-bound ACE2 in the brain, thus promoting the development of neurogenic hypertension. Methods and Results To test this hypothesis, we used the DOCA-salt model of neurogenic hypertension in non-transgenic (NT) and syn-hACE2 mice over-expressing ACE2 in neurons. DOCA-salt treatment in NT mice led to significant increases in blood pressure, hypothalamic Ang-II levels, inflammation, impaired baroreflex sensitivity, autonomic dysfunction, as well as decreased hypothalamic ACE2 activity and expression, while these changes were blunted or prevented in syn-hACE2 mice. In addition, reduction of ACE2 expression and activity in the brain paralleled a rise in ACE2 activity in the cerebrospinal fluid of NT mice following DOCA-salt treatment and was accompanied by enhanced ADAM17 expression and activity in the hypothalamus. Chronic knockdown of ADAM17 in the brain blunted the development of hypertension and restored ACE2 activity and baroreflex function. Conclusions Our data provide the first evidence that ADAM17-mediated shedding impairs brain ACE2 compensatory activity, thus contributing to the development of neurogenic hypertension. PMID:24014829

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

DTIC Science & Technology

1991-04-01

tine-consuming, and if the left pack is malfunctioning, can allow large quantities of smoke to enter the passenger cabin, creating high levels of...airport, thus providing the crew additional time to evc’,ataIe th airplanc . ’li maved in landing the aircraft safely results from: a0 I)ctectioi n (f

A qualitative evaluation of the 2005-2011 National Academic Centers of Excellence in Youth Violence Prevention Program.

PubMed

Holland, Kristin M; Vivolo-Kantor, Alana M; Dela Cruz, Jason; Massetti, Greta M; Mahendra, Reshma

2015-12-01

The Centers for Disease Control and Prevention's Division of Violence Prevention (DVP) funded eight National Academic Centers of Excellence (ACEs) in Youth Violence Prevention from 2005 to 2010 and two Urban Partnership Academic Centers of Excellence (UPACEs) in Youth Violence Prevention from 2006 to 2011. The ACEs and UPACEs constitute DVP's 2005-2011 ACE Program. ACE Program goals include partnering with communities to promote youth violence (YV) prevention and fostering connections between research and community practice. This article describes a qualitative evaluation of the 2005-2011 ACE Program using an innovative approach for collecting and analyzing data from multiple large research centers via a web-based Information System (ACE-IS). The ACE-IS was established as an efficient mechanism to collect and document ACE research and programmatic activities. Performance indicators for the ACE Program were established in an ACE Program logic model. Data on performance indicators were collected through the ACE-IS biannually. Data assessed Centers' ability to develop, implement, and evaluate YV prevention activities. Performance indicator data demonstrate substantial progress on Centers' research in YV risk and protective factors, community partnerships, and other accomplishments. Findings provide important lessons learned, illustrate progress made by the Centers, and point to new directions for YV prevention research and programmatic efforts. Published by Elsevier Ltd.

Adverse childhood experiences (ACE) and adult attachment interview (AAI) in a non-clinical population.

PubMed

Thomson, Paula; Jaque, S Victoria

2017-08-01

Adverse childhood experiences (ACE) tend to be interrelated rather than independently occurring. There is a graded effect associated with ACE exposure and pathology, with an increase when ACE exposure is four or more. This study examined a sample of active individuals (n=129) to determine distribution patterns and relationships between ACEs, attachment classification, unresolved mourning (U), and disclosure difficulty. The results of this study demonstrated a strong relationship between increased ACEs and greater unresolved mourning. Specifically, the group differences for individuals who experienced no ACE (n=42, 33%), those with 1-3 ACEs (n=48, 37.8%), and those with ≥4 ACEs (n=37, 29.1%) revealed a pattern in which increased group ACE exposure was associated with greater lack of resolution for past trauma/loss experiences, more adult traumatic events, and more difficulty disclosing past trauma. Despite ≥4 ACEs, 51.4% of highly exposed individuals were classified as secure in the Adult Attachment Interview. Resilience in this group may be related to a combination of attachment security, college education, and engagement in meaningful activities. Likewise, adversity may actually encourage the cultivation of more social support, goal efficacy, and planning behaviors; factors that augment resilience to adversity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparative Study of Three Methods for Affinity Measurements: Capillary Electrophoresis Coupled with UV Detection and Mass Spectrometry, and Direct Infusion Mass Spectrometry

NASA Astrophysics Data System (ADS)

Mironov, Gleb G.; Logie, Jennifer; Okhonin, Victor; Renaud, Justin B.; Mayer, Paul M.; Berezovski, Maxim V.

2012-07-01

We present affinity capillary electrophoresis and mass spectrometry (ACE-MS) as a comprehensive separation technique for label-free solution-based affinity analysis. The application of ACE-MS for measuring affinity constants between eight small molecule drugs [ibuprofen, s-flurbiprofen, diclofenac, phenylbutazone, naproxen, folic acid, resveratrol, and 4,4'-(propane-1,3-diyl) dibenzoic acid] and β-cyclodextrin is described. We couple on-line ACE with MS to combine the separation and kinetic capability of ACE together with the molecular weight and structural elucidation of MS in one system. To understand the full potential of ACE-MS, we compare it with two other methods: Direct infusion mass spectrometry (DIMS) and ACE with UV detection (ACE-UV). After the evaluation, DIMS provides less reliable equilibrium dissociation constants than separation-based ACE-UV and ACE-MS, and cannot be used solely for the study of noncovalent interactions. ACE-MS determines apparent dissociation constants for all reacting small molecules in a mixture, even in cases when drugs overlap with each other during separation. The ability of ACE-MS to interact, separate, and rapidly scan through m/z can facilitate the simultaneous affinity analysis of multiple interacting pairs, potentially leading to the high-throughput screening of drug candidates.

Adverse childhood experiences (ACEs) and later-life depression: perceived social support as a potential protective factor.

PubMed

Cheong, E Von; Sinnott, Carol; Dahly, Darren; Kearney, Patricia M

2017-09-01

To investigate associations between adverse childhood experiences (ACEs) and later-life depressive symptoms; and to explore whether perceived social support (PSS) moderates these. We analysed baseline data from the Mitchelstown (Ireland) 2010-2011 cohort of 2047 men and women aged 50-69 years. Self-reported measures included ACEs (Centre for Disease Control ACE questionnaire), PSS (Oslo Social Support Scale) and depressive symptoms (CES-D). The primary exposure was self-report of at least one ACE. We also investigated the effects of ACE exposure by ACE scores and ACE subtypes abuse, neglect and household dysfunction. Associations between each of these exposures and depressive symptoms were estimated using logistic regression, adjusted for socio-demographic factors. We tested whether the estimated associations varied across levels of PSS (poor, moderate and strong). 23.7% of participants reported at least one ACE (95% CI 21.9% to 25.6%). ACE exposures (overall, subtype or ACE scores) were associated with a higher odds of depressive symptoms, but only among individuals with poor PSS. Exposure to any ACE (vs none) was associated with almost three times the odds of depressive symptoms (adjusted OR 2.85; 95% CI 1.64 to 4.95) among individuals reporting poor PSS, while among those reporting moderate and strong PSS, the adjusted ORs were 2.21 (95% CI 1.52 to 3.22) and 1.39 (95% CI 0.85 to 2.29), respectively. This pattern of results was similar when exposures were based on ACE subtype and ACE scores, though the interaction was clearly strongest among those reporting abuse. ACEs are common among older adults in Ireland and are associated with higher odds of later-life depressive symptoms, particularly among those with poor PSS. Interventions that enhance social support, or possibly perceptions of social support, may help reduce the burden of depression in older populations with ACE exposure, particularly in those reporting abuse. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

ACE Inhibitor and ARB utilization and expenditures in the Medicaid fee-for-service program from 1991 to 2008.

PubMed

Bian, Boyang; Kelton, Christina M L; Guo, Jeff J; Wigle, Patricia R

2010-01-01

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are widely prescribed for the treatment of hypertension and heart failure, as well as for kidney disease prevention in patients with diabetes mellitus and the management of patients after myocardial infarction. To (a) describe ACE inhibitor and ARB utilization and spending in the Medicaid fee-for-service program from 1991 through 2008, and (b) estimate the potential cost savings for the collective Medicaid programs from a higher ratio of generic ACE inhibitor utilization. A retrospective, descriptive analysis was performed using the National Summary Files from the Medicaid State Drug Utilization Data, which are composed of pharmacy claims that are subject to federally mandated rebates from pharmaceutical manufacturers. For the years 1991-2008, quarterly claim counts and expenditures were calculated by summing data for individual ACE inhibitors and ARBs. Quarterly per-claim expenditure as a proxy for drug price was computed for all brand and generic drugs. Market shares were calculated based on the number of pharmacy claims and Medicaid expenditures. In the Medicaid fee-for-service program, ACE inhibitors accounted for 100% of the claims in the combined market for ACE inhibitors and ARBs in 1991, 80.6% in 2000, and 64.7% in 2008. The Medicaid expenditure per ACE inhibitor claim dropped from $37.24 in 1991 to $24.03 in 2008 when generics accounted for 92.5% of ACE inhibitor claims; after adjusting for inflation for the period from 1991 to 2008, the real price drop was 59.2%. Brand ACE inhibitors accounted for only 7.5% of the claims in 2008 for all ACE inhibitors but 32.1% of spending; excluding the effects of manufacturer rebates, Medicaid spending would have been reduced by $28.7 million (9%) in 2008 if all ACE inhibitor claims were generic. The average price per ACE inhibitor claim in 2008 was $24.03 ($17.64 per generic claim vs. $103.45 per brand claim) versus $81.98 per ARB claim. If the ACE inhibitor ratio had been 75% in 2008 rather than 64.7%, the Medicaid program would have saved approximately 13% or about $41.8 million, again excluding the effects of manufacturer rebates. If the ACE inhibitor ratio had been 90% in 2008, the cost savings for the combined Medicaid fee-forservice programs would have been about 33% or about $102.3 million. The total cost savings opportunity with 100% generic ACE inhibitor utilization in 2008 and an ACE inhibitor ratio of 75% was $75.1 million (24%) or $142.3M (46%) with a 90% ACE inhibitor ratio. Factors that affect Medicaid spending by contributing to increased utilization of ACE inhibitors and ARBs, such as the rising prevalence of hypertension, heart disease, and diabetes, can be offset by reduction in the average price attained through a higher proportion of ACE inhibitors and a higher percentage of generic versus brand ACE inhibitors.

An ace-1 gene duplication resorbs the fitness cost associated with resistance in Anopheles gambiae, the main malaria mosquito.

PubMed

Assogba, Benoît S; Djogbénou, Luc S; Milesi, Pascal; Berthomieu, Arnaud; Perez, Julie; Ayala, Diego; Chandre, Fabrice; Makoutodé, Michel; Labbé, Pierrick; Weill, Mylène

2015-10-05

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-1(R) allele), is already present. Furthermore, a duplicated allele (ace-1(D)) 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-1(D) confers less resistance than ace-1(R), the high fitness cost associated with ace-1(R) 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.

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

Phase separation between nucleoid and cytoplasm in Escherichia coli as defined by immersive refractometry.

PubMed Central

Valkenburg, J A; Woldringh, C L

1984-01-01

The refractive indices of nucleoid and cytoplasm in Escherichia coli were derived theoretically and experimentally. For the theoretical estimates, we made use of the known macromolecular composition of E. coli B/r (G. Churchward and H. Bremer, J. Theor. Biol. 94:651-670, 1982) and of estimates of cell and nucleoid volumes. These were obtained from micrographs of living bacteria made with a confocal scanning light microscope. The theoretical values were calculated, assuming that all DNA occurred in the nucleoid and that all protein and RNA occurred in the cytoplasm. Comparison with experimental refractive index values directly obtained by immersive refractometry showed that, besides its DNA, the nucleoid must contain an additional amount of solids equivalent to 8.6% (wt/vol) protein. With the nucleoid containing 6.8% (wt/vol) DNA and 8.6% (wt/vol) protein and the cytoplasm containing 21% (wt/vol) protein and 4% (wt/vol) RNA, a mass difference is obtained, which accounts for the phase separation observed between the nucleoid and cytoplasm in living cells by phase-contrast microscopy. The decrease in the refractive index of the nucleoid relative to that of the cytoplasm observed upon, for instance, OsO4 fixation was interpreted as being indicative of the loss of protein content in the nucleoid. Images PMID:6389508

ACE blood test

MedlinePlus

... to help diagnose and monitor a disorder called sarcoidosis . People with sarcoidosis may have their ACE level tested regularly to ... normal ACE level may be a sign of sarcoidosis. ACE levels may rise or fall as sarcoidosis ...

Modes of hurricane activity variability in the eastern Pacific: Implications for the 2016 season

NASA Astrophysics Data System (ADS)

Boucharel, Julien; Jin, Fei-Fei; England, Matthew H.; Lin, I. I.

2016-11-01

A gridded product of accumulated cyclone energy (ACE) in the eastern Pacific is constructed to assess the dominant mode of tropical cyclone (TC) activity variability. Results of an empirical orthogonal function decomposition and regression analysis of environmental variables indicate that the two dominant modes of ACE variability (40% of the total variance) are related to different flavors of the El Niño-Southern Oscillation (ENSO). The first mode, more active during the later part of the hurricane season (September-November), is linked to the eastern Pacific El Niño through the delayed oceanic control associated with the recharge-discharge mechanism. The second mode, dominant in the early months of the hurricane season, is related to the central Pacific El Niño mode and the associated changes in atmospheric variability. A multilinear regression forecast model of the dominant principal components of ACE variability is then constructed. The wintertime subsurface state of the eastern equatorial Pacific (characterizing ENSO heat discharge), the east-west tilt of the thermocline (describing ENSO phase transition), the anomalous ocean surface conditions in the TC region in spring (portraying atmospheric changes induced by persistence of local surface anomalies), and the intraseasonal atmospheric variability in the western Pacific are found to be good predictors of TC activity. Results complement NOAA's official forecast by providing additional spatial and temporal information. They indicate a more active 2016 season ( 2 times the ACE mean) with a spatial expansion into the central Pacific associated with the heat discharge from the 2015/2016 El Niño.

Characterization of Dust Properties at the Source Region During ACE-Asia

NASA Technical Reports Server (NTRS)

Tsay, Si-Chee; Lau, William (Technical Monitor)

2001-01-01

ACE (Aerosol Characterization Experiment)-Asia is designed to study the compelling variability in spatial and temporal scale of both pollution-derived and naturally-occurring aerosols, which often exist in high concentrations over eastern Asia and along the rim of the western Pacific. The phase-I of ACE-Asia was conducted from March-May 2001 in the vicinity of the Gobi desert, east coast of China, Yellow Sea, Korea, and Japan, along the pathway of Kosa (severe events that blanket East Asia with yellow desert dust, peaked in the Spring season). Asian dust typically originates in desert areas far from polluted urban regions. During transport, dust layers can interact with anthropogenic sulfate and soot aerosols from heavily polluted urban areas. Added to the complex effects of clouds and natural marine aerosols, dust particles reaching the marine environment can have drastically different properties than those from the source. Thus, understanding the unique temporal and spatial variations of Asian dust is of special importance in regional-to-global climate issues such as radiative forcing, the hydrological cycle, and primary biological productivity in the mid-Pacific Ocean. During ACE-Asia we have measured continuously aerosol optical/radiative properties, column precipitable water amount, and surface reflectivity over homogeneous areas from surface. The inclusion of flux measurements permits the determination of dust aerosol radiative flux in addition to measurements of loading and optical thickness. At the time of the Terra/MODIS overpass, these ground-based observations can provide valuable data to compare with MODIS retrievals over land. Preliminary results will be presented and discussed their implications in regional climatic effects.

Patterns of adverse childhood experiences and substance use among young adults: A latent class analysis.

PubMed

Shin, Sunny H; McDonald, Shelby Elaine; Conley, David

2018-03-01

Adverse childhood experiences (ACEs) have been strongly linked with subsequent substance use. The aim of this study was to investigate how different patterns of ACEs influence substance use in young adulthood. Using a community sample of young individuals (N=336; ages 18-25), we performed latent class analyses (LCA) to identify homogenous groups of young people with similar patterns of ACEs. Exposure to ACEs incorporates 13 childhood adversities including childhood maltreatment, household dysfunction, and community violence. Multiple linear and logistic regression models were used in an effort to examine the associations between ACEs classes and four young adult outcomes such as alcohol-related problems, current tobacco use, drug dependence symptoms, and psychological distress. LCA identified four heterogeneous classes of young people distinguished by different patterns of ACEs exposure: Low ACEs (56%), Household Dysfunction/Community Violence (14%), Emotional ACEs (14%), and High/Multiple ACEs (16%). Multiple regression analyses found that compared to those in the Low ACEs class, young adults in the High/Multiple ACEs class reported more alcohol-related problems, current tobacco use, and psychological symptoms, controlling for sociodemographic characteristics and common risk factors for substance use such as peer substance use. Our findings confirm that for many young people, ACEs occur as multiple rather than single experiences. The results of this research suggest that exposure to poly-victimization during childhood is particularly related to substance use during young adulthood. Copyright © 2017 Elsevier Ltd. All rights reserved.

Maternal adverse childhood experiences and antepartum risks: the moderating role of social support.

PubMed

Racine, Nicole; Madigan, Sheri; Plamondon, Andre; Hetherington, Erin; McDonald, Sheila; Tough, Suzanne

2018-03-28

The aims of the current study were to examine the association between maternal adverse childhood experiences (ACEs) and antepartum health risks, and to investigate whether social support moderated this association. It was hypothesized that ACEs would be associated with antepartum health risks; however, social support in the prenatal period would buffer mothers from the deleterious consequences of ACEs. Data from 1994 women (mean age = 31 years) and their infants were collected from a longitudinal cohort recruited in health care offices in Alberta, Canada. Pregnant women completed questionnaires related to ACEs prior to the age of 18 and prenatal social support, and a health care professional assessed the mother's antepartum health risk. ACEs included physical, emotional, and sexual abuse, exposure to domestic violence, as well as exposure to household dysfunction such as parental substance use, mental illness, or incarceration. Regression analyses demonstrated a positive association between ACEs and antepartum health risks. However, a significant interaction between maternal ACEs and social support was also observed. Specifically, women exposed to high ACEs and low social support in pregnancy had high antepartum health risks. However, among mothers who had high ACEs but also high levels of social support, there was no association between ACEs and antepartum health risk. A history of ACEs can place mothers at risk of antepartum health complications. However, a resiliency effect was observed: women with a history of ACEs were buffered from experiencing antepartum health risks if they reported high levels of social support in pregnancy.

A simple solid-phase extraction method for the analysis of red cell phospholipids by liquid chromatography- tandem mass spectrometry.

PubMed

Nguyen, Van Long

2018-02-25

There has been increasing interest in the analysis of phospholipids in red blood cells as potential long-term biomarkers of different disease states. Here, we describe a simple method for the analysis of two phospholipids: 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanol (PE 16:0/18:1) and 1-Palmitoyl-2-linoleoyl-sn-glycero-3-phosphoethanol (PE 16:/0/18:2) in erythrocytes by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Whole blood samples were removed free of plasma and washed in isotonic saline. Red cells were lysed with ultrapure water. Lysate samples were processed using a hybrid solid-phase extraction (SPE) phospholipid cartridge (1 mL, 30 mg). Both PE 16:0/18:1 and PE 16:0/18:2 and their deuterated internal standards were separated on an ACE C4 (150 mm × 2.1 mm, 2.7 μm particle size) by gradient elution at a flow rate of 0.5 mL per minute using mobile phases consisting of 0.01 mol/L ammonium acetate in: water (A), methanol (B), and isopropanol (C). The phospholipid species were quantified by the following transitions: PE 16:0/18:1: 701.5→281.3 and PE 16:0/18:2: 699.5→279.3. Both PE species displayed linearity ranging from 10 to 500 μg/L. The coefficient of variation (CV%) of PE 16:0/18:1 concerning intraday and interday precision was between 1.9%-2.6% and 3.0%-4.3%, respectively. For PE 16:0/18:2, this was between 1.8%-3.4% and 3.7%-4.1%, respectively. Both phospholipid species had accuracy (PE 16:0/18:1: 91%-98% and PE 16:0/18:2: 94%-103%) and extraction recovery (PE 16:0/18:1: 95%-106% and PE 16:0/18:2: 92%-102%) exceeding 90% over the analytical range. The limit of detection was 5 μg/L. Here we propose a simple SPE LC-MS/MS method for analyzing phospholipids in erythrocytes, which can be easily adopted. © 2018 Wiley Periodicals, Inc.

Angiotensin-converting enzyme activity and cognitive impairment during hypoglycaemia in healthy humans.

PubMed

Pedersen-Bjergaard, Ulrik; Thomsen, Carsten E; Høgenhaven, Hans; Smed, Annelise; Kjaer, Troels W; Holst, Jens J; Dela, Flemming; Hilsted, Linda; Frandsen, Erik; Pramming, Stig; Thorsteinsson, Birger

2008-03-01

In type 1 diabetes increased risk of severe hypoglycaemia is associated with high angiotensin-converting enzyme (ACE) activity. We tested in healthy humans the hypothesis that this association is explained by the reduced ability of subjects with high ACE activity to maintain normal cognitive function during hypoglycaemia. Sixteen healthy volunteers selected by either particularly high or low serum ACE activity were subjected to hypoglycaemia (plasma glucose 2.7 mmol/L). Cognitive function was assessed by choice reaction tests. Despite a similar hypoglycaemic stimulus in the two groups, only the group with high ACE activity showed significant deterioration in cognitive performance during hypoglycaemia. In the high ACE group mean reaction time (MRT) in the most complex choice reaction task was prolonged and error rate (ER) was increased in contrast to the low ACE group. The total hypoglycaemic symptom response was greater in the high ACE group than in the low ACE group (p=0.031). There were no differences in responses of counterregulatory hormones or in concentrations of substrates between the groups. Healthy humans with high ACE activity are more susceptible to cognitive dysfunction and report higher symptom scores during mild hypoglycaemia than subjects with low ACE activity.

Fine-Mapping Angiotensin-Converting Enzyme Gene: Separate QTLs Identified for Hypertension and for ACE Activity

PubMed Central

Chung, Chia-Min; Wang, Ruey-Yun; Fann, Cathy S. J.; Chen, Jaw-Wen; Jong, Yuh-Shiun; Jou, Yuh-Shan; Yang, Hsin-Chou; Kang, Chih-Sen; Chen, Chien-Chung; Chang, Huan-Cheng; Pan, Wen-Harn

2013-01-01

Angiotensin-converting enzyme (ACE) has been implicated in multiple biological system, particularly cardiovascular diseases. However, findings associating ACE insertion/deletion polymorphism with hypertension or other related traits are inconsistent. Therefore, in a two-stage approach, we aimed to fine-map ACE in order to narrow-down the function-specific locations. We genotyped 31 single nucleotide polymorphisms (SNPs) of ACE from 1168 individuals from 305 young-onset (age ≤40) hypertension pedigrees, and found four linkage disequilibrium (LD) blocks. A tag-SNP, rs1800764 on LD block 2, upstream of and near the ACE promoter, was significantly associated with young-onset hypertension (p = 0.04). Tag-SNPs on all LD blocks were significantly associated with ACE activity (p-value: 10–16 to <10–33). The two regions most associated with ACE activity were found between exon13 and intron18 and between intron 20 and 3′UTR, as revealed by measured haplotype analysis. These two major QTLs of ACE activity and the moderate effect variant upstream of ACE promoter for young-onset hypertension were replicated by another independent association study with 842 subjects. PMID:23469169

Association of Angiotensin-Converting Enzyme ACE Gene Polymorphism with ACE Activity and Susceptibility to Vitiligo in Egyptian Population.

PubMed

Badran, Dahlia I; Nada, Hesham; Hassan, Ranya

2015-05-01

The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with vitiligo in the Indians and Koreans, but not in those of English or Turkish background. We investigated the ACE (I/D) polymorphism in vitiligo patients for the first time in Egypt and compared serum ACE levels between vitiligo patients and controls. The present study was carried out in 100 vitiligo patients (40 males and 60 females) and in 100 healthy controls of an Egyptian population using the polymerase chain reaction genotyping method. The ACE genotype and allele frequency was significantly different between vitiligo patients and controls. Our results revealed a significant increase in the frequency of the ACE I allele (p=0.002; odds ratio: 1.99; 95% confidence intervals: 1.207-3.284) with an overrepresentation of I/D genotype in the vitiligo patient group. Furthermore, there was a significant difference between the segmental, nonsegmental, and focal vitiligo in ACE gene genotype distribution. Serum ACE levels were significantly increased in vitiligo patients compared to controls (p=0.034). This study suggests that, for the first time, ACE gene polymorphism confers susceptibility to vitiligo in the Egyptian population.

A novel acetylcholinesterase gene in mosquitoes codes for the insecticide target and is non-homologous to the ace gene in Drosophila.

PubMed Central

Weill, Mylène; Fort, Philippe; Berthomieu, Arnaud; Dubois, Marie Pierre; Pasteur, Nicole; Raymond, Michel

2002-01-01

Acetylcholinesterase (AChE) is the target of two major insecticide families, organophosphates (OPs) and carbamates. AChE insensitivity is a frequent resistance mechanism in insects and responsible mutations in the ace gene were identified in two Diptera, Drosophila melanogaster and Musca domestica. However, for other insects, the ace gene cloned by homology with Drosophila does not code for the insensitive AChE in resistant individuals, indicating the existence of a second ace locus. We identified two AChE loci in the genome of Anopheles gambiae, one (ace-1) being a new locus and the other (ace-2) being homologous to the gene previously described in Drosophila. The gene ace-1 has no obvious homologue in the Drosophila genome and was found in 15 mosquito species investigated. In An. gambiae, ace-1 and ace-2 display 53% similarity at the amino acid level and an overall phylogeny indicates that they probably diverged before the differentiation of insects. Thus, both genes are likely to be present in the majority of insects and the absence of ace-1 in Drosophila is probably due to a secondary loss. In one mosquito (Culex pipiens), ace-1 was found to be tightly linked with insecticide resistance and probably encodes the AChE OP target. These results have important implications for the design of new insecticides, as the target AChE is thus encoded by distinct genes in different insect groups, even within the Diptera: ace-2 in at least the Drosophilidae and Muscidae and ace-1 in at least the Culicidae. Evolutionary scenarios leading to such a peculiar situation are discussed. PMID:12396499

Association of Increased Serum ACE Activity with Logical Memory Ability in Type 2 Diabetic Patients with Mild Cognitive Impairment

PubMed Central

Tian, Sai; Han, Jing; Huang, Rong; Xia, Wenqing; Sun, Jie; Cai, Rongrong; Dong, Xue; Shen, Yanjue; Wang, Shaohua

2016-01-01

Background: Angiotensin-converting enzyme (ACE) is involved in the chronic complications of type 2 diabetes mellitus (T2DM) and Alzheimer's disease. This study aimed to assess the pathogenetic roles of ACE and the genetic predisposition of its insertion/deletion (I/D) polymorphism in mild cognitive impairment (MCI) among T2DM patients. Methods: A total of 210 T2DM patients were enrolled. Among these patients, 116 satisfied the MCI diagnostic criteria and 94 exhibited healthy cognition. The cognitive functions of the patients were extensively assessed. The serum level and activity of ACE were measured via enzyme-linked immunosorbent assay and ultraviolet spectrophotography. The single-nucleotide polymorphisms of I/D gene of ACE were analyzed. Results: The serum level and activity of ACE in diabetic MCI patients (p = 0.022 and p = 0.008, respectively) were both significantly higher than those in the healthy controls. A significant negative correlation was found between their ACE activity and logical memory test score (LMT) (p = 0.002). Multiple stepwise regression iterated the negative correlation between ACE activity and LMT score (p = 0.035). Although no significant difference was found in the genotype or allele distribution of ACE I/D polymorphism between the groups, the serum levels and activity of ACE were higher in the DD group than in the ID and II groups (p < 0.05). Conclusions: Serum ACE activity could better predict logical memory in T2DM patients than ACE level. Further investigations on a large population size are necessary to test whether the D-allele of the ACE gene polymorphism is susceptible to memory deterioration. PMID:28066203

Association of Increased Serum ACE Activity with Logical Memory Ability in Type 2 Diabetic Patients with Mild Cognitive Impairment.

PubMed

Tian, Sai; Han, Jing; Huang, Rong; Xia, Wenqing; Sun, Jie; Cai, Rongrong; Dong, Xue; Shen, Yanjue; Wang, Shaohua

2016-01-01

Background: Angiotensin-converting enzyme (ACE) is involved in the chronic complications of type 2 diabetes mellitus (T2DM) and Alzheimer's disease. This study aimed to assess the pathogenetic roles of ACE and the genetic predisposition of its insertion/deletion (I/D) polymorphism in mild cognitive impairment (MCI) among T2DM patients. Methods: A total of 210 T2DM patients were enrolled. Among these patients, 116 satisfied the MCI diagnostic criteria and 94 exhibited healthy cognition. The cognitive functions of the patients were extensively assessed. The serum level and activity of ACE were measured via enzyme-linked immunosorbent assay and ultraviolet spectrophotography. The single-nucleotide polymorphisms of I/D gene of ACE were analyzed. Results: The serum level and activity of ACE in diabetic MCI patients ( p = 0.022 and p = 0.008, respectively) were both significantly higher than those in the healthy controls. A significant negative correlation was found between their ACE activity and logical memory test score (LMT) ( p = 0.002). Multiple stepwise regression iterated the negative correlation between ACE activity and LMT score ( p = 0.035). Although no significant difference was found in the genotype or allele distribution of ACE I/D polymorphism between the groups, the serum levels and activity of ACE were higher in the DD group than in the ID and II groups ( p < 0.05). Conclusions: Serum ACE activity could better predict logical memory in T2DM patients than ACE level. Further investigations on a large population size are necessary to test whether the D-allele of the ACE gene polymorphism is susceptible to memory deterioration.

Functional characterisation of a cyst nematode acetylcholinesterase gene using Caenorhabditis elegans as a heterologous system.

PubMed

Costa, Joana C; Lilley, Catherine J; Atkinson, Howard J; Urwin, Peter E

2009-06-01

Migration of plant-parasitic nematode infective larval stages through soil and invasion of roots requires perception and integration of sensory cues culminating in particular responses that lead to root penetration and parasite establishment. Components of the chemoreceptive neuronal circuitry involved in these responses are targets for control measures aimed at preventing infection. Here we report, to our knowledge, the first isolation of cyst nematode ace-2 genes encoding acetylcholinesterase (AChE). The ace-2 genes from Globodera pallida (Gp-ace-2) and Heterodera glycines (Hg-ace-2) show homology to ace-2 of Caenorhabditis elegans (Ce-ace-2). Gp-ace-2 is expressed most highly in the infective J2 stage with lowest expression in the early parasitic stages. Expression and functional analysis of the Globodera gene were carried out using the free-living nematode C. elegans in order to overcome the refractory nature of the obligate parasite G. pallida to many biological studies. Caenorhabditis elegans transformed with a GFP reporter construct under the control of the Gp-ace-2 promoter exhibited specific and restricted GFP expression in neuronal cells in the head ganglia. Gp-ACE-2 protein can functionally complement its C. elegans homologue. A chimeric construct containing the Ce-ace-2 promoter region and the Gp-ace-2 coding region and 3' untranslated region was able to restore a normal phenotype to the uncoordinated C. elegans double mutant ace-1;ace-2. This study demonstrates conservation of AChE function and expression between free-living and plant-parasitic nematode species, and highlights the utility of C. elegans as a heterologous system to study neuronal aspects of plant-parasitic nematode biology.

Novel angiotensin I-converting enzyme inhibitory peptides isolated from Alcalase hydrolysate of mung bean protein.

PubMed

Li, Guan-Hong; Wan, Ju-Zhen; Le, Guo-Wei; Shi, Yong-Hui

2006-08-01

Mung bean protein isolates were hydrolyzed for 2 h by Alcalase. The generated hydrolysate showed angiotensin I-converting enzyme (ACE) inhibitory activity with the IC(50) value of 0.64 mg protein/ml. Three kinds of novel ACE inhibitory peptides were isolated from the hydrolysate by Sephadex G-15 and reverse-phase high performance liquid chromatography (RP-HPLC). These peptides were identified by amino acid composition analysis and matrix assisted-laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF MS/MS), as Lys-Asp-Tyr-Arg-Leu, Val-Thr-Pro-Ala-Leu-Arg and Lys-Leu-Pro-Ala-Gly-Thr-Leu-Phe with the IC(50) values of 26.5 microM, 82.4 microM and 13.4 microM, respectively. Copyright (c) 2006 European Peptide Society and John Wiley & Sons, Ltd.

Rural–urban differences in exposure to adverse childhood experiences among South Carolina adults.

PubMed

Radcliff, Elizabeth; Crouch, Elizabeth; Strompolis, Melissa

2018-02-01

Adverse childhood experiences (ACEs) are traumatic events that occur in a child's life between birth and 18 years. Exposure to one or more ACE has been linked to participation in risky health behaviors and the experience of chronic health conditions in adulthood. The risk for poor outcomes increases as the number of ACEs experienced increases. This research investigates rural-urban differences in exposure to ACEs using a sample from a representative southern US state, South Carolina. Using data from the 2014-2015 South Carolina Behavioral Risk Factor Surveillance System (BRFSS) and residential rurality based on UICs, ACE exposure among South Carolina adults was tabulated by urban versus rural residence and selected other demographic characteristics. Using standard descriptive statistics, frequencies and proportions were calculated for each categorical variable. Multivariable regression modeling was used to examine the impact of residential rurality and selected sociodemographic characteristics on overall and specific types of ACE exposure. All analyses used survey sampling weights that accounted for the BRFSS sampling strategy. The analytic sample of 18 176 respondents comprised 15.9% rural residents. Top reported ACEs for both rural and urban residents were the same: parental divorce/separation, emotional abuse, and household substance use. Compared to urban residents, a higher proportion of rural respondents reported experiencing no ACEs (41.4% vs 38.3%, p<0.01). The prevalence of four or more ACEs in rural respondents was 15.0%; in comparison, 17.6% of urban respondents had four or more ACEs (p<0.01). In logistic regression predicting exposure to four or more ACEs and adjusting for sex, age, race/ethnicity, education, and income, rural respondents were less likely than urban respondents to report four or more ACEs (adjusted odds ratio 0.75, 95% confidence interval 0.74-0.75). Despite reporting less ACE exposure than urban counterparts, almost 60% of rural residents reported at least one ACE and 15% reported experiencing four or more ACEs. In contrast to urban residents, rural residents may experience more social connections within their families and communities, which may influence ACE exposure; however, care coordination, social support services, and access to health care are limited in rural areas. Thus, families in rural areas may be less equipped to mitigate and manage the effects of ACEs. Findings from this study thus suggest that interventions to prevent ACE exposure are just as needed in rural southern communities as they are in urban southern communities. Topics important for future research could include an examination of ACEs in rural communities in terms of individuals' health outcomes and their access to health care, as well as the role of protective factors. Programs and policies that assist in ACE prevention in rural areas are important to reducing these multigenerational threats to health and wellbeing.

Adverse Childhood Experiences, Support, and the Perception of Ability to Work in Adults with Disability.

PubMed

Schüssler-Fiorenza Rose, Sophia Miryam; Eslinger, Jessica G; Zimmerman, Lindsey; Scaccia, Jamie; Lai, Betty S; Lewis, Catrin; Alisic, Eva

2016-01-01

To examine the impact of adverse childhood experiences (ACEs) and support on self-reported work inability of adults reporting disability. Adults (ages 18-64) who participated in the Behavioral Risk Factor Surveillance System in 2009 or 2010 and who reported having a disability (n = 13,009). The study used a retrospective cohort design with work inability as the main outcome. ACE categories included abuse (sexual, physical, emotional) and family dysfunction (domestic violence, incarceration, mental illness, substance abuse, divorce). Support included functional (perceived emotional/social support) and structural (living with another adult) support. Logistic regression was used to adjust for potential confounders (age, sex and race) and to evaluate whether there was an independent effect of ACEs on work inability after adding other important predictors (support, education, health) to the model. ACEs were highly prevalent with almost 75% of the sample reporting at least one ACE category and over 25% having a high ACE burden (4 or more categories). ACEs were strongly associated with functional support. Participants experiencing a high ACE burden had a higher adjusted odds ratio (OR) [95% confidence interval] of 1.9 [1.5-2.4] of work inability (reference: zero ACEs). Good functional support (adjusted OR 0.52 [0.42-0.63]) and structural support (adjusted OR 0.48 [0.41-0.56]) were protective against work inability. After adding education and health to the model, ACEs no longer appeared to have an independent effect. Structural support remained highly protective, but functional support only appeared to be protective in those with good physical health. ACEs are highly prevalent in working-age US adults with a disability, particularly young adults. ACEs are associated with decreased support, lower educational attainment and worse adult health. Health care providers are encouraged to screen for ACEs. Addressing the effects of ACEs on health and support, in addition to education and retraining, may increase ability to work in those with a disability.

Angiotensin-converting enzyme gene polymorphism predicts the time-course of blood pressure response to angiotensin converting enzyme inhibition in the AASK trial

PubMed Central

Bhatnagar, Vibha; O’Connor, Daniel T.; Schork, Nicholas J.; Salem, Rany M.; Nievergelt, Caroline M.; Rana, Brinda K.; Smith, Douglas W.; Bakris, George L.; Middleton, John P.; Norris, Keith C.; Wright, Jackson T.; Cheek, Deanna; Hiremath, Leena; Contreras, Gabriel; Appel, Lawrence J.; Lipkowitz, Michael S.

2009-01-01

Objective It has yet to be determined whether genotyping at the angiotensin-converting enzyme (ACE) locus is predictive of blood pressure response to an ACE inhibitor. Methods Participants from the African American Study of Kidney Disease and Hypertension trial randomized to the ACE inhibitor ramipril (n = 347) were genotyped at three polymorphisms on ACE, just downstream from the ACE insertion/deletion polymorphism (Ins/Del): G12269A, C17888T, and G20037A. Time to reach target mean arterial pressure (≤ 107 mmHg) was analyzed by genotype and ACE haplotype using Kaplan–Meier survival curves and Cox proportional hazard models. Results Individuals with a homozygous genotype at G12269A responded significantly faster than those with a heterozygous genotype; the adjusted (average number of medications and baseline mean arterial pressure) hazard ratio (homozygous compared to heterozygous genotype) was 1.86 (95% confidence limits 1.32–3.23; P < 0.001 for G12269A genotype). The adjusted hazard ratio for participants with homozygous ACE haplotypes compared to those heterozygous ACE haplotypes was 1.40 (1.13–1.75; P = 0.003 for haplotype). The ACE genotype effects were specific for ACE inhibition (i.e., not seen among those randomized to a calcium channel blocker), and were independent of population stratification. Conclusions African-Americans with a homozygous genotype at G12269A or homozygous ACE haplotypes responded to ramipril significantly faster than those with a heterozygous genotype or heterozygous haplotypes, suggesting that heterosis may be an important determinant of responsiveness to an ACE inhibitor. These associations may be a result of biological activity of this polymorphism, or of linkage disequilibrium with nearby variants such as the ACE Ins/Del, perhaps in the regulation of ACE splicing. PMID:17885551

Role of Renin-Angiotensin-converting Enzyme Level and ACE Gene Polymorphism in Patients with Nonalcoholic Fatty Liver Disease.

PubMed

Tekatas, Demet D; Bahcecioglu, Ibrahim H; Ispiroglu, Murat; Sahin, Abdurrahman; Ilhan, Necip; Yalniz, Mehmet; Demirel, Ulvi

2016-01-01

In this study, we aimed to investigate the histological and clinical effect of angiotensin-converting enzyme (ACE) and ACE gene polymorphism in nonalcoholic fatty liver disease (NAFLD) and their roles in the progression of the disease. Liver function tests, body mass index, waist circumference, lipid parameters, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), homeostasis model assessment-IR (HOMA-IR), ACE, and ACE gene polymorphism were evaluated in the NAFLD group and control group. The study group was evaluated by dividing the group into four subgroups by ACE gene polymorphism (D/D homozygous, I/I homozygous, D/I heterozygous, I/D heterozygous). Liver biopsies were evaluated according to Brunt Classification. A total of 31 patients who were diagnosed with NAFLD and 40 healthy individuals were included in the study. The ACE level was found to be 11.69 ± 1.99 in the NAFLD group and 11.52 ± 1.72 in the control group (p = 0.70). There was a negative correlation between ACE levels and HOMA-IR levels (p = 0.008, r= -0.512). Biochemical parameters were not different among ACE gene polimorphism subgroups, except FBG (between D/D, I/D and D/I, I/D; p = 0.02). When the ACE levels were compared in terms of grade and stage, no significant difference was found (for stage and grade p = 0.68). The ACE gene polymorphism subgroups did not differ by histopathologic findings; grade and stage (for grade p = 0.42, for stage p = 0.92). In this study, we could not find a correlation of ACE and ACE gene polymorphism with metabolic risk factors and the disease severity in NAFLD. Tekatas DD, Bahcecioglu IH, Ispiroglu M, Sahin A, Ilhan N, Yalniz M, Demirel U. Role of Renin-Angiotensin-converting Enzyme Level and ACE Gene Polymorphism in Patients with Nonalcoholic Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2016;6(2):137-142.

ACE ID genotype and the muscle strength and size response to unilateral resistance training.

PubMed

Pescatello, Linda S; Kostek, Matthew A; Gordish-Dressman, Heather; Thompson, Paul D; Seip, Richard L; Price, Thomas B; Angelopoulos, Theodore J; Clarkson, Priscilla M; Gordon, Paul M; Moyna, Niall M; Visich, Paul S; Zoeller, Robert F; Devaney, Joseph M; Hoffman, Eric P

2006-06-01

To examine associations among the angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism and the response to a 12-wk (2 d.wk) unilateral, upper-arm resistance training (RT) program in the trained (T, nondominant) and untrained (UT, dominant) arms. Subjects were 631 (mean+/-SEM, 24.2+/-0.2 yr) white (80%) men (42%) and women (58%). The ACE ID genotype was in Hardy-Weinberg equilibrium with frequencies of 23.1, 46.1, and 30.8% for ACE II, ID, and DD, respectively (chi=1.688, P=0.430). Maximum voluntary contraction (MVC) and one-repetition maximum (1RM) assessed peak elbow flexor muscle strength. Magnetic resonance imaging measured biceps muscle cross-sectional area (CSA). Multiple variable and repeated-measures ANCOVA tested whether muscle strength and size differed at baseline and pre- to post-RT among T and UT and ACE ID genotype. Baseline muscle strength and size were greater in UT than T (P<0.001) and did not differ among ACE ID genotype in either arm (P >or= 0.05). In T, MVC increases were greater for ACE II/ID (22%) than DD (17%) (P<0.05), whereas 1RM (51%) and CSA (19%) gains were not different among ACE ID genotype pre- to post-RT (P >or= 0.05). In UT, MVC increased among ACE II/ID (7%) (P<0.001) but was similar among ACE DD (2%) pre- to post-RT (P >or= 0.05). In UT, 1RM (11%) and CSA (2%) increases were greater for ACE DD/ID than ACE II (1RM, 7%; CSA, -0.1%) (P<0.05). ACE ID genotype explained approximately 1% of the MVC response to RT in T and approximately 2% of MVC, 2% of 1RM, and 4% of CSA response in UT (P<0.05). ACE ID genotype is associated with the contralateral effects of unilateral RT, perhaps more so than with the muscle strength and size adaptations that result from RT.

A qualitative evaluation of the 2005–2011 National Academic Centers of Excellence in Youth Violence Prevention Program☆

PubMed Central

Holland, Kristin M.; Vivolo-Kantor, Alana M.; Cruz, Jason Dela; Massetti, Greta M.; Mahendra, Reshma

2018-01-01

The Centers for Disease Control and Prevention’s Division of Violence Prevention (DVP) funded eight National Academic Centers of Excellence (ACEs) in Youth Violence Prevention from 2005 to 2010 and two Urban Partnership Academic Centers of Excellence (UPACEs) in Youth Violence Prevention from 2006 to 2011. The ACEs and UPACEs constitute DVP’s 2005–2011 ACE Program. ACE Program goals include partnering with communities to promote youth violence (YV) prevention and fostering connections between research and community practice. This article describes a qualitative evaluation of the 2005–2011 ACE Program using an innovative approach for collecting and analyzing data from multiple large research centers via a web-based Information System (ACE-IS). The ACE-IS was established as an efficient mechanism to collect and document ACE research and programmatic activities. Performance indicators for the ACE Program were established in an ACE Program logic model. Data on performance indicators were collected through the ACE-IS biannually. Data assessed Centers’ ability to develop, implement, and evaluate YV prevention activities. Performance indicator data demonstrate substantial progress on Centers’ research in YV risk and protective factors, community partnerships, and other accomplishments. Findings provide important lessons learned, illustrate progress made by the Centers, and point to new directions for YV prevention research and programmatic efforts. PMID:26319174

RNA Characterization by Solid-State NMR Spectroscopy.

PubMed

Yang, Yufei; Wang, Shenlin

2018-06-21

The structures of RNAs, which play critical roles in various biological processes, provide important clues and insights into the biological functions of these molecules. However, RNA structure determination remains a challenging topic. In recent years, magic-angle-spinning solid-state NMR (MAS SSNMR) has emerged as an alternative technique for structural and dynamic characterization of RNA. MAS SSNMR has been successfully applied to provide atomic-level structural information about several RNA molecules and RNA-protein complexes. In this Minireview, we give an overview of recent progress in the field of MAS SSNMR based RNA structural characterization, and introduce sample preparation strategies and SSNMR spectroscopic techniques that have been incorporated to identify RNA structural elements. We also highlight a few impressive examples of RNAs that have been investigated extensively by SSNMR. Finally, we briefly discuss future technical trends in the use of MAS SSNMR to facilitate RNA structure determination. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Blood type gene locus has no influence on ACE association with Alzheimer's disease.

PubMed

Braae, Anne; Medway, Christopher; Carrasquillo, Minerva; Younkin, Steven; Kehoe, Patrick G; Morgan, Kevin

2015-04-01

The ABO blood group locus was recently found to contribute independently and via interactions with angiotensin-converting enzyme (ACE) gene variation to plasma levels of ACE. Variation in ACE has previously been not only implicated as individually conferring susceptibility for Alzheimer's disease (AD) but also proposed to confer risk via interactions with other as yet unknown genes. More recently, larger studies have not supported ACE as a risk factor for AD, whereas the role of ACE pathway in AD has come under increased levels of scrutiny with respect to various aspects of AD pathology and possible therapies. We explored the potential combined involvement of ABO and ACE variations in the genetic susceptibility of 2067 AD cases compared with 1376 nondemented elderly. Including the effects of ABO haplotype did not provide any evidence for the genetic association of ACE with AD. Copyright © 2015 Elsevier Inc. All rights reserved.

Reporting of the translation and cultural adaptation procedures of the Addenbrooke's Cognitive Examination version III (ACE-III) and its predecessors: a systematic review.

PubMed

Mirza, Nadine; Panagioti, Maria; Waheed, Muhammad Wali; Waheed, Waquas

2017-09-13

The ACE-III, a gold standard for screening cognitive impairment, is restricted by language and culture, with no uniform set of guidelines for its adaptation. To develop guidelines a compilation of all the adaptation procedures undertaken by adapters of the ACE-III and its predecessors is needed. We searched EMBASE, Medline and PsychINFO and screened publications from a previous review. We included publications on adapted versions of the ACE-III and its predecessors, extracting translation and cultural adaptation procedures and assessing their quality. We deemed 32 papers suitable for analysis. 7 translation steps were identified and we determined which items of the ACE-III are culturally dependent. This review lists all adaptations of the ACE, ACE-R and ACE-III, rates the reporting of their adaptation procedures and summarises adaptation procedures into steps that can be undertaken by adapters.

Adverse childhood events and current depressive symptoms among women in Hawaii: 2010 BRFSS, Hawaii.

PubMed

Remigio-Baker, Rosemay A; Hayes, Donald K; Reyes-Salvail, Florentina

2014-12-01

Research on the association between adverse childhood events (ACEs) and depression among women in Hawaii is scarce. ACEs have been linked to unfavorable health behaviors such as smoking and binge drinking which are more prevalent in the state compared to the US overall. The concomitant presence of ACEs with smoking or binge drinking may explain the excess depression prevalence in Hawaii compared to the national average. Using data of women residing in the state (2010 Hawaii Behavioral Risk Factor Surveillance System Survey), we examined the association between ACEs count or type (household dysfunction and physical, verbal and sexual abuse) and current depressive symptoms (CDS), in addition to modification by current smoking status (smoked >100 cigarettes in a lifetime and currently smoke) and binge drinking (consumed ≥4 alcoholic beverage within the past month and in ≥1 occasion(s)). Evaluation of ACEs before age 18 consisted of 11 indicators. Eight indicators of the Patient Health Questionnaire (PHQ-8) were used to assess CDS. All analyses utilized logistic regression taking into account sampling design. The odds ratio of having CDS between those with versus without ACEs increased per increasing number of ACEs (1 ACE: OR = 2.11, CI = 1.16-3.81; 2 ACEs: OR = 2.90, CI = 1.51-5.58; 3 or 4 ACEs: OR = 3.94, CI = 2.13-7.32; 5+ ACEs: OR = 4.04, CI = 2.26-7.22). Household dysfunction (OR = 2.10, CI = 1.37-3.23), physical abuse (OR = 1.67, CI = 1.08-2.59), verbal abuse (OR = 3.21, CI = 2.03-5.09) and sexual abuse (OR = 1.68, CI = 1.04-2.71) were all positively associated with CDS. Verbal abuse had the strongest magnitude of association. Neither current smoking status nor binge drinking modified the relationship between ACEs count (or type) and CDS. In conclusion, the presence of ACEs among women in Hawaii was indicative of CDS in adulthood, notably verbal abuse. Further, a dose response existed between the number of ACEs and the odds for CDS. The concomitant exposure to ACEs and current smoking status or binge drinking did not elevate odds for CDS.

Adverse Childhood Experiences (ACEs) questionnaire and Adult Attachment Interview (AAI): implications for parent child relationships.

PubMed

Murphy, Anne; Steele, Miriam; Dube, Shanta Rishi; Bate, Jordan; Bonuck, Karen; Meissner, Paul; Goldman, Hannah; Steele, Howard

2014-02-01

Although Adverse Childhood Experiences (ACEs) are linked to increased health problems and risk behaviors in adulthood, there are no studies on the association between ACEs and adults' states of mind regarding their early childhood attachments, loss, and trauma experiences. To validate the ACEs questions, we analyzed the association between ACEs and emotional support indicators and Adult Attachment Interview (AAI) classifications in terms of unresolved mourning regarding past loss or trauma and discordant states of mind in cannot classify (U/CC) interviews. Seventy-five urban women (41 clinical and 34 community) completed a questionnaire on ACEs, which included 10 categories of abuse, neglect, and household dysfunction, in addition to emotional support. Internal psychological processes or states of mind concerning attachment were assessed using the AAI. ACE responses were internally consistent (Cronbach's α=.88). In the clinical sample, 84% reported≥4 ACEs compared to 27% among the community sample. AAIs judged U/CC occurred in 76% of the clinical sample compared to 9% in the community sample. When ACEs were≥4, 65% of AAIs were classified U/CC. Absence of emotional support in the ACEs questionnaire was associated with 72% of AAIs being classified U/CC. As the number of ACEs and the lack of emotional support increases so too does the probability of AAIs being classified as U/CC. Findings provide rationale for including ACEs questions in pediatric screening protocols to identify and offer treatment reducing the intergenerational transmission of risk associated with problematic parenting. Copyright © 2013 Elsevier Ltd. All rights reserved.

Identification and in silico characterization of a novel peptide inhibitor of angiotensin converting enzyme from pigeon pea (Cajanus cajan).

PubMed

Nawaz, K A Ayub; David, Swapna Merlin; Murugesh, Easwaran; Thandeeswaran, Murugesan; Kiran, Kalarikkal Gopikrishnan; Mahendran, Ramasamy; Palaniswamy, Muthusamy; Angayarkanni, Jayaraman

2017-12-01

Plants are important sources of bioactive peptides. Among these, angiotensin converting enzyme (ACE) inhibitory peptides have a major focus on their ability to prevent hypertension. Inhibition of ACE has been established as an effective approach for the treatment of ACE associated diseases. Some synthetic ACE inhibitory drugs cause side effects and hence there is a constant interest in natural compounds as alternatives. The study was designed to identify and characterize a peptide molecule from pigeon pea which has the biological property to inhibit ACE and can be developed as a therapeutic approach towards hypertension. Seeds of pigeon pea (Cajanus cajan (L.) Millsp.) was fermented with Aspergillus niger, a proteolytic fungus isolated from spoiled milk sweet. The extract was purified by size exclusion chromatography by FPLC system. The fractions that showed ACE inhibition was subjected to LC-MS/MS for sequence identification. The stability of the peptide was analyzed by molecular dynamic simulations and the interaction sites with ACE were identified by molecular docking. The study report a novel ACE inhibitory octapeptide Val-Val-Ser-Leu-Ser-Ile-Pro-Arg with a molecular mass of 869.53 Da. The Lineweaver-Burk plot indicated that the inhibition of ACE by this peptide is in competitive mode. Also, molecular docking and simulation studies showed a strong and stable interaction of the peptide with ACE. The results clearly show the inhibitory property of the peptide against ACE and hence it can be explored as a therapeutic strategy towards hypertension and other ACE associated diseases. Copyright © 2017 Elsevier GmbH. All rights reserved.

DNA Methylation Analysis of the Angiotensin Converting Enzyme (ACE) Gene in Major Depression

PubMed Central

Zill, Peter; Baghai, Thomas C.; Schüle, Cornelius; Born, Christoph; Früstück, Clemens; Büttner, Andreas; Eisenmenger, Wolfgang; Varallo-Bedarida, Gabriella; Rupprecht, Rainer; Möller, Hans-Jürgen; Bondy, Brigitta

2012-01-01

Background The angiotensin converting enzyme (ACE) has been repeatedly discussed as susceptibility factor for major depression (MD) and the bi-directional relation between MD and cardiovascular disorders (CVD). In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ∼40%–50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood. Materials and Methods The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls. Results We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008) and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02). Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04). Conclusion The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders. PMID:22808171

The two-component system GrvRS (EtaRS) regulates ace expression in Enterococcus faecalis OG1RF.

PubMed

Roh, Jung Hyeob; Singh, Kavindra V; La Rosa, Sabina Leanti; Cohen, Ana Luisa V; Murray, Barbara E

2015-01-01

Expression of ace (adhesin to collagen of Enterococcus faecalis), encoding a virulence factor in endocarditis and urinary tract infection models, has been shown to increase under certain conditions, such as in the presence of serum, bile salts, urine, and collagen and at 46 °C. However, the mechanism of ace/Ace regulation under different conditions is still unknown. In this study, we identified a two-component regulatory system GrvRS as the main regulator of ace expression under these stress conditions. Using Northern hybridization and β-galactosidase assays of an ace promoter-lacZ fusion, we found transcription of ace to be virtually absent in a grvR deletion mutant under the conditions that increase ace expression in wild-type OG1RF and in the complemented strain. Moreover, a grvR mutant revealed decreased collagen binding and biofilm formation as well as attenuation in a murine urinary tract infection model. Here we show that GrvR plays a major role in control of ace expression and E. faecalis virulence. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Spatial patterning of P granules by RNA-induced phase separation of the intrinsically-disordered protein MEG-3

PubMed Central

Smith, Jarrett; Calidas, Deepika; Schmidt, Helen; Lu, Tu; Rasoloson, Dominique; Seydoux, Geraldine

2016-01-01

RNA granules are non-membrane bound cellular compartments that contain RNA and RNA binding proteins. The molecular mechanisms that regulate the spatial distribution of RNA granules in cells are poorly understood. During polarization of the C. elegans zygote, germline RNA granules, called P granules, assemble preferentially in the posterior cytoplasm. We present evidence that P granule asymmetry depends on RNA-induced phase separation of the granule scaffold MEG-3. MEG-3 is an intrinsically disordered protein that binds and phase separates with RNA in vitro. In vivo, MEG-3 forms a posterior-rich concentration gradient that is anti-correlated with a gradient in the RNA-binding protein MEX-5. MEX-5 is necessary and sufficient to suppress MEG-3 granule formation in vivo, and suppresses RNA-induced MEG-3 phase separation in vitro. Our findings suggest that MEX-5 interferes with MEG-3’s access to RNA, thus locally suppressing MEG-3 phase separation to drive P granule asymmetry. Regulated access to RNA, combined with RNA-induced phase separation of key scaffolding proteins, may be a general mechanism for controlling the formation of RNA granules in space and time. DOI: http://dx.doi.org/10.7554/eLife.21337.001 PMID:27914198

Angiotensin I-Converting-Enzyme-Inhibitory and Antibacterial Peptides from Lactobacillus helveticus PR4 Proteinase-Hydrolyzed Caseins of Milk from Six Species

PubMed Central

Minervini, F.; Algaron, F.; Rizzello, C. G.; Fox, P. F.; Monnet, V.; Gobbetti, M.

2003-01-01

Sodium caseinates prepared from bovine, sheep, goat, pig, buffalo or human milk were hydrolyzed by a partially purified proteinase of Lactobacillus helveticus PR4. Peptides in each hydrolysate were fractionated by reversed-phase fast-protein liquid chromatography. The fractions which showed the highest angiotensin I-converting-enzyme (ACE)-inhibitory or antibacterial activity were sequenced by mass spectrum and Edman degradation analyses. Various ACE-inhibitory peptides were found in the hydrolysates: the bovine αS1-casein (αS1-CN) 24-47 fragment (f24-47), f169-193, and β-CN f58-76; ovine αS1-CN f1-6 and αS2-CN f182-185 and f186-188; caprine β-CN f58-65 and αS2-CN f182-187; buffalo β-CN f58-66; and a mixture of three tripeptides originating from human β-CN. A mixture of peptides with a C-terminal sequence, Pro-Gly-Pro, was found in the most active fraction of the pig sodium caseinate hydrolysate. The highest ACE-inhibitory activity of some peptides corresponded to the concentration of the ACE inhibitor (S)-N-(1-[ethoxycarbonyl]-3-phenylpropyl)-ala-pro maleate (enalapril) of 49.253 μg/ml (100 μmol/liter). Several of the above sequences had features in common with other ACE-inhibitory peptides reported in the literature. The 50% inhibitory concentration (IC50) of some of the crude peptide fractions was very low (16 to 100 μg/ml). Some identified peptides were chemically synthesized, and the ACE-inhibitory activity and IC50s were confirmed. An antibacterial peptide corresponding to β-CN f184-210 was identified in human sodium caseinate hydrolysate. It showed a very large spectrum of inhibition against gram-positive and -negative bacteria, including species of potential clinical interest, such as Enterococcus faecium, Bacillus megaterium, Escherichia coli, Listeria innocua, Salmonella spp., Yersinia enterocolitica, and Staphylococcus aureus. The MIC for E. coli F19 was ca. 50 μg/ml. Once generated, the bioactive peptides were resistant to further degradation by proteinase of L. helveticus PR4 or by trypsin and chymotrypsin. PMID:12957917

Pharmacologic modulation of ACE2 expression.

PubMed

Soler, María José; Barrios, Clara; Oliva, Raymond; Batlle, Daniel

2008-10-01

Angiotensin-converting enzyme 2 (ACE2) is an enzymatically active homologue of angiotensin-converting enzyme that degrades angiotensin I, angiotensin II, and other peptides. Recent studies have shown that under pathologic conditions, ACE2 expression in the kidney is altered. In this review, we briefly summarize recent studies dealing with pharmacologic interventions that modulate ACE2 expression. ACE2 amplification may have a potential therapeutic role for kidney disease and hypertension.

A Discussion of Aerodynamic Control Effectors (ACEs) for Unmanned Air Vehicles (UAVs)

NASA Technical Reports Server (NTRS)

Wood, Richard M.

2002-01-01

A Reynolds number based, unmanned air vehicle classification structure has been developed which identifies four classes of unmanned air vehicle concepts. The four unmanned air vehicle (UAV) classes are; Micro UAV, Meso UAV, Macro UAV, and Mega UAV. In a similar fashion a labeling scheme for aerodynamic control effectors (ACE) was developed and eleven types of ACE concepts were identified. These eleven types of ACEs were laid out in a five (5) layer scheme. The final section of the paper correlated the various ACE concepts to the four UAV classes and ACE recommendations are offered for future design activities.

A Low-Protein Diet Enhances Angiotensin II Production in the Lung of Pregnant Rats but Not Nonpregnant Rats

PubMed Central

Gao, Haijun; Tanchico, Daren Tubianosa; Yallampalli, Uma; Yallampalli, Chandrasekhar

2016-01-01

Pulmonary angiotensin II production is enhanced in pregnant rats fed a low-protein (LP) diet. Here we assessed if LP diet induces elevations in angiotensin II production in nonpregnant rats and whether Ace expression and ACE activity in lungs are increased. Nonpregnant rats were fed a normal (CT) or LP diet for 8, 12, or 17 days and timed pregnant rats fed for 17 days from Day 3 of pregnancy. Plasma angiotensin II, expressions of Ace and Ace2, and activities of these proteins in lungs, kidneys, and plasma were measured. These parameters were compared among nonpregnant rats or between nonpregnant and pregnant rats fed different diets. Major findings are as follows: (1) plasma angiotensin II levels were slightly higher in the LP than CT group on Days 8 and 12 in nonpregnant rats; (2) expression of Ace and Ace2 and abundance and activities of ACE and ACE2 in lungs, kidneys, and plasma of nonpregnant rats were unchanged by LP diet except for minor changes; (3) the abundance and activities of ACE in lungs of pregnant rats fed LP diet were greater than nonpregnant rats, while those of ACE2 were decreased. These results indicate that LP diet-induced increase in pulmonary angiotensin II production depends on pregnancy. PMID:27195150

Associations between ACE-Inhibitors, Angiotensin Receptor Blockers, and Lean Body Mass in Community Dwelling Older Women.

PubMed

Bea, Jennifer W; Wassertheil-Smoller, Sylvia; Wertheim, Betsy C; Klimentidis, Yann; Chen, Zhao; Zaslavsky, Oleg; Manini, Todd M; Womack, Catherine R; Kroenke, Candyce H; LaCroix, Andrea Z; Thomson, Cynthia A

2018-01-01

Studies suggest that ACE-inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) may preserve skeletal muscle with aging. We evaluated longitudinal differences in lean body mass (LBM) among women diagnosed with hypertension and classified as ACE-I/ARB users and nonusers among Women's Health Initiative participants that received dual energy X-ray absorptiometry scans to estimate body composition ( n =10,635) at baseline and at years 3 and 6 of follow-up. Of those, 2642 were treated for hypertension at baseline. Multivariate linear regression models, adjusted for relevant demographics, behaviors, and medications, assessed ACE-I/ARB use/nonuse and LBM associations at baseline, as well as change in LBM over 3 and 6 years. Although BMI did not differ by ACE-I/ARB use, LBM (%) was significantly higher in ACE-I/ARB users versus nonusers at baseline (52.2% versus 51.3%, resp., p =0.001). There was no association between ACE-I/ARB usage and change in LBM over time. Reasons for higher LBM with ACE-I/ARB use cross sectionally, but not longitundinally, are unclear and may reflect a threshold effect of these medications on LBM that is attenuated over time. Nevertheless, ACE-I/ARB use does not appear to negatively impact LBM in the long term.

Adverse Childhood Experiences and Disordered Gambling: Assessing the Mediating Role of Emotion Dysregulation.

PubMed

Poole, Julia C; Kim, Hyoun S; Dobson, Keith S; Hodgins, David C

2017-12-01

Adverse childhood experiences (ACEs), such as sexual and physical abuse, have been established as risk factors for the development of disordered gambling. The underlying mechanism by which ACEs influence disordered gambling, however, remains unknown. The aims of the present research were to comprehensively investigate ten types of childhood adversity and their relationships to disordered gambling in adulthood, and to test whether emotion dysregulation mediated the relationship between ACEs and disordered gambling. A sample of community gamblers (N = 414) completed self-report measures of ACEs, emotion dysregulation, and gambling severity. Results revealed a significant association between all but one type (physical abuse) of ACEs and disordered gambling. Further, the results highlighted the cumulative impact of ACEs on gambling. Specifically, individuals who experienced three or more types of ACEs were more than three times as likely to report disordered gambling as compared to individuals with no history of childhood adversity. Importantly, as hypothesized, emotion dysregulation mediated the relationship between ACEs and disordered gambling. Findings from this research describe the association between ACEs and gambling and indicate a causal link between childhood adversity and disordered gambling. Results suggest that treatment initiatives may do well to address both ACEs and emotion dysregulation in the treatment of problem gambling.

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

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-06

... designed to replace a specific legacy ACS function. Each release will begin with a test and will end with... Pre-Approval Please be advised that this first phase of the DIS test is limited to the above CBP and... all interested parties to comment on the design, implementation and conduct of the test at any time...

Microbial diversity and dynamics during methane production from municipal solid waste

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bareither, Christopher A., E-mail: christopher.bareither@colostate.edu; Geological Engineering, University of Wisconsin-Madison, Madison, WI 53706; Wolfe, Georgia L., E-mail: gwolfe@wisc.edu

2013-10-15

Highlights: ► Similar bacterial communities developed following different start-up operation. ► Total methanogens in leachate during the decelerated methane phase reflected overall methane yield. ► Created correlations between methanogens, methane yield, and available substrate. ► Predominant bacteria identified with syntrophic polysaccharide degraders. ► Hydrogenotrophic methanogens were dominant in the methane generation process. - Abstract: The objectives of this study were to characterize development of bacterial and archaeal populations during biodegradation of municipal solid waste (MSW) and to link specific methanogens to methane generation. Experiments were conducted in three 0.61-m-diameter by 0.90-m-tall laboratory reactors to simulate MSW bioreactor landfills. Pyrosequencing ofmore » 16S rRNA genes was used to characterize microbial communities in both leachate and solid waste. Microbial assemblages in effluent leachate were similar between reactors during peak methane generation. Specific groups within the Bacteroidetes and Thermatogae phyla were present in all samples and were particularly abundant during peak methane generation. Microbial communities were not similar in leachate and solid fractions assayed at the end of reactor operation; solid waste contained a more abundant bacterial community of cellulose-degrading organisms (e.g., Firmicutes). Specific methanogen populations were assessed using quantitative polymerase chain reaction. Methanomicrobiales, Methanosarcinaceae, and Methanobacteriales were the predominant methanogens in all reactors, with Methanomicrobiales consistently the most abundant. Methanogen growth phases coincided with accelerated methane production, and cumulative methane yield increased with increasing total methanogen abundance. The difference in methanogen populations and corresponding methane yield is attributed to different initial cellulose and hemicellulose contents of the MSW. Higher initial cellulose and hemicellulose contents supported growth of larger methanogen populations that resulted in higher methane yield.« less

Optimal attitude maneuver execution for the Advanced Composition Explorer (ACE) mission

NASA Technical Reports Server (NTRS)

Woodard, Mark A.; Baker, David

1995-01-01

The Advanced Composition Explorer (ACE) spacecraft will require frequent attitude reorientations in order to maintain the spacecraft high gain antenna (HGA) within 3 deg of earth-pointing. These attitude maneuvers will be accomplished by employing a series of ground-commanded thruster pulses, computed by ground operations personnel, to achieve the desired change in the spacecraft angular momentum vector. With each maneuver, attitude nutation will be excited. Large nutation angles are undesirable from a science standpoint. It is important that the thruster firings be phased properly in order to minimize the nutation angle at the end of the maneuver so that science collection time is maximized. The analysis presented derives a simple approximation for the nutation contribution resulting from a series of short thruster burns. Analytic equations are derived which give the induced nutation angle as a function of the number of small thruster burns used to execute the attitude maneuver and the phasing of the burns. The results show that by properly subdividing the attitude burns, the induced nutation can be kept low. The analytic equations are also verified through attitude dynamics simulation and simulation results are presented. Finally, techniques for quantifying the post-maneuver nutation are discussed.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Daud, A.I.; Bumpus, F.M.; Husain, A.

Ovarian angiotensin I (Ang I)-converting enzyme (ACE), estimated by the specific binding of the ACE inhibitor (125I)iodo-MK-351A, is localized on multiple ovarian structures, including follicular granulosa cells, corpora lutea, terminal epithelium, and ovarian blood vessels, but total ovarian ACE does not display a cyclic pattern of variation during the rat estrous cycle. We have previously shown that ACE is localized on the granulosa cell layer of a subpopulation of rat ovarian follicles. Our present study shows that ovarian granulosa cells contain high affinity (binding site affinity (Kd), approximately 90 pM) and low capacity (binding site density (Bmax), approximately 12 fmol/2.5more » X 10(5) cells) (125I)iodo-MK-351A-binding sites and convert (125I)iodo-Ang I to (125I)iodo-Ang II (greater than 85% of this conversion was inhibited by the ACE inhibitor captopril). Throughout the rat estrous cycle, 94-100% of developing follicles and 89-96% of atretic follicles contained high levels of ACE; however, ACE was either not observed or its levels were very low in preovulatory follicles. These findings indicate the presence of high levels of biologically active ACE on the surface of granulosa cells and suggest a potential role for follicular ACE in early stages of follicular maturation and atresia. Although ACE is known to process a variety of peptides found within the ovary, and these peptides may have opposing effects on follicular maturation, we attempted to define the cumulative effect of ACE inhibition on follicular maturation.« less

ACE genotype, phenotype and all-cause mortality in different cohorts of patients with type 1 diabetes.

PubMed

Færch, Louise H; Sejling, Anne-Sophie; Lajer, Maria; Tarnow, Lise; Thorsteinsson, Birger; Pedersen-Bjergaard, Ulrik

2015-06-01

Carrying the D-allele of the angiotensin-converting enzyme (ACE) I/D polymorphism and high ACE activity are prognostic factors in diabetic nephropathy, which predicts mortality in type 1 diabetes. We studied the association between the ACE D-allele and ACE phenotype and long-term all-cause mortality in three single-institution outpatient cohorts. Genotype-based analyses were performed in 269 patients from Hillerød Hospital (HIH) (follow-up: 12 years) and in 439 patients with diabetic nephropathy and 437 patients with persistent normoalbuminuria from the Steno Diabetes Center (SDC) (follow-up: 9.5 years). Patients not on renin-angiotensin system (RAS)-blocking treatment were included in analyses of serum ACE activity (HIH: n = 208) and plasma ACE concentration (SDC: n=269). In the HIH cohort, carrying a D-allele was associated with excess mortality (hazard ratio (HR) = 4.0 (95% confidence interval (CI) 1.0-16)), but not in the SDC cohorts. At HIH, serum ACE activity was associated with excess mortality (HR=1.04 (95% CI 1.0-1.1 per unit increase)), but in the SDC cohort plasma ACE concentration was not. In unselected patients with type 1 diabetes, carrying the ACE D-allele and high spontaneous serum ACE activity were associated with 12-year excess mortality. These findings could not be reproduced in two other cohorts with persistent normoalbuminuria or diabetic nephropathy. © The Author(s) 2013.

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

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-14

... Program (NCAP) Test Concerning Automated Commercial Environment (ACE) Simplified Entry: Modification of... Automated Commercial Environment (ACE). The test's participant selection criteria are modified to reflect... (NCAP) test concerning Automated Commercial Environment (ACE) Simplified Entry functionality (Simplified...

ACE2 alterations in kidney disease.

PubMed

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

2013-11-01

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

ACE2 alterations in kidney disease

PubMed Central

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

2013-01-01

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

Activation of cardiac renin-angiotensin system and plasminogen activator inhibitor-1 gene expressions in oral contraceptive-induced cardiometabolic disorder.

PubMed

Olatunji, Lawrence A; Usman, Taofeek O; Seok, Young-Mi; Kim, In-Kyeom

2017-02-01

Clinical studies have shown that combined oral contraceptive (COC) use is associated with cardiometabolic disturbances. Elevated renin-angiotensin system (RAS) and plasminogen activator inhibitor-1 (PAI-1) have also been implicated in the development of cardiometabolic events. To determine the effect of COC treatment on cardiac RAS and PAI-1 gene expressions, and whether the effect is circulating aldosterone or corticosterone dependent. Female rats were treated (p.o.) with olive oil (vehicle) or COC (1.0 µg ethinylestradiol and 10.0 µg norgestrel) daily for six weeks. COC treatment led to increases in blood pressure, HOMA-IR, Ace1 mRNA, Atr1 mRNA, Pai1 mRNA, cardiac PAI-1, plasma PAI-1, C-reactive protein, uric acid, insulin and corticosterone. COC treatment also led to dyslipidemia, decreased glucose tolerance and plasma 17β-estradiol. These results demonstrates that hypertension and insulin resistance induced by COC is associated with increased cardiac RAS and PAI-1 gene expression, which is likely to be through corticosterone-dependent but not aldosterone-dependent mechanism.

Chronic School Absenteeism and the Role of Adverse Childhood Experiences.

PubMed

Stempel, Hilary; Cox-Martin, Matthew; Bronsert, Michael; Dickinson, L Miriam; Allison, Mandy A

To examine the association between chronic school absenteeism and adverse childhood experiences (ACEs) among school-age children. We conducted a secondary analysis of data from the 2011-2012 National Survey of Children's Health including children 6 to 17 years old. The primary outcome variable was chronic school absenteeism (≥15 days absent in the past year). We examined the association between chronic school absenteeism and ACEs by logistic regression with weighting for individual ACEs, summed ACE score, and latent class analysis of ACEs. Among the 58,765 school-age children in the study sample, 2416 (4.1%) experienced chronic school absenteeism. Witnessing or experiencing neighborhood violence was the only individual ACE significantly associated with chronic absenteeism (adjusted odds ratio [aOR] 1.55, 95% confidence interval [CI] 1.20-2.01). Having 1 or more ACE was significantly associated with chronic absenteeism: 1 ACE (aOR 1.35, 95% CI 1.02-1.79), 2 to 3 ACEs (aOR 1.81, 95% CI 1.39-2.36), and ≥4 ACEs (aOR 1.79, 95% CI 1.32-2.43). Three of the latent classes were also associated with chronic absenteeism, and children in these classes had a high probability of endorsing neighborhood violence, family substance use, or having multiple ACEs. ACE exposure was associated with chronic school absenteeism in school-age children. To improve school attendance, along with future graduation rates and long-term health, these findings highlight the need for an interdisciplinary approach to address child adversity that involves pediatricians, mental health providers, schools, and public health partners. Copyright © 2017 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

Poster - 07: Investigations of the Advanced Collapsed-cone Engine for HDR Brachytherapy Scalp Treatments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cawston-Grant, Brie; Morrison, Hali; Sloboda, Ron

Purpose: To present an investigation of the Advanced Collapsed-cone Engine (ACE) in Oncentraê Brachy (OcB) v4.5 using a tissue equivalent phantom modeling scalp brachytherapy (BT) treatments. Methods: A slab phantom modeling the skin, skull, brain and mold was used. A dose of 400cGy was prescribed to just above the skull layer using TG-43 and was delivered using an HDR afterloader. Measurements were made using Gafchromic™ EBT3 film at four depths within the phantom. The TG-43 planned and film measured doses were compared to the standard (sACE) and high (hACE) accuracy ACE options in OcB between the surface and below themore » skull. Results: The average difference between the TG-43 calculated and film measured doses was −11.25±3.38% when there was no air gap between the mold and skin; sACE and hACE doses were on average lower than TG-43 calculated doses by 3.41±0.03% and 2.45±0.03%, respectively. With a 3mm air gap between the mold and skin, the difference between the TG-43 calculated and measured doses was −8.28±5.76%; sACE and hACE calculations yielded average doses 1.87±0.03% and 1.78±0.04% greater than TG-43, respectively. Conclusions: TG-43, sACE, and hACE were found to overestimate doses below the skull layer compared to film. With a 3mm air gap between the mold and skin, sACE and hACE more accurately predicted the film dose to the skin surface than TG-43. More clinical variations and their implications are currently being investigated.« less

Angiotensin I-Converting Enzyme Inhibitor Derived from Cross-Linked Oyster Protein

PubMed Central

Xie, Cheng-Liang; Kim, Jin-Soo; Ha, Jong-Myung; Choung, Se-Young

2014-01-01

Following cross-linking by microbial transglutaminase, modified oyster proteins were hydrolyzed to improve inhibitory activity against angiotensin-converting enzyme (ACE) inhibitory activity with the use of a single protease, or a combination of six proteases. The oyster hydrolysate with the lowest 50% ACE inhibitory concentration (IC50) of 0.40 mg/mL was obtained by two-step hydrolysis of the cross-linked oyster protein using Protamex and Neutrase. Five ACE inhibitory peptides were purified from the oyster hydrolysate using a multistep chromatographic procedure comprised of ion-exchange, size exclusion, and reversed-phase liquid chromatography. Their sequences were identified as TAY, VK, KY, FYN, and YA, using automated Edman degradation and mass spectrometry. These peptides were synthesized, and their IC50 values were measured to be 16.7, 29.0, 51.5, 68.2, and 93.9 μM, respectively. Toxicity of the peptides on the HepG2 cell line was not detected. The oyster hydrolysate also significantly decreased the systolic blood pressure of spontaneously hypertensive rats (SHR). The antihypertensive effect of the oyster hydrolysate on SHR was rapid and long-lasting, compared to commercially obtained sardine hydrolysate. These results suggest that the oyster hydrolysate could be a source of effective nutraceuticals against hypertension. PMID:25140307

Single molecule tracking of Ace1p in Saccharomyces cerevisiae defines a characteristic residence time for non-specific interactions of transcription factors with chromatin.

PubMed

Ball, David A; Mehta, Gunjan D; Salomon-Kent, Ronit; Mazza, Davide; Morisaki, Tatsuya; Mueller, Florian; McNally, James G; Karpova, Tatiana S

2016-12-01

In vivo single molecule tracking has recently developed into a powerful technique for measuring and understanding the transient interactions of transcription factors (TF) with their chromatin response elements. However, this method still lacks a solid foundation for distinguishing between specific and non-specific interactions. To address this issue, we took advantage of the power of molecular genetics of yeast. Yeast TF Ace1p has only five specific sites in the genome and thus serves as a benchmark to distinguish specific from non-specific binding. Here, we show that the estimated residence time of the short-residence molecules is essentially the same for Hht1p, Ace1p and Hsf1p, equaling 0.12-0.32 s. These three DNA-binding proteins are very different in their structure, function and intracellular concentration. This suggests that (i) short-residence molecules are bound to DNA non-specifically, and (ii) that non-specific binding shares common characteristics between vastly different DNA-bound proteins and thus may have a common underlying mechanism. We develop new and robust procedure for evaluation of adverse effects of labeling, and new quantitative analysis procedures that significantly improve residence time measurements by accounting for fluorophore blinking. Our results provide a framework for the reliable performance and analysis of single molecule TF experiments in yeast. Published by Oxford University Press on behalf of Nucleic Acids Research 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Mechanisms of Host Receptor Adaptation by Severe Acute Respiratory Syndrome Coronavirus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Kailang; Peng, Guiqing; Wilken, Matthew

The severe acute respiratory syndrome coronavirus (SARS-CoV) from palm civets has twice evolved the capacity to infect humans by gaining binding affinity for human receptor angiotensin-converting enzyme 2 (ACE2). Numerous mutations have been identified in the receptor-binding domain (RBD) of different SARS-CoV strains isolated from humans or civets. Why these mutations were naturally selected or how SARS-CoV evolved to adapt to different host receptors has been poorly understood, presenting evolutionary and epidemic conundrums. In this study, we investigated the impact of these mutations on receptor recognition, an important determinant of SARS-CoV infection and pathogenesis. Using a combination of biochemical, functional,more » and crystallographic approaches, we elucidated the molecular and structural mechanisms of each of these naturally selected RBD mutations. These mutations either strengthen favorable interactions or reduce unfavorable interactions with two virus-binding hot spots on ACE2, and by doing so, they enhance viral interactions with either human (hACE2) or civet (cACE2) ACE2. Therefore, these mutations were viral adaptations to either hACE2 or cACE2. To corroborate the above analysis, we designed and characterized two optimized RBDs. The human-optimized RBD contains all of the hACE2-adapted residues (Phe-442, Phe-472, Asn-479, Asp-480, and Thr-487) and possesses exceptionally high affinity for hACE2 but relative low affinity for cACE2. The civet-optimized RBD contains all of the cACE2-adapted residues (Tyr-442, Pro-472, Arg-479, Gly-480, and Thr-487) and possesses exceptionally high affinity for cACE2 and also substantial affinity for hACE2. These results not only illustrate the detailed mechanisms of host receptor adaptation by SARS-CoV but also provide a molecular and structural basis for tracking future SARS-CoV evolution in animals.« less

Mechanisms of Host Receptor Adaptation by Severe Acute Respiratory Syndrome Coronavirus*

PubMed Central

Wu, Kailang; Peng, Guiqing; Wilken, Matthew; Geraghty, Robert J.; Li, Fang

2012-01-01

The severe acute respiratory syndrome coronavirus (SARS-CoV) from palm civets has twice evolved the capacity to infect humans by gaining binding affinity for human receptor angiotensin-converting enzyme 2 (ACE2). Numerous mutations have been identified in the receptor-binding domain (RBD) of different SARS-CoV strains isolated from humans or civets. Why these mutations were naturally selected or how SARS-CoV evolved to adapt to different host receptors has been poorly understood, presenting evolutionary and epidemic conundrums. In this study, we investigated the impact of these mutations on receptor recognition, an important determinant of SARS-CoV infection and pathogenesis. Using a combination of biochemical, functional, and crystallographic approaches, we elucidated the molecular and structural mechanisms of each of these naturally selected RBD mutations. These mutations either strengthen favorable interactions or reduce unfavorable interactions with two virus-binding hot spots on ACE2, and by doing so, they enhance viral interactions with either human (hACE2) or civet (cACE2) ACE2. Therefore, these mutations were viral adaptations to either hACE2 or cACE2. To corroborate the above analysis, we designed and characterized two optimized RBDs. The human-optimized RBD contains all of the hACE2-adapted residues (Phe-442, Phe-472, Asn-479, Asp-480, and Thr-487) and possesses exceptionally high affinity for hACE2 but relative low affinity for cACE2. The civet-optimized RBD contains all of the cACE2-adapted residues (Tyr-442, Pro-472, Arg-479, Gly-480, and Thr-487) and possesses exceptionally high affinity for cACE2 and also substantial affinity for hACE2. These results not only illustrate the detailed mechanisms of host receptor adaptation by SARS-CoV but also provide a molecular and structural basis for tracking future SARS-CoV evolution in animals. PMID:22291007

Sexual Identity, Adverse Childhood Experiences, and Suicidal Behaviors.

PubMed

Clements-Nolle, Kristen; Lensch, Taylor; Baxa, Amberlee; Gay, Christopher; Larson, Sandra; Yang, Wei

2018-02-01

The objective of this study was to examine the influence of sexual identity and adverse childhood experiences (ACEs) on suicidal behaviors in a population-based sample of high school students. A two-stage cluster random sampling design was used to recruit 5,108 students from 97 high schools. A total of 4,955 students (97%) provided information that allowed for classification of sexual identity into three groups: (1) lesbian, gay, or bisexual (LGB) (10%); (2) not sure (4.6%); and (3) heterosexual (85.4%). Five measures of childhood abuse and household dysfunction were summed, and the ACE score was categorized as 0, 1, 2, and 3-5 ACEs. Weighted logistic regression was used to assess the influence of sexual identity, ACEs, and their interaction on suicide ideation and attempts in the past 12 months. Compared with heterosexual students, those who were LGB and were not sure had higher odds of suicide ideation and attempts. There was also a graded relationship between cumulative ACE exposure and suicidal behaviors. Although sexual identity/ACE interaction was not observed, LGB/not sure students who experienced a high number of ACEs were disproportionately affected. Compared with heterosexual students with 0 ACE, LGB/not sure students with 0 ACE (adjusted odds ratio [AOR] = 3.32, 95% confidence interval [CI] = 1.96-5.61), 1 ACE (AOR = 6.58, 95% CI = 4.05-10.71), 2 ACEs (AOR 13.50, 95% CI = 8.45-21.58), and 3-5 ACEs (AOR = 14.04, 95% CI = 8.72, 22.62) had higher odds of suicide ideation. A similar pattern was observed for suicide attempts. LGB and students not sure of their sexual identity with greater exposure to ACEs have disproportionately high levels of suicide ideation and attempts. Trauma-informed interventions for these populations are warranted. Copyright © 2017 The Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dhawale, Vaibhav Shrirang; Amara, Venkateswara Rao

Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2 weeks. 48 h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocytemore » count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1β, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers. - Highlights: • Diminazene aceturate (DIZE), an ACE2 activator prevents ovalbumin-induced asthma. • DIZE acted by upregulating ACE2, downregulating ACE1, MAPKs, markers of inflammation, apoptosis. • DIZE reduced airway inflammation, fibrosis, right ventricular hypertrophy and restored airway responsiveness.« less

Antiproliferative effect of Antrodia camphorata polysaccharides encapsulated in chitosan-silica nanoparticles strongly depends on the metabolic activity type of the cell line

NASA Astrophysics Data System (ADS)

Kong, Zwe-Ling; Chang, Jenq-Sheng; Chang, Ke Liang B.

2013-09-01

Chitosan molecules interact with silica and encapsulate the Antrodia camphorata extract (ACE) polysaccharides to form composite nanoparticles. The nanoparticle suspensions of ACE polysaccharides encapsulated in silica-chitosan and silica nanoparticles approach an average particle size of 210 and 294 nm in solution, respectively. The encapsulation efficiencies of ACE polysaccharides are 66 and 63.5 %, respectively. Scanning electron micrographs confirm the formation of near-spherical nanoparticles. ACE polysaccharides solution had better antioxidative capability than ACE polysaccharides encapsulated in silica or silica-chitosan nanoparticles suspensions. The antioxidant capacity of nanoparticles increases with increasing dissolution time. The antitumor effects of ACE polysaccharides, ACE polysaccharides encapsulated in silica, or silica-chitosan nanoparticles increased with increasing concentration of nanoparticles. This is the first report demonstrating the potential of ACE polysaccharides encapsulated in chitosan-silica nanoparticles for cancer chemoprevention. Furthermore, this study suggests that antiproliferative effect of nanoparticle-encapsulated bioactive could significantly depend on the metabolic activity type of the cell line.

[Angiotensin converting enzyme: the antigenic properties of the domain, role in Alzheimer's disease and tumor progression].

PubMed

Kugaevskaya, E V; Timoshenko, O S; Solovyeva, N I

2015-01-01

Angiotensin converting enzyme (ACE, EC 3.4.15.1) was discovered and characterized in the Laboratory of biochemistry and chemical pathology of proteins under the direction of academician V.N. Orekhovich, where its physiological function, associated with a key role in the regulation of the renin-angiotensin (RAS) and the kallikrein-kinin systems that control blood flow in the body and homeostasis was first deciphered. We carried out a search for structural differences between the two highly homologous domains (N- and C-domains) of somatic ACE (sACE); it was based on a comparative analysis of antigenic determinants (or B-epitopes) of both domains. The revealed epitopes were classified with variable and conserved regions and functionally important sites of the molecule ACE. Essential difference was demonstrated between locations of the epitopes in the N- and C-domains. These data indicate the existence of structural differences between the domains of sACE. We studied the role of the domains of ACE in the metabolism of human amyloid beta peptide (Ab) - the main component of senile plaques, found in the brains of patients with Alzheimer's disease (AD). Our results demonstrated that only N-domain ACE cleaved the Ab between residues R5-H6, while, the C-domain of ACE failed to hydrolyze this region. In addition, the effect of post-translational modifications of Ab on its hydrolysis by the ACE was investigated. We show that isomerization of residue D7, a common non-enzymatic age-related modification found in AD-associated species, does not reduce the affinity of the peptide to the N-domain of ACE, and conversely, it increases. According to our data, the role of ACE in the metabolism of Ab becomes more significant in the development of AD. RAS is involved in malignant transformation and tumor progression. RAS components, including ACE and angiotensin II receptors type 1 (AT1R) are expressed in various human tumors. We found a significant increase in the level of ACE activity in the tumor tissue of squamous cell carcinoma of the cervix. In our viewpoint, the increase in ACE activity may be a marker of poor clinical prognosis.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Villard, E.; Soubrier, F.; Tiret, L.

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 couldmore » 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.« less

The Angiotensin Converting Enzyme Insertion/Deletion Polymorphism Modifies Exercise-Induced Muscle Metabolism

PubMed Central

Vaughan, David; Brogioli, Michael; Maier, Thomas; White, Andy; Waldron, Sarah; Rittweger, Jörn; Toigo, Marco; Wettstein, Jessica; Laczko, Endre; Flück, Martin

2016-01-01

Objective A silencer region (I-allele) within intron 16 of the gene for the regulator of vascular perfusion, angiotensin-converting enzyme (ACE), is implicated in phenotypic variation of aerobic fitness and the development of type II diabetes. We hypothesised that the reportedly lower aerobic performance in non-carriers compared to carriers of the ACE I-allele, i.e. ACE-DD vs. ACE-ID/ACE-II genotype, is associated with alterations in activity-induced glucose metabolism and capillarisation in exercise muscle. Methods Fifty-three, not-specifically trained Caucasian men carried out a one-legged bout of cycling exercise to exhaustion and/or participated in a marathon, the aim being to identify and validate genotype effects on exercise metabolism. Respiratory exchange ratio (RER), serum glucose and lipid concentration, glycogen, and metabolite content in vastus lateralis muscle based on ultra-performance lipid chromatography-mass spectrometry (UPLC-MS), were assessed before and after the cycling exercise in thirty-three participants. Serum metabolites were measured in forty subjects that completed the marathon. Genotype effects were assessed post-hoc. Results Cycling exercise reduced muscle glycogen concentration and this tended to be affected by the ACE I-allele (p = 0.09). The ACE-DD genotype showed a lower maximal RER and a selective increase in serum glucose concentration after exercise compared to ACE-ID and ACE-II genotypes (+24% vs. +2% and –3%, respectively). Major metabolites of mitochondrial metabolism (i.e. phosphoenol pyruvate, nicotinamide adenine dinucleotide phosphate, L-Aspartic acid, glutathione) were selectively affected in vastus lateralis muscle by exercise in the ACE-DD genotype. Capillary-to-fibre ratio was 24%-lower in the ACE-DD genotype. Individuals with the ACE-DD genotype demonstrated an abnormal increase in serum glucose to 7.7 mM after the marathon. Conclusion The observations imply a genetically modulated role for ACE in control of glucose import and oxidation in working skeletal muscle. ACE-DD genotypes thereby transit into a pre-diabetic state with exhaustive exercise, which relates to a lowered muscle capillarisation, and deregulation of mitochondria-associated metabolism. PMID:26982073

Identification and the molecular mechanism of a novel myosin-derived ACE inhibitory peptide.

PubMed

Yu, Zhipeng; Wu, Sijia; Zhao, Wenzhu; Ding, Long; Shiuan, David; Chen, Feng; Li, Jianrong; Liu, Jingbo

2018-01-24

The objective of this work was to identify a novel ACE inhibitory peptide from myosin using a number of in silico methods. Myosin was evaluated as a substrate for use in the generation of ACE inhibitory peptides using BIOPEP and ExPASy PeptideCutter. Then the ACE inhibitory activity prediction of peptides in silico was evaluated using the program peptide ranker, following the database search of known and unknown peptides using the program BIOPEP. In addition, the interaction mechanisms of the peptide and ACE were evaluated by DS. All of the tripeptides were predicted to be nontoxic. Results suggested that the tripeptide NCW exerted potent ACE inhibitory activity with an IC 50 value of 35.5 μM. Furthermore, the results suggested that the peptide NCW comes into contact with Zn 701, Tyr 523, His 383, Glu 384, Glu 411, and His 387. The potential molecular mechanism of the NCW/ACE interaction was investigated. Results confirmed that the higher inhibitory potency of NCW might be attributed to the formation of more hydrogen bonds with the ACE's active site. Therefore, the in silico method is effective to predict and identify novel ACE inhibitory peptides from protein hydrolysates.

Activation pattern of ACE2/Ang-(1-7) and ACE/Ang II pathway in course of heart failure assessed by multiparametric MRI in vivo in Tgαq*44 mice.

PubMed

Tyrankiewicz, Urszula; Olkowicz, Mariola; Skórka, Tomasz; Jablonska, Magdalena; Orzylowska, Anna; Bar, Anna; Gonet, Michal; Berkowicz, Piotr; Jasinski, Krzysztof; Zoladz, Jerzy A; Smolenski, Ryszard T; Chlopicki, Stefan

2018-01-01

Here, we analyzed systemic (plasma) and local (heart/aorta) changes in ACE/ACE-2 balance in Tgαq*44 mice in course of heart failure (HF). Tgαq*44 mice with cardiomyocyte-specific Gαq overexpression and late onset of HF were analyzed at different age for angiotensin pattern in plasma, heart, and aorta using liquid chromatography/mass spectrometry, for progression of HF by in vivo magnetic resonance imaging under isoflurane anesthesia, and for physical activity by voluntary wheel running. Six-month-old Tgαq*44 mice displayed decreased ventricle radial strains and impaired left atrial function. At 8-10 mo, Tgαq*44 mice showed impaired systolic performance and reduced voluntary wheel running but exhibited preserved inotropic reserve. At 12 mo, Tgαq*44 mice demonstrated a severe impairment of basal cardiac performance and modestly compromised inotropic reserve with reduced voluntary wheel running. Angiotensin analysis in plasma revealed an increase in concentration of angiotensin-(1-7) in 6- to 10-mo-old Tgαq*44 mice. However, in 12- to 14-mo-old Tgαq*44 mice, increased angiotensin II was noted with a concomitant increase in Ang III, Ang IV, angiotensin A, and angiotensin-(1-10). The pattern of changes in the heart and aorta was also compatible with activation of ACE2, followed by activation of the ACE pathway. In conclusion, mice with cardiomyocyte Gαq protein overexpression develop HF that is associated with activation of the systemic and the local ACE/Ang II pathway. However, it is counterbalanced by a prominent ACE2/Ang-(1-7) activation, possibly allowing to delay decompensation. NEW & NOTEWORTHY Changes in ACE/ACE-2 balance were analyzed based on measurements of a panel of nine angiotensins in plasma, heart, and aorta of Tgαq*44 mice in relation to progression of heart failure (HF) characterized by multiparametric MRI and exercise performance. The early stage of HF was associated with upregulation of the ACE2/angiotensin-(1-7) pathway, whereas the end-stage HF was associated with downregulation of ACE2/angiotensin-(1-7) and upregulation of the ACE/Ang II pathway. ACE/ACE-2 balance seems to determine the decompensation of HF in this model.

ACES--Today and Tomorrow.

ERIC Educational Resources Information Center

Hackney, Harold

1991-01-01

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

Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease.

PubMed

Anguiano, Lidia; Riera, Marta; Pascual, Julio; Valdivielso, José Manuel; Barrios, Clara; Betriu, Angels; Mojal, Sergi; Fernández, Elvira; Soler, María José

2015-07-01

Patients with cardiovascular (CV) disease have an increased circulating angiotensin-converting enzyme 2 (ACE2) activity, but there is little information about changes in ACE2 in chronic kidney disease (CKD) patients without history of CV disease. We examined circulating ACE2 activity in CKD patients at stages 3-5 (CKD3-5) and in dialysis (CKD5D) without any history of CV disease. Circulating ACE2 activity was measured in human ethylenediamine-tetraacetic acid (EDTA)-plasma samples from the NEFRONA study (n = 2572): control group (CONT) (n = 568), CKD3-5 (n = 1458) and CKD5D (n = 546). Different clinical and analytical variables such as gender; age; history of diabetes mellitus (DM), dyslipidemia and hypertension; glycaemic, renal, lipid and anaemia profiles; vitamin D analogues treatment and antihypertensive treatments (angiotensin-converting enzyme inhibitor and angiotensin receptor blockade) were analysed. Circulating ACE2 and ACE activities were measured using modified fluorimetric assay for EDTA-plasma samples, where zinc chloride was added to recover enzymatic activity. In CKD3-5 and CKD5D, significant decrease in circulating ACE2 activity was observed when compared with CONT, but no differences were found between CKD3-5 and CKD5 when performing paired case-control studies. By multivariate linear regression analysis, male gender and advanced age were identified as independent predictors of ACE2 activity in all groups. Diabetes was identified as independent predictor of ACE2 activity in CKD3-5. Significant increase in the activity of circulating ACE was found in CKD3-5 and CKD5D when compared with CONT and in CKD5D when compared with CKD3-5. By multiple regression analysis, female gender and younger age were identified as independent predictors of ACE activity in CONT and CKD3-5. Diabetes was also identified as an independent predictor of ACE activity in CKD3-5 patients. Circulating ACE2 and ACE activities can be measured in human EDTA-plasma samples with zinc added to recover enzymatic activity. In a CKD population without previous history of CV disease, ACE2 activity from human EDTA-plasma samples directly correlated with the classical CV risk factors namely older age, diabetes and male gender. Our data suggest that circulating ACE2 is altered in CKD patients at risk for CV event. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Impact of angiotensin-converting enzyme gene polymorphism on neurohormonal responses to high- versus low-dose enalapril in advanced heart failure.

PubMed

Tang, W H Wilson; Vagelos, Randall H; Yee, Yin-Gail; Fowler, Michael B

2004-11-01

The impact of angiotensin-converting enzyme (ACE) gene polymorphism on neurohormonal dose response to ACE inhibitor therapy is unclear. ACE Insertion (I) or Deletion (D) genotype was determined in 74 patients with chronic heart failure who were randomly assigned to receive either high-dose or low-dose enalapril over a period of 6 months. Monthly pre-enalapril and post-enalapril neurohormone levels (serum ACE activity (sACE), plasma angiotensin II (A-II), plasma renin activity (PRA), and serum aldosterone (ALDO) were compared between genotype subgroups and between patients who received high- or low-dose enalapril within each genotype subgroup. At baseline, predose/postdose sACE and postdose PRA were significantly higher in the DD genotype. At 6-month follow-up, postdose sACE was reduced in a dose-dependent fashion in all three genotypes (P < .05). However, predose and postdose ALDO and A-II levels did not differ between each genotype subgroup at baseline or by enalapril dose within each genotype subgroup. ALDO escape and A-II reactivation were not affected by ACE genotype or enalapril dosage. Predose sACE were consistently higher in the DD genotype when compared with ID or II subgroups. Despite a dose-dependent suppression of sACE, there were no observed statistically significant differences in ALDO and A-II suppression or escape with escalating doses of enalapril within each subgroup.

CD36/Sirtuin 1 Axis Impairment Contributes to Hepatic Steatosis in ACE2-Deficient Mice

PubMed Central

Qadri, Fatimunnisa; Penninger, Josef M.; Santos, Robson Augusto S.; Bader, Michael

2016-01-01

Background and Aims. Angiotensin converting enzyme 2 (ACE2) is an important component of the renin-angiotensin system. Since angiotensin peptides have been shown to be involved in hepatic steatosis, we aimed to evaluate the hepatic lipid profile in ACE2-deficient (ACE2−/y) mice. Methods. Male C57BL/6 and ACE2−/y mice were analyzed at the age of 3 and 6 months for alterations in the lipid profiles of plasma, faeces, and liver and for hepatic steatosis. Results. ACE2−/y mice showed lower body weight and white adipose tissue at all ages investigated. Moreover, these mice had lower levels of cholesterol, triglycerides, and nonesterified fatty acids in plasma. Strikingly, ACE2−/y mice showed high deposition of lipids in the liver. Expression of CD36, a protein involved in the uptake of triglycerides in liver, was increased in ACE2−/y mice. Concurrently, these mice exhibited an increase in hepatic oxidative stress, evidenced by increased lipid peroxidation and expression of uncoupling protein 2, and downregulation of sirtuin 1. ACE2−/y mice also showed impairments in glucose metabolism and insulin signaling in the liver. Conclusions. Deletion of ACE2 causes CD36/sirtuin 1 axis impairment and thereby interferes with lipid homeostasis, leading to lipodystrophy and steatosis. PMID:28101297

Activation of renin-angiotensin-aldosterone system (RAAS) in the lung of smoking-induced pulmonary arterial hypertension (PAH) rats.

PubMed

Yuan, Yi-Ming; Luo, Li; Guo, Zhen; Yang, Ming; Ye, Ren-Song; Luo, Chuan

2015-06-01

To explore the role of the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of pulmonary arterial hypertension (PAH) induced by chronic exposure to cigarette smoke. 48 healthy male SD rats were randomly divided into four groups (12/group): control group (group A); inhibitor alone group (group B); cigarette induction group (group C); cigarette induction + inhibitor group (group D). After the establishment of smoking-induced PAH rat model, the right ventricular systolic pressure (RVSP) was detected using an inserted catheter; western blotting was used to detect the protein expression of angiotensin-converting enzyme-2 (ACE2) and angiotensin-converting enzyme (ACE); expression levels of angiotensin II (AngII) in lung tissue were measured by radioimmunoassay. After six months of cigarette exposure, the RVSP of chronic cigarette induction group was significantly higher than that of the control group; expression levels of AngII and ACE increased in lung tissues, but ACE2 expression levels reduced. Compared with cigarette exposure group, after losartan treatment, RVSP, ACE and AngII obviously decreased (P<0.05), and ACE2 expression levels significantly increased. Chronic cigarette exposure may result in PAH and affect the protein expression of ACE2 and ACE in lung tissue, suggesting that ACE2 and ACE play an important role in the pathogenesis of smoking-induced PAH. © The Author(s) 2015.

ACE2 activity was increased in atherosclerotic plaque by losartan: Possible relation to anti-atherosclerosis.

PubMed

Zhang, Yue Hui; Hao, Qing Qing; Wang, Xiao Yu; Chen, Xu; Wang, Nan; Zhu, Li; Li, Shu Ying; Yu, Qing Tao; Dong, Bo

2015-06-01

Angiotensin-converting enzyme 2 (ACE2) is a new member of the renin-angiotensin system (RAS) and it has been proposed that ACE2 is a potential therapeutic target for the control of cardiovascular disease. The effect of losartan on the ACE2 activity in atherosclerosis was studied. Atherosclerosis was induced in New Zealand white rabbits by high-cholesterol diet for 3 months. An Angiotensin II (Ang II) receptor blocker (losartan, 25 mg/kg/d) was given for 3 months. ACE2 activity was measured by fluorescence assay and the extent of atherosclerosis was evaluated by H&E and Oil Red O staining. In addition, the effect of losartan on ACE2 activity in smooth muscle cells (SMCs) in vitro was also evaluated. Losartan increased ACE2 activity in atherosclerosis in vivo and SMCs in vitro. Losartan inhibited atherosclerotic evolution. Addition of losartan blocked Ang II-induced down-regulation of ACE2 activity, and blockade of extracellular signal-regulated kinase (ERK1/2) with PD98059 prevented Ang II-induced down-regulation of ACE2 activity. The results showed that ACE2 activity was regulated in atherosclerotic plaque by losartan, which may play an important role in treatment of atherosclerosis. The mechanism involves Ang II-AT1R-mediated mitogen-activated protein kinases, MAPKs (MAPKs) signaling pathway. © The Author(s) 2014.

Clinical and biochemical presentation of sarcoidosis with high and normal serum angiotensin-converting enzyme.

PubMed

Sejdic, A; Graudal, N; Baslund, B

2018-06-22

The presentation of sarcoidosis can involve symptoms from all organs and the diagnosis is therefore often difficult. A raised serum level of serum angiotensin-converting enzyme (sACE) can be detected in 41-58% of patients. However, whether the sACE level per se reflects the severity of the sarcoid inflammation at the onset of the disease is not well described. The purpose of this study was to investigate the clinical and laboratory significance of high versus normal sACE levels in sarcoidosis. Journal data were retrospectively extracted from 101 patients from our clinic. Clinical and biochemical data were compared between patients with high sACE levels (> 115 U/L) on at least one occasion and normal sACE levels (< 115 U/L). In total, 48% (n = 48) of the patients had high ACE and 52% (n = 53) had normal ACE. The most common extrapulmonary manifestation for both groups was arthritis, followed by skin and eye involvement, but none of these differed between the two groups. Serum ionized calcium was significantly higher in the high sACE group, with a correlation coefficient of 0.112 (p = 0.460). Our study demonstrates that serum ionized calcium is significantly higher in the high sACE group but there was no statistical correlation to sACE. No other clinical or biochemical differences were observed.

[Angiotensin converting enzyme 2 and its emerging role in the regulation of the renin angiotensin system].

PubMed

Soler, María José; Lloveras, Josep; Batlle, Daniel

2008-07-12

The renin-angiotensin system (RAS) plays a key role in the regulation of cardiovascular and renal function. Thus, RAS blockade with an angiotensin-converting enzyme (ACE) and/or angiotensin receptor blocker decreases blood pressure, cardiovascular events, and delays the progression of kidney disease. The discovery of ACE2, a homologue of ACE, capable of degrading angiotensin II to angiotensin 1-7, may offer new insights into the RAS. In this review we discuss the possible protective role of ACE2 in different organs, namely heart, lungs and kidneys. The role of this enzyme is inferred from recent studies performed using genetically manipulated mice that lack the ACE2 gene and also mice treated with pharmacological ACE2 inhibitors. These results suggest that ACE2 might be a new therapeutic target within the RAS.

Necessity of angiotensin-converting enzyme-related gene for cardiac functions and longevity of Drosophila melanogaster assessed by optical coherence tomography

NASA Astrophysics Data System (ADS)

Liao, Fang-Tsu; Chang, Cheng-Yi; Su, Ming-Tsan; Kuo, Wen-Chuan

2014-01-01

Prior studies have established the necessity of an angiotensin-converting enzyme-related (ACER) gene for heart morphogenesis of Drosophila. Nevertheless, the physiology of ACER has yet to be comprehensively understood. Herein, we employed RNA interference to down-regulate the expression of ACER in Drosophila's heart and swept source optical coherence tomography to assess whether ACER is required for cardiac functions in living adult flies. Several contractile parameters of Drosophila heart, including the heart rate (HR), end-diastolic diameter (EDD), end-systolic diameter (ESD), percent fractional shortening (%FS), and stress-induced cardiac performance, are shown, which are age dependent. These age-dependent cardiac functions declined significantly when ACER was down-regulated. Moreover, the lifespans of ACER knock-down flies were significantly shorter than those of wild-type control flies. Thus, we posit that ACER, the Drosophila ortholog of mammalian angiotensin-converting enzyme 2 (ACE2), is essential for both heart physiology and longevity of animals. Since mammalian ACE2 controls many cardiovascular physiological features and is implicated in cardiomyopathies, our findings that ACER plays conserved roles in genetically tractable animals will pave the way for uncovering the genetic pathway that controls the renin-angiotensin system.

Keeping pace with ACE: are ACE inhibitors and angiotensin II type 1 receptor antagonists potential doping agents?

PubMed

Wang, Pei; Fedoruk, Matthew N; Rupert, Jim L

2008-01-01

In the decade since the angiotensin-converting enzyme (ACE) gene was first proposed to be a 'human gene for physical performance', there have been numerous studies examining the effects of ACE genotype on physical performance phenotypes such as aerobic capacity, muscle function, trainability, and athletic status. While the results are variable and sometimes inconsistent, and corroborating phenotypic data limited, carriers of the ACE 'insertion' allele (the presence of an alu repeat element in intron 16 of the gene) have been reported to have higher maximum oxygen uptake (VO2max), greater response to training, and increased muscle efficiency when compared with individuals carrying the 'deletion' allele (absence of the alu repeat). Furthermore, the insertion allele has been reported to be over-represented in elite athletes from a variety of populations representing a number of endurance sports. The mechanism by which the ACE insertion genotype could potentiate physical performance is unknown. The presence of the ACE insertion allele has been associated with lower ACE activity (ACEplasma) in number of studies, suggesting that individuals with an innate tendency to have lower ACE levels respond better to training and are at an advantage in endurance sporting events. This could be due to lower levels of angiotensin II (the vasoconstrictor converted to active form by ACE), higher levels of bradykinin (a vasodilator degraded by ACE) or some combination of the two phenotypes. Observations that individuals carrying the ACE insertion allele (and presumably lower ACEplasma) have an enhanced response to training or are over-represented amongst elite athletes raises the intriguing question: would individuals with artificially lowered ACEplasma have similar training or performance potential? As there are a number of drugs (i.e. ACE inhibitors and angiotensin II type 1 receptor antagonists [angiotensin receptor blockers--ARBs]) that have the ability to either reduce ACEplasma activity or block the action of angiotensin II, the question is relevant to the study of ergogenic agents and to the efforts to rid sports of 'doping'. This article discusses the possibility that ACE inhibitors and ARBs, by virtue of their effects on ACE or angiotensin II function, respectively, have performance-enhancing capabilities; it also reviews the data on the effects of these medications on VO2max, muscle composition and endurance capacity in patient and non-patient populations. We conclude that, while the direct evidence supporting the hypothesis that ACE-related medications are potential doping agents is not compelling, there are insufficient data on young, athletic populations to exclude the possibility, and there is ample, albeit indirect, support from genetic studies to suggest that they should be. Unfortunately, given the history of drug experimentation in athletes and the rapid appropriation of therapeutic agents into the doping arsenal, this indirect evidence, coupled with the availability of ACE-inhibiting and ACE-receptor blocking medications may be sufficiently tempting to unscrupulous competitors looking for a shortcut to the finish line.

Adverse childhood experiences and association with health, mental health, and risky behavior in the kingdom of Saudi Arabia.

PubMed

Almuneef, Maha; Hollinshead, Dana; Saleheen, Hassan; AlMadani, Sereen; Derkash, Bridget; AlBuhairan, Fadia; Al-Eissa, Majid; Fluke, John

2016-10-01

The aim of this study is to determine if ACEs impact the health and risk behavior burden among Kingdom of Saudi Arabia (KSA) adults. In 2013, a cross-sectional study was conducted across KSA to identify the retrospective prevalence of ACEs and their association with high risk behaviors and chronic diseases. Surveys from 10,156 adults in all 13 Saudi regions were obtained using an Arabic version of the WHO ACE-IQ (KSA ACE-IQ). Compared to respondents reporting no ACEs, even just one ACE contributed significantly to the odds of experiencing diabetes mellitus (OR=1.3), depression (OR=1.32), or anxiety (OR=1.79) outcomes. Two ACEs were necessary for statistically significant, higher odds to emerge for hypertension (OR=1.46), mental illness (OR=1.93), smoking (OR=1.17), alcohol use (OR=1.75), and drug use (OR=1.45). Respondents who reported four or more ACEs had greater odds of coronary heart disease (OR=1.94), and obesity (OR=2.25). Compared to those reporting no ACEs, respondents reporting four or more ACEs had over four times the odds of Alcohol or Drug Use, Mental Illness, Depression, and/or Anxiety outcomes and more than twice the odds of diabetes, hypertension, obesity, and/or smoking outcomes. Findings from this analysis underscore the potential benefit of providing focused preventative approaches to mitigating ACEs in KSA in relation to both the specific and cumulative burden of health and risky behavior outcomes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Adverse childhood experiences and blood pressure trajectories from childhood to young adulthood: the Georgia stress and Heart study.

PubMed

Su, Shaoyong; Wang, Xiaoling; Pollock, Jennifer S; Treiber, Frank A; Xu, Xiaojing; Snieder, Harold; McCall, W Vaughn; Stefanek, Michael; Harshfield, Gregory A

2015-05-12

The purposes of this study were to assess the long-term effect of adverse childhood experiences (ACEs) on blood pressure (BP) trajectories from childhood to young adulthood and to examine whether this relation is explained by childhood socioeconomic status (SES) or risk behaviors that are associated with ACEs. Systolic and diastolic BPs were measured up to 16 times (13 times on average) over a 23-year period in 213 African Americans and 181 European Americans 5 to 38 years of age. Retrospective data on traumatic experiences before 18 years of age were collected, including abuse, neglect, and household dysfunction. Individual growth curve modeling within a multilevel framework was used to examine the relation between exposure to ACEs and BP development. No main effect of ACEs on average BP levels was found. However, a significant interaction of ACE score with age(3) was observed (systolic BP, P=0.033; diastolic BP, P=0.017). Subjects who experienced multiple traumatic events during childhood showed a faster rise in BP levels after 30 years of age than those without ACEs. As expected, a graded association of ACEs with childhood socioeconomic status and negative health behaviors was observed (P<0.001). The ACE-systolic BP relation was not explained by these factors, whereas the ACE-diastolic BP relation was partially mediated by illicit drug use. In this novel longitudinal study, we observed that participants who were exposed to multiple ACEs displayed a greater increase in BP levels in young adulthood compared with their counterparts without ACEs. © 2015 American Heart Association, Inc.

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

PubMed Central

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

2015-01-01

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

Our ACE in the HOLE: Justifying the Use of Angiotensin-converting Enzyme Inhibitors as Adjuvants to Standard Chemotherapy.

PubMed

Radin, Daniel P; Krebs, Austin; Maqsudlu, Arman; Patel, Parth

2018-01-01

Angiotensin-I-converting enzyme (ACE) inhibitors have been very effective in treating cardiac hypertension since their clinical inception over four decades ago. Since then, it has been established that angiotensin II, the product of ACE, has oncogenic and pro-proliferative qualities, which begs the question as to whether ACE inhibitors may have oncolytic characteristics. In fact, scattered reports suggest that ACE inhibitors are oncolytic and oncopreventive, but the available literature has yet to be thoroughly examined. In the present review, we examine the available literature and determine that ACE inhibitors would have great utility in the prevention and treatment of cancer. At the same time, they would augment the efficacy of chemo- and radiotherapy as well as mitigating damage to healthy tissue by standard chemotherapeutic regimens. We review some of the mounting clinical evidence and show that ACE inhibitors have oncolytic activity in multiple types of cancer and discuss the ability of ACE inhibitors to prevent cardiotoxicity of multiple chemotherapies. Our analysis demonstrates that the actions of ACE inhibitors converge on vascular endolthelial growth factor to reduce its levels in tumors and prevent construction of blood vessels to masses, leaving them nutrient-depleted and subsequently hindering their growth. Given that ACE inhibitors are approved by the Federal Drug Administration and the therapeutic dose for hypertension treatment also slows the growth of multiple cancers types, ACE inhibitors are in a perfect position to be repurposed as oncolytic agents, that would widely increase their utility in the clinic. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Adverse Childhood Experiences and Blood Pressure Trajectories from Childhood to Young Adulthood: The Georgia Stress and Heart Study

PubMed Central

Su, Shaoyong; Wang, Xiaoling; Pollock, Jennifer S.; Treiber, Frank A.; Xu, Xiaojing; Snieder, Harold; McCall, W. Vaughn; Stefanek, Michael; Harshfield, Gregory A.

2015-01-01

Background The purpose of this study was to assess the long-term effect of adverse childhood experiences (ACEs) on blood pressure (BP) trajectories from childhood to young adulthood and to examine whether this relation is explained by childhood socioeconomic status (SES) and/or risk behaviors that are associated with ACEs. Methods and Results Systolic and diastolic blood pressure (SBP and DBP) were measured up to 16 times (13 times on average) over a 23-year period in 213 African Americans (AAs) and 181 European Americans (EAs) aged 5 to 38 years. Retrospective data on traumatic experiences prior to age 18 were collected, including abuse, neglect and household dysfunction. Individual growth curve modeling within a multilevel framework was used to examine the relation between exposure to ACEs and BP development. No main effect of ACEs on average BP levels was found. However, a significant interaction of ACE score with age3 was observed (SBP: p=0.033; DBP: p=0.017). Subjects who experienced multiple traumatic events during childhood showed a faster rise of BP levels after age of 30 years than those without ACEs. As expected, a graded association of ACEs with childhood SES and negative health behaviors was observed (p<0.001). The ACE-SBP relation was not explained by these factors, while the ACE-DBP relation was partially mediated by illicit drug use. Conclusions In this novel longitudinal study, we observed that participants who were exposed to multiple ACEs displayed a greater increase of BP levels in young adulthood compared to their counterparts without ACEs. PMID:25858196

Adverse childhood experiences, gender, and HIV risk behaviors: Results from a population-based sample.

PubMed

Fang, Lin; Chuang, Deng-Min; Lee, Yookyong

2016-12-01

Recent HIV research suggested assessing adverse childhood experiences (ACEs) as contributing factors of HIV risk behaviors. However, studies often focused on a single type of adverse experience and very few utilized population-based data. This population study examined the associations between ACE (individual and cumulative ACE score) and HIV risk behaviors. We analyzed the 2012 Behavioral Risk Factor Surveillance Survey (BRFSS) from 5 states. The sample consisted of 39,434 adults. Eight types of ACEs that included different types of child abuse and household dysfunctions before the age of 18 were measured. A cumulative score of ACEs was also computed. Logistic regression estimated of the association between ACEs and HIV risk behaviors using odds ratio (OR) with 95% confidence intervals (CIs) for males and females separately. We found that ACEs were positively associated with HIV risk behaviors overall, but the associations differed between males and females in a few instances. While the cumulative ACE score was associated with HIV risk behaviors in a stepwise manner, the pattern varied by gender. For males, the odds of HIV risk increased at a significant level as long as they experienced one ACE, whereas for females, the odds did not increase until they experienced three or more ACEs. Future research should further investigate the gender-specific associations between ACEs and HIV risk behaviors. As childhood adversities are prevalent among general population, and such experiences are associated with increased risk behaviors for HIV transmission, service providers can benefit from the principles of trauma-informed practice.

Do Pediatricians Ask About Adverse Childhood Experiences in Pediatric Primary Care?

PubMed

Kerker, Bonnie D; Storfer-Isser, Amy; Szilagyi, Moira; Stein, Ruth E K; Garner, Andrew S; O'Connor, Karen G; Hoagwood, Kimberly E; Horwitz, Sarah M

2016-03-01

The stress associated with adverse childhood experiences (ACEs) has immediate and long-lasting effects. The objectives of this study were to examine 1) how often pediatricians ask patients' families about ACEs, 2) how familiar pediatricians are with the original ACE study, and 3) physician/practice characteristics, physicians' mental health training, and physicians' attitudes/beliefs that are associated with asking about ACEs. Data were collected from 302 nontrainee pediatricians exclusively practicing general pediatrics who completed the 2013 American Academy of Pediatrics Periodic Survey. Pediatricians indicated whether they usually, sometimes, or never inquired about or screened for 7 ACEs. Sample weights were used to reduce nonresponse bias. Weighted descriptive and logistic regression analyses were conducted. Only 4% of pediatricians usually asked about all 7 ACEs; 32% did not usually ask about any. Less than 11% of pediatricians reported being very or somewhat familiar with the ACE study. Pediatricians who screened/inquired about ACEs usually asked about maternal depression (46%) and parental separation/divorce (42%). Multivariable analyses showed that pediatricians had more than twice the odds of usually asking about ACEs if they disagreed that they have little effect on influencing positive parenting skills, disagreed that screening for social emotional risk factors within the family is beyond the scope of pediatricians, or were very interested in receiving further education on managing/treating mental health problems in children and adolescents. Few pediatricians ask about all ACEs. Pediatric training that emphasizes the importance of social/emotional risk factors may increase the identification of ACEs in pediatric primary care. Copyright © 2016 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

Serum angiotensin-1 converting enzyme activity processes a human immunodeficiency virus 1 gp160 peptide for presentation by major histocompatibility complex class I molecules

PubMed Central

1992-01-01

T cell stimulation by the human immunodeficiency virus 1 gp160-derived peptide p18 presented by H-2Dd class I major histocompatibility complex molecules in a cell-free system was found to require proteolytic cleavage. This extracellular processing was mediated by peptidases present in fetal calf serum. In vitro processing of p18 resulted in a distinct reverse phase high performance liquid chromatography profile, from which a biologically active product was isolated and sequenced. This peptide processing can be specifically blocked by the angiotensin- 1 converting enzyme (ACE) inhibitor captopril, and can occur by exposing p18 to purified ACE. The ability of naturally occurring extracellular proteases to convert inactive peptides to T cell antigens has important implications for understanding cytotoxic T lymphocyte responses in vivo, and for rational peptide vaccine design. PMID:1316930

Aloe vera inhibits proliferation of human breast and cervical cancer cells and acts synergistically with cisplatin.

PubMed

Hussain, Arif; Sharma, Chhavi; Khan, Saniyah; Shah, Kruti; Haque, Shafiul

2015-01-01

Many of the anti-cancer agents currently used have an origin in natural sources including plants. Aloe vera is one such plant being studied extensively for its diverse health benefits, including cancer prevention. In this study, the cytotoxic potential of Aloe vera crude extract (ACE) alone or in combination with cisplatin in human breast (MCF-7) and cervical (HeLa) cancer cells was studied by cell viability assay, nuclear morphological examination and cell cycle analysis. Effects were correlated with modulation of expression of genes involved in cell cycle regulation, apoptosis and drug metabolism by RT-PCR. Exposure of cells to ACE resulted in considerable loss of cell viability in a dose- and time-dependent fashion, which was found to be mediated by through the apoptotic pathway as evidenced by changes in the nuclear morphology and the distribution of cells in the different phases of the cell cycle. Interestingly, ACE did not have any significant cytotoxicity towards normal cells, thus placing it in the category of safe chemopreventive agent. Further, the effects were correlated with the downregulation of cyclin D1, CYP 1A1, CYP 1A2 and increased expression of bax and p21 in MCF-7 and HeLa cells. In addition, low dose combination of ACE and cisplatin showed a combination index less than 1, indicating synergistic growth inhibition compared to the agents applied individually. In conclusion, these results signify that Aloe vera may be an effective anti-neoplastic agent to inhibit cancer cell growth and increase the therapeutic efficacy of conventional drugs like cispolatin. Thus promoting the development of plant-derived therapeutic agents appears warranted for novel cancer treatment strategies.

Dust Aerosols at the Source Region During ACE-ASIA: A Surface/Satellite Perspective

NASA Technical Reports Server (NTRS)

Tsay, Si-Chee; Lau, William K. M. (Technical Monitor)

2001-01-01

ACE (Aerosol Characterization Experiment)-Asia is designed to study the compelling variability in spatial and temporal scale of both pollution-derived and naturally occurring aerosols, which often exist in high concentrations over eastern Asia and along the rim of the western Pacific. The phase-I of ACE-Asia was conducted from March-May 2001 in the vicinity of the Gobi desert, East Coast of China, Yellow Sea, Korea, and Japan, along the pathway of Kosa (severe events that blanket East Asia with yellow desert dust, peaked in the Spring season). Asian dust typically originates in desert areas far from polluted urban regions. During transport, dust layers can interact with anthropogenic sulfate and soot aerosols from heavily polluted urban areas. Added to the complex effects of clouds and natural marine aerosols, dust particles reaching the marine environment can have drastically different properties than those from the source. Thus, understanding the unique temporal and spatial variations of Asian dust is of special importance in regional-to-global climate issues such as radiative forcing, the hydrological cycle, and primary biological productivity in the mid-Pacific Ocean. During ACE-Asia we have measured continuously aerosol physical/optical/radiative properties, column precipitable water amount, and surface reflectivity over homogeneous areas from surface. The inclusion of flux measurements permits the determination of dust aerosol radiative flux in addition to measurements of loading and optical thickness. At the time of the Terra/MODIS, SeaWiFS, TOMS and other satellite overpasses, these ground-based observations can provide valuable data to compare with satellite retrievals over land. Preliminary results will be presented and discussed their implications in regional climatic effects.

ACE-Asia Aerosol Optical Depth and Water Vapor Measured by Airborne Sunphotometers and Related to Other Measurements and Calculations

NASA Technical Reports Server (NTRS)

Livingston, John M.; Russell, P. B.; Schmid, B.; Redemann, J.; Eilers, J. A.; Ramirez, S. A.; Kahn, R.; Hegg, D.; Pilewskie, P.; Anderson, T.;

Production of Angiotensin-I-Converting-Enzyme-Inhibitory Peptides in Fermented Milks Started by Lactobacillus delbrueckii subsp. bulgaricus SS1 and Lactococcus lactis subsp. cremoris FT4

PubMed Central

Gobbetti, M.; Ferranti, P.; Smacchi, E.; Goffredi, F.; Addeo, F.

2000-01-01

Two fermented milks containing angiotensin-I-converting-enzyme (ACE)-inhibitory peptides were produced by using selected Lactobacillus delbrueckii subsp. bulgaricus SS1 and L. lactis subsp. cremoris FT4. The pH 4.6-soluble nitrogen fraction of the two fermented milks was fractionated by reversed-phase fast-protein liquid chromatography. The fractions which showed the highest ACE-inhibitory indexes were further purified, and the related peptides were sequenced by tandem fast atom bombardment-mass spectrometry. The most inhibitory fractions of the milk fermented by L. delbrueckii subsp. bulgaricus SS1 contained the sequences of β-casein (β-CN) fragment 6-14 (f6-14), f7-14, f73-82, f74-82, and f75-82. Those from the milk fermented by L. lactis subsp. cremoris FT4 contained the sequences of β-CN f7-14, f47-52, and f169-175 and κ-CN f155-160 and f152-160. Most of these sequences had features in common with other ACE-inhibitory peptides reported in the literature. In particular, the β-CN f47-52 sequence had high homology with that of angiotensin-II. Some of these peptides were chemically synthesized. The 50% inhibitory concentrations (IC50s) of the crude purified fractions containing the peptide mixture were very low (8.0 to 11.2 mg/liter). When the synthesized peptides were used individually, the ACE-inhibitory activity was confirmed but the IC50s increased considerably. A strengthened inhibitory effect of the peptide mixtures with respect to the activity of individual peptides was presumed. Once generated, the inhibitory peptides were resistant to further proteolysis either during dairy processing or by trypsin and chymotrypsin. PMID:10966406

FIRE III ACE

Atmospheric Science Data Center

2013-01-23

FIRE III ACE Data Sets The First International Satellite Cloud ... Regional Experiment (FIRE) - Arctic Cloud Experiment (ACE) was conducted April through July of 1998. It was held in conjunction with ... Heat Budget of the Arctic Ocean (SHEBA) Experiment. The FIRE-ACE focused on all aspects of Arctic cloud systems. The main facility was ...

Left ventricular wall stress and sarcoplasmic reticulum Ca(2+)-ATPase gene expression in renal hypertensive rats: dose-dependent effects of ACE inhibition and AT1-receptor blockade.

PubMed

Zierhut, W; Studer, R; Laurent, D; Kästner, S; Allegrini, P; Whitebread, S; Cumin, F; Baum, H P; de Gasparo, M; Drexler, H

1996-05-01

Cardiac hypertrophy is associated with altered Ca2+ handling and may predispose to the development of LV dysfunction and cardiac failure. At the cellular level, the re-expression of ANF represents a well-established marker of myocyte hypertrophy while the decreased expression of the sarcoplasmatic reticulum (SR) Ca(2+)-ATPase is thought o play a crucial role in the alterations of Ca2+ handling and LV function. We assessed the dose-dependent effect of chronic ACE inhibition or AT1 receptor blockade on cardiac function in relation to the cardiac expression of the SR Ca(2+)-ATPase and ANF. Renal hypertensive rats (2K-1C) were treated for 12 weeks with three different doses of the ACE inhibitor benazepril, the AT1-receptor antagonist valsartan (each drug 0.3, 3, and 10 mg/kg per day i.p.) or placebo. LV dimensions, hypertrophy and wall stress were determined in vivo by magnetic resonance imaging and the gene expressions of ANF and SR Ca(2+)-ATPase were quantified by Northern blot. Low doses of both drugs did not affect blood pressure, hypertrophy, systolic wall stress and the ANF and SR Ca(2+)-ATPase gene expression. High doses of each drug reduced systolic blood pressure, wall stress, and LV hypertrophy to a similar extent and to values comparable to normotensive, age-matched rats. In addition, high dose treatment reduced LV end-systolic and end-diastolic volume as compared to untreated 2K-1C animals and normalized the mRNA levels of both ANF and SR Ca(2+)-ATPase (as compared to normotensive animals). We conclude that in this model, high doses of ACE inhibition and AT1-receptor blockade are necessary to normalize systolic blood pressure, LV hypertrophy and systolic LV wall stress which, in turn, is associated with restoration of a normal cardiac phenotype with respect to SR Ca(2+)-ATPase and ANF and normalization of cardiac function.

Modified sedimentation-dispersion model for solids in a three-phase slurry column

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, D.N.; Ruether, J.A.; Shah, Y.T.

1986-03-01

Solids distribution data for a three-phase, batch-fluidized slurry bubble column (SBC) are presented, using air as the gas phase, pure liquids and solutions as the liquid phase, and glass beads and carborundum catalyst powder as the solid phase. Solids distribution data for the three-phase SBC operated in a continuous mode of operation are also presented, using nitrogen as the gas phase, water as the liquid phase, and glass beads as the solid phase. A new model to provide a reasonable approach to predict solids concentration distributions for systems containing polydispersed solids is presented. The model is a modification of standardmore » sedimentation-dispersion model published earlier. Empirical correlations for prediction of hindered settling velocity and solids dispersion coefficient for systems containing polydispersed solids are presented. A new method of evaluating critical gas velocity (CGV) from concentrations of the sample withdrawn at the same port of the SBC is presented. Also presented is a new mapping for CGV which separates the two regimes in the SBC, namely, incomplete fluidization and complete fluidization.« less

Noncaloric Sweeteners Induce Peripheral Serotonin Secretion via the T1R3-Dependent Pathway in Human Gastric Parietal Tumor Cells (HGT-1).

PubMed

Zopun, Muhammet; Lieder, Barbara; Holik, Ann-Katrin; Ley, Jakop P; Hans, Joachim; Somoza, Veronika

2018-06-25

The role of sweet taste in energy intake and satiety regulation is still controversial. Noncaloric artificial sweeteners (NCSs) are thought to help reduce energy intake, although little is known about their impact on the satiating neurotransmitter serotonin (5-HT). In the gastrointestinal (GI) tract, 5-HT regulates gastric acid secretion and gastric motility, both part of the complex network of mechanisms regulating food intake and satiety. This study demonstrated a stimulating impact compared to controls (100%) on 5-HT release in human gastric tumor cells (HGT-1) by the NCSs cyclamate (50 mM, 157% ± 6.3%), acesulfame potassium (Ace K, 50 mM, 197% ± 8.6%), saccharin (50 mM, 147% ± 6.7%), sucralose (50 mM, 194% ± 11%), and neohesperidin dihydrochalcone (NHDC, 1 mM, 201% ± 13%). Although these effects were not associated with the sweet taste intensity of the NCSs tested, involvement of the sweet receptor subunit T1R3 in the NCS-evoked response was demonstrated by mRNA expression of TAS1R3, co-incubation experiments using the T1R3 receptor antagonist lactisole, and a TAS1R3 siRNA knockdown approach. Analysis of the downstream signaling revealed activation of the cAMP/ERK/Ca 2+ cascade. Co-treatment experiments with 10 mM glucose enhanced the 5-HT release induced by cyclamate, Ace K, saccharin, and sucralose, thereby supporting the enhancing effect of glucose on a NCS-mediated response. Overall, the results obtained identify NCSs as potent inducers of 5-HT release via T1R3 in human gastric parietal cells in culture and warrant in vivo studies to demonstrate their efficacy.

Cardiovascular-renal and metabolic characterization of a rat model of polycystic ovary syndrome.

PubMed

Yanes, Licy L; Romero, Damian G; Moulana, Mohaddetheh; Lima, Roberta; Davis, Deborah D; Zhang, Huimin; Lockhart, Rachel; Racusen, Lorraine C; Reckelhoff, Jane F

2011-04-01

Polycystic ovary syndrome (PCOS) is the most common reproductive dysfunction in premenopausal women. PCOS is also associated with increased risk of cardiovascular disease when PCOS first occurs and later in life. Hypertension, a common finding in women with PCOS, is a leading risk factor for cardiovascular disease. The mechanisms responsible for hypertension in women with PCOS have not been elucidated. This study characterized the cardiovascular-renal consequences of hyperandrogenemia in a female rat model. Female Sprague-Dawley rats (aged 4-6 weeks) were implanted with dihydrotestosterone or placebo pellets lasting 90 days. After 10 to 12 weeks, blood pressure (by radiotelemetry), renal function (glomerular filtration rate, morphology, protein, and albumin excretion), metabolic parameters (plasma insulin, glucose, leptin, cholesterol, and oral glucose tolerance test), inflammation (plasma tumor necrosis factor-α), oxidative stress (mRNA expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, p22(phox), p47(phox), gp91(phox), and NOX4), nitrate/nitrite excretion and mRNA expression of components of the renin-angiotensin system (angiotensinogen, angiotensin-I-converting enzyme [ACE], and AT1 receptor) were determined. Plasma dihydrotestosterone increased 3-fold in hyperandrogenemic female (HAF) rats, whereas plasma estradiol levels did not differ compared with control females. HAF rats exhibited estrus cycle dysfunction. They also had increased food intake and body weight, increased visceral fat, glomerular filtration rate, renal injury, insulin resistance and metabolic dysfunction, oxidative stress, and increased expression of angiotensinogen and ACE and reduced AT1 receptor expression. The HAF rat is a unique model that exhibits many of the characteristics of PCOS in women and is a useful model to study the mechanisms responsible for PCOS-mediated hypertension. Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

Identification of Major Enzymes Involved in the Synthesis of Diadenosine Tetraphosphate and/or Adenosine Tetraphosphate in Myxococcus xanthus.

PubMed

Kimura, Yoshio; Tanaka, Chihiro; Oka, Manami

2018-07-01

Myxococcus xanthus generates diadenosine tetraphosphates (Ap 4 A) and diadenosine pentaphosphates (Ap 5 A) under various stress conditions. M. xanthus lysyl-tRNA synthetase (LysS) efficiently synthesizes Ap 4 A from ATP, Ap 5 A from ATP and adenosine tetraphosphate (Ap 4 ), and Ap 4 from ATP and triphosphate. To identify other M. xanthus enzymes that can catalyze Ap 4 A and Ap 4 synthesis, 15 M. xanthus aminoacyl-tRNA synthetases (aaRSs), four acyl-CoA synthetases (Acys), three acetyl-CoA synthetases (Aces), phosphoglycerate kinase (Pgk), and adenylate kinase (Adk) were expressed in Escherichia coli and examined for Ap 4 A or Ap 4 synthetase activity using ATP or ATP and triphosphate as substrates. Among the tested enzymes, LysS had the highest Ap 4 A synthetase activity. AlaRS, SerRS, and LeuRS1 showed high ADP synthetase activity with ATP as a substrate in the presence of pyrophosphatase, and also demonstrated the ability to produce Ap 4 from ATP and triphosphate in the absence of pyrophosphatase. Ap 4 formation by AlaRS, SerRS, and LeuRS1 was approximately 4- to 13-fold higher compared with that of Ap 4 A, suggesting that these enzymes prefer triphosphate over ATP as a substrate in the second reaction. Some of the recombinant M. xanthus Acys and Aces also synthesized Ap 4 from ATP and triphosphate. However, Pgk was capable of catalyzing the production of Ap 4 from ATP and 3-phosphoglycerate in the presence of Mg 2+ and did not require triphosphate, suggesting that this enzyme is mainly responsible for Ap 4 synthesis in M. xanthus.

Role of the Renin-Angiotensin System, Renal Sympathetic Nerve System, and Oxidative Stress in Chronic Foot Shock-Induced Hypertension in Rats

PubMed Central

Dong, Tao; Chen, Jing-Wei; Tian, Li-Li; Wang, Lin-Hui; Jiang, Ren-Di; Zhang, Zhe; Xu, Jian-Bing; Zhao, Xiao-Dong; Zhu, Wei; Wang, Guo-Qing; Sun, Wan-Ping; Zhang, Guo-Xing

2015-01-01

Objective: The renin-angiotensin system (RAS) and renal sympathetic nerve system (RSNS) are involved in the development of hypertension. The present study is designed to explore the possible roles of the RAS and the RSNS in foot shock-induced hypertension. Methods: Male Sprague-Dawley rats were divided into six groups: control, foot shock, RSNS denervation, denervation plus foot shock, Captopril (angiotensin I converting enzyme inhibitor, ACE inhibitor) plus foot shock, and Tempol (superoxide dismutase mimetic) plus foot shock. Rats received foot shock for 14 days. We measured the quantity of thiobarbituric acid reactive substances (TBARS), corticosterone, renin, and angiotensin II (Ang II) in plasma, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and renal noradrenaline content. RAS component mRNA and protein levels were quantified in the cerebral cortex and hypothalamus. Results: The two week foot shock treatment significantly increased systolic blood pressure, which was accompanied by an increase in angiotensinogen, renin, ACE1, and AT1a mRNA and protein expression in the cerebral cortex and hypothalamus, an increase of the plasma concentrations of renin, Ang II, corticosterone, and TBARS, as well as a decrease in plasma SOD and GSH-Px activities. Systolic blood pressure increase was suppressed by denervation of the RSNS or treatment with Captopril or Tempol. Interestingly, denervation or Tempol treatment both decreased main RAS components not only in the circulatory system, but also in the central nervous system. In addition, decreased antioxidant levels and increased TBARS and corticosterone levels were also partially restored by denervation or treatment with Tempol or Captopril. Conclusions: RAS, RSNS and oxidative stress reciprocally potentiate to play important roles in the development of foot shock-induced hypertension. PMID:25999788

Role of the renin-angiotensin system, renal sympathetic nerve system, and oxidative stress in chronic foot shock-induced hypertension in rats.

PubMed

Dong, Tao; Chen, Jing-Wei; Tian, Li-Li; Wang, Lin-Hui; Jiang, Ren-Di; Zhang, Zhe; Xu, Jian-Bing; Zhao, Xiao-Dong; Zhu, Wei; Wang, Guo-Qing; Sun, Wan-Ping; Zhang, Guo-Xing

2015-01-01

The renin-angiotensin system (RAS) and renal sympathetic nerve system (RSNS) are involved in the development of hypertension. The present study is designed to explore the possible roles of the RAS and the RSNS in foot shock-induced hypertension. Male Sprague-Dawley rats were divided into six groups: control, foot shock, RSNS denervation, denervation plus foot shock, Captopril (angiotensin I converting enzyme inhibitor, ACE inhibitor) plus foot shock, and Tempol (superoxide dismutase mimetic) plus foot shock. Rats received foot shock for 14 days. We measured the quantity of thiobarbituric acid reactive substances (TBARS), corticosterone, renin, and angiotensin II (Ang II) in plasma, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and renal noradrenaline content. RAS component mRNA and protein levels were quantified in the cerebral cortex and hypothalamus. The two week foot shock treatment significantly increased systolic blood pressure, which was accompanied by an increase in angiotensinogen, renin, ACE1, and AT1a mRNA and protein expression in the cerebral cortex and hypothalamus, an increase of the plasma concentrations of renin, Ang II, corticosterone, and TBARS, as well as a decrease in plasma SOD and GSH-Px activities. Systolic blood pressure increase was suppressed by denervation of the RSNS or treatment with Captopril or Tempol. Interestingly, denervation or Tempol treatment both decreased main RAS components not only in the circulatory system, but also in the central nervous system. In addition, decreased antioxidant levels and increased TBARS and corticosterone levels were also partially restored by denervation or treatment with Tempol or Captopril. RAS, RSNS and oxidative stress reciprocally potentiate to play important roles in the development of foot shock-induced hypertension.

Economic evaluation of the Annual Cycle Energy System (ACES). Volume 1: Executive summary

NASA Astrophysics Data System (ADS)

1980-05-01

Three different classes of building are investigated, namely: single family residence; multifamily residence; and commercial office building. For each building type in each geographic location, the economic evaluation of the annual cycle energy system (ACES) is based on a comparison of the present worth of the ACES to the present worth of a number of conventional systems. The results of this analysis indicate that the economic viability of the ACES is very sensitive to the assumed value of the property tax, maintenance cost, and fuel escalation rates, while it is relatively insensitive to the assumed values of other parameters. Fortunately, any conceivable change in the fuel escalation rates would tend to increase the viability of the ACES concept. An increase in the assumed value of the maintenance cost or property tax would tend to make the ACES concept less viable; a decrease in either would tend to make the ACES concept more viable.

ACE Over Expression in Myelomonocytic Cells: Effect on a Mouse Model of Alzheimer's Disease

PubMed Central

Koronyo-Hamaoui, Maya; Shah, Kandarp; Koronyo, Yosef; Bernstein, Ellen; Giani, Jorge F.; Janjulia, Tea; Black, Keith L.; Shi, Peng D.; Gonzalez-Villalobos, Romer A.; Fuchs, Sebastien; Shen, Xiao Z.; Bernstein, Kenneth E.

2014-01-01

While it is well known that angiotensin converting enzyme (ACE) plays an important role in blood pressure control, ACE also has effects on renal function, hematopoiesis, reproduction, and aspects of the immune response. ACE 10/10 mice over express ACE in myelomonocytic cells. Macrophages from these mice have an increased polarization towards a pro-inflammatory phenotype that results in a very effective immune response to challenge by tumors or bacterial infection. In a mouse model of Alzheimer's disease (AD), the ACE 10/10 phenotype provides significant protection against AD pathology, including reduced inflammation, reduced burden of the neurotoxic amyloid-β protein and preserved cognitive function. Taken together, these studies show that increased myelomonocytic ACE expression in mice alters the immune response to better defend against many different types of pathologic insult, including the cognitive decline observed in an animal model of AD. PMID:24792094

Identification of an ACE-Inhibitory Peptide from Walnut Protein and Its Evaluation of the Inhibitory Mechanism.

PubMed

Wang, Cong; Tu, Maolin; Wu, Di; Chen, Hui; Chen, Cheng; Wang, Zhenyu; Jiang, Lianzhou

2018-04-11

In the present study, a novel angiotensin I-converting enzyme inhibitory (ACE inhibitory) peptide, EPNGLLLPQY, derived from walnut seed storage protein, fragment residues 80-89, was identified by ultra-high performance liquid chromatography electrospray ionization quadrupole time of flight mass spectrometry (UPLC-ESI-Q-TOF-MS/MS) from walnut protein hydrolysate. The IC 50 value of the peptide was 233.178 μM, which was determined by the high performance liquid chromatography method by measuring the amount of hippuric acid (HA) generated from the ACE decomposition substrate (hippuryl-l-histidyl-l-leucine (HHL) to assess the ACE activity. Enzyme inhibitory kinetics of the peptide against ACE were also conducted, by which the inhibitory mechanism of ACE-inhibitory peptide was confirmed. Moreover, molecular docking was simulated by Discovery Studio 2017 R2 software to provide the potential mechanisms underlying the ACE-inhibitory activity of EPNGLLLPQY.

Angiotensin-I-Converting Enzyme (ACE)-Inhibitory Peptides from Plants

PubMed Central

Daskaya-Dikmen, Ceren; Yucetepe, Aysun; Karbancioglu-Guler, Funda; Daskaya, Hayrettin; Ozcelik, Beraat

2017-01-01

Hypertension is an important factor in cardiovascular diseases. Angiotensin-I-converting enzyme (ACE) inhibitors like synthetic drugs are widely used to control hypertension. ACE-inhibitory peptides from food origins could be a good alternative to synthetic drugs. A number of plant-based peptides have been investigated for their potential ACE inhibitor activities by using in vitro and in vivo assays. These plant-based peptides can be obtained by solvent extraction, enzymatic hydrolysis with or without novel food processing methods, and fermentation. ACE-inhibitory activities of peptides can be affected by their structural characteristics such as chain length, composition and sequence. ACE-inhibitory peptides should have gastrointestinal stability and reach the cardiovascular system to show their bioactivity. This paper reviews the current literature on plant-derived ACE-inhibitory peptides including their sources, production and structure, as well as their activity by in vitro and in vivo studies and their bioavailability. PMID:28333109

Solid phase sequencing of biopolymers

DOEpatents

Cantor, Charles; Koster, Hubert

2010-09-28

This invention relates to methods for detecting and sequencing target nucleic acid sequences, to mass modified nucleic acid probes and arrays of probes useful in these methods, and to kits and systems which contain these probes. Useful methods involve hybridizing the nucleic acids or nucleic acids which represent complementary or homologous sequences of the target to an array of nucleic acid probes. These probes comprise a single-stranded portion, an optional double-stranded portion and a variable sequence within the single-stranded portion. The molecular weights of the hybridized nucleic acids of the set can be determined by mass spectroscopy, and the sequence of the target determined from the molecular weights of the fragments. Nucleic acids whose sequences can be determined include DNA or RNA in biological samples such as patient biopsies and environmental samples. Probes may be fixed to a solid support such as a hybridization chip to facilitate automated molecular weight analysis and identification of the target sequence.

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.

Trauma-Sensitive Schools: An Evidence-Based Approach

ERIC Educational Resources Information Center

Plumb, Jacqui L.; Bush, Kelly A.; Kersevich, Sonia E.

2016-01-01

Adverse childhood experiences (ACEs) are a common and pervasive problem. There is a positive correlation between ACEs and difficulties across the lifespan. Unlike healthy forms of stress, ACEs have a detrimental impact on the developing brain. There are three types of trauma: acute, chronic, and complex. Most ACEs are considered complex trauma,…

Adverse childhood experiences, family functioning and adolescent health and emotional well-being.

PubMed

Balistreri, K S; Alvira-Hammond, M

2016-03-01

Adverse childhood experiences (ACEs) have been consistently linked in a strong and graded fashion to a host of health problems in later adulthood but few studies have examined the more proximate effect of ACEs on health and emotional well-being in adolescence. Nationally representative cross-sectional study. Using logistic regression on the 2011/12 National Survey of Children's Health, we examined the cumulative effect of total ACE score on the health and emotional well-being of US adolescents aged 12 to 17 years. We investigated the moderating effect of family functioning on the impact of ACE on adolescent health and emotional well-being. Adolescents with higher ACE scores had worse reported physical and emotional well-being than adolescents with fewer ACEs net of key demographic and socio-economic characteristics. Family functioning moderated the negative impact of cumulative ACE on adolescent health and emotional well-being. Adolescent well-being has enduring consequences; identifying children with ACE exposure who also have lower-functioning family could also help identify those families at particular risk. Copyright © 2015 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

ACE2 activation by xanthenone prevents leptin-induced increases in blood pressure and proteinuria during pregnancy in Sprague-Dawley rats.

PubMed

Ibrahim, Hisham Saleh; Froemming, Gabrielle Ruth Anisah; Omar, Effat; Singh, Harbindar Jeet

2014-11-01

This study investigates the effect of ACE2 activation on leptin-induced changes in systolic blood pressure (SBP), proteinuria, endothelial activation and ACE2 expression during pregnancy in Sprague-Dawley rats. Pregnant rats were given subcutaneous injection of either saline, or leptin, or leptin plus xanthenone (ACE2 activator), or xanthenone (XTN) alone. SBP, serum ACE, ACE2, endothelin-1, E-selectin and ICAM-1 levels were estimated; also their gene expressions were determined in the kidney and aorta respectively. Compared to control, SBP was higher in the leptin-only treated group (P<0.001) and lower in rats treated with xanthenone alone (P<0.01). Proteinuria, markers of endothelial activation were significantly higher than controls in leptin-only treated rats (P<0.05). ACE2 activity and expression were lower in leptin-only treated rats when compared to controls (P<0.05). It seems, leptin administration during pregnancy significantly increases SBP, proteinuria, endothelial activation, but decreases ACE2 level and expression. These effects are prevented by concurrent administration of xanthenone. Copyright © 2014 Elsevier Inc. All rights reserved.

Does acute care for the elderly (ACE) unit decrease the incidence of falls?

PubMed

Abdalla, Ahmed; Adhaduk, Mehul; Haddad, Raad A; Alnimer, Yanal; Ríos-Bedoya, Carlos F; Bachuwa, Ghassan

2017-11-11

To determine whether acute care for the elderly (ACE) units decrease the incidence of patient falls compared to general medical and surgical (GMS) units, a non-concurrent prospective study included individuals aged 65 and older admitted to ACE or GMS units over a 2-year span was done. There were 7069 admissions corresponded to 28,401 patient-days. A total of 149 falls were reported for an overall incidence rate (IR) of 5.2 falls per 1000 patient-days, 95% CI, 4.4/1000-6.1/1000 patient-days. The falls IR ratio for patients in ACE unit compared to those in non-ACE units after adjusting for age, sex, prescribed psychotropics and hypnotics, and Morse Fall Score was 0.27/1000 patient-days; 95% CI, 0.13-0.54; p < 0.001. So, an estimated 73% reduction in patient falls between ACE unit and non-ACE units. Hospitals may consider investing in ACE units to decrease the risk of falls and the associated medical and financial costs. Copyright © 2017 Elsevier Inc. All rights reserved.

Bioavailability of angiotensin I-converting enzyme (ACE) inhibitory peptides derived from Virgibacillus halodenitrificans SK1-3-7 proteinases hydrolyzed tilapia muscle proteins.

PubMed

Toopcham, Tidarat; Mes, Jurriaan J; Wichers, Harry J; Roytrakul, Sittiruk; Yongsawatdigul, Jirawat

2017-04-01

The angiotensin I-converting enzyme (ACE) inhibitory activity of protein hydrolysates from tilapia muscle fractions, namely mince (M), washed mince (WM), and sarcoplasmic protein (SP), were investigated. Each fraction was hydrolyzed by Virgibacillus halodenitrificans SK1-3-7 proteinases for up to 24h. After 8h of hydrolysis, the M hydrolysate (48% degree of hydrolysis (DH)) showed the highest ACE inhibitory activity, with an IC 50 value of 0.54mg/ml, while the SP hydrolysate exhibited the lowest DH and ACE inhibition. In vitro gastrointestinal digestion reduced the ACE inhibitory activity of the M hydrolysate but enhanced its transport across Caco-2 cell monolayers. The transported peptides were found to contain 3-4 amino acid residues showing strong ACE inhibition. The novel ACE inhibitory peptide with the highest inhibition was found to be MCS, with an IC 50 value of 0.29μM. Therefore, tilapia mince hydrolyzed by V. halodenitrificans proteinases contained ACE inhibitory peptides that are potentially bioavailable. Copyright © 2016 Elsevier Ltd. All rights reserved.

ADVERSE CHILDHOOD EXPERIENCES, FAMILY FUNCTIONING AND ADOLESCENT HEALTH AND EMOTIONAL WELL-BEING

PubMed Central

Balistreri, Kelly Stamper; Alvira-Hammond, Marta

2015-01-01

Objectives Adverse childhood experiences (ACE) have been consistently linked in a strong and graded fashion to a host of health problems in later adulthood but few studies have examined the more proximate effect of ACE on health and emotional well-being in adolescence. Study Design Nationally representative cross-sectional study. Methods Using logistic regression on the 2011/12 National Survey of Children’s Health, we examined the cumulative effect of total ACE score on the health and emotional well-being of US adolescents ages 12 through 17. We investigated the moderating effect of family functioning on the impact of ACE on adolescent health and emotional well-being. Results Adolescents with higher ACE scores had worse reported physical and emotional well-being than adolescents with fewer ACEs net of key demographic and socioeconomic characteristics. Family functioning moderated the negative impact of cumulative ACE on adolescent health and emotional well-being. Conclusions Adolescent well-being has enduring consequences; identifying children with ACE exposure who also have lower-functioning family could also help identify those families at particular risk. PMID:26718424

Adverse Childhood Experiences (ACEs), Stress and Mental Health in College Students.

PubMed

Karatekin, Canan

2018-02-01

The goal of this short-term longitudinal study was to examine whether adverse childhood experiences (ACEs) could be used to identify college students at risk for mental health problems and whether current level of stress mediates the relationship between ACEs and mental health. Data on ACEs and mental health (depression, anxiety and suicidality) were collected at the beginning of the semester, and data on current stressors and mental health were collected toward the end of the semester (n = 239). Findings indicated that ACEs predicted worsening of mental health over the course of a semester and suggested current number of stressors as a mediator of the relationship between ACEs and mental health. Results suggest that screening for ACEs might be useful to identify students at high risk for deterioration in mental health. Results further suggest that stress-related interventions would be beneficial for students with high levels of ACEs and point to the need for more research and strategies to increase help-seeking in college students. Copyright © 2017 John Wiley & Sons, Ltd.

Inhibition of the renin-angiotensin system improves physiological outcomes in mice with mild or severe cancer cachexia.

PubMed

Murphy, Kate T; Chee, Annabel; Trieu, Jennifer; Naim, Timur; Lynch, Gordon S

2013-09-01

Cancer cachexia describes the progressive skeletal muscle wasting and weakness associated with many cancers. Cachexia reduces mobility and quality of life and accounts for 20-30% of all cancer-related deaths. Activation of the renin-angiotensin system causes skeletal muscle wasting and weakness. We tested the hypothesis that treatment with the angiotensin converting enzyme (ACE) inhibitor, perindopril, would enhance whole body and skeletal muscle function in cachectic mice bearing Colon-26 (C-26) tumors. CD2F1 mice received a subcutaneous injection of phosphate buffered saline or C-26 tumor cells inducing either a mild or severe cachexia. The following day, one cohort of C-26 mice began receiving perindopril in their drinking water (4 mg kg(-1) day(-1) ) for 21 days. In mild and severe cachexia, perindopril increased measures of whole body function (grip strength and rotarod) and reduced fatigue in isolated contracting diaphragm muscle strips (p < 0.05). In severely cachectic mice, perindopril reduced tumor growth, improved locomotor activity and reduced fatigue of tibialis anterior muscles in situ (p < 0.05), which was associated with increased oxidative enzyme capacity (succinate deyhydrogenase, p < 0.05). Perindopril attenuated the increase in MuRF-1 and IL-6 mRNA expression and enhanced Akt phosphorylation in severely cachectic mice but neither body nor muscle mass was increased. These findings support the therapeutic potential of ACE inhibition for enhancing whole body function and reducing fatigue of respiratory muscles in early and late stage cancer cachexia and should be confirmed in future clinical trials. Since ACE inhibition alone did not enhance body or muscle mass, co-treatment with an anabolic agent may be required to address these aspects of cancer cachexia. Copyright © 2013 UICC.

The γ-aminobutyric acid-producing ability under low pH conditions of lactic acid bacteria isolated from traditional fermented foods of Ishikawa Prefecture, Japan, with a strong ability to produce ACE-inhibitory peptides.

PubMed

Barla, Florin; Koyanagi, Takashi; Tokuda, Naoko; Matsui, Hiroshi; Katayama, Takane; Kumagai, Hidehiko; Michihata, Toshihide; Sasaki, Tetsuya; Tsuji, Atsushi; Enomoto, Toshiki

2016-06-01

Many traditional fermented products are onsumed in Ishikawa Prefecture, Japan, such as kaburazushi , narezushi , konkazuke , and ishiru. Various kinds of lactic acid bacteria (LAB) are associated with their fermentation, however, characterization of LAB has not yet been elucidated in detail. In this study, we evaluated 53 isolates of LAB from various traditional fermented foods by taxonomic classification at the species level by analyzing the 16S ribosomal RNA gene (rDNA) sequences and carbohydrate assimilation abilities. We screened isolates that exhibited high angiotensin-converting enzyme (ACE) inhibitory activities in skim milk or soy protein media and produced high γ-aminobutyric acid (GABA) concentrations in culture supernatants when grown in de Man Rogosa Sharpe broth in the presence of 1% (w/v) glutamic acid. The results revealed that 10 isolates, i.e., Lactobacillus buchneri (2 isolates), Lactobacillus brevis (6 isolates), and Weissella hellenica (2 isolates) had a high GABA-producing ability of >500 mg/100 ml after 72 h of incubation at 35 °C. The ACE inhibitory activity of the whey cultured with milk protein by using L. brevis (3 isolates), L. buchneri (2 isolates), and W. hellenica (2 isolates) was stronger than that of all whey cultured with soy protein media, and these IC 50 were < 1 mg protein/ml. Three of 10 isolates had high GABA-producing activities at pH 3, suggesting that they could be powerful candidates for use in the fermentation of food materials having low pH.

The role of glycosylation and domain interactions in the thermal stability of human angiotensin-converting enzyme.

PubMed

O'Neill, Hester G; Redelinghuys, Pierre; Schwager, Sylva L U; Sturrock, Edward D

2008-09-01

The N and C domains of somatic angiotensin-converting enzyme (sACE) differ in terms of their substrate specificity, inhibitor profiling, chloride dependency and thermal stability. The C domain is thermally less stable than sACE or the N domain. Since both domains are heavily glycosylated, the effect of glycosylation on their thermal stability was investigated by assessing their catalytic and physicochemical properties. Testis ACE (tACE) expressed in mammalian cells, mammalian cells in the presence of a glucosidase inhibitor and insect cells yielded proteins with altered catalytic and physicochemical properties, indicating that the more complex glycans confer greater thermal stabilization. Furthermore, a decrease in tACE and N-domain N-glycans using site-directed mutagenesis decreased their thermal stability, suggesting that certain N-glycans have an important effect on the protein's thermodynamic properties. Evaluation of the thermal stability of sACE domain swopover and domain duplication mutants, together with sACE expressed in insect cells, showed that the C domain contained in sACE is less dependent on glycosylation for thermal stabilization than a single C domain, indicating that stabilizing interactions between the two domains contribute to the thermal stability of sACE and are decreased in a C-domain-duplicating mutant.

Small-angle neutron scattering study of specific interaction and coordination structure formed by mono-acetyl-substituted dibenzo-20-crown-6-ether and cesium ions

DOE PAGES

Motokawa, Ryuhei; Kobayashi, Tohru; Endo, Hitoshi; ...

2015-10-26

This study uses small-angle neutron scattering (SANS) to elucidate the coordination structure of the complex of mono-acetyl-substituted dibenzo-20-crown-6-ether (ace-DB20C6) with cesium ions (Cs +). SANS profiles obtained for the complex of ace-DB20C6 and Cs + (ace-DB20C6/Cs) in deuterated dimethyl sulfoxide indicated that Cs + coordination resulted in a more compact structure than the free ace-DB20C6. The data were fitted well with SANS profiles calculated using Debye function for scattering on an absolute scattering intensity scale. For this theoretical calculation of the scattering profiles, the coordination structure proposed based on density functional theory calculation was used. Furthermore, we conclude that themore » SANS analysis experimentally supports the proposed coordination structure of ace-DB20C6/Cs and suggests the following: (1) the complex of ace-DB20C6 and Cs + is formed with an ace-DB20C6/Cs molar ratio of 1/1 and (2) the two benzene rings of ace-DB20C6 fold around Cs + above the center of the crown ether ring of ace-DB20C6.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strittmatter, S.M.

(/sup 3/H)Captopril binds to angiotensin converting enzyme (ACE) in rat tissue homogenates. The pharmacology, regional distribution and copurification of (/sup 3/H)captopril binding with enzymatic activity demonstrate the selectivity of (/sup 3/H)captopril labeling of ACE. (/sup 3/H)Captopril binding to purified ACE reveals differences in cationic dependence and anionic regulation between substrate catalysis and inhibitor recognition. (/sup 3/H)Captopril association with ACE is entropically driven. The selectivity of (/sup 3/H)captopril binding permits autoradiographic localization of the ACE in the brain, male reproductive system, pituitary gland and adrenal gland. In the brain, ACE is visualized in a striatonigral neuronal pathway which develops between 1more » and 7 d after birth. In the male reproductive system, (/sup 3/H)captopril associated silver grains are found over spermatid heads and in the lumen of seminiferous tubules in stages I-VIII and XII-XIV. In the pituitary gland, ACE is localized to the posterior lobe and patches of the anterior lobe. The adrenal medulla contains moderate ACE levels while low levels are found in the adrenal cortex. Adrenal medullary ACE is increased after hypophysectomy and after reserpine treatment. The general of ligand binding techniques for the study of enzymes is demonstrated by the specific labeling of another enzyme, enkephaline convertase, in crude tissue homogenates by the inhibitor (/sup 3/H)GEMSA.« less

Small-angle neutron scattering study of specific interaction and coordination structure formed by mono-acetyl-substituted dibenzo-20-crown-6-ether and cesium ions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Motokawa, Ryuhei; Kobayashi, Tohru; Endo, Hitoshi

This study uses small-angle neutron scattering (SANS) to elucidate the coordination structure of the complex of mono-acetyl-substituted dibenzo-20-crown-6-ether (ace-DB20C6) with cesium ions (Cs +). SANS profiles obtained for the complex of ace-DB20C6 and Cs + (ace-DB20C6/Cs) in deuterated dimethyl sulfoxide indicated that Cs + coordination resulted in a more compact structure than the free ace-DB20C6. The data were fitted well with SANS profiles calculated using Debye function for scattering on an absolute scattering intensity scale. For this theoretical calculation of the scattering profiles, the coordination structure proposed based on density functional theory calculation was used. Furthermore, we conclude that themore » SANS analysis experimentally supports the proposed coordination structure of ace-DB20C6/Cs and suggests the following: (1) the complex of ace-DB20C6 and Cs + is formed with an ace-DB20C6/Cs molar ratio of 1/1 and (2) the two benzene rings of ace-DB20C6 fold around Cs + above the center of the crown ether ring of ace-DB20C6.« less

The Atmospheric Chemistry Experiment (ACE): Status and Latest Results

NASA Astrophysics Data System (ADS)

Bernath, P. F.; Boone, C. D.; McElroy, C. T.

2017-12-01

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°) 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. A second instrument, a dual spectrophotometer called MAESTRO, extends the wavelength coverage to the 400-1000 nm spectral region. Aerosols and clouds are being monitored through the extinction of solar radiation using two filtered imagers and by MAESTRO as well as by their infrared spectra. After 14 years in orbit, the ACE is still operating well. A short overview of the ACE mission will be presented (see http://www.ace.uwaterloo.ca for more information). The current version (v. 3.5/3.6) of ACE-FTS processing includes more than 30 molecules and twenty isotopologues; v.3.5/3.6 is now available in near-real time. This talk will focus on recent ACE results and the new version 4.0 of ACE-FTS processing.

Angiotensin-converting enzyme in Spodoptera littoralis: molecular characterization, expression and activity profile during development.

PubMed

Lemeire, Els; Vanholme, Bartel; Van Leeuwen, Thomas; Van Camp, John; Smagghe, Guy

2008-02-01

The characterization of the full-length angiotensin-converting enzyme (ACE) cDNA sequence of the lepidopteran Spodoptera littoralis is reported in this study. The predicted open reading frame encodes a 647 amino acids long protein (SlACE) and shows 63.6% identity with the Bombyx mori ACE sequence. A 3D-model, consisting of 26 alpha-helices and three beta-sheets, was predicted for the sequence. SlACE expression was studied in the embryonic, larval and pupal stages of S. littoralis and in different tissues of the last larval stage by reverse-transcribed PCR. This revealed that the gene is expressed throughout the life cycle and especially in brain, gut and fat body tissue of the last stage. These results are in agreement with a role of ACE in the metabolism of neuropeptides and gut hormones. In addition, ACE activity has been studied in more detail during development, making use of a fluorescent assay. High ACE peptidase activity coincides with every transition state, from embryo to larva, from larva to larva and from larva to pupa. A peak value in activity occurs during the early pupal stage. These results indicate the importance of SlACE during metamorphosis and reveal the high correlation of ACE activity with the insect's development, which is regulated by growth and developmental hormones.

Comparative Diagnostic Accuracy of the ACE-III, MIS, MMSE, MoCA, and RUDAS for Screening of Alzheimer Disease.

PubMed

Matías-Guiu, Jordi A; Valles-Salgado, María; Rognoni, Teresa; Hamre-Gil, Frank; Moreno-Ramos, Teresa; Matías-Guiu, Jorge

2017-01-01

Our aim was to evaluate and compare the diagnostic properties of 5 screening tests for the diagnosis of mild Alzheimer disease (AD). We conducted a prospective and cross-sectional study of 92 patients with mild AD and of 68 healthy controls from our Department of Neurology. The diagnostic properties of the following tests were compared: Mini-Mental State Examination (MMSE), Addenbrooke's Cognitive Examination III (ACE-III), Memory Impairment Screen (MIS), Montreal Cognitive Assessment (MoCA), and Rowland Universal Dementia Assessment Scale (RUDAS). All tests yielded high diagnostic accuracy, with the ACE-III achieving the best diagnostic properties. The area under the curve was 0.897 for the ACE-III, 0.889 for the RUDAS, 0.874 for the MMSE, 0.866 for the MIS, and 0.856 for the MoCA. The Mini-ACE score from the ACE-III showed the highest diagnostic capacity (area under the curve 0.939). Memory scores of the ACE-III and of the RUDAS showed a better diagnostic accuracy than those of the MMSE and of the MoCA. All tests, especially the ACE-III, conveyed a higher diagnostic accuracy in patients with full primary education than in the less educated group. Implementing normative data improved the diagnostic accuracy of the ACE-III but not that of the other tests. The ACE-III achieved the highest diagnostic accuracy. This better discrimination was more evident in the more educated group. © 2017 S. Karger AG, Basel.

Adverse Childhood Experiences among Veterinary Medical Students: A Multi-Site Study.

PubMed

Strand, Elizabeth B; Brandt, Jennifer; Rogers, Kenita; Fonken, Laurie; Chun, Ruthanne; Conlon, Peter; Lord, Linda

This research explores Adverse Childhood Experiences (ACEs) among veterinary medical students across six academic institutions of veterinary medicine, and their relationship with depression, stress, and desire to become a veterinarian. Between April 1, 2016, and May 23, 2016, 1,118 veterinary medical students in all 4 years of the curriculum (39% response rate) completed an anonymous web-based questionnaire about ACEs, depression using the Center for Epidemiological Studies Depression scale (CESD), stress using the Perceived Stress Scale (PSS), and the age at which they wanted to become a veterinarian. Sixty-one percent (677) of respondents reported having at least one ACE. The most prevalent ACE reported was living with a household member with a mental illness (31%). Students who had experienced four or more ACEs had an approximately threefold increase in signs of clinical depression and higher than average stress when compared to students who had experienced no ACEs. The number of ACEs showed an overall graded relationship to signs of clinical depression and higher than average stress. There was no statistically significant relationship between age at which a student wanted to become a veterinarian and exposure to ACEs. Veterinary students report being exposed to ACEs before age 18 at a rate similar to that of other population-based studies. These findings do not suggest that veterinary students enter the veterinary medical education system more at risk for poor mental health due to ACEs than the general population.

Evaluation of ACE gene I/D polymorphism in Iranian elite athletes.

PubMed

Shahmoradi, Somayeh; Ahmadalipour, Ali; Salehi, Mansoor

2014-01-01

Angiotensin converting enzyme (ACE) is an important gene, which is associated with the successful physical activity. The ACE gene has a major polymorphism (I/D) in intron 16 that determines its plasma and tissue levels. In this study, we aimed to determine whether there is an association between this polymorphism and sports performance in our studied population including elite athletes of different sports disciplines. We investigated allele frequency and genotype distribution of the ACE gene in 156 Iranian elite athletes compared to 163 healthy individuals. We also investigated this allele frequency between elite athletes in three functional groups of endurance, power, and mixed sports performances. DNA was extracted from peripheral blood, and polymerase chain reaction (PCR) method was performed on intron 16 of the ACE gene. The ACE genotype was determined for each subject. Statistical analysis was performed by SPSS 15, and results were analyzed by Chi-Square test. There was a significant difference in genotype distribution and allele frequency of the ACE gene in athletes and control group (P = 0.05, P = 0.03, respectively). There was also a significant difference in allele frequency of the ACE gene in 3 groups of athletes with different sports disciplines (P = 0.045). Proportion of the ACE gene D allele was greater in elite endurance athletes (37 high-distance cyclists) than two other groups. Findings of the present study demonstrated that there is an association between the ACE gene I/D polymorphism and sports performance in Iranian elite athletes.

Income Inequality and the Differential Effect of Adverse Childhood Experiences in US Children.

PubMed

Halfon, Neal; Larson, Kandyce; Son, John; Lu, Michael; Bethell, Christina

Adverse childhood experiences (ACEs) can affect health and development across the life course. Despite a general understanding that adversity is associated with lower income, we know less about how ACEs manifest at different income levels and how these income-related patterns affect children's health and development. Data from the 2011 to 2012 National Survey of Children's Health were used to examine the prevalence of 9 ACEs in US children, across 4 levels of household income, and in relationship to 5 parent-reported measures of child health. Bivariate analyses and multivariable logistic regression models were used to examine the associations between number of ACEs and children's health outcomes on the basis of the 4 income groups. When partitioned according to income strata, the proportion of children who experienced ACEs showed a steep income gradient, particularly for children who experienced ≥4 ACEs. The linear gradient across income groups was less pronounced for each specific ACE, with several ACEs (experience of divorce, drug and alcohol exposure, parental mental illness) showing high reported prevalence in all but the highest income group. Multivariate analysis showed a consistent income-related gradient for each of the health outcomes. However, higher income was not necessarily found to be a protective factor against ACEs. ACEs are distributed across the income ladder and not just concentrated below the poverty level. This suggests that a more comprehensive policy strategy that includes targeted as well as universal interventions is warranted. Copyright © 2016 Academic Pediatric Association. All rights reserved.

High-resolution crystal structures of Drosophila melanogaster angiotensin-converting enzyme in complex with novel inhibitors and antihypertensive drugs.

PubMed

Akif, Mohd; Georgiadis, Dimitris; Mahajan, Aman; Dive, Vincent; Sturrock, Edward D; Isaac, R Elwyn; Acharya, K Ravi

2010-07-16

Angiotensin I-converting enzyme (ACE), one of the central components of the renin-angiotensin system, is a key therapeutic target for the treatment of hypertension and cardiovascular disorders. Human somatic ACE (sACE) has two homologous domains (N and C). The N- and C-domain catalytic sites have different activities toward various substrates. Moreover, some of the undesirable side effects of the currently available and widely used ACE inhibitors may arise from their targeting both domains leading to defects in other pathways. In addition, structural studies have shown that although both these domains have much in common at the inhibitor binding site, there are significant differences and these are greater at the peptide binding sites than regions distal to the active site. As a model system, we have used an ACE homologue from Drosophila melanogaster (AnCE, a single domain protein with ACE activity) to study ACE inhibitor binding. In an extensive study, we present high-resolution structures for native AnCE and in complex with six known antihypertensive drugs, a novel C-domain sACE specific inhibitor, lisW-S, and two sACE domain-specific phosphinic peptidyl inhibitors, RXPA380 and RXP407 (i.e., nine structures). These structures show detailed binding features of the inhibitors and highlight subtle changes in the orientation of side chains at different binding pockets in the active site in comparison with the active site of N- and C-domains of sACE. This study provides information about the structure-activity relationships that could be utilized for designing new inhibitors with improved domain selectivity for sACE. 2010 Elsevier Ltd. All rights reserved.

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

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

Angiotensin Converting Enzyme Inhibitors and the Reduced Risk of Alzheimer’s Disease in the Absence of Apolipoprotein E4 Allele

PubMed Central

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

2014-01-01

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. PMID:23948883

An investigation of the concomitant use of angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs and diuretics.

PubMed

Bucsa, C; Moga, D C; Farcas, A; Mogosan, C; Dumitrascu, D L

2015-08-01

To determine in retrospective data the prevalence at hospital discharge of co-prescribing angiotensin-converting enzyme inhibitors (ACE-I) and non-steroidal anti-inflammatory drugs (NSAIDs) and ACE-I/NSAIDs and diuretics and to identify factors associated with the co-prescription. Secondary, we evaluated the extent of serum creatinine and potassium monitoring in patients treated with ACE-I and these associations and determined the prevalence of values above the upper normal limit (UNL) in monitored patients. Hospitalized patients with ACE-I in their therapy at discharge were included in 3 groups as follows: ACE-I, DT (double therapy with ACE-I and NSAIDs) and TT (triple therapy with ACE-I, NSAIDs and diuretics) groups. We evaluated differences on demographic characteristics, co-morbidities, medications, laboratory monitoring and quantified the patients with serum creatinine and potassium levels above the UNL using descriptive statistics. Logistic regression analysis with backward elimination was performed to identify significant predictors of combination therapy. Of 9960 admitted patients, 1214 were prescribed ACE-I, 40 were prescribed ACE-I/NSAIDs and 22 were prescribed ACE-I/NSAIDs/diuretics (3.13% and 1.72%, respectively, of the patients prescribed with ACE-I). Serum creatinine and potassium were monitored for the great majority of patients from all groups. The highest percentage of hyperkalemia was found in the DT group (10% of the patients) and of serum creatinine above UNL in the TT group (45.45%). The logistic regression final model showed that younger patients and monitoring for potassium were significantly associated with combination therapy. The prevalence of patients receiving DT/TT was relatively low and their monitoring during hospitalization was high. Factors associated with the combinations were younger patients and patients not tested for serum potassium.

ACE-FTS ozone, water vapour, nitrous oxide, nitric acid, and carbon monoxide profile comparisons with MIPAS and MLS

NASA Astrophysics Data System (ADS)

Sheese, Patrick E.; Walker, Kaley A.; Boone, Chris D.; Bernath, Peter F.; Froidevaux, Lucien; Funke, Bernd; Raspollini, Piera; von Clarmann, Thomas

2017-01-01

The atmospheric limb sounders, ACE-FTS on the SCISAT satellite, MIPAS on ESA's Envisat satellite, and MLS on NASA's Aura satellite, take measurements used to retrieve atmospheric profiles of O3, N2O, H2O, HNO3, and CO. Each was taking measurements between February 2004 and April 2012 (ACE-FTS and MLS are currently operational), providing hundreds of profile coincidences in the Northern and Southern hemispheres, and during local morning and evening. Focusing on determining diurnal and hemispheric biases in the ACE-FTS data, this study compares ACE-FTS version 3.5 profiles that are collocated with MIPAS and MLS, and analyzes the differences between instrument retrievals for Northern and Southern hemispheres and for local morning and evening data. For O3, ACE-FTS is typically within ±5% of mid-stratospheric MIPAS and MLS data and exhibits a positive bias of 10 to 20% in the upper stratosphere - lower mesosphere. For H2O, ACE-FTS exhibits an average bias of -5% between 20 and 60 km. For N2O, ACE-FTS agrees with MIPAS and MLS within -20 to +10% up to 45 km and 35 km, respectively. For HNO3, ACE-FTS typically agrees within ±10% below 30 km, and exhibits a positive bias of 10 to 20% above 30 km. With respect to MIPAS CO, ACE-FTS exhibits an average -11% bias between 28 and 50 km, and at higher altitudes a positive bias on the order of 10% (>100%) in the winter (summer). With respect to winter MLS CO, ACE-FTS is typically within ±10% between 25 and 40 km, and has an average bias of -11% above 40 km.

Adverse Childhood Experiences and School-Based Victimization and Perpetration.

PubMed

Forster, Myriam; Gower, Amy L; McMorris, Barbara J; Borowsky, Iris W

2017-01-01

Retrospective studies using adult self-report data have demonstrated that adverse childhood experiences (ACEs) increase risk of violence perpetration and victimization. However, research examining the associations between adolescent reports of ACE and school violence involvement is sparse. The present study examines the relationship between adolescent reported ACE and multiple types of on-campus violence (bringing a weapon to campus, being threatened with a weapon, bullying, fighting, vandalism) for boys and girls as well as the risk of membership in victim, perpetrator, and victim-perpetrator groups. The analytic sample was comprised of ninth graders who participated in the 2013 Minnesota Student Survey ( n ~ 37,000). Multinomial logistic regression models calculated the risk of membership for victim only, perpetrator only, and victim-perpetrator subgroups, relative to no violence involvement, for students with ACE as compared with those with no ACE. Separate logistic regression models assessed the association between cumulative ACE and school-based violence, adjusting for age, ethnicity, family structure, poverty status, internalizing symptoms, and school district size. Nearly 30% of students were exposed to at least one ACE. Students with ACE represent 19% of no violence, 38% of victim only, 40% of perpetrator only, and 63% of victim-perpetrator groups. There was a strong, graded relationship between ACE and the probability of school-based victimization: physical bullying for boys but not girls, being threatened with a weapon, and theft or property destruction ( ps < .001) and perpetration: bullying and bringing a weapon to campus ( ps < .001), with boys especially vulnerable to the negative effects of cumulative ACE. We recommend that schools systematically screen for ACE, particularly among younger adolescents involved in victimization and perpetration, and develop the infrastructure to increase access to trauma-informed intervention services. Future research priorities and implications are discussed.

Increased frequency of angiotensin-converting enzyme DD genotype in patients with type 2 diabetes in Taiwan.

PubMed

Hsieh, M C; Lin, S R; Hsieh, T J; Hsu, C H; Chen, H C; Shin, S J; Tsai, J H

2000-07-01

Diabetes is one of the major causes of end-stage renal failure in the Taiwanese population. Previous studies have shown that angiotensin-converting enzyme (ACE) inhibitor can improve glucose utilization and suppress hepatic glucose production and the renin-angiotensin system may play an important role in the initiation and progression of diabetic nephropathy. Thus, ACE gene polymorphism may be associated with type 2 diabetes and diabetic nephropathy. To investigate the distribution of ACE-I/D genotype in type 2 diabetes and diabetic nephropathy, we examined 336 patients with type 2 diabetes (157 without nephropathy and 179 with nephropathy) and 263 age-matched normal controls. The diagnosis of nephropathy was made when daily protein loss exceeded 500 mg. ACE gene polymorphism was analysed by use of polymerase chain reaction. Our study revealed that the frequency of the D allele of the ACE gene was 29.3% in normal controls. The frequency of ACE DD genotype was significantly higher in type 2 diabetics compared with normal controls (18.2 vs 9.1%, P<0.01). The frequency of ACE DD genotype in patients with diabetic nephropathy was significantly higher than in patients without nephropathy (22.3 vs 13.4%, P<0.05). To determine whether ACE gene polymorphism was associated with the severity of diabetic nephropathy, we divided patients with diabetic nephropathy into dialysis and non-dialysis groups. The frequency of ACE DD genotype in the dialysis group was significantly higher than in non-dialysis group (28.7 vs 15.3%, P<0.05). Our results indicate that the frequency of ACE DD genotype is markedly higher in patients with type 2 diabetes, and the ACE DD genotype is significantly associated with diabetic nephropathy.

High frequency of DD polymorphism of the angiotensin-converting enzyme gene in Turkish asthmatic patients.

PubMed

Urhan, Meral; Degirmenci, Irfan; Harmanci, Emel; Gunes, Hasan V; Metintas, Muzaffer; Basaran, Ayse

2004-01-01

The aim of this study is to detect the incidence of the angiotensin-converting enzyme (ACE) gene polymorphism in Turkish asthmatic patients and to examine whether there is an association between the disease and ACE gene polymorphism. In our study, the genomic DNA of 100 asthmatic patients and 88 healthy subjects was analyzed Genomic DNA was isolated from peripheral blood by using standard methods. The intron 16 of the ACE gene was amplified by the polymerase chain reaction (PCR) method using primers ACE and ACEX to examine the presence and absence of a 287-base pair (bp) DNA fragment that showed I/D polymorphism genotypes. PCR products were separated by agarose gel electrophoresis and were visualized by a charge-coupled device camera. Serum ACE activities were measured using an ACE kit. The results were evaluated statistically using the chi-square test and one-way analysis of variance. Although the population of patients with asthma was characterized by a higher frequency (30%) of the DD genotype of ACE, they were characterized by lower frequency (48%) of the ID genotype of ACE (DD, 16%, and ID, 64%, in healthy control subjects). The frequency of the I and D alleles of the ACE gene was not significantly different between asthmatic patients (0.46/0.54) and healthy controls (0.52/ 0.48). In addition, in both asthmatic patients and controls, there was a significant decrease of the levels of ACE activity in individuals that have II genotypes when compared with individuals that have DD genotypes. ACE activities were increased significantly in all asthmatic patients (67.20 +/- 1.95 IU/L) compared with all healthy controls (60.90 +/- 2.12 IU/L).

Association of Angiotensin-Converting Enzyme (ACE) Gene Polymorphism with Inflammation and Cellular Cytotoxicity in Vitiligo Patients.

PubMed

Rashed, Laila; Abdel Hay, Rania; Mahmoud, Rania; Hasan, Nermeen; Zahra, Amr; Fayez, Salwa

2015-01-01

Vitiligo is a disorder with profound heterogeneity in its aetio-pathophysiology. Angiotensin converting enzyme (ACE) plays an important role in the physiology of the vasculature, blood pressure and inflammation. An insertion/deletion (I/D) polymorphism of the ACE gene was reported be associated with the development of vitiligo. Our aim was to evaluate the ACE I/D polymorphism in vitiligo patients and controls. Our second aim was to find a possible association between ACE gene polymorphism and inflammatory mediators (as interleukin (IL)-6) and/or cellular cytotoxicity induced by serum nitrite (as a breakdown product of the cytotoxic nitric oxide) in vitiligo patients. This case-control study included 74 vitiligo patients and 75 apparently healthy controls. The distribution of ACE gene I/D genotype was investigated using PCR. Serum ACE, IL-6 and nitrite were measured by colorimetric method, ELISA and Griess assay respectively. The ACE allele frequency was significantly different between vitiligo patients and healthy controls (P = 0.026). However there was no significant difference between the ACE genotyping frequency in both groups (P = 0.115). There were statistically significant higher VIDA score (P = 0.007), and serum IL-6 (P < 0.001) in patients with the DD genotype when compared to other genotypes. Serum nitrite in patients with the DD genotype was significantly higher (P = 0.007) when compared to patients with II genotype. Serum levels of ACE, IL-6 and nitrite in vitiligo patients were statistically significantly higher than those in controls. As a conclusion, ACE gene polymorphism might grant susceptibility to develop vitiligo. Serum IL-6 and nitrite levels might have an important role in the pathogenesis of vitiligo. Targeting these two factors might have an implication in the treatment of some resistant cases.

Screening for Adverse Childhood Experiences in a Family Medicine Setting: A Feasibility Study.

PubMed

Glowa, Patricia T; Olson, Ardis L; Johnson, Deborah J

2016-01-01

The role of adverse childhood experiences (ACEs) in predicting later adverse adult health outcomes is being widely recognized by makers of public policy. ACE questionnaires have the potential to identify in clinical practice unaddressed key social issues that can influence current health risks, morbidity, and early mortality. This study seeks to explore the feasibility of implementing the ACE screening of adults during routine family medicine office visits. At 3 rural clinical practices, the 10-question ACE screen was used before visits with 111 consecutive patients of 7 clinicians. Clinician surveys about the use of the results and the effect on the visits were completed immediately after the visits. The presence of any ACE risk and "high-risk" ACE scores (≥4) were compared with clinician survey responses. A risk of ACEs was present in 62% of patients; 22% had scores ≥4. Clinicians were more likely to have discussed ACE issues for high-risk patients (score 0-3, 36.8%; score ≥4, 83.3%; P =. 00). Clinicians also perceived that they gained new information (score 0-3, 35.6%; score ≥4, 83.3%; P = .00). Clinical care changed for a small proportion of high-risk patients, with no change in immediate referrals or plan for follow-up. In 91% of visits where a risk of ACEs was present, visit length increased by ≤5 minutes. Incorporation of ACE screening during routine care is feasible and merits further study. ACE screening offers clinicians a more complete picture of important social determinants of health. Primary care-specific interventions that incorporate treatment of early life trauma are needed. © Copyright 2016 by the American Board of Family Medicine.

Convergent evidences from human and animal studies implicate angiotensin I-converting enzyme activity in cognitive performance in schizophrenia.

PubMed

Gadelha, A; Vendramini, A M; Yonamine, C M; Nering, M; Berberian, A; Suiama, M A; Oliveira, V; Lima-Landman, M T; Breen, G; Bressan, R A; Abílio, V; Hayashi, M A F

2015-12-08

In schizophrenia (SCZ), higher angiotensin I-converting enzyme (ACE) levels have been reported in patient's blood and cerebrospinal fluid (CSF). Hereby, we propose to explore whether the ACE activity levels are associated to cognitive performance in SCZ. Seventy-two patients with SCZ or schizoaffective disorder diagnosis, and 69 healthy controls (HCs) underwent a cognitive battery with parallel collection of peripheral blood samples to measure ACE activity. Significant higher ACE activity levels were confirmed in the plasma of SCZ patients compared with HCs (Student's t=-5.216; P<0.001). ACE activity significantly correlated to Hopkins delayed recall measures (r=-0.247; P=0.004) and Hopkins total (r=-0.214; P=0.012). Subjects grouped as high ACE activity (above average) had worse performance compared with low ACE activity level group for Hopkins delayed recall measure, even after correction for clinical condition, age, gender and years of education (P=0.029). The adjusted R squared for this final model was 0.343. This result was evident only comparing extreme groups for ACE activity, when splitting the sample in three groups with similar number of subjects. To clarify this finding, we performed an evaluation of the cognitive performance of transgenic mice with three copies of ACE gene in novel object recognition (NOR) test, which showed that such animals presented impairment in NOR (P<0.05) compared with two copies of wild-type animals. The results observed in SCZ patients and animal model suggest both the association of ACE to cognitive deficits in SCZ. This finding may support the evaluation of novel treatment protocols and/or of innovative drugs for specific intervention of cognitive deficits in SCZ envisioning concomitant ACE activity and behavior evaluations.

Production of the angiotensin I converting enzyme inhibitory peptides and isolation of four novel peptides from jellyfish (Rhopilema esculentum) protein hydrolysate.

PubMed

Liu, Xin; Zhang, Miansong; Shi, Yaping; Qiao, Ruojin; Tang, Wei; Sun, Zhenliang

2016-07-01

Angiotensin I converting enzyme (ACE) plays an important role in regulating blood pressure in the human body. ACE inhibitory peptides derived from food proteins could exert antihypertensive effects without side effects. Jellyfish (Rhopilema esculentum) is an important fishery resource suitable for production of ACE inhibitory peptides. The objective of this study was to optimize the hydrolysis conditions for production of protein hydrolysate from R. esculentum (RPH) with ACE inhibitory activity, and to isolate and identify the ACE inhibitory peptides from RPH. Rhopilema esculentum protein was hydrolyzed with Compound proteinase AQ to produce protein hydrolysate with ACE inhibitory activity, and the hydrolysis conditions were optimized using response surface methodology. The optimum parameters for producing peptides with the highest ACE inhibitory activity were as follows: hydrolysis time 3.90 h, hydrolysis temperature 58 °C, enzyme:substrate ratio 2.8% and pH 7.60. Under these conditions, the ACE inhibitory rate reached 32.21%. In addition, four novel ACE inhibitory peptides were isolated, and their amino acids sequences were identified as Val-Gly-Pro-Tyr, Phe-Thr-Tyr-Val-Pro-Gly, Phe-Thr-Tyr-Val-Pro-Gly-Ala and Phe-Gln-Ala-Val-Trp-Ala-Gly, respectively. The IC50 value of the purified peptides for ACE inhibitory activity was 8.40, 23.42, 21.15 and 19.11 µmol L(-1) . These results indicate that the protein hydrolysate prepared from R. esculentum might be a commercial competitive source of ACE inhibitory ingredients to be used in functional foods. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

Adverse childhood experiences and frequent insufficient sleep in 5 U.S. States, 2009: a retrospective cohort study.

PubMed

Chapman, Daniel P; Liu, Yong; Presley-Cantrell, Letitia R; Edwards, Valerie J; Wheaton, Anne G; Perry, Geraldine S; Croft, Janet B

2013-01-03

Although adverse childhood experiences (ACEs) have previously been demonstrated to be adversely associated with a variety of health outcomes in adulthood, their specific association with sleep among adults has not been examined. To better address this issue, this study examines the relationship between eight self-reported ACEs and frequent insufficient sleep among community-dwelling adults residing in 5 U.S. states in 2009. To assess whether ACEs were associated with frequent insufficient sleep (respondent did not get sufficient rest or sleep ≥ 14 days in past 30 days) in adulthood, we analyzed ACE data collected in the 2009 Behavioral Risk Factor Surveillance System, a random-digit-dialed telephone survey in Arkansas, Louisiana, New Mexico, Tennessee, and Washington. ACEs included physical abuse, sexual abuse, verbal abuse, household mental illness, incarcerated household members, household substance abuse, parental separation/divorce, and witnessing domestic violence before age 18. Smoking status and frequent mental distress (FMD) (≥ 14 days in past 30 days when self-perceived mental health was not good) were assessed as potential mediators in multivariate logistic regression analyses of frequent insufficient sleep by ACEs adjusted for race/ethnicity, gender, education, and body mass index. Overall, 28.8% of 25,810 respondents reported frequent insufficient sleep, 18.8% were current smokers, 10.8% reported frequent mental distress, 59.5% percent reported ≥ 1 ACE, and 8.7% reported ≥ 5 ACEs. Each ACE was associated with frequent insufficient sleep in multivariate analyses. Odds of frequent insufficient sleep were 2.5 (95% CI, 2.1-3.1) times higher in persons with ≥ 5 ACEs compared to those with no ACEs. Most relationships were modestly attenuated by smoking and FMD, but remained significant. Childhood exposures to eight indicators of child maltreatment and household dysfunction were significantly associated with frequent insufficient sleep during adulthood in this population. ACEs could be potential indicators promoting further investigation of sleep insufficiency, along with consideration of FMD and smoking.

Angiotensin converting enzyme 2 amplification limited to the circulation does not protect mice from development of diabetic nephropathy

PubMed Central

Wysocki, Jan; Ye, Minghao; Khattab, Ahmed M.; Fogo, Agnes; Martin, Aline; David, Nicolae Valentin; Kanwar, Yashpal; Osborn, Mark; Batlle, Daniel

2016-01-01

Blockers of the renin-angiotensin system are effective in the treatment of experimental and clinical diabetic nephropathy. An approach different from blocking the formation or action of angiotensin II(1-8) that could also be effective involves fostering its degradation. Angiotensin converting enzyme 2 (ACE2) is a monocarboxypeptidase than cleaves angiotensin II (1-8) to form angiotensin (1-7). Therefore, we examined the renal effects of murine recombinant ACE2 in mice with streptozotocin-induced diabetic nephropathy as well as that of amplification of circulating ACE2 using minicircle DNA delivery prior to induction of experimental diabetes. This delivery resulted in a long-term sustained and profound increase in serum ACE2 activity and enhanced ability to metabolize an acute angiotensin II (1-8) load. In mice with streptozotocin-induced diabetes pretreated with minicircle ACE2, ACE2 protein in plasma increased markedly and this was associated with a more than 100-fold increase in serum ACE2 activity. However, minicircle ACE2 did not result in changes in urinary ACE2 activity as compared to untreated diabetic mice. In both diabetic groups, glomerular filtration rate increased significantly and to the same extent as compared to non-diabetic controls. Albuminuria, glomerular mesangial expansion, glomerular cellularity and glomerular size, were all increased to a similar extent in minicircle ACE2-treated and untreated diabetic mice, as compared to non-diabetic controls. Recombinant mouse ACE2 given for 4 weeks by intraperitoneal daily injections in mice with streptozotocin-induced diabetic nephropathy also failed to improve albuminuria or kidney pathology. Thus, a profound augmentation of ACE2 confined to the circulation failed to ameliorate the glomerular lesions and hyperfiltration characteristic of early diabetic nephropathy. These findings emphasize the importance of targeting the kidney rather than the circulatory renin angiotensin system to combat diabetic nephropathy. PMID:27927599

Angiotensin-converting enzyme 2 amplification limited to the circulation does not protect mice from development of diabetic nephropathy.

PubMed

Wysocki, Jan; Ye, Minghao; Khattab, Ahmed M; Fogo, Agnes; Martin, Aline; David, Nicolae Valentin; Kanwar, Yashpal; Osborn, Mark; Batlle, Daniel

2017-06-01

Blockers of the renin-angiotensin system are effective in the treatment of experimental and clinical diabetic nephropathy. An approach different from blocking the formation or action of angiotensin II (1-8) that could also be effective involves fostering its degradation. Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that cleaves angiotensin II (1-8) to form angiotensin (1-7). Therefore, we examined the renal effects of murine recombinant ACE2 in mice with streptozotocin-induced diabetic nephropathy as well as that of amplification of circulating ACE2 using minicircle DNA delivery prior to induction of experimental diabetes. This delivery resulted in a long-term sustained and profound increase in serum ACE2 activity and enhanced ability to metabolize an acute angiotensin II (1-8) load. In mice with streptozotocin-induced diabetes pretreated with minicircle ACE2, ACE2 protein in plasma increased markedly and this was associated with a more than 100-fold increase in serum ACE2 activity. However, minicircle ACE2 did not result in changes in urinary ACE2 activity as compared to untreated diabetic mice. In both diabetic groups, glomerular filtration rate increased significantly and to the same extent as compared to non-diabetic controls. Albuminuria, glomerular mesangial expansion, glomerular cellularity, and glomerular size were all increased to a similar extent in minicircle ACE2-treated and untreated diabetic mice, as compared to non-diabetic controls. Recombinant mouse ACE2 given for 4 weeks by intraperitoneal daily injections in mice with streptozotocin-induced diabetic nephropathy also failed to improve albuminuria or kidney pathology. Thus, a profound augmentation of ACE2 confined to the circulation failed to ameliorate the glomerular lesions and hyperfiltration characteristic of early diabetic nephropathy. These findings emphasize the importance of targeting the kidney rather than the circulatory renin angiotensin system to combat diabetic nephropathy. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Circulating angiotensin-converting enzyme 2 activity in kidney transplantation: a longitudinal pilot study.

PubMed

Soler, María José; Riera, Marta; Crespo, Marta; Mir, Marisa; Márquez, Eva; Pascual, María José; Puig, Josep M; Pascual, Julio

2012-01-01

Angiotensin-converting enzyme 2 (ACE2) is the only known active homologue of ACE, and degrades angiotensin (Ang) II and Ang I to Ang(1-7) and Ang(1-9), respectively. The role of ACE2 in kidney transplant (KT) is unknown. Our objective was to investigate circulating ACE2 activity in KT patients, and the relationship between serum ACE2 activity and age, gender, graft function and cardiovascular risk markers in KT patients. 113 KT patients with stable graft function were included in this cross-sectional study. Circulating ACE2 activity was assessed using a fluorescent assay. Circulating ACE2 activity was detectable in KT patients and was increased in KT with ischemic heart disease as compared to KT without ischemic heart disease (105.9 ± 8.7 vs. 97.1 ± 7.05 relative fluorescence units (RFU)/µl/h, p < 0.05). ACE2 activity was increased in male KT as compared to females (105.2 ± 9.1 vs. 84.7 ± 6.9 RFU/µl/h, p = 0.05). ACE2 activity correlated positively with serum creatinine (r = 0.27), serum urea (r = 0.29), age (r = 0.24), aspartate transaminase (r = 0.39), alanine transaminase (r = 0.48), γ-glutamyl transferase (γ-GT) (r = 0.52), age (r = 0.24), and glycosylated hemoglobin (r = 0.19) (p < 0.05). By multiple regression analysis, age, serum creatinine, and serum γ-GT were independent predictors of serum ACE2 activity (r = 0.66, p < 0.001). Circulating ACE2 activity is measurable in KT patients and directly correlates with age, renal allograft and liver function parameters. These findings suggest that measurement of serum ACE2 may be used as a non-invasive marker to understand the role of the renin-angiotensin system in KT patients. Copyright © 2012 S. Karger AG, Basel.

A Single Nucleotide Polymorphism Uncovers a Novel Function for the Transcription Factor Ace2 during Candida albicans Hyphal Development

PubMed Central

Orellana-Muñoz, Sara; Gutiérrez-Escribano, Pilar; Arnáiz-Pita, Yolanda; Dueñas-Santero, Encarnación; Suárez, M. Belén; Bougnoux, Marie-Elisabeth; del Rey, Francisco; Sherlock, Gavin; d’Enfert, Christophe; Correa-Bordes, Jaime; de Aldana, Carlos R. Vázquez

2015-01-01

Candida albicans is a major invasive fungal pathogen in humans. An important virulence factor is its ability to switch between the yeast and hyphal forms, and these filamentous forms are important in tissue penetration and invasion. A common feature for filamentous growth is the ability to inhibit cell separation after cytokinesis, although it is poorly understood how this process is regulated developmentally. In C. albicans, the formation of filaments during hyphal growth requires changes in septin ring dynamics. In this work, we studied the functional relationship between septins and the transcription factor Ace2, which controls the expression of enzymes that catalyze septum degradation. We found that alternative translation initiation produces two Ace2 isoforms. While full-length Ace2, Ace2L, influences septin dynamics in a transcription-independent manner in hyphal cells but not in yeast cells, the use of methionine-55 as the initiation codon gives rise to Ace2S, which functions as the nuclear transcription factor required for the expression of cell separation genes. Genetic evidence indicates that Ace2L influences the incorporation of the Sep7 septin to hyphal septin rings in order to avoid inappropriate activation of cell separation during filamentous growth. Interestingly, a natural single nucleotide polymorphism (SNP) present in the C. albicans WO-1 background and other C. albicans commensal and clinical isolates generates a stop codon in the ninth codon of Ace2L that mimics the phenotype of cells lacking Ace2L. Finally, we report that Ace2L and Ace2S interact with the NDR kinase Cbk1 and that impairing activity of this kinase results in a defect in septin dynamics similar to that of hyphal cells lacking Ace2L. Together, our findings identify Ace2L and the NDR kinase Cbk1 as new elements of the signaling system that modify septin ring dynamics in hyphae to allow cell-chain formation, a feature that appears to have evolved in specific C. albicans lineages. PMID:25875512

Solid state phase change materials for thermal energy storage in passive solar heated buildings

NASA Astrophysics Data System (ADS)

Benson, D. K.; Christensen, C.

1983-11-01

A set of solid state phase change materials was evaluated for possible use in passive solar thermal energy storage systems. The most promising materials are organic solid solutions of pentaerythritol, pentaglycerine and neopentyl glycol. Solid solution mixtures of these compounds can be tailored so that they exhibit solid-to-solid phase transformations at any desired temperature within the range from less than 25 deg to 188 deg. Thermophysical properties such as thermal conductivity, density and volumetric expansion were measured. Computer simulations were used to predict the performance of various Trombe wall designs incorporating solid state phase change materials. Optimum performance was found to be sensitive to the choice of phase change temperatures and to the thermal conductivity of the phase change material. A molecular mechanism of the solid state phase transition is proposed and supported by infrared spectroscopic evidence.

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 angiotensin...

Repeated sampling of genes from a single cell - implications for gravitropism research

NASA Astrophysics Data System (ADS)

Scherp, P.; Hasenstein, K. H.

The need for repeated but independent extractions of mRNA from single cells and plant tissues prompted the development of Solid Phase Gene Extraction (SPGE, patent pending). Oligo dT18 coated glass needles hybridize during a 2 to 3 min sampling time with the poly A+ mRNA. The needle is withdrawn and can be used directly for RT-PCR. Because of the small probe size, no cytoplasm is lost and repeated sampling of the same cell is possible. SPGE of Chara rhizoids and internodal cells showed fluctuations of type and quantity of mRNA in specific areas of the cytoplasm of rhizoids and time-dependent gene expression in internodal cells as a function of light/dark intervals. Despite extensive cytoplasmic streaming, mRNA-samples taken in the vicinity of the nucleus revealed a higher variability than the distal ends of the cell. In rhizoids, the mRNA/cDNA varied between the different zones of cytoplasm. In Arabidopsis, we isolated cDNA species from root tips, shoots and leaves and determined their sequences. Growth studies on SPGE-sampled individuals showed that after a short recovery period, all sampled plants resumed growth with normal growth rates and graviresponse. The data indicate that SPGE is a powerful method to study gene expression in single cells and in tissues of higher plants with high spatial and temporal resolution. Supported by NASA: NAG 2-1423

Immunological quality and performance of tumor vessel-targeting CAR-T cells prepared by mRNA-EP for clinical research

PubMed Central

Inoo, Kanako; Inagaki, Ryo; Fujiwara, Kento; Sasawatari, Shigemi; Kamigaki, Takashi; Nakagawa, Shinsaku; Okada, Naoki

2016-01-01

We previously reported that tumor vessel-redirected T cells, which were genetically engineered with chimeric antigen receptor (CAR) specific for vascular endothelial growth factor receptor 2 (VEGFR2), demonstrated significant antitumor effects in various murine solid tumor models. In the present study, we prepared anti-VEGFR2 CAR-T cells by CAR-coding mRNA electroporation (mRNA-EP) and analyzed their immunological characteristics and functions for use in clinical research. The expression of anti-VEGFR2 CAR on murine and human T cells was detected with approximately 100% efficiency for a few days, after peaking 6–12 hours after mRNA-EP. Triple transfer of murine anti-VEGFR2 CAR-T cells into B16BL6 tumor-bearing mice demonstrated an antitumor effect comparable to that for the single transfer of CAR-T cells engineered with retroviral vector. The mRNA-EP did not cause any damage or defects to human T-cell characteristics, as determined by viability, growth, and phenotypic parameters. Additionally, two kinds of human anti-VEGFR2 CAR-T cells, which expressed different CAR construction, differentiated to effector phase with cytokine secretion and cytotoxic activity in antigen-specific manner. These results indicate that our anti-VEGFR2 CAR-T cells prepared by mRNA-EP have the potential in terms of quality and performance to offer the prospect of safety and efficacy in clinical research as cellular medicine. PMID:27909701

Near-Infrared Ag2S Quantum Dots-Based DNA Logic Gate Platform for miRNA Diagnostics.

PubMed

Miao, Peng; Tang, Yuguo; Wang, Bidou; Meng, Fanyu

2016-08-02

Dysregulation of miRNA expression is correlated with the development and progression of many diseases. These miRNAs are regarded as promising biomarkers. However, it is challenging to measure these low abundant molecules without employing time-consuming radioactive labeling or complex amplification strategies. Here, we present a DNA logic gate platform for miRNA diagnostics with fluorescence outputs from near-infrared (NIR) Ag2S quantum dots (QDs). Carefully designed toehold exchange-mediated strand displacements with different miRNA inputs occur on a solid-state interface, which control QDs release from solid-state interface to solution, responding to multiplex information on initial miRNAs. Excellent fluorescence emission properties of NIR Ag2S QDs certify the great prospect for amplification-free and sensitive miRNA assay. We demonstrate the potential of this platform by achieving femtomolar level miRNA analysis and the versatility of a series of logic circuits computation.

Comparison of bacteriophage and enteric virus removal in pilot scale activated sludge plants.

PubMed

Arraj, A; Bohatier, J; Laveran, H; Traore, O

2005-01-01

The aim of this experimental study was to determine comparatively the removal of two types of bacteriophages, a somatic coliphage and an F-specific RNA phage and of three types of enteric viruses, hepatitis A virus (HAV), poliovirus and rotavirus during sewage treatment by activated sludge using laboratory pilot plants. The cultivable simian rotavirus SA11, the HAV HM 175/18f cytopathic strain and poliovirus were quantified by cell culture. The bacteriophages were quantified by plaque formation on the host bacterium in agar medium. In each experiment, two pilots simulating full-scale activated sludge plants were inoculated with viruses at known concentrations, and mixed liquor and effluent samples were analysed regularly. In the mixed liquor, liquid and solid fractions were analysed separately. The viral behaviour in both the liquid and solid phases was similar between pilots of each experiment. Viral concentrations decreased rapidly following viral injection in the pilots. Ten minutes after the injections, viral concentrations in the liquid phase had decreased from 1.0 +/- 0.4 log to 2.2 +/- 0.3 log. Poliovirus and HAV were predominantly adsorbed on the solid matters of the mixed liquor while rotavirus was not detectable in the solid phase. In our model, the estimated mean log viral reductions after 3-day experiment were 9.2 +/- 0.4 for rotavirus, 6.6 +/- 2.4 for poliovirus, 5.9 +/- 3.5 for HAV, 3.2 +/- 1.2 for MS2 and 2.3 +/- 0.5 for PhiX174. This study demonstrates that the pilots are useful models to assess the removal of infectious enteric viruses and bacteriophages by activated sludge treatment. Our results show the efficacy of the activated sludge treatment on the five viruses and suggest that coliphages could be an acceptable indicator of viral removal in this treatment system.

ACE2 Therapy Using Adeno-associated Viral Vector Inhibits Liver Fibrosis in Mice

PubMed Central

Mak, Kai Y; Chin, Ruth; Cunningham, Sharon C; Habib, Miriam R; Torresi, Joseph; Sharland, Alexandra F; Alexander, Ian E; Angus, Peter W; Herath, Chandana B

2015-01-01

Angiotensin converting enzyme 2 (ACE2) which breaks down profibrotic peptide angiotensin II to antifibrotic peptide angiotensin-(1–7) is a potential therapeutic target in liver fibrosis. We therefore investigated the long-term therapeutic effect of recombinant ACE2 using a liver-specific adeno-associated viral genome 2 serotype 8 vector (rAAV2/8-ACE2) with a liver-specific promoter in three murine models of chronic liver disease, including carbon tetrachloride-induced toxic injury, bile duct ligation-induced cholestatic injury, and methionine- and choline-deficient diet-induced steatotic injury. A single injection of rAAV2/8-ACE2 was administered after liver disease has established. Hepatic fibrosis, gene and protein expression, and the mechanisms that rAAV2/8-ACE2 therapy associated reduction in liver fibrosis were analyzed. Compared with control group, rAAV2/8-ACE2 therapy produced rapid and sustained upregulation of hepatic ACE2, resulting in a profound reduction in fibrosis and profibrotic markers in all diseased models. These changes were accompanied by reduction in hepatic angiotensin II levels with concomitant increases in hepatic angiotensin-(1–7) levels, resulting in significant reductions of NADPH oxidase assembly, oxidative stress and ERK1/2 and p38 phosphorylation. Moreover, rAAV2/8-ACE2 therapy normalized increased intrahepatic vascular tone in fibrotic livers. We conclude that rAAV2/8-ACE2 is an effective liver-targeted, long-term therapy for liver fibrosis and its complications without producing unwanted systemic effects. PMID:25997428

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ryan, J.W.; Anderson, D.R.

Eye tissues contain kininase activities, including an angiotensin converting enzyme (ACE)-like activity. The authors have begun further to characterize the ACE-like activity and to examine for another reputed kininase, carboxypeptidase N (CPN). Homogenates of tissues of 6 cat eyes and paired plasmas were assayed for ACE using 3 acyl-tripeptide substrates, /sup 3/H-benzoylated F-A-P, F-G-P and A-G-P (respectively, BFAP, BFGP and BAGP). CPN was assayed using /sup 3/H-benzoyl-A-R. All eye tissues and fluids contained ACE- and CPN-like activities. The ACE activity was clearly owing to ACE: relative values of Kc/Km for BFAP, BFGP and BAGP were those for pure ACE (2.213,more » 1.751 and 1.0); reactivities with inhibitors were as expected (Ki for captopril, MK 422 and RAC-X-65: 2.7, 0.62 and 0.31 nM). EDTA inhibited both ACE and CPN (I/sub 50/'s: 43 and 47 ..mu..M). CPN activity was inhibited by 2-mercaptomethyl-3-guanidinoethylthiopropionate (Ki 2.4 nM). However, distributions of the two enzymes differed markedly. Virtually all tissues contained ACE at specific activities higher than that of plasma. Specific activities appeared to be a function of tissue vascularity (for choroid, ciliary body, iris, retina and plasma: 7.31, 2.57, 1.98, 1.53 and 0.21 pmol/mg protein). Only iris contained more CPN that did plasma (23.0 v. 7.21 pmol/mg protein). The tissue distribution of ACE is that expected for an endothelial-associated enzyme. Plasma may be the major source of CPN in eye tissues other than iris.« less

On Becoming Trauma-Informed: Role of the Adverse Childhood Experiences Survey in Tertiary Child and Adolescent Mental Health Services and the Association with Standard Measures of Impairment and Severity.

PubMed

Rahman, Abdul; Perri, Andrea; Deegan, Avril; Kuntz, Jennifer; Cawthorpe, David

2018-01-01

There is a movement toward trauma-informed, trauma-focused psychiatric treatment. To examine Adverse Childhood Experiences (ACE) survey items by sex and by total scores by sex vs clinical measures of impairment to examine the clinical utility of the ACE survey as an index of trauma in a child and adolescent mental health care setting. Descriptive, polychoric factor analysis and regression analyses were employed to analyze cross-sectional ACE surveys (N = 2833) and registration-linked data using past admissions (N = 10,400) collected from November 2016 to March 2017 related to clinical data (28 independent variables), taking into account multicollinearity. Distinct ACE items emerged for males, females, and those with self-identified sex and for ACE total scores in regression analysis. In hierarchical regression analysis, the final models consisting of standard clinical measures and demographic and system variables (eg, repeated admissions) were associated with substantial ACE total score variance for females (44%) and males (38%). Inadequate sample size foreclosed on developing a reduced multivariable model for the self-identified sex group. The ACE scores relate to independent clinical measures and system and demographic variables. There are implications for clinical practice. For example, a child presenting with anxiety and a high ACE score likely requires treatment that is different from a child presenting with anxiety and an ACE score of zero. The ACE survey score is an important index of presenting clinical status that guides patient care planning and intervention in the progress toward a trauma-focused system of care.

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. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

In vitro autoradiographic localization of angiotensin-converting enzyme in sarcoid lymph nodes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allen, R.K.; Chai, S.Y.; Dunbar, M.S.

1986-09-01

Angiotensin-converting enzyme (ACE) was localized in sarcoid lymph nodes by an in vitro autoradiographic technique using a synthetic ACE inhibitor of high affinity, /sup 125/I-labelled 351A. The lymph nodes were from seven patients with active sarcoidosis who underwent mediastinoscopy and from six control subjects who had nodes resected at either mediastinoscopy or laparotomy. Angiotensin-converting enzyme was localized in the epithelioid cells of sarcoid granulomata in markedly increased amounts compared with control nodes, where it was restricted to vessels and some histiocytes. In sarcoid lymph nodes, there was little ACE present in lymphocytes or fibrous tissue. Sarcoid nodes with considerable fibrosismore » had much less intense ACE activity than the nonfibrotic nodes. The specific activity of ACE measured by an enzymatic assay in both the control and sarcoid lymph nodes closely reflected the ACE activity demonstrated by autoradiography. Sarcoid lymph nodes with fibrosis had an ACE specific activity of half that of nonfibrotic nodes (p less than 0.05). There was a 15-fold increase in specific ACE activity in sarcoid nodes (p less than 0.05) compared to normal. Serum ACE was significantly higher in those sarcoid patients whose lymph nodes were not fibrosed compared with those with fibrosis (p less than 0.01). This technique offers many advantages over the use of polyclonal antibodies. The 351A is a highly specific ACE inhibitor, chemically defined and in limitless supply. This method enables the quantitation of results, and autoradiographs may be stored indefinitely for later comparison.« less

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

PubMed Central

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

2014-01-01

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). PMID:24163131

Validity of the T-ACE in pregnancy in predicting child outcome and risk drinking.

PubMed

Chiodo, Lisa M; Sokol, Robert J; Delaney-Black, Virginia; Janisse, James; Hannigan, John H

2010-01-01

Preventing fetal alcohol spectrum disorders (FASDs) requires detection of in-pregnancy maternal risk drinking. The widely used T-ACE screen has been applied in various ways, although the impact of those different uses on effectiveness is uncertain. We examined relations among different T-ACE scoring criteria, maternal drinking, and child outcome. Self-reported across-pregnancy maternal drinking was assessed in 75 African-American women. The different T-ACE criteria used varied the level of drinking that defined tolerance (two or three drinks) and the total T-ACE score cut-points (two or three). Receiver operator curves and regression analysis assessed the significance of relations. Increasing the total T-ACE score cut-point to 3 almost doubled specificity in detecting risk drinking whereas maintaining adequate sensitivity, equivalent to that in the original report, and identified substantially more neurobehavioral deficits in children. Redefining tolerance at three drinks did not improve T-ACE effectiveness in predicting outcomes. This study is among the first to show the ability of an in-pregnancy T-ACE assessment to predict child neurodevelopmental outcome. In addition, increasing the total T-ACE score criterion (from 2 to 3) improved identification of non-drinking mothers and unaffected children with little loss in detection of drinkers and affected children. Efficient in-pregnancy screens for risk drinking afford greater opportunities for intervention that could prevent/limit FASDs. Published by Elsevier Inc.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsuura-Hachiya, Yuko; Arai, Koji Y.; Ozeki, Rieko

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 recoverymore » 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.« less

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.

Effect of protease inhibitors on angiotensin-converting enzyme activity in human T-lymphocytes.

PubMed

Petrov, V; Fagard, R; Lijnen, P

2000-05-01

The purpose of these investigations was to determine whether the aminopeptidase B and leucine aminopeptidase inhibitor bestatin, the chymase inhibitor chymostatin, the calpain inhibitor E-64, and the neutral serine protease inhibitor leupeptin affect the angiotensin converting enzyme (ACE) activity in T-lymphocytes. ACE activity in homogenates of T-lymphocytes or in intact T-lymphocytes in suspension was measured by determining fluorimetrically histidyl-leucine, formed from the conversion of hippuryl-histidyl-leucine, coupled with ophtaldialdehyde. The effect of various concentrations (10(-9) to 10(-3) mol/L) of the angiotensin-converting enzyme inhibitors lisinopril and captopril and of the various protease inhibitors on ACE activity was studied. Lisinopril and captopril reduced the ACE activity in homogenates of T-lymphocytes in a concentration-dependent manner. Lisinopril exhibited a more pronounced inhibition of ACE in T-lymphocytes than did captopril. Chymostatin and E-64 had no effect on the ACE activity in T-lymphocytes, whereas leupeptin inhibited its activity in a dose-dependent fashion. Bestatin, on the contrary, increased the ACE activity in homogenates of T-lymphocytes as well as in intact T-lymphocytes in proportion to the concentration. Our data showed that the ACE activity in T-lymphocytes was stimulated by bestatin and inhibited by leupeptin, whereas chymostatin and E-64 did not affect the ACE activity in T-lymphocytes.

Study and development of reversed-phase HPLC systems for the determination of 2-imidazolines in the presence of preservatives in pharmaceutical preparations.

PubMed

Antoniou, Constantinos G; Markopoulou, Catherine K; Kouskoura, Maria G; Koundourellis, John E

2011-01-01

Different HPLC chromatographic systems were investigated on a C18 ACE 5 pm, 150 x 4.6 mm id column for the determination of tymazoline, tramazoline, and antazoline, with either naphazoline or xylometazoline, in commercial preparations. For the development and optimization of the systems, a Response Surface Method (r=0.925-0.980) was used to illustrate the changes in k as a function of pH values and different salt concentrations. The simultaneous separation of 2-imidazolines was accomplished at 40 degrees C with 0.01 M ammonium acetate-methanol (50+50, v/v, pH 6.0) mobile phase at a flow rate of 1.2 mL/min. In order to deal with the usual coexistence of 2-imidazolines with benzethonium and benzalkonium chloride preservatives, it was necessary to use another chromatographic system, 0.01 M ammonium acetate-methanol (50+50, v/v) mobile phase on a cyano ACE 5 pm, 150 x 4.6 mm id column. As part of a more thorough theoretical investigation, a partial least-squares (PLS) technique was used for modeling the RP-HPLC retention data. The model was based on molecular structure descriptors of the analytes' X variables and on their retention time (Log K) Y. The goodness of fit was estimated by the PLS correlation coefficient (r2) and root mean square error of estimation values, which were 0.994 and 0.0479, respectively.

The ABLE ACE wavefront sensor

NASA Astrophysics Data System (ADS)

Butts, Robert R.

1997-08-01

A low noise, high resolution Shack-Hartmann wavefront sensor was included in the ABLE-ACE instrument suite to obtain direct high resolution phase measurements of the 0.53 micrometers pulsed laser beam propagated through high altitude atmospheric turbulence. The wavefront sensor employed a Fired geometry using a lenslet array which provided approximately 17 sub-apertures across the pupil. The lenslets focused the light in each sub-aperture onto a 21 by 21 array of pixels in the camera focal plane with 8 pixels in the camera focal plane with 8 pixels across the central lobe of the diffraction limited spot. The goal of the experiment was to measure the effects of the turbulence in the free atmosphere on propagation, but the wavefront sensor also detected the aberrations induced by the aircraft boundary layer and the receiver aircraft internal beam path. Data analysis methods used to extract the desired atmospheric contribution to the phase measurements from the data corrupted by non-atmospheric aberrations are described. Approaches which were used included a reconstruction of the phase as a linear combination of Zernike polynomials coupled with optical estimator sand computation of structure functions of the sub-aperture slopes. The theoretical basis for the data analysis techniques is presented. Results are described, and comparisons with theory and simulations are shown. Estimates of average turbulence strength along the propagation path from the wavefront sensor showed good agreement with other sensor. The Zernike spectra calculated from the wavefront sensor data were consistent with the standard Kolmogorov model of turbulence.

ACE [Adult and Community Education] into the 21st Century: A Vision.

ERIC Educational Resources Information Center

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

This document outlines a vision for adult and community education (ACE) in Victoria for the next 3 years and provides a broad map of how to reach that vision. A description of the context is followed by the ACE vision statement: ACE delivers accessible, quality, and timely learning in autonomous, community settings as a valued and essential…

Vibrio cholerae ACE stimulates Ca(2+)-dependent Cl(-)/HCO(3)(-) secretion in T84 cells in vitro.

PubMed

Trucksis, M; Conn, T L; Wasserman, S S; Sears, C L

2000-09-01

ACE, accessory cholera enterotoxin, the third enterotoxin in Vibrio cholerae, has been reported to increase short-circuit current (I(sc)) in rabbit ileum and to cause fluid secretion in ligated rabbit ileal loops. We studied the ACE-induced change in I(sc) and potential difference (PD) in T84 monolayers mounted in modified Ussing chambers, an in vitro model of a Cl(-) secretory cell. ACE added to the apical surface alone stimulated a rapid increase in I(sc) and PD that was concentration dependent and immediately reversed when the toxin was removed. Ion replacement studies established that the current was dependent on Cl(-) and HCO(3)(-). ACE acted synergistically with the Ca(2+)-dependent acetylcholine analog, carbachol, to stimulate secretion in T84 monolayers. In contrast, the secretory response to cAMP or cGMP agonists was not enhanced by ACE. The ACE-stimulated secretion was dependent on extracellular and intracellular Ca(2+) but was not associated with an increase in intracellular cyclic nucleotides. We conclude that the mechanism of secretion by ACE involves Ca(2+) as a second messenger and that this toxin stimulates a novel Ca(2+)-dependent synergy.

ACE Gene I/D Polymorphism and Obesity in 1,574 Patients with Type 2 Diabetes Mellitus.

PubMed

Pan, Yan-Hong; Wang, Min; Huang, Yan-Mei; Wang, Ying-Hui; Chen, Yin-Ling; Geng, Li-Jun; Zhang, Xiao-Xi; Zhao, Hai-Lu

2016-01-01

Association between ACE gene I/D polymorphism and the risk of overweight/obesity remains controversial. We investigated the possible relationship between ACE gene I/D polymorphism and obesity in Chinese type 2 diabetes mellitus (T2DM) patients. In this study, obesity was defined as a body mass index (BMI) value ≥ 25 kg/m 2 and subjects were classified into 4 groups (lean, normal, overweight, and obese). PCR (polymerase chain reaction) was used to detect the ACE gene I/D polymorphism in T2DM patients. Metabolic measurements including blood glucose, lipid profile, and blood pressure were obtained. Frequencies of the ACE genotypes (DD, ID, and II) were not significant among the 4 groups of BMI-defined patients ( P = 0.679) while ACE II carriers showed higher systolic blood pressure (SBP) and pulse pressure (PP) (all P < 0.050). Hyperglycemia, hypertension, and dyslipidemia in these T2DM patients were found to be significantly associated with BMI. In conclusion, the relationship of ACE gene I/D polymorphism with obesity is insignificant in Chinese patients with T2DM. SBP and PP might be higher in the ACE II carriers than in the DD and ID carriers.

Production of angiotensin I converting enzyme inhibitory (ACE-I) peptides during milk fermentation and their role in reducing hypertension.

PubMed

Rai, Amit Kumar; Sanjukta, Samurailatpam; Jeyaram, Kumaraswamy

2017-09-02

Fermented milk is a potential source of various biologically active peptides with specific health benefits. Angiotensin converting enzyme inhibitory (ACE-I) peptides are one of the most studied bioactive peptides produced during milk fermentation. The presence of these peptides is reported in various fermented milk products such as, yoghurt, cheese, sour milk, etc., which are also available as commercial products. Many of the ACE-I peptides formed during milk fermentation are resistant to gastrointestinal digestion and inhibit angiotensin converting enzyme (ACE) in the rennin angiotension system (RAS). There are various factors, which affect the formation ACE-I peptides and their ability to reach the target tissue in active form, which includes type of starters (lactic acid bacteria (LAB), yeast, etc.), substrate composition (casein type, whey protein, etc.), composition of ACE-I peptide, pre and post-fermentation treatments, and its stability during gastrointestinal digestion. The antihypertensive effect of fermented milk products has also been proved by various in vitro and in vivo (animal and human trials) experiments. This paper reviews the literature on fermented milk products as a source of ACE-I peptides and various factors affecting the production and activity of ACE-I peptides.

The Role of RNA in Biological Phase Separations.

PubMed

Fay, Marta M; Anderson, Paul J

2018-05-10

Phase transitions that alter the physical state of ribonucleoprotein particles contribute to the spacial and temporal organization of the densely packed intracellular environment. This allows cells to organize biologically coupled processes as well as respond to environmental stimuli. RNA plays a key role in phase separation events that modulate various aspects of RNA metabolism. Here, we review the role that RNA plays in ribonucleoprotein phase separations. Copyright © 2018 Elsevier Ltd. All rights reserved.

A method combining immunocapture and PCR amplification in a microtiter plate for the detection of plant viruses and subviral pathogens.

PubMed

Nolasco, G; de Blas, C; Torres, V; Ponz, F

1993-12-15

A method for the detection of RNA viral and subviral plant pathogens was developed that combines pathogen partial purification by solid-phase adsorbed antibodies, reverse transcriptional-polymerase chain reaction (RT-PCR) and quantitation of the amplified products by fluorescence. The reverse transcription of the RNA is performed directly on the retained material without any previous thermal or chemical disruption of the virus particles. The whole procedure can be carried out in a microtiter plate. Its validity has been successfully confirmed for the detection of bean yellow mosaic virus, cherry leafroll virus, cucumber mosaic virus, citrus tristeza virus, grapevine fanleaf virus, potato leafroll virus, pepper mild mottle virus, and tomato spotted wilt virus, as well as the satellite RNA of cucumber mosaic virus and potato spindle tuber viroid. In this procedure virus-specific antibodies can be replaced by monoclonal antibodies against double-stranded RNA, thus offering the possibility of detection when no specific virus antibodies are available, or immunological methods are difficult to use (i.e., subviral pathogens like satellite-RNAs or viroids). The method described has the typical sensitivity of assays based on the polymerase chain reaction, it is not more laborious than ELISA, and an equivalent degree of automation is possible.

Focus on increased serum angiotensin-converting enzyme level: From granulomatous diseases to genetic mutations.

PubMed

Lopez-Sublet, Marilucy; di Lanzacco, Lorenzo Caratti; Jan Danser, A H; Lambert, Michel; Elourimi, Ghassan; Persu, Alexandre

2018-06-18

Angiotensin I-converting enzyme (ACE) is a well-known zinc-metallopeptidase that converts angiotensin I to the potent vasoconstrictor angiotensin II and degrades bradykinin, a powerful vasodilator, and as such plays a key role in the regulation of vascular tone and cardiac function. Increased circulating ACE (cACE) activity has been reported in multiple diseases, including but not limited to granulomatous disorders. Since 2001, genetic mutations leading to cACE elevation have also been described. This review takes advantage of the identification of a novel ACE mutation (25-IVS25 + 1G > A) in two Belgian pedigrees to summarize current knowledge about the differential diagnosis of cACE elevation, based on literature review and the experience of our centre. Furthermore, we propose a practical approach for the evaluation and management of patients with elevated cACE and discuss in which cases search for genetic mutations should be considered. Copyright © 2018. Published by Elsevier Inc.

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

Assessment of the rs4340 ACE gene polymorphism in acute coronary syndrome in a Western Mexican population.

PubMed

Valdez-Haro, A; Valle, Y; Valdes-Alvarado, E; Casillas-Muñoz, F; Muñoz-Valle, J F; Reynoso-Villalpando, G L; Flores-Salinas, H E; Padilla-Gutiérrez, J R

2017-09-27

Acute coronary syndrome (ACS) is considered one of the main causes of death worldwide. Contradictory findings concerning the impact of the angiotensin-converting enzyme (ACE) gene on cardiovascular diseases have been reported. Previous conclusions point out that the variability in results depends on ethnicity and genetic polymorphisms to determine the association of rs4340 polymorphisms of the ACE gene and ACE circulating levels in ACS. Genotyping of rs4340 polymorphisms was performed in a total of 600 individuals from Western Mexico divided into two groups: the ACS and the control group (CG). The polymorphisms were identified by polymerase chain reaction. Serum ACE concentration was determined by enzyme-linked immunosorbent assay. D/D carriers had higher ACE levels than I/I carriers (3.6 vs 2.8 ng/mL, P < 0.0021) in the CG. The D/D genotype of the rs4340 polymorphism is associated with higher ACE concentration levels; however, the polymorphism was not associated with ACS.

ACE I/D and MMP-7 A-181G variants and the risk of end stage renal disease.

PubMed

Rahimi, Zohreh; Abdi, Hamed; Tanhapoor, Maryam; Rahimi, Ziba; Vaisi-Raygani, Asad; Nomani, Hamid

2017-03-01

The variants of angiotensin converting enzyme ( ACE ) and matrix metalloproteinases (MMPs) genes might be involved in the pathogenesis of end stage renal disease (ESRD) and hypertension. We studied the ACE insertion/deletion (I/D) and MMP-7 A-181G variants in 99 unrelated ESRD patients and 117 individuals without renal complications from Western Iran with Kurdish ethnic background. The frequency of ACE I/D variants was not significantly different between ESRD patients and controls. However, the presence of ACE D allele increased the risk of hypertension in ESRD patients by 2.14-fold (P=0.036). The MMP-7 -181 AG genotype increased the risk of ESRD by 2.04 times (P=0.026). The present study indicated the absence of an association between the ACE I/D polymorphism with the risk of ESRD. However, the ACE D allele increased the risk of hypertension in ESRD patients. Also, the present study suggests a role for MMP-7 AG genotype in the pathogenesis of ESRD.

Bacterial RNA isolation.

PubMed

Ares, Manuel

2012-09-01

In this bacterial RNA isolation protocol, an "RNA-protective" treatment is followed by lysozyme digestion of the peptidoglycan component of the cell wall. EDTA promotes the loss of the outer membrane of Gram-negative bacteria and allows the lysozyme better access to the peptidoglycan. Cells begin to lyse during digestion in hypotonic lysozyme buffer and lysis is completed by sodium dodecyl sulfate (SDS) and hot phenol:chloroform:isoamyl alcohol (PCA) extraction. SDS and hot phenol disrupt membranes, denature protein (including RNase), and strip proteins from RNA. The separation of the organic phase from the aqueous phase is achieved using Phase Lock Gel, an inert material with a density intermediate between the organic and aqueous samples. The sample is split into three phases: from bottom to top, these are phenol and chloroform (organic phase), the inert gel with the interface material, and the aqueous phase with the RNA. The gel acts as a physical barrier between the sample and the organic phase plus interface. Following organic extraction, the RNA is concentrated by ethanol precipitation.

The effects analysis of two neonicotinoid insecticides on in vitro maturation of porcine oocytes using hanging drop monoculture method.

PubMed

Ishikawa, Sadamasa; Hiraga, Kou; Hiradate, Yuuki; Tanemura, Kentaro

2015-06-01

Acetamiprid (ACE) and imidacroprid (IMI) are known neonicotinoid insecticides with strong affinities for the insect-selective nicotinic acetylcholine receptor. These provide insect control by hyperstimulating insect nerves and are used for agricultural pest management. However, it has also been reported that ACE and IMI affect mammalian reproductive function. We determined the effects of ACE and IMI on the in vitro maturation of porcine oocytes. Significant decreases in nuclear maturation rates were observed in the ACE or IMI-exposed groups. Also, in matured oocytes from the ACE or IMI-exposed groups, irregular chromosomes were observed. Our results suggest that ACE and IMI exposure was detrimental to porcine oocytes and the extent of the effects depends on the concentration of exposure.

Adverse childhood experiences, posttraumatic stress disorder symptoms, and emotional intelligence in partner aggression.

PubMed

Swopes, Rachael M; Simonet, Daniel V; Jaffe, Anna E; Tett, Robert P; Davis, Joanne L

2013-01-01

Intimate partner violence (IPV) has been linked to childhood abuse, posttraumatic stress disorder (PTSD), and low emotional intelligence (EI). Relationships among adverse childhood experiences (ACE), PTSD symptoms, and partner aggression (i.e., generalized tendency to aggress toward one's partner) were assessed in 108 male IPV offenders. It was hypothesized that ACE is positively correlated with partner aggression, PTSD mediates the ACE-aggression relationship, and the ACE-PTSD-aggression mediation varies by selected EI facets. Results indicate that ACE has an indirect effect on partner aggression via PTSD and PTSD mediates the ACE-aggression link when emotional self-regulation is low and when intuition (vs. reason) is high. Trauma-exposed IPV offenders may benefit from comprehensive treatments focusing on PTSD symptoms, emotional control, and reasoning skills to reduce aggression.

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

PubMed

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

2014-11-01

A series of novel diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate embedded triazole and mannich bases were synthesized, and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. Screening of above synthesized compounds for ACE inhibition showed that triazoles functionalized compounds have better ACE inhibitory activity compared to that of mannich bases analogues. Among all triazoles we found 6 h, 6 i and 6 j to have good ACE inhibition activity with IC50 values 0.713 μM, 0.409 μM and 0.653 μM, respectively. Among mannich bases series compounds, only 7c resulted as most active ACE inhibitor with IC50 value of 0.928 μM. Copyright © 2014. Published by Elsevier Ltd.

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

Correlation of the National Board of Medical Examiners Emergency Medicine Advanced Clinical Examination Given in July to Intern American Board of Emergency Medicine in-training Examination Scores: A Predictor of Performance?

PubMed

Hiller, Katherine; Franzen, Doug; Heitz, Corey; Emery, Matthew; Poznanski, Stacy

2015-11-01

There is great variation in the knowledge base of Emergency Medicine (EM) interns in July. The first objective knowledge assessment during residency does not occur until eight months later, in February, when the American Board of EM (ABEM) administers the in-training examination (ITE). In 2013, the National Board of Medical Examiners (NBME) released the EM Advanced Clinical Examination (EM-ACE), an assessment intended for fourth-year medical students. Administration of the EM-ACE to interns at the start of residency may provide an earlier opportunity to assess the new EM residents' knowledge base. The primary objective of this study was to determine the correlation of the NBME EM-ACE, given early in residency, with the EM ITE. Secondary objectives included determination of the correlation of the United States Medical Licensing Examination (USMLE) Step 1 or 2 scores with early intern EM-ACE and ITE scores and the effect, if any, of clinical EM experience on examination correlation. This was a multi-institutional, observational study. Entering EM interns at six residencies took the EM-ACE in July 2013 and the ABEM ITE in February 2014. We collected scores for the EM-ACE and ITE, age, gender, weeks of clinical EM experience in residency prior to the ITE, and USMLE Step 1 and 2 scores. Pearson's correlation and linear regression were performed. Sixty-two interns took the EM-ACE and the ITE. The Pearson's correlation coefficient between the ITE and the EM-ACE was 0.62. R-squared was 0.5 (adjusted 0.4). The coefficient of determination was 0.41 (95% CI [0.3-0.8]). For every increase of one in the scaled EM-ACE score, we observed a 0.4% increase in the EM in-training score. In a linear regression model using all available variables (EM-ACE, gender, age, clinical exposure to EM, and USMLE Step 1 and Step 2 scores), only the EM-ACE score was significantly associated with the ITE (p<0.05). We observed significant colinearity among the EM-ACE, ITE and USMLE scores. Gender, age and number of weeks of EM prior to the ITE had no effect on the relationship between EM-ACE and the ITE. Given early during intern year, the EM-ACE score showed positive correlation with ITE. Clinical EM experience prior to the in-training exam did not affect the correlation.

Correlation of the National Board of Medical Examiners Emergency Medicine Advanced Clinical Examination Given in July to Intern American Board of Emergency Medicine in-training Examination Scores: A Predictor of Performance?

PubMed Central

Hiller, Katherine; Franzen, Doug; Heitz, Corey; Emery, Matthew; Poznanski, Stacy

2015-01-01

Introduction There is great variation in the knowledge base of Emergency Medicine (EM) interns in July. The first objective knowledge assessment during residency does not occur until eight months later, in February, when the American Board of EM (ABEM) administers the in-training examination (ITE). In 2013, the National Board of Medical Examiners (NBME) released the EM Advanced Clinical Examination (EM-ACE), an assessment intended for fourth-year medical students. Administration of the EM-ACE to interns at the start of residency may provide an earlier opportunity to assess the new EM residents’ knowledge base. The primary objective of this study was to determine the correlation of the NBME EM-ACE, given early in residency, with the EM ITE. Secondary objectives included determination of the correlation of the United States Medical Licensing Examination (USMLE) Step 1 or 2 scores with early intern EM-ACE and ITE scores and the effect, if any, of clinical EM experience on examination correlation. Methods This was a multi-institutional, observational study. Entering EM interns at six residencies took the EM-ACE in July 2013 and the ABEM ITE in February 2014. We collected scores for the EM-ACE and ITE, age, gender, weeks of clinical EM experience in residency prior to the ITE, and USMLE Step 1 and 2 scores. Pearson’s correlation and linear regression were performed. Results Sixty-two interns took the EM-ACE and the ITE. The Pearson’s correlation coefficient between the ITE and the EM-ACE was 0.62. R-squared was 0.5 (adjusted 0.4). The coefficient of determination was 0.41 (95% CI [0.3–0.8]). For every increase of one in the scaled EM-ACE score, we observed a 0.4% increase in the EM in-training score. In a linear regression model using all available variables (EM-ACE, gender, age, clinical exposure to EM, and USMLE Step 1 and Step 2 scores), only the EM-ACE score was significantly associated with the ITE (p<0.05). We observed significant colinearity among the EM-ACE, ITE and USMLE scores. Gender, age and number of weeks of EM prior to the ITE had no effect on the relationship between EM-ACE and the ITE. Conclusion Given early during intern year, the EM-ACE score showed positive correlation with ITE. Clinical EM experience prior to the in-training exam did not affect the correlation. PMID:26594299

Production of the blood pressure lowing peptides from brown alga ( Undaria pinnatifida)

NASA Astrophysics Data System (ADS)

Minoru, Sato; Takashi, Oba; Takao, Hosokawa; Toshiyasu, Yamaguchi; Toshiki, Nakano; Tadao, Saito; Koji, Muramoto; Takashi, Kahara; Katsura, Funayama; Akio, Kobayashi; Takahisa, Nakano

2005-07-01

Brown alga ( Undaria pinnatifida) was treated with alginate lyase and hydrolyzed using 17 kinds of proteases and the inhibitory activity of the hydrolysates for the angiotensin-I-converting enzyme (ACE) was measured. Four hydrolysates with potent ACE-inhibitory activity were administered singly and orally to spontaneously hypertensive rats (SHRs). The systolic blood pressure of SHRs decreases significantly after single oral administration of the brown alga hydrolysates by protease S ‘Amano’ (from Bacillus stearothermophilus) at the concentration of 10 (mg protein) (kg body weight)-1. In the 17 weeks of feeding experiment, 7-week-old SHRs were fed standard diet supplemented with the brown alga hydrolysates for 10 weeks. In SHRs fed 1.0 and 0.1% brown alga hydrolysates, elevating of systolic bloodpressure was significantly suppressed for 7 weeks. To elucidate the active components, the brown alga hydrolysates were fractionated by 1-butanol extraction and HPLC on a reverse-phase column. Seven kinds of ACE-inhibitory peptides were isolated and identified by amino acid composition analysis, sequence analysis, and LC-MS with the results Val-Tyr, Ile-Tyr, Ala-Trp, Phe-Tyr, Val-Trp, Ile-Trp, and Leu-Trp. Each peptide was determined to have an antihypertensive effect after a single oral administration in SHRs. The brown alga hydrolysates were also confirmed to decrease the blood pressure in humans.

MicroRNA-like RNAs from the same miRNA precursors play a role in cassava chilling responses.

PubMed

Zeng, Changying; Xia, Jing; Chen, Xin; Zhou, Yufei; Peng, Ming; Zhang, Weixiong

2017-12-07

MicroRNAs (miRNAs) are known to play important roles in various cellular processes and stress responses. MiRNAs can be identified by analyzing reads from high-throughput deep sequencing. The reads realigned to miRNA precursors besides canonical miRNAs were initially considered as sequencing noise and ignored from further analysis. Here we reported a small-RNA species of phased and half-phased miRNA-like RNAs different from canonical miRNAs from cassava miRNA precursors detected under four distinct chilling conditions. They can form abundant multiple small RNAs arranged along precursors in a tandem and phased or half-phased fashion. Some of these miRNA-like RNAs were experimentally confirmed by re-amplification and re-sequencing, and have a similar qRT-PCR detection ratio as their cognate canonical miRNAs. The target genes of those phased and half-phased miRNA-like RNAs function in process of cell growth metabolism and play roles in protein kinase. Half-phased miR171d.3 was confirmed to have cleavage activities on its target gene P-glycoprotein 11, a broad substrate efflux pump across cellular membranes, which is thought to provide protection for tropical cassava during sharp temperature decease. Our results showed that the RNAs from miRNA precursors are miRNA-like small RNAs that are viable negative gene regulators and may have potential functions in cassava chilling responses.

40 CFR 227.32 - Liquid, suspended particulate, and solid phases of a material.

Code of Federal Regulations, 2010 CFR

2010-07-01

... solid phases of a material. 227.32 Section 227.32 Protection of Environment ENVIRONMENTAL PROTECTION... MATERIALS Definitions § 227.32 Liquid, suspended particulate, and solid phases of a material. (a) For the... obtained above prior to centrifugation and filtration. The solid phase includes all material settling to...

40 CFR 227.32 - Liquid, suspended particulate, and solid phases of a material.

Code of Federal Regulations, 2011 CFR

2011-07-01

... solid phases of a material. 227.32 Section 227.32 Protection of Environment ENVIRONMENTAL PROTECTION... MATERIALS Definitions § 227.32 Liquid, suspended particulate, and solid phases of a material. (a) For the... obtained above prior to centrifugation and filtration. The solid phase includes all material settling to...

Principles of Adaptive Array Processing

DTIC Science & Technology

2006-09-01

ACE with and without tapering (homogeneous case). These analytical results are less suited to predict the detection performance of a real system ...Nickel: Adaptive Beamforming for Phased Array Radars. Proc. Int. Radar Symposium IRS’98 (Munich, Sept. 1998), DGON and VDE /ITG, pp. 897-906.(Reprint also...strategies for airborne radar. Asilomar Conf. on Signals, Systems and Computers, Pacific Grove, CA, 1998, IEEE Cat.Nr. 0-7803-5148-7/98, pp. 1327-1331. [17

Aerobic exercise training differentially affects ACE C- and N-domain activities in humans: Interactions with ACE I/D polymorphism and association with vascular reactivity

PubMed Central

Alves, Cléber Rene; Fernandes, Tiago; Lemos, José Ribeiro; Magalhães, Flávio de Castro; Trombetta, Ivani Credidio; Alves, Guilherme Barreto; da Mota, Glória de Fátima Alves; Dias, Rodrigo Gonçalves; Pereira, Alexandre Costa; Krieger, José Eduardo; Negrão, Carlos Eduardo; Oliveira, Edilamar Menezes

2018-01-01

Introduction: Previous studies have linked angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism (II, ID and DD) to physical performance. Moreover, ACE has two catalytic domains: NH2 (N) and COOH (C) with distinct functions, and their activity has been found to be modulated by ACE polymorphism. The aim of the present study is to investigate the effects of the interaction between aerobic exercise training (AET) and ACE I/D polymorphism on ACE N- and C-domain activities and vascular reactivity in humans. Materials and methods: A total of 315 pre-selected healthy males were genotyped for II, ID and DD genotypes. Fifty completed the full AET (II, n = 12; ID, n = 25; and DD, n = 13), performed in three 90-minute sessions weekly, in the four-month exercise protocol. Pre- and post-training resting heart rate (HR), peak O2 consumption (VO2 peak), mean blood pressure (MBP), forearm vascular conduction (FVC), total circulating ACE and C- and N-domain activities were assessed. One-way ANOVA and two-way repeated-measures ANOVA were used. Results: In pre-training, all variables were similar among the three genotypes. In post-training, a similar increase in FVC (35%) was observed in the three genotypes. AET increased VO2 peak similarly in II, ID and DD (49±2 vs. 57±1; 48±1 vs. 56±3; and 48±5 vs. 58±2 ml/kg/min, respectively). Moreover, there were no changes in HR and MBP. The DD genotype was also associated with greater ACE and C-domain activities at pre- and post-training when compared to II. AET decreased similarly the total ACE and C-domain activities in all genotypes, while increasing the N-domain activity in the II and DD genotypes. However, interestingly, the measurements of N-domain activity after training indicate a greater activity than the other genotypes. These results suggest that the vasodilation in response to AET may be associated with the decrease in total ACE and C-domain activities, regardless of genotype, and that the increase in N-domain activity is dependent on the DD genotype. Conclusions: AET differentially affects the ACE C- and N-domain activities, and the N-domain activity is dependent on ACE polymorphism. PMID:29629833

Angiotensin converting enzyme (ACE) and neprilysin hydrolyze neuropeptides: a brief history, the beginning and follow-ups to early studies.

PubMed

Skidgel, Randal A; Erdös, Ervin G

2004-03-01

Our investigations started when synthetic bradykinin became available and we could characterize two enzymes that cleaved it: kininase I or plasma carboxypeptidase N and kininase II, a peptidyl dipeptide hydrolase that we later found to be identical with the angiotensin I converting enzyme (ACE). When we noticed that ACE can cleave peptides without a free C-terminal carboxyl group (e.g., with a C-terminal nitrobenzylamine), we investigated inactivation of substance P, which has a C-terminal Met(11)-NH(2). The studies were extended to the hydrolysis of the neuropeptide, neurotensin and to compare hydrolysis of the same peptides by neprilysin (neutral endopeptidase 24.11, CD10, NEP). Our publication in 1984 dealt with ACE and NEP purified to homogeneity from human kidney. NEP cleaved substance P (SP) at Gln(6)-Phe(7), Phe(7)[see text]-Phe(8), and Gly(9)-Leu(10) and neurotensin (NT) at Pro(10)-Tyr(11) and Tyr(11)-Ile(12). Purified ACE also rapidly inactivated SP as measured in bioassay. HPLC analysis showed that ACE cleaved SP at Phe(8)-Gly(9) and Gly(9)-Leu(10) to release C-terminal tri- and dipeptide (ratio = 4:1). The hydrolysis was Cl(-) dependent and inhibited by captopril. ACE released only dipeptide from SP free acid. ACE hydrolyzed NT at Tyr(11)-Ile(12) to release Ile(12)-Leu(13). Then peptide substrates were used to inhibit ACE hydrolyzing Fa-Phe-Gly-Gly and NEP cleaving Leu(5)-enkephalin. The K(i) values in microM were as follows: for ACE, bradykinin = 0.4, angiotensin I = 4, SP = 25, SP free acid = 2, NT = 14, and Met(5)-enkephalin = 450, and for NEP, bradykinin = 162, angiotensin I = 36, SP = 190, NT = 39, Met(5)-enkephalin = 22. These studies showed that ACE and NEP, two enzymes widely distributed in the body, are involved in the metabolism of SP and NT. Below we briefly survey how NEP and ACE in two decades have gained the reputation as very important factors in health and disease. This is due to the discovery of more endogenous substrates of the enzymes and to the very broad and beneficial therapeutic applications of ACE inhibitors.

Aerobic exercise training differentially affects ACE C- and N-domain activities in humans: Interactions with ACE I/D polymorphism and association with vascular reactivity.

PubMed

Alves, Cléber Rene; Fernandes, Tiago; Lemos, José Ribeiro; Magalhães, Flávio de Castro; Trombetta, Ivani Credidio; Alves, Guilherme Barreto; Mota, Glória de Fátima Alves da; Dias, Rodrigo Gonçalves; Pereira, Alexandre Costa; Krieger, José Eduardo; Negrão, Carlos Eduardo; Oliveira, Edilamar Menezes

2018-01-01

Previous studies have linked angiotensin-converting enzyme ( ACE) insertion (I)/deletion (D) polymorphism (II, ID and DD) to physical performance. Moreover, ACE has two catalytic domains: NH2 (N) and COOH (C) with distinct functions, and their activity has been found to be modulated by ACE polymorphism. The aim of the present study is to investigate the effects of the interaction between aerobic exercise training (AET) and ACE I/D polymorphism on ACE N- and C-domain activities and vascular reactivity in humans. A total of 315 pre-selected healthy males were genotyped for II, ID and DD genotypes. Fifty completed the full AET (II, n = 12; ID, n = 25; and DD, n = 13), performed in three 90-minute sessions weekly, in the four-month exercise protocol. Pre- and post-training resting heart rate (HR), peak O 2 consumption (VO 2 peak), mean blood pressure (MBP), forearm vascular conduction (FVC), total circulating ACE and C- and N-domain activities were assessed. One-way ANOVA and two -way repeated-measures ANOVA were used. In pre-training, all variables were similar among the three genotypes. In post-training, a similar increase in FVC (35%) was observed in the three genotypes. AET increased VO 2 peak similarly in II, ID and DD (49±2 vs. 57±1; 48±1 vs. 56±3; and 48±5 vs. 58±2 ml/kg/min, respectively). Moreover, there were no changes in HR and MBP. The DD genotype was also associated with greater ACE and C-domain activities at pre- and post-training when compared to II. AET decreased similarly the total ACE and C-domain activities in all genotypes, while increasing the N-domain activity in the II and DD genotypes. However, interestingly, the measurements of N-domain activity after training indicate a greater activity than the other genotypes. These results suggest that the vasodilation in response to AET may be associated with the decrease in total ACE and C-domain activities, regardless of genotype, and that the increase in N-domain activity is dependent on the DD genotype. AET differentially affects the ACE C- and N-domain activities, and the N-domain activity is dependent on ACE polymorphism.

The effect of structural motifs on the ectodomain shedding of human angiotensin-converting enzyme.

PubMed

Conrad, Nailah; Schwager, Sylva L U; Carmona, Adriana K; Sturrock, Edward D

2016-12-02

Somatic angiotensin converting enzyme (sACE) is comprised of two homologous domains (N and C domains), whereas the smaller germinal isoform (tACE) is identical to the C domain. Both isozymes share an identical stalk, transmembrane and cytoplasmic domain, and undergo ectodomain shedding by an as yet unknown protease. Here we present evidence for the role of regions distal and proximal to the cleavage site in human ACE shedding. First, because of intrinsic differences between the N and C domains, discrete secondary structures (α-helix 7 and 8) on the surface of tACE were replaced with their N domain counterparts. Surprisingly, neither α-helix 7 nor α-helix 8 proved to be an absolute requirement for shedding. In the proximal ectodomain of tACE residues H 610 -L 614 were mutated to alanines and this resulted in a decrease in ACE shedding. An N-terminal extension of this mutation caused a reduction in cellular ACE activity. More importantly, it affected the processing of the protein to the membrane, resulting in expression of an underglycosylated form of ACE. When E 608 -H 614 was mutated to the homologous region of the N domain, processing was normal and shedding only moderately decreased suggesting that this region is more crucial for the processing of ACE than it is for regulating shedding. Finally, to determine whether glycosylation of the asparagine proximal to the Pro1199-Leu polymorphism in sACE affected shedding, the equivalent P 623 L mutation in tACE was investigated. The P 623 L tACE mutant showed an increase in shedding and MALDI MS analysis of a tryptic digest indicated that N 620 WT was glycosylated. The absence of an N-linked glycan at N 620 , resulted in an even greater increase in shedding. Thus, the conformational flexibility that the leucine confers to the stalk, is increased by the lack of glycosylation reducing access of the sheddase to the cleavage site. Copyright © 2016 Elsevier Inc. All rights reserved.

The Relationship of Adverse Childhood Events to Smoking, Overweight, Obesity and Binge Drinking Among Women in Hawaii.

PubMed

Remigio-Baker, Rosemay A; Hayes, Donald K; Reyes-Salvail, Florentina

2017-02-01

To evaluate how the associations of adverse childhood events (ACEs) with smoking, overweight, obesity and binge drinking differ by race/ethnicity among women, including a large, understudied cohort of Asians and Native Hawaiians/Pacific Islanders (NHOPIs). The number and type (household dysfunction, and physical, verbal and sexual abuse) of ACEs were examined in relation to adulthood smoking, overweight, obesity and binge drinking among 3354 women in Hawaii using the 2010 Behavioral Risk Factor Surveillance System data using Poisson regression with robust error variance. We additionally investigated for interaction by race/ethnicity. Covariates included age, race/ethnicity, education, emotional support, healthcare coverage, and the other health outcomes. Overall, 54.9 % reported at least 1 ACE. The prevalence of smoking (PR = 1.40 (1 ACE) to PR = 2.55 [5+ ACEs]), overweight (PR = 1.22 [1 ACE] to PR = 1.31 [5+ ACEs]) and obesity (PR = 1.00 [1 ACE] to PR = 1.85 [5+ ACEs]) increased with increasing ACE count. Smoking was associated with household dysfunction (PR = 1.67, CI = 1.26-2.22), and physical (PR = 2.04, CI = 1.50-2.78) and verbal (PR = 1.62, CI = 1.25-2.10) abuse. Obesity was also significantly related to household dysfunction (PR = 1.22, CI = 1.01-1.48), and physical (PR = 1.36, CI = 1.10-1.70), verbal (PR = 1.35, CI = 1.11-1.64) and sexual (PR = 1.53, CI = 1.25-1.88) abuse. Among Asians, sexual abuse was associated with a lower prevalence of binge drinking (PR = 0.26, CI = 0.07-0.93), which was significantly different from the null association among Whites (interaction p = 0.02). Preventing/addressing ACEs may help optimize childhood health, and reduce the likelihood of smoking/obesity among women including Asians/NHOPIs. Further studies are warranted to evaluate the sexual abuse-binge drinking association among Asians, which may support the need for culturally-tailored programs to address ACEs.

Beneficial role of D allele in controlling ACE levels: a study among Brahmins of north India.

PubMed

Kumari, Shobha; Sharma, Nidhi; Thakur, Sunil; Mondal, Prakash R; Saraswathy, Kallur N

2016-06-01

India being a country with vast diversity is expected to have different dietary and life style patterns which in turn may lead to population-specific environmental risk factors. Further, the interaction of these risk factors with the genetic makeup of population makes it either susceptible or resistant to cardiovascular disease. One such candidate gene is angiotensin converting enzyme (ACE) for various cardiovascular mechanisms. ACE is the key enzyme of the renin angiotensin aldosterone system pathway which maintains homeostasis blood pressure in the body and any variation in the levels is reported to be associated with various complex diseases. The DD genotype is found to increase ACE levels, which is associated with cardiovascular diseases and decrease in ACE levels are associated with kidney diseases. The aim of this study was to understand the distribution of ACE I/D polymorphism and ACE levels among Brahmins of National Capital Region (NCR) north India, with respect to age and sex ratio distribution. In this study, 136 subjects of which 50 males and 86 females, who were unrelated up to first cousin, aged 25 to70 years were studied. ACE gene was found to be polymorphic with high frequency of heterozygote (ID) followed by II and DD genotypes. The studied population was found to be in Hardy-Weinberg equilibrium with respect to ACE I/D polymorphism (P = 0.55). I allele frequency was found to be higher (0.560) than the D allele (0.44). The median level of ACE was found to be 65.96 ng/mL (48.12-86.24) which is towards lower side of the normal range. ACE levels were found to be increased among individual having either of the homozygotes that is II or DD and higher frequency of heterozygote (ID) is indicative of advantage in the population by maintaining lower ACE levels. The limitation of the present study is low sample size, however, the merit is that the subjects belonged to a Mendalian population with a common gene pool.

The Relationship of Adverse Childhood Events To Smoking, Overweight, Obesity and Binge Drinking Among Women In Hawaii

PubMed Central

Remigio-Baker, Rosemay A.; Hayes, Donald K.; Reyes-Salvail, Florentina

2016-01-01

OBJECTIVES To evaluate how the associations of adverse childhood events (ACEs) with smoking, overweight, obesity and binge drinking differ by race/ethnicity among women, including a large, understudied cohort of Asians and Native Hawaiians/Pacific Islanders (NHOPIs). METHODS The number and type (household dysfunction, and physical, verbal and sexual abuse) of ACEs were examined in relation to adulthood smoking, overweight, obesity and binge drinking among 3,354 women in Hawaii using the 2010 Behavioral Risk Factor Surveillance System data using Poisson regression. We additionally investigated for interaction by race/ethnicity. Covariates included age, race/ethnicity, education, emotional support, healthcare coverage, and the other health outcomes. RESULTS Overall, 54.9% reported at least 1 ACE. The prevalence of smoking (Prevalence Ratio [PR]=1.40 [1 ACE] to PR=2.55 [5+ ACEs]), overweight (PR=1.22 [1 ACE] to PR=1.31 [5+ ACEs]) and obesity (PR=1.00 [1 ACE] to PR=1.85 [5+ ACEs]) increased with increasing ACE count. Smoking was associated with household dysfunction (PR=1.67, CI=1.26–2.22), and physical (PR=2.04, CI=1.50–2.78) and verbal (PR=1.62, CI=1.25–2.10) abuse. Obesity was also significantly related to household dysfunction (PR=1.22, CI=1.01–1.48), and physical (PR=1.36, CI=1.10–1.70), verbal (PR=1.35, CI=1.11–1.64) and sexual (PR=1.53, CI=1.25–1.88) abuse. Among Asians, sexual abuse was associated with a lower prevalence of binge drinking (PR=0.26, CI=0.07, 0.93), which was significantly different from the null association among Whites (interaction p=0.02). CONCLUSION Preventing/addressing ACEs may help optimize childhood health, and reduce the likelihood of smoking/obesity among women including Asians/NHOPIs. Further studies are warranted to evaluate the sexual abuse-binge drinking association among Asians, which may support the need for culturally-tailored programs to address ACEs. PMID:27449778

Angiotensin-Converting Enzyme Inhibition as an Adjunct to Pulmonary Rehabilitation in Chronic Obstructive Pulmonary Disease

PubMed Central

Curtis, Katrina J.; Meyrick, Victoria M.; Mehta, Bhavin; Haji, Gulam S.; Li, Kawah; Montgomery, Hugh; Man, William D.-C.; Polkey, Michael I.

2016-01-01

Rationale: Epidemiological studies in older individuals have found an association between the use of angiotensin-converting enzyme (ACE) inhibition (ACE-I) therapy and preserved locomotor muscle mass, strength, and walking speed. ACE-I therapy might therefore have a role in the context of pulmonary rehabilitation (PR). Objectives: To investigate the hypothesis that enalapril, an ACE inhibitor, would augment the improvement in exercise capacity seen during PR. Methods: We performed a double-blind, placebo-controlled, parallel-group randomized controlled trial. Patients with chronic obstructive pulmonary disease, who had at least moderate airflow obstruction and were taking part in PR, were randomized to either 10 weeks of therapy with an ACE inhibitor (10 mg enalapril) or placebo. Measurements and Main Results: The primary outcome measurement was the change in peak power (assessed using cycle ergometry) from baseline. Eighty patients were enrolled, 78 were randomized (age 67 ± 8 years; FEV1 48 ± 21% predicted), and 65 completed the trial (34 on placebo, 31 on the ACE inhibitor). The ACE inhibitor–treated group demonstrated a significant reduction in systolic blood pressure (Δ, −16 mm Hg; 95% confidence interval [CI], −22 to −11) and serum ACE activity (Δ, −18 IU/L; 95% CI, −23 to −12) versus placebo (between-group differences, P < 0.0001). Peak power increased significantly more in the placebo group (placebo Δ, +9 W; 95% CI, 5 to 13 vs. ACE-I Δ, +1 W; 95% CI, −2 to 4; between-group difference, 8 W; 95% CI, 3 to 13; P = 0.001). There was no significant between-group difference in quadriceps strength or health-related quality of life. Conclusions: Use of the ACE inhibitor enalapril, together with a program of PR, in patients without an established indication for ACE-I, reduced the peak work rate response to exercise training in patients with chronic obstructive pulmonary disease. PMID:27248440

Anoctamin 6 Contributes to Cl− Secretion in Accessory Cholera Enterotoxin (Ace)-stimulated Diarrhea

PubMed Central

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

2016-01-01

Accessory cholera enterotoxin (Ace) of Vibrio cholerae has been shown to contribute to diarrhea. However, the signaling mechanism and specific type of Cl− channel activated by Ace are still unknown. We have shown here that the recombinant Ace protein induced ICl of apical plasma membrane, which was inhibited by classical CaCC blockers. Surprisingly, an Ace-elicited rise of current was neither affected by ANO1 (TMEM16A)-specific inhibitor T16A(inh)-AO1(TAO1) nor by the cystic fibrosis transmembrane conductance regulator (CFTR) blocker, CFTR inh-172. Ace stimulated whole-cell current in Caco-2 cells. However, the apical ICl was attenuated by knockdown of ANO6 (TMEM16F). This impaired phenotype was restored by re-expression of ANO6 in Caco-2 cells. Whole-cell patch clamp recordings of ANO currents in HEK293 cells transiently expressing mouse ANO1-mCherry or ANO6-GFP confirmed that Ace induced Cl− secretion. Application of Ace produced ANO6 but not the ANO1 currents. Ace was not able to induce a [Ca2+]i rise in Caco-2 cells, but cellular abundance of phosphatidylinositol 4,5-bisphosphate (PIP2) increased. Identification of the PIP2-binding motif at the N-terminal sequence among human and mouse ANO6 variants along with binding of PIP2 directly to ANO6 in HEK293 cells indicate likely PIP2 regulation of ANO6. The biophysical and pharmacological properties of Ace stimulated Cl− current along with intestinal fluid accumulation, and binding of PIP2 to the proximal KR motif of channel proteins, whose mutagenesis correlates with altered binding of PIP2, is comparable with ANO6 stimulation. We conclude that ANO6 is predominantly expressed in intestinal epithelia, where it contributes secretory diarrhea by Ace stimulation in a calcium-independent mechanism of RhoA-ROCK-PIP2 signaling. PMID:27799301

DNA methylation and genetic variation of the angiotensin converting enzyme (ACE) in depression.

PubMed

Lam, Dilys; Ancelin, Marie-Laure; Ritchie, Karen; Saffery, Richard; Ryan, Joanne

2018-02-01

Depression is one of the most prevalent psychiatric disorders, and in older persons is associated with high levels of comorbidity and under-treatment. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) stress axis is consistently observed in the older population as well as depressed patients, with the angiotensin converting enzyme (ACE) a key regulator of the stress response. Epigenetic regulation of ACE may play an important role in HPA axis (dys)regulation. To investigate ACE promoter methylation as a biomarker of late-life depression, and its association with genetic variation and cortisol secretion. The longitudinal general population ESPRIT study is aimed at investigating psychiatric disorders in older persons (n=1863, average age=73). Depression was assessed using the Mini International Neuropsychiatric Interview according to DSM-IV criteria and the Centre for Epidemiologic Studies Depression Scale (CES-D). Genotype information for seven polymorphisms across the ACE gene was also available. Blood and saliva samples collected at baseline and used to extract DNA and measure cortisol, respectively. Sequenom MassARRAY was used to measure promoter DNA methylation of the ACE gene (n=552). There was no evidence of an association between ACE promoter methylation and depression. However, there was evidence that ACE genetic variants influenced methylation, and modified the association between depression and methylation (Δ at various sites; -2.05% to 1.74%; p=0.019 to 0.039). Multivariate analyses were adjusted for participants' lifestyle, health and medical history. Independent of depression status, ACE methylation was inversely correlated with cortisol levels (r=-0.336, p=0.042). This study provides evidence that associations between ACE methylation and depression are genotype-dependent, suggesting that the development of reliable depression biomarkers may need to consider methylation levels in combination with underlying genetic variation. ACE methylation may also be a suitable biomarker of cortisol and/or HPA axis activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Adverse Childhood Experiences and ADHD Diagnosis at Age 9 Years in a National Urban Sample.

PubMed

Jimenez, Manuel E; Wade, Roy; Schwartz-Soicher, Ofira; Lin, Yong; Reichman, Nancy E

To examine associations between adverse childhood experiences (ACEs) and attention-deficit/hyperactivity disorder (ADHD) at age 9 years using longitudinal data and assess the extent to which ACEs during middle childhood are independently associated with ADHD at age 9 years. We conducted a secondary analysis of data from the Fragile Families urban birth cohort 5- and 9-year interviews. The sample was limited to children for whom mothers were the primary caregiver and mother-reported information on 8 ACEs and ADHD were available at age 5 and 9 years. We examined associations between ACEs and parent-reported ADHD at age 9 years using logistic regression and controlling for potential confounders. We included 1572 children; 48% were African American, 11% had parent-reported ADHD at age 9 years, 41% and 42% experienced ≥1 ACE by age 5 years and between the ages of 5 and 9 years, respectively. ACEs before age 5 years were associated with ADHD at age 9 years. One, 2, and ≥3 ACEs between age 5 and 9 years were associated with ADHD at age 9 years even after controlling for ACEs before age 5 years and ADHD at age 5 years (adjusted odds ratio [AOR], 1.9; 95% confidence interval [CI], 1.2-3; AOR, 2.1; 95% CI, 1.2-3.8; and AOR, 2.2; 95% CI, 1.1-4.3). In this study of urban children, ACEs occurring before age 5 years as well as between the ages of 5 and 9 years were associated with ADHD at age 9 years. Even after controlling for early childhood ACEs and ADHD at age 5 years, the association between ADHD and ACEs in middle childhood remained significant, highlighting the importance of screening and intervention throughout childhood. Copyright © 2016 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling.

PubMed

Walters, Tomos E; Kalman, Jonathan M; Patel, Sheila K; Mearns, Megan; Velkoska, Elena; Burrell, Louise M

2017-08-01

Angiotensin converting enzyme 2 (ACE2) is an integral membrane protein whose main action is to degrade angiotensin II. Plasma ACE2 activity is increased in various cardiovascular diseases. We aimed to determine the relationship between plasma ACE2 activity and human atrial fibrillation (AF), and in particular its relationship to left atrial (LA) structural remodelling. One hundred and three participants from a tertiary arrhythmia centre, including 58 with paroxysmal AF (PAF), 20 with persistent AF (PersAF), and 25 controls, underwent clinical evaluation, echocardiographic analysis, and measurement of plasma ACE2 activity. A subgroup of 20 participants underwent invasive LA electroanatomic mapping. Plasma ACE2 activity levels were increased in AF [control 13.3 (9.5-22.3) pmol/min/mL; PAF 16.9 (9.7-27.3) pmol/min/mL; PersAF 22.8 (13.7-33.4) pmol/min/mL, P = 0.006]. Elevated plasma ACE2 was associated with older age, male gender, hypertension and vascular disease, elevated left ventricular (LV) mass, impaired LV diastolic function and advanced atrial disease (P < 0.05 for all). Independent predictors of elevated plasma ACE2 activity were AF (P = 0.04) and vascular disease (P < 0.01). There was a significant relationship between elevated ACE2 activity and low mean LA bipolar voltage (adjusted R2 = 0.22, P = 0.03), a high proportion of complex fractionated electrograms (R2 = 0.32, P = 0.009) and a long LA activation time (R2 = 0.20, P = 0.04). Plasma ACE2 activity is elevated in human AF. Both AF and vascular disease predict elevated plasma ACE2 activity, and elevated plasma ACE2 is significantly associated with more advanced LA structural remodelling. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Flavonoids-Rich Orthosiphon stamineus Extract as New Candidate for Angiotensin I-Converting Enzyme Inhibition: A Molecular Docking Study.

PubMed

Shafaei, Armaghan; Sultan Khan, Md Shamsuddin; F A Aisha, Abdalrahim; Abdul Majid, Amin Malik Shah; Hamdan, Mohammad Razak; Mordi, Mohd Nizam; Ismail, Zhari

2016-11-09

This study aims to evaluate the in vitro angiotensin-converting enzyme (ACE) inhibition activity of different extracts of Orthosiphon stamineus (OS) leaves and their main flavonoids, namely rosmarinic acid (RA), sinensetin (SIN), eupatorin (EUP) and 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (TMF). Furthermore, to identify possible mechanisms of action based on structure-activity relationships and molecular docking. The in vitro ACE inhibition activity relied on determining hippuric acid (HA) formation from ACE-specific substrate (hippuryl-histidyl-leucine (HHL)) by the action of ACE enzyme. A High Performance Liquid Chromatography method combined with UV detection was developed and validated for measurement the concentration of produced HA. The chelation ability of OS extract and its reference compounds was evaluated by tetramethylmurexide reagent. Furthermore, molecular docking study was performed by LeadIT-FlexX : BioSolveIT's LeadIT program. OS ethanolic extract (OS-E) exhibited highest inhibition and lowest IC 50 value (45.77 ± 1.17 µg/mL) against ACE compared to the other extracts. Among the tested reference compounds, EUP with IC 50 15.35 ± 4.49 µg/mL had highest inhibition against ACE and binding ability with Zn (II) (56.03% ± 1.26%) compared to RA, TMF and SIN. Molecular docking studies also confirmed that flavonoids inhibit ACE via interaction with the zinc ion and this interaction is stabilized by other interactions with amino acids in the active site. In this study, we have demonstrated that changes in flavonoids active core affect their capacity to inhibit ACE. Moreover, we showed that ACE inhibition activity of flavonoids compounds is directly related to their ability to bind with zinc ion in the active site of ACE enzyme. It was also revealed that OS extract contained high amount of flavonoids other than RA, TMF, SIN and EUP. As such, application of OS extract is useful as inhibitors of ACE.

Biological treatment of soils contaminated with hydrophobic organics using slurry- and solid-phase techniques

NASA Astrophysics Data System (ADS)

Cassidy, Daniel H.; Irvine, Robert L.

1995-10-01

Both slurry-phase and solid-phase bioremediation are effective ex situ soil decontamination methods. Slurrying is energy intensive relative to solid-phase treatment, but provides homogenization and uniform nutrient distribution. Limited contaminant bioavailability at concentrations above the required cleanup level reduces biodegradation rates and renders solid phase bioremediation more cost effective than complete treatment in a bio-slurry reactor. Slurrying followed by solid-phase bioremediation combines the advantages and minimizes the weaknesses of each treatment method when used alone. A biological treatment system consisting of slurrying followed by aeration in solid phase bioreactors was developed and tested in the laboratory using a silty clay loam contaminated with diesel fuel. The first set of experiments was designed to determine the impact of the water content and mixing time during slurrying on the rate an extent of contaminant removal in continuously aerated solid phase bioreactors. The second set of experiments compared the volatile and total diesel fuel removal in solid phase bioreactors using periodic and continuous aeration strategies. Results showed that slurrying for 1.5 hours at a water content less than saturation markedly increased the rate and extent of contaminant biodegradation in the solid phase bioreactors compared with soil having no slurry pretreatment. Slurrying the soil at or above its saturation moisture content resulted in lengthy dewatering times which prohibited aeration, thereby delaying the onset of biological treatment in the solid phase bioreactors. Results also showed that properly operated periodic aeration can provide less volatile contaminant removal and a grater fraction of biological contaminant removal than continuous aeration.

Delivery of kinesin spindle protein targeting siRNA in solid lipid nanoparticles to cellular models of tumor vasculature

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ying, Bo; Campbell, Robert B., E-mail: robert.campbell@mcphs.edu

2014-04-04

Highlights: • siRNA-lipid nanoparticles are solid particles not lipid bilayers with aqueous core. • High, but not low, PEG content can prevent nanoparticle encapsulation of siRNA. • PEG reduces cellular toxicity of cationic nanoparticles in vitro. • PEG reduces zeta potential while improving gene silencing of siRNA nanoparticles. • Kinesin spindle protein can be an effective target for tumor vascular targeting. - Abstract: The ideal siRNA delivery system should selectively deliver the construct to the target cell, avoid enzymatic degradation, and evade uptake by phagocytes. In the present study, we evaluated the importance of polyethylene glycol (PEG) on lipid-based carriermore » systems for encapsulating, and delivering, siRNA to tumor vessels using cellular models. Lipid nanoparticles containing different percentage of PEG were evaluated based on their physical chemical properties, density compared to water, siRNA encapsulation, toxicity, targeting efficiency and gene silencing in vitro. siRNA can be efficiently loaded into lipid nanoparticles (LNPs) when DOTAP is included in the formulation mixture. However, the total amount encapsulated decreased with increase in PEG content. In the presence of siRNA, the final formulations contained a mixed population of particles based on density. The major population which contains the majority of siRNA exhibited a density of 4% glucose, and the minor fraction associated with a decreased amount of siRNA had a density less than PBS. The inclusion of 10 mol% PEG resulted in a greater amount of siRNA associated with the minor fraction. Finally, when kinesin spindle protein (KSP) siRNA was encapsulated in lipid nanoparticles containing a modest amount of PEG, the proliferation of endothelial cells was inhibited due to the efficient knock down of KSP mRNA. The presence of siRNA resulted in the formation of solid lipid nanoparticles when prepared using the thin film and hydration method. LNPs with a relatively modest amount of PEG can sufficiently encapsulate siRNA, improve cellular uptake and the efficiency of gene silencing.« less

On Becoming Trauma-Informed: Role of the Adverse Childhood Experiences Survey in Tertiary Child and Adolescent Mental Health Services and the Association with Standard Measures of Impairment and Severity

PubMed Central

Rahman, Abdul; Perri, Andrea; Deegan, Avril; Kuntz, Jennifer; Cawthorpe, David

2018-01-01

Context There is a movement toward trauma-informed, trauma-focused psychiatric treatment. Objective To examine Adverse Childhood Experiences (ACE) survey items by sex and by total scores by sex vs clinical measures of impairment to examine the clinical utility of the ACE survey as an index of trauma in a child and adolescent mental health care setting. Design Descriptive, polychoric factor analysis and regression analyses were employed to analyze cross-sectional ACE surveys (N = 2833) and registration-linked data using past admissions (N = 10,400) collected from November 2016 to March 2017 related to clinical data (28 independent variables), taking into account multicollinearity. Results Distinct ACE items emerged for males, females, and those with self-identified sex and for ACE total scores in regression analysis. In hierarchical regression analysis, the final models consisting of standard clinical measures and demographic and system variables (eg, repeated admissions) were associated with substantial ACE total score variance for females (44%) and males (38%). Inadequate sample size foreclosed on developing a reduced multivariable model for the self-identified sex group. Conclusion The ACE scores relate to independent clinical measures and system and demographic variables. There are implications for clinical practice. For example, a child presenting with anxiety and a high ACE score likely requires treatment that is different from a child presenting with anxiety and an ACE score of zero. The ACE survey score is an important index of presenting clinical status that guides patient care planning and intervention in the progress toward a trauma-focused system of care. PMID:29401055

Disability and Exposure to High Levels of Adverse Childhood Experiences: Effect on Health and Risk Behavior.

PubMed

Austin, Anna; Herrick, Harry; Proescholdbell, Scott; Simmons, Jacqueline

2016-01-01

Health disparities among persons with disabilities have been previously documented. However, there is little research specific to adverse childhood experiences (ACEs) in this population and how ACE exposure affects health outcomes in adulthood. Data from the 2012 North Carolina Behavioral Risk Factor Surveillance System (BRFSS) survey were analyzed to compare the prevalence of ACEs between adults with and without disabilities and high ACE exposure (3-8 ACEs). Adjusted risk ratios of health risks and perceived poor health by disability status were calculated using predicted marginals. A higher percentage of persons with disabilities (36.5%) than those without disabilities (19.6%) reported high ACE exposure. Among those with high ACE exposure, persons with disabilities were more likely to report several ACE categories, particularly childhood sexual abuse. In adjusted analyses, persons with disabilities had an increased risk of smoking (relative risk [RR] = 1.29; 95% CI, 1.10-1.51), poor physical health (RR = 4.34; 95% CI, 3.08-6.11), poor mental health (RR = 4.69; 95% CI, 3.19-6.87), and doctor-diagnosed depression (RR = 2.16; 95% CI, 1.82-2.56) compared to persons without disabilities. The definition of disability derived from the BRFSS survey does not allow for those with disabilities to be categorized according to physical disabilities versus mental or emotional disabilities. In addition, we were unable to determine the timing of ACE exposure in relation to disability onset. A better understanding of the life course associations between ACEs and disability and the impact of exposure to multiple types of childhood adversity on disability and health is needed to inform research and services specific to this vulnerable population. ©2016 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.

Correlation of the NBME advanced clinical examination in EM and the national EM M4 exams.

PubMed

Hiller, Katherine; Miller, Emily S; Lawson, Luan; Wald, David; Beeson, Michael; Heitz, Corey; Morrissey, Thomas; House, Joseph; Poznanski, Stacey

2015-01-01

Since 2011 two online, validated exams for fourth-year emergency medicine (EM) students have been available (National EM M4 Exams). In 2013 the National Board of Medical Examiners offered the Advanced Clinical Examination in Emergency Medicine (EM-ACE). All of these exams are now in widespread use; however, there are no data on how they correlate. This study evaluated the correlation between the EM-ACE exam and the National EM M4 Exams. From May 2013 to April 2014 the EM-ACE and one version of the EM M4 exam were administered sequentially to fourth-year EM students at five U.S. medical schools. Data collected included institution, gross and scaled scores and version of the EM M4 exam. We performed Pearson's correlation and random effects linear regression. 305 students took the EM-ACE and versions 1 (V1) or 2 (V2) of the EM M4 exams (281 and 24, respectively) [corrected].The mean percent correct for the exams were as follows: EM-ACE 74.9 (SD-9.82), V1 83.0 (SD-6.39), V2 78.5 (SD-7.70) [corrected]. Pearson's correlation coefficient for the V1/EM-ACE was 0.53 (0.43 scaled) and for the V2/EM-ACE was 0.58 (0.41 scaled) [corrected]. The coefficient of determination for V1/ EM-ACE was 0.73 and for V2/EM-ACE 0.71 (0.65 and .49 for scaled scores) [ERRATUM]. The R-squared values were 0.28 and 0.30 (0.18 and 0.13 scaled), respectively [corrected]. There was significant cluster effect by institution. There was moderate positive correlation of student scores on the EM-ACE exam and the National EM M4 Exams.

Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System.

PubMed

Wang, Wang; McKinnie, Shaun M K; Farhan, Maikel; Paul, Manish; McDonald, Tyler; McLean, Brent; Llorens-Cortes, Catherine; Hazra, Saugata; Murray, Allan G; Vederas, John C; Oudit, Gavin Y

2016-08-01

Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, apelin peptides have extremely short biological half-lives, and improved understanding of apelin peptide metabolism may lead to the discovery of biologically stable analogues with therapeutic potential. We examined the ability of angiotensin-converting enzyme 2 (ACE2) to cleave and inactivate pyr-apelin 13 and apelin 17, the dominant apelin peptides. Computer-assisted modeling shows a conserved binding of pyr-apelin 13 and apelin 17 to the ACE2 catalytic site. In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated, with a corresponding greater elevation in plasma apelin levels. Similarly, pharmacological inhibition of ACE2 potentiated the vasodepressor action of apelin peptides. Biochemical analysis confirmed that recombinant human ACE2 can cleave pyr-apelin 13 and apelin 17 efficiently, and apelin peptides are degraded slower in ACE2-deficient plasma. The biological relevance of ACE2-mediated proteolytic processing of apelin peptides was further supported by the reduced potency of pyr-apelin 12 and apelin 16 on the activation of signaling pathways and nitric oxide production from endothelial cells. Importantly, although pyr-apelin 13 and apelin 17 rescued contractile function in a myocardial ischemia-reperfusion model, ACE2 cleavage products, pyr-apelin 12 and 16, were devoid of these cardioprotective effects. We designed and synthesized active apelin analogues that were resistant to ACE2-mediated degradation, thereby confirming that stable apelin analogues can be designed as potential drugs. We conclude that ACE2 represents a major negative regulator of apelin action in the vasculature and heart. © 2016 American Heart Association, Inc.

ACE2-Independent Action Of Presumed ACE2 Activators: Studies In Vivo, Ex Vivo and In Vitro

PubMed Central

Haber, Philipp K.; Ye, Minghao; Wysocki, Jan; Maier, Christoph; Haque, Syed K.; Batlle, Daniel

2014-01-01

Angiotensin converting enzyme 2, (ACE2), is a key enzyme in the metabolism of angiotensin II. 1-[[2-(dimetilamino)ethyl]amino]-4-(hidroximetil)-7-[[(4-metilfenil)sulfonil]oxi]-9H-xantona-9 (XNT)and Diminazene (DIZE)have been reported to exert various organ-protective effects that have been attributed to activation of ACE2. To test the effect of these compounds we studied Ang II degradation in vivo and in vitro as well as their effect on ACE2 activity in vivo and in vitro. In a model of Ang II induced acute hypertension, blood pressure recovery was markedly enhanced by XNT (slope with XNT -3.26±0.2 vs.-1.6±0.2 mmHg/min without XNT, p<0.01). After Ang II infusion, neither plasma nor kidney ACE2 activity was affected by XNT. Plasma Ang II and Ang (1-7) levels also were not significantly affected by XNT. The blood pressure lowering effect of XNT seen in WT animals was also observed in ACE2 KO mice (slope with XNT -3.09±0.30 mmHg/min vs. -1.28±0.22 mmHg/min without XNT, p<0.001). These findings show that the blood pressure lowering effect of XNT in Ang II induced hypertension cannot be due to activation of ACE2. In vitro and ex vivo experiments in both mice and rat kidney confirmed a lack of enhancement of ACE2 enzymatic activity by XNT and DIZE. Moreover, Ang II degradation in vitro and ex vivo was unaffected by XNT and DIZE. We conclude that the biologic effects of these compounds are ACE2 independent and should not be attributed to activation of this enzyme. PMID:24446061

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

PubMed Central

de Queiroz, Thyago Moreira; Sriramula, Srinivas; Feng, Yumei; Johnson, Tanya; Mungrue, Imran N.; Lazartigues, Eric

2014-01-01

Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA-salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress. PMID:25519733

Enhancement of bradykinin and resensitization of its B2 receptor.

PubMed

Marcic, B; Deddish, P A; Jackman, H L; Erdös, E G

1999-03-01

We studied the enhancement of the effects of bradykinin B2 receptor agonists by agents that react with active centers of angiotensin-converting enzyme (ACE) independent of enzymatic inactivation. The potentiation and the desensitization and resensitization of B2 receptor were assessed by measuring [3H]arachidonic acid release and [Ca2+]i mobilization in Chinese hamster ovary cells transfected to express human ACE and B2 receptor, or in endothelial cells with constitutively expressed ACE and receptor. Administration of bradykinin or its ACE-resistant analogue desensitized the receptor, but it was resensitized (arachidonic acid release or [Ca2+]i mobilization) by agents such as enalaprilat (1 micromol/L). Enalaprilat was inactive in the absence of ACE expression. La3+ (100 micromol/L) inhibited the apparent resensitization, probably by blocking the entry of extracellular calcium. Enalaprilat resensitized the receptor via ACE to release arachidonic acid by bradykinin at a lower concentration (5 nmol/L) than required to mobilize [Ca2+]i (1 micromol/L). Monoclonal antibodies inhibiting the ACE N-domain active center and polyclonal antiserum potentiated bradykinin. The snake venom peptide BPP5a and metabolites of angiotensin and bradykinin (angiotensin-[1-9], angiotensin-[1-7], bradykinin-[1-8]; 1 micromol/L) enhanced arachidonic acid release by bradykinin. Angiotensin-(1-9) and -(1-7) also resensitized the receptor. Enalaprilat potentiated the bradykinin effect in cells expressing a mutant ACE with a single N-domain active site. Agents that reacted with a single active site, on the N-domain or on the C-domain, potentiated bradykinin not by blocking its inactivation but by inducing crosstalk between ACE and the receptor. Enalaprilat enhanced signaling via ACE by Galphai in lower concentration than by Galphaq-coupled receptor.