Health-promoting properties of bioactive peptides derived from milk proteins in infant food : a review

Peer reviewed

Screening for albuminuria in diabetes:the need to do more

Aims: To reassess the utilisation rate of urinary albumin to creatinine ratio (ACR) screening in our centre; and the rate of repeat testing, where appropriate. To look at risk factors for albuminuria in our outpatient population. Methods: All patients attending one of our two weekly diabetes outpatient clinics in 2011–2012 were enrolled in this study. Demographic and relevant clinical data were extracted from electronic care records and analysed using SPSS 21. Results: Our study cohort comprised 998 people (51.4% men;59.6% White, 30.5% Southeast Asian, 9.9% Afro-Caribbean),most of whom had Type 2 diabetes (82.6%). The ACR testing rate in our centre was 62.8% (2012–2013 data; previously 62.4%). The incidence of initial albuminuria was 32.2% in women vs42.8% in men. Just 48.7% of patients (44.4% of women, 51.8% of men) with initial albuminuria were retested: 36.4% of women and 19.7% of men with initial albuminuria had no evidence of this on follow-up. Logistic regression modelling confirmed an association of high systolic blood pressure with albuminuria [odds ratio1.92 (1.01–3.70 in women, 1.08–3.57 in men)]. Treatment with anangiotens in converting enzyme inhibitor (ACEi) or angiotens in 2 receptor blocker (A2RB) was negatively associated with albuminuria in men [odds ratio 0.42 (0.20–0.89)], but not in women. Conclusions: A relatively high, albeit suboptimal, albuminuria screening rate in our outpatient population has been sustained.High systolic blood pressure was confirmed as a risk factor foralbuminuria. The incidence of albuminuria was higher in men, who had a lower rate of negative repeat testing and appeared to benefit more from ACEi/A2RB therapy. More rigorous screening for albuminuria is warranted to identify at-risk individuals.

The effects of centrally acting ACE inhibitors on the rate of cognitive and functional decline in dementia: a KDD approach

Alzheimer’s Disease and other dementias are one of the most challenging illnesses confronting countries with ageing populations. Treatment options for dementia are limited, and the costs are significant. There is a growing need to develop new treatments for dementia, especially for the elderly. There is also growing evidence that centrally acting angiotensin converting enzyme (ACE) inhibitors, which cross the blood-brain barrier, are associated with a reduced rate of cognitive and functional decline in dementia, especially in Alzheimer’s disease (AD). The aim of this research is to investigate the effects of centrally acting ACE inhibitors (CACE-Is) on the rate of cognitive and functional decline in dementia, using a three phased KDD process. KDD, as a scientific way to process and analysis clinical data, is used to find useful insights from a variety of clinical databases. The data used are from three clinic databases: Geriatric Assessment Tool (GAT), the Doxycycline and Rifampin for Alzheimer’s Disease (DARAD), and the Qmci validation databases, which were derived from several different geriatric clinics in Canada. This research involves patients diagnosed with AD, vascular or mixed dementia only. Patients were included if baseline and end-point (at least six months apart) Standardised Mini-Mental State Examination (SMMSE), Quick Mild Cognitive Impairment (Qmci) or Activities Daily Living (ADL) scores were available. Basically, the rates of change are compared between patients taking CACE-Is, and those not currently treated with CACE-Is. The results suggest that there is a statistically significant difference in the rate of decline in cognitive and functional scores between CACE-I and NoCACE-I patients. This research also validates that the Qmci, a new short assessment test, has potential to replace the current popular screening tests for cognition in the clinic and clinical trials.

Tubular Urinary Enzymes in Acute Post-infectious Glomerulonephritis

Tubular function of 17 pediatric patients with a mild form of acute post-infectious glomerulonephritis was prospectively evaluated by assessment of the urinary activity of proximal and distal tubule enzymes. Neutral-like endopeptidase (NEP-like) and angiotensin-converting enzyme (ACE) were the proximal tubule enzymes assessed, while prolyl-endopeptidase (PE) and serine-endopeptidase H1 and H2 were the distal tubule enzymes analyzed. Urine was collected at diagnosis (T0) and after 2 (T2) and 6 (T6) months of follow-up. NEP-like enzyme activity (nmol/mg creatinine; median±quartile range) was increased at diagnosis, and this remained stable during the first 6 months (T0 18.30±83.26, T2 17.32±49.56, T6 23.38±107.18). Urinary activity of the other enzymes was as follows: ACE (mU/ml per mg creatinine) T0 0.08±0.16, T2 0.06±0.10, T6 0.18±0.29; PE (nmol/mg creatinine) T0 6.70±84.87, T2 9.55±69.00, T6 13.67±28.70; serine-endopeptidase H1 (nmol/mg creatinine) T0 7.86±26.95, T2 17.17±59.37, T6 18.19± 79.14; and serine-thiol-endopeptidase H2 (nmol/mg creatinine) T0 3.06±21.97, T2 12.06±32.42, T6 16.22± 44.06. Thirty other healthy children matched for age and gender were considered as a control group. This group was assessed once and the results were: NEP-like activity 6.05±10.54, ACE 0.11±0.22, PE 7.10±13.36, H1 5.00±17.30, and H2 6.00±20.16. In conclusion, we observed that NEP-like and H1 enzymes exhibited significant increased urinary activity 6 months after the diagnosis. This increase occurred in spite of the disappearance of clinical symptoms, which occurred 2 months after the diagnosis. We believe that the increase in urinary enzymatic activity could be a manifestation of a silent tubular dysfunction following an episode of acute post-infectious glomerulonephritis.

Di and tripeptides from marine sources can target adipogenic process and contribute to decrease adipocyte number and functions

The effect of 11 marine-derived cryptides was investigated on proliferation, differentiation and maturation of human white pre-adipocytes (HWP). They were all formerly identified as potent Angiotensin-Converting-Enzyme inhibitors.Val-Trp (VW),Val-Tyr (VY), Lys-Tyr (KY), Lys-Trp (KW), Ile-Tyr (IY), Ala-Pro (AP),Val-Ile-Tyr (VIY), Leu-Lys-Pro (LKP), Gly-Pro-Leu (GPL), Ala-Lys-Lys (AKK) and Val-Ala-Pro (VAP) were previously found in fish products and coproducts as well as other marine resources like wakame. Treatment with AP, VAP and AKK greatly affected viability of HWP during the proliferation period while KW and VW treatment reduced the number of viable cells during the differentiation stage. A GPL and IY incubation during the differentiation stage allowed the decrease of their final lipid content, of the GPDH activity and of the mRNA level of adipocyte markers (aP2, GLUT4, LPL and AGT). Moreover, a down regulation of both PPARγ and C/EBPα expression, two key regulators of adipogenesis,was observed.These findings indicate that small bioactive peptides from marine protein hydrolysates can target adipogenesis and thus could regulate energy metabolism disorders

Angiotensin processing is partially carried out by carboxypeptidases in the rat mesenteric arterial bed perfusate

Here we investigated the possible association between the carboxypeptidase A (CPA)-like activity of the rat mesenteric arterial bed (MAB) perfusate and the ability of this fluid of forming angiotensin (Ang) 1-9 and Ang 1-7 upon incubation with Ang I and Ang II, respectively. Initially, we observed that anion exchange chromatography of the perfusate would consistently split the characteristic Z-Val-Phe-hydrolyzing activity of CPA-like enzymes into five distinct peaks, whose proteolytic activities were then determined using also Ang I and Ang II as substrates. The resulting proteolytic profile for each peak indicated that rat MAB perfusate contains a complex mixture of carboxypeptidases; tentatively, five carboxypeptidases were distinguished based on their substrate preferences toward Z-Val-Phe. Ang I and Ang II. The respective reactions, namely, Z-Val-Phe cleavage, Ang I to Ang 1-9 conversion and Ang II to Ang 1-7 conversion, were inhibited by 1,10-phenanthroline and nearly fully blocked by potato carboxypeptidase inhibitor. Also, all the CPA-like activity peaks prepared by anion exchange chromatography were tested negative for contaminating Ang I-converting enzyme-2, cathepsin A and prolylcarboxypeptidase. Overall, our results indicate that rat MAB perfusate contains a multiplicity of Ang I and Ang II-processing CPA-like enzymes whose proteolytic specificities suggest they might perform peculiar regulatory roles in the local resin-angiotensin system. (C) 2008 Elsevier B.V. All rights reserved.

Angiotensin-(1-7) decreases LPS-induced inflammatory response in macrophages

It has been previously shown that besides its classical role in blood pressure control the reninangiotensin system, mainly by action of angiotensin II on the AT1 receptor, exerts pro-inflammatory effects such as by inducing the production of cytokines. More recently, alternative pathways to this system were described, such as binding of angiotensin-(17) to receptor Mas, which was shown to counteract some of the effects evoked by activation of the angiotensin IIAT1 receptor axis. Here, by means of different molecular approaches we investigated the role of angiotensin-(17) in modulating inflammatory responses triggered in mouse peritoneal macrophages. Our results show that receptor Mas transcripts were up-regulated by eightfold in LPS-induced macrophages. Interestingly, macrophage stimulation with angiotensin-(17), following to LPS exposure, evoked an attenuation in expression of TNF-a and IL-6 pro-inflammatory cytokines; where this event was abolished when the receptor Mas selective antagonist A779 was also included. We then used heterologous expression of the receptor Mas in HEK293T cells to search for the molecular mechanisms underlying the angiotensin-(17)-mediated anti-inflammatory responses by a kinase array; what suggested the involvement of the Src kinase family. In LPS-induced macrophages, this finding was corroborated using the PP2 compound, a specific Src kinase inhibitor; and also by Western blotting when we observed that Ang-(17) attenuated the phosphorylation levels of Lyn, a member of the Src kinase family. Our findings bring evidence for an anti-inflammatory role for angiotensin-(17) at the cellular level, as well as show that its probable mechanism of action includes the modulation of Src kinases activities. J. Cell. Physiol. 227: 21172122, 2012. (C) 2011 Wiley Periodicals, Inc.

Reduced Plasma Angiotensin Ii Levels Are Reversed By Hydroxyurea Treatment In Mice With Sickle Cell Disease.

Sickle cell disease (SCD) pathogenesis leads to recurrent vaso-occlusive and hemolytic processes, causing numerous clinical complications including renal damage. As vasoconstrictive mechanisms may be enhanced in SCD, due to endothelial dysfunction and vasoactive protein production, we aimed to determine whether the expression of proteins of the renin-angiotensin system (RAS) may be altered in an animal model of SCD. Plasma angiotensin II (Ang II) was measured in C57BL/6 (WT) mice and mice with SCD by ELISA, while quantitative PCR was used to compare the expressions of the genes encoding the angiotensin-II-receptors 1 and 2 (AT1R and AT2R) and the angiotensin-converting enzymes (ACE1 and ACE2) in the kidneys, hearts, livers and brains of mice. The effects of hydroxyurea (HU; 50-75mg/kg/day, 4weeks) treatment on these parameters were also determined. Plasma Ang II was significantly diminished in SCD mice, compared with WT mice, in association with decreased AT1R and ACE1 expressions in SCD mice kidneys. Treatment of SCD mice with HU reduced leukocyte and platelet counts and increased plasma Ang II to levels similar to those of WT mice. HU also increased AT1R and ACE2 gene expression in the kidney and heart. Results indicate an imbalanced RAS in an SCD mouse model; HU therapy may be able to restore some RAS parameters in these mice. Further investigations regarding Ang II production and the RAS in human SCD may be warranted, as such changes may reflect or contribute to renal damage and alterations in blood pressure.

Evaluation of Indigenous Grains from the Peruvian Andean Region for Antidiabetes and Antihypertension Potential Using In Vitro Methods

The health-relevant functionality of 10 thermally processed Peruvian Andean grains (five cereals, three pseudocereals, and two legumes) was evaluated for potential type 2 diabetes-relevant antihyperglycemia and antihypertension activity using in vitro enzyme assays. Inhibition of enzymes relevant for managing early stages of type 2 diabetes such as hyperglycemia-relevant alpha-glucosidase and alpha-amylase and hypertension-relevant angiotensin I-converting enzyme (ACE) were assayed along with the total phenolic content, phenolic profiles, and antioxidant activity based on the 1,1-diphenyl-2-picrylhydrazyl radical assay. Purple corn (Zea mays L.) (cereal) exhibited high free radical scavenging-linked antioxidant activity (77%) and had the highest total phenolic content (8 +/- 1 mg of gallic acid equivalents/g of sample weight) and alpha-glucosidase inhibitory activity (51% at 5 mg of sample weight). The major phenolic compound in this cereal was protocatechuic acid (287 +/- 15 mu g/g of sample weight). Pseudocereals such as Quinoa (Chenopodium quinoa Willd) and Kaniwa (Chenopodium pallidicaule Aellen) were rich in quercetin derivatives (1,131 +/- 56 and 943 +/- 35 mu g [expressed as quercetin aglycone]/g of sample weight, respectively) and had the highest antioxidant activity (86% and 75%, respectively). Andean legumes (Lupinus mutabilis cultivars SLP-1 and H-6) inhibited significantly the hypertension-relevant ACE (52% at 5 mg of sample weight). No alpha-amylase inhibitory activity was found in any of the evaluated Andean grains. This in vitro study indicates the potential of combination of Andean whole grain cereals, pseudocereals, and legumes to develop effective dietary strategies for managing type 2 diabetes and associated hypertension and provides the rationale for animal and clinical studies.

Thyroid Hormone Increases TGF-beta 1 in Cardiomyocytes Cultures Independently of Angiotensin II Type 1 and Type 2 Receptors

TH-induced cardiac hypertrophy in vivo is accompanied by increased cardiac Transforming Growth Factor-beta 1 (TGF-beta 1) levels, which is mediated by Angiotensin II type 1 receptors (AT1R) and type 2 receptors (AT2R). However, the possible involvement of this factor in TH-induced cardiac hypertrophy is unknown. In this study we evaluated whether TH is able to modulate TGF-beta 1 in isolated cardiac, as well as the possible contribution of AT1R and AT2R in this response. The cardiac fibroblasts treated with T(3) did not show alteration on TGF-beta 1 expression. However, cardiomyocytes treated with T(3) presented an increase in TGF-beta 1 expression, as well as an increase in protein synthesis. The AT1R blockade prevented the T(3)-induced cardiomyocyte hypertrophy, while the AT2R blockage attenuated this response. The T(3)-induced increase on TGF-beta 1 expression in cardiomyocytes was not changed by the use of AT1R and AT2R blockers. These results indicate that Angiotensin II receptors are not implicated in T(3)-induced increase on TGF-beta expression and suggest that the trophic effects exerted by T(3) on cardiomyocytes are not dependent on the higher TGF-beta 1 levels, since the AT1R and AT2R blockers were able to attenuate the T(3)-induced cardiomyocyte hypertrophy but were not able to attenuate the increase on TGF-beta 1 levels promoted by T(3).

The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice

Sympathetic hyperactivity (SH) and renin angiotensin system (RAS) activation are commonly associated with heart failure (HF), even though the relative contribution of these factors to the cardiac derangement is less understood. The role of SH on RAS components and its consequences for the HF were investigated in mice lacking alpha(2A) and alpha(2C) adrenoceptor knockout (alpha(2A)/alpha(2C) ARKO) that present SH with evidence of HF by 7 mo of age. Cardiac and systemic RAS components and plasma norepinephrine (PN) levels were evaluated in male adult mice at 3 and 7 mo of age. In addition, cardiac morphometric analysis, collagen content, exercise tolerance, and hemodynamic assessments were made. At 3 mo, alpha(2A)/alpha(2C)ARKO mice showed no signs of HF, while displaying elevated PN, activation of local and systemic RAS components, and increased cardiomyocyte width (16%) compared with wild-type mice (WT). In contrast, at 7 mo, alpha(2A)/alpha(2C)ARKO mice presented clear signs of HF accompanied only by cardiac activation of angiotensinogen and ANG II levels and increased collagen content (twofold). Consistent with this local activation of RAS, 8 wk of ANG II AT(1) receptor blocker treatment restored cardiac structure and function comparable to the WT. Collectively, these data provide direct evidence that cardiac RAS activation plays a major role underlying the structural and functional abnormalities associated with a genetic SH-induced HF in mice.

EFFECT OF THERMAL TREATMENT ON PHENOLIC COMPOUNDS AND FUNCTIONALITY LINKED TO TYPE 2 DIABETES AND HYPERTENSION MANAGEMENT OF PERUVIAN AND BRAZILIAN BEAN CULTIVARS (PHASEOLUS VULGARIS L.) USING IN VITRO METHODS

The effect of thermal treatment on phenolic compounds and type 2 diabetes functionality linked to alpha-glucosidase and alpha-amylase inhibition and hypertension relevant angiotensin I-converting enzyme (ACE) inhibition were investigated in selected bean (Phaseolus vulgaris L,) cultivars from Peru and Brazil using in vitro models. Thermal processing by autoclaving decreased the total phenolic content in all cultivars, whereas the 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity-linked antioxidant activity increased among Peruvian cultivars, alpha-Amylase and alpha-glucosidase inhibitory activities were reduced significantly after heat treatment (73-94% and 8-52%, respectively), whereas ACE inhibitory activity was enhanced (9-15%). Specific phenolic acids such as chlorogenic and caffeic acid increased moderately following thermal treatment (2-16% and 5-35%, respectively). No correlation was found between phenolic contents and functionality associated to antidiabetes and antihypertension potential, indicating that non phenolic compounds may be involved. Thermally processed bean cultivars are interesting sources of phenolic acids linked to high antioxidant activity and show potential for hypertension prevention.

Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and attenuates growth of murine melanoma

Purpose We evaluated the involvement of angiotensin II (AngII)-dependent pathways in melanoma growth, through the pharmacological blockage of AT1 receptor by the antihypertensive drug losartan (LOS). Results We showed immunolabeling for both AngII and the AT1 receptor within the human melanoma microenvironment. Like human melanomas, we showed that murine melanomas also express the AT1 receptor. Growth of murine melanoma, both locally and at distant sites, was limited in mice treated with LOS. The reduction in tumor growth was accompanied by a twofold decrease in tumorassociated microvessel density and by a decrease in CD31 mRNA levels. While no differences were found in the VEGF expression levels in tumors from treated animals, reduction in the expression of the VEGFR1 (Flt-1) at the mRNA and protein levels was observed. We also showed downregulation of mRNA levels of both Flt-4 and its ligand, VEGF-C. Conclusions Together, these results show that blockage of AT1 receptor signaling may be a promising anti-tumor strategy, interfering with angiogenesis by decreasing the expression of angiogenic factor receptors.

Local renin-angiotensin system regulates left ventricular hypertrophy induced by swimming training independent of circulating renin: a pharmacological study

Introduction. This study addressed the role of the local renin-angiotensin system (RAS) in the left ventriular hypertropy (LVH) induced by swimming training using pharmacological blockade. Materials and methods. Female Wistar rats treated with enalapril maleate (60 mg.kg(-1).d(-1), n = 38), losartan (20 mg.kg(-1).d(-1), n = 36) or high salt diet (1% NaCl, n = 38) were trained by two protocols (T1: 60-min swimming session, 5 days per week for 10 weeks and T2: the same T1 protocol until the 8(th) week, then 9(th) week they trained twice a day and 10(th) week they trained three times a day). Salt loading prevented activation of the systemic RAS. Haemodynamic parameters, soleus citrate synthase (SCS) activity and LVH (left ventricular/body weight ratio, mg/g) were evaluated. Results. Resting heart rate decreased in all trained groups. SCS activity increased 41% and 106% in T1 and T2 groups, respectively. LVH was 20% and 30% in T1 and T2 groups, respectively. Enalapril prevented 39% of the LVH in T2 group (p < 0.05). Losartan prevented 41% in T1 and 50% in T2 (P < 0.05) of the LVH in trained groups. Plasma renin activity (PRA) was inhibited in all salt groups and it was increased in T2 group. Conclusions. These data provide evidence that the physiological LVH induced by swimming training is regulated by local RAS independent from the systemic, because the hypertrophic response was maintained even when PRA was inhibited by chronic salt loading. However, other systems can contribute to this process.

ANGIOTENSIN III MODULATES THE NOCICEPTIVE CONTROL MEDIATED BY THE PERIAQUEDUCTAL GRAY MATTER

Endogenous angiotensin (Ang) II and/or an Ang II-derived peptide, acting on Ang type I (AT(1)) and Ang type 2 (AT(2)) receptors, can carry out part of the nociceptive control modulated by periaqueductal gray matter (PAG). However, neither the identity of this putative Ang-peptide, nor its relationship to Ang II antinociceptive activity was clarified. Therefore, we have used tail-flick and incision allodynia models combined with an HPLC time course of Ang metabolism, to study the Ang III antinociceptive effect in the rat ventrolateral (vi) PAG using peptidase inhibitors and receptor antagonists. Ang III injection into the vIPAG increased tail-flick latency, which was fully blocked by Losartan and CGP 42,112A, but not by divalinal-Ang IV, indicating that. Ang III effect was mediated by AT(1) and AT(2) receptors, but not by the AT(4) receptor. Ang III injected into the vIPAG reduced incision allodynia. Incubation of Ang II with punches of vIPAG homogenate formed Ang III, Ang (1-7) and Ang IV. Amastatin (AM) inhibited the formation of Ang III from Ang II by homogenate, and blocked the antinociceptive activity of Ang II injection into vIPAG, suggesting that aminopeptidase A (APA) formed Ang III from Ang II. Ang III can also be formed from Ang I by a vIPAG alternative pathway. Therefore, the present work shows, for the first time, that: (i) Ang III, acting on AT(1) and AT(2) receptors, can elicit vIPAG-mediated antinociception, (ii) the conversion of Ang II to Ang III in the vIPAG is required to elicit antinociception, and (iii) the antinociceptive activity of endogenous Ang II in vIPAG can be ascribed preponderantly to Ang III. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.