Peptidases and the Renin-Angiotensin System: The Alternative Angiotensin-(1-7) Cascade

The renin-angiotensin system (RAS) constitutes a key hormonal system in the physiological regulation of blood pressure via peripheral and central mechanisms. Dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies, and pharmacologic blockades of this system by the inhibition of angiotensin-converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) are effective therapeutic regimens. The RAS is now defined as a system composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS comprises the ACE-Ang II-AT1R axis that promotes vasoconstriction, water intake, sodium retention and increased oxidative stress, fibrosis, cellular growth, and inflammation. The nonclassical or alternative RAS is composed primarily of the ACE2-Ang-(1-7)-AT7R pathway that opposes the Ang II-AT1R axis. In lieu of the complex aspects of this system, the current review assesses the enzymatic cascade of the alternative Ang-(1-7) axis of the RAS

A transfer function approach to measuring cell inheritance

<p>Abstract</p> <p>Background</p> <p>The inheritance of cellular material between parent and daughter cells during mitosis is highly influential in defining the properties of the cell and therefore the population lineage. This is of particular relevance when studying cell population evolution to assess the impact of a disease or the perturbation due to a drug treatment. The usual technique to investigate inheritance is to use time-lapse microscopy with an appropriate biological marker, however, this is time consuming and the number of inheritance events captured are too low to be statistically meaningful.</p> <p>Results</p> <p>Here we demonstrate the use of a high throughput fluorescence measurement technique e.g. flow cytometry, to measure the fluorescence from quantum dot markers which can be used to target particular cellular sites. By relating, the fluorescence intensity measured between two time intervals to a transfer function we are able to deconvolve the inheritance of cellular material during mitosis. To demonstrate our methodology we use CdTe/ZnS quantum dots to measure the ratio of endosomes inherited by the two daughter cells during mitosis in the U2-OS, human osteoscarcoma cell line. The ratio determined is in excellent agreement with results obtained previously using a more complex and computational intensive bespoke stochastic model.</p> <p>Conclusions</p> <p>The use of a transfer function approach allows us to utilise high throughput measurement of large cell populations to derive statistically relevant measurements of the inheritance of cellular material. This approach can be used to measure the inheritance of organelles, proteins etc. and also particles introduced to cells for drug delivery.</p

A new framework for evaluating dust emission model development using dichotomous satellite observations of dust emission

Dust models are essential for understanding the impact of mineral dust on Earth's systems, human health, and global economies, but dust emission modelling has large uncertainties. Satellite observations of dust emission point sources (DPS) provide a valuable dichotomous inventory of regional dust emissions. We develop a framework for evaluating dust emission model performance using existing DPS data before routine calibration of dust models. To illustrate this framework's utility and arising insights, we evaluated the albedo-based dust emission model (AEM) with its areal (MODIS 500 m) estimates of soil surface wind friction velocity (u(s*)) and common, poorly constrained grain-scale entrainment threshold (u(*ts)) adjusted by a function of soil moisture (H). The AEM simulations are reduced to its frequency of occurrence, P(u(s*) > u(*ts)H). The spatio-temporal variability in observed dust emission frequency is described by the collation of nine existing DPS datasets. Observed dust emission occurs rarely, even in North Africa and the Middle East, where DPS frequency averages 1.8 %, (similar to 7 days y(-1)), indicating extreme, large wind speed events. The AEM coincided with observed dust emission similar to 71.4 %, but simulated dust emission similar to 27.4 % when no dust emission was observed, while dust emission occurrence was over-estimated by up to 2 orders of magnitude. For estimates to match observations, results showed that grain- scale u(*ts) needed restricted sediment supply and compatibility with areal u(s*). Failure to predict dust emission during observed events, was due to u(s*) being too small because reanalysis winds (ERA5-Land) were averaged across 11 km pixels, and inconsistent with u(s*)across 0.5 km pixels representing local maxima. Assumed infinite sediment supply caused the AEM to simulate dust emission whenever P(u(s*)>u(*ts)H), producing false positives when wind speeds were large. The dust emission model scales of existing parameterisations need harmonising and a new parameterisation for u(*ts) is required to restrict sediment supply over space and time

Antenatal corticosteroids and the renin-angiotensin-aldosterone system in adolescents born preterm

Antenatal corticosteroid (ANCS) treatment hastens fetal lung maturity and improves survival of premature infants, but the long-term effects of ANCS are not well-described. Animal models suggest ANCS increases the risk of cardiovascular disease through programmed changes in the renin-angiotensin (Ang)-aldosterone system (RAAS). We hypothesized that ANCS exposure alters the RAAS in adolescents born prematurely

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

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system (RAAS), is a promising candidate as a treatment for cancer that reflects its antiproliferative 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 DDP3 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

Reliability of two techniques for assessing cerebral iron deposits from structural MRI

Purpose: To test the reliability of two computational methods for segmenting cerebral iron deposits (IDs) in the ageing brain, given that its measurement in MRI is challenging due to the similar effect produced by other minerals, especially calcium, on T2*-weighted sequences. Materials and Methods: T1-, T2*-weighted and FLAIR MR brain images obtained at 1.5T from 70 subjects in their early 70s who displayed a wide range of brain IDs were analyzed. The first segmentation method used a multispectral approach based on the fusion of two or more structural sequences registered and mapped in the red/green color space followed by Minimum Variance Quantization. The second method employed a combined thresholding, size and shape analysis using T2*-weighted images augmented with visual information from T1-weighted data. Results: Both segmentation techniques had high intra- and inter-observer agreement (95 % CI = ± 57 voxels in a range from 0 to 1800), which decreased in subjects with significant microbleeds and/or IDs. However, the thresholding method was more observer dependent in identifying microbleeds and IDs boundaries than the multispectral approach. Conclusion: Both techniques proved to be in agreement and have good intra- and inter-observer reliability. However, they have limitations, specifically with regard to automation and observer independence, so further work is required to develop fully user-independent methods of identifying cerebral IDs

Topological relationships between perivascular spaces and progression of white matter hyperintensities:A pilot study in a sample of the Lothian Birth Cohort 1936

Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH) are features of cerebral small vessel disease which can be seen in brain magnetic resonance imaging (MRI). Given the associations and proposed mechanistic link between PVS and WMH, they are hypothesized to also have topological proximity. However, this and the influence of their spatial proximity on WMH progression are unknown. We analyzed longitudinal MRI data from 29 out of 32 participants (mean age at baseline = 71.9 years) in a longitudinal study of cognitive aging, from three waves of data collection at 3-year intervals, alongside semi-automatic segmentation masks for PVS and WMH, to assess relationships. The majority of deep WMH clusters were found adjacent to or enclosing PVS (waves−1: 77%; 2: 76%; 3: 69%), especially in frontal, parietal, and temporal regions. Of the WMH clusters in the deep white matter that increased between waves, most increased around PVS (waves−1–2: 73%; 2–3: 72%). Formal statistical comparisons of severity of each of these two SVD markers yielded no associations between deep WMH progression and PVS proximity. These findings may suggest some deep WMH clusters may form and grow around PVS, possibly reflecting the consequences of impaired interstitial fluid drainage via PVS. The utility of these relationships as predictors of WMH progression remains unclear

Attenuation of Salt-Induced Cardiac Remodeling and Diastolic Dysfunction by the GPER Agonist G-1 in Female mRen2.Lewis Rats

The G protein-coupled estrogen receptor (GPER) is expressed in various tissues including the heart. Since the mRen2.Lewis strain exhibits salt-dependent hypertension and early diastolic dysfunction, we assessed the effects of the GPER agonist (G-1, 40 nmol/kg/hr for 14 days) or vehicle (VEH, DMSO/EtOH) on cardiac function and structure.Intact female mRen2.Lewis rats were fed a normal salt (0.5% sodium; NS) diet or a high salt (4% sodium; HS) diet for 10 weeks beginning at 5 weeks of age.Prolonged intake of HS in mRen2.Lewis females resulted in significantly increased blood pressure, mildly reduced systolic function, and left ventricular (LV) diastolic compliance (as signified by a reduced E deceleration time and E deceleration slope), increased relative wall thickness, myocyte size, and mid-myocardial interstitial and perivascular fibrosis. G-1 administration attenuated wall thickness and myocyte hypertrophy, with nominal effects on blood pressure, LV systolic function, LV compliance and cardiac fibrosis in the HS group. G-1 treatment significantly increased LV lusitropy [early mitral annular descent (e')] independent of prevailing salt, and improved the e'/a' ratio in HS versus NS rats (P<0.05) as determined by tissue Doppler.Activation of GPER improved myocardial relaxation in the hypertensive female mRen2.Lewis rat and reduced cardiac myocyte hypertrophy and wall thickness in those rats fed a high salt diet. Moreover, these advantageous effects of the GPER agonist on ventricular lusitropy and remodeling do not appear to be associated with overt changes in blood pressure