Blood pressure lowering effects of Lactobacillus helveticus fermented milk containing bioactive peptides Ile-Pro-Pro and Val-Pro-Pro; mechanistic, kinetic and clinical studies

The purpose of the present study was to evaluate the effects of Lactobacillus helveticus fermented milk (peptide milk) containing the casein-derived tripeptides Isoleucyl-prolyl-proline (Ile-Pro-Pro) and Valyl-prolyl-proline (Val-Pro-Pro) on blood pressure and vascular function in hypertensive subjects. The peptide milk lowered systolic and diastolic blood pressure in long-term use in hypertensive subjects when blood pressure was measured by using 24-hour ambulatory blood pressure measurement (ABPM). The blood pressure lowering effect was seen with the dose of 50 mg of tripeptides, and a tendency for lowering blood pressure was also observed when the dose was 5 mg. No adverse effects compared to the placebo group were reported or detected in laboratory analysis. The effect of the peptide milk on arterial stiffness was shown using two different methods, the ambulatory arterial stiffness index (AASI) and pulse wave analysis (PWA). According to the AASI, arterial stiffness was significantly reduced in the peptide milk group compared to the baseline level, but the difference was not significant compared to the placebo group. PWA showed that the peptide milk reduced arterial stiffness significantly compared to the placebo group. Endothelium-independent relaxation (nitroglycerin) and endothelium-dependent relaxation (salbutamol) did not differ between the groups. The blood pressure lowering mechanisms of the tripeptides and the kinetics of Ile-Pro-Pro were investigated using spontaneously hypertensive rats (SHR) and Sprague-Dawley rats. Previous studies have suggested that the blood pressure lowering effect of the tripeptides Ile-Pro-Pro and Val-Pro-Pro is based on angiotensin-converting enzyme inhibition, but the present findings did not agree with these previous studies. It was shown in SHR that calcium, potassium and magnesium may also have an important role in attenuating the development of hypertension as part of the peptide milk effect. In addition, the present study suggests indirectly that improved endothelial nitric oxide release capacity is not the mechanism by which peptide milk mediates its favourable circulatory effects. The kinetics of Ile-Pro-Pro were studied using adult Sprague-Dawley rats. The results showed that orally administered Ile-Pro-Pro is absorbed at least partly intact from the gastrointestinal tract. Radiolabelled Ile-Pro-Pro was distributed in different tissues and considerable radioactivity levels were found in tissues related to the renin-angiotensin system (RAS), adrenals, aorta and kidneys. Ile-Pro-Pro does not bind to plasma proteins, and therefore it is possible that its blood pressure lowering effect is mediated by free Ile-Pro-Pro. In conclusion, consumption of the peptide milk lowers blood pressure and reduces arterial stiffness in hypertensive subjects. Ile-Pro-Pro can be absorbed partly intact from the gastrointestinal tract and might accumulate in tissues related to the RAS. The precise blood pressure lowering mechanism of peptide milk remains to be studied.

Metallization and crystallization of semiconducting amorphous Ga20Te80 alloy under high pressure

Pressure and temperature dependence of the electrical resistivity of amorphous Ga20Te80 alloy is reported for the first time. The alloy undergoes a pressure induced amorphous semiconductor-to-crystalline metal phase transition at 6.5 ± 0.5 GPa. The high pressure crystalline phase is a mixture of Te and GaTe3 phases.

Pressure-induced electronic and structural transformations in bulk gese2 glass

The pressure dependence of the electrical of the electrical resistivity of bulk GeSe2 glass shows a semiconductor-to-metal transition at 7 GPa pressure. The high pressure phase is examined using he x-ray diffractometer and is found to be crystalline, with a face-centered cubic structure having a =4.06A. The electrical conductivity has also been studied as a function of temperature at various pressures.

Milk casein-derived tripeptides : A special focus on blood pressure and vascular function

Increased consumption of low-fat milk products is inversely associated with the risk of hypertension. The beneficial effect of milk on blood pressure is attributed to high calcium and potassium content but also to specific peptide sequences, which are cleaved from milk protein during gastrointestinal digestion, fermentation of milk with proteolytic starter cultures or enzymatic hydrolysis. Milk products fermented with Lactobacillus helveticus contain casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro), which have been shown to possess antihypertensive effects in humans and in experimental animals. The aim of the present series of studies was to investigate the effects of tripeptides Ile-Pro-Pro and Val-Pro-Pro or fermented milk products containing them on vascular function and blood pressure and to elucidate the mechanisms behind them by using different experimental models of hypertension. Another aim was to characterize the acute effects of tripeptides on blood pressure and arterial stiffness in mildly hypertensive humans. Ile-Pro-Pro and Val-Pro-Pro or fermented milk products containing them attenuated the development of hypertension in two experimental models of hypertension, spontaneously hypertensive rat (SHR) and type 2 diabetic Goto-Kakizaki (GK) rat fed with high-salt diet. Significant differences in systolic blood pressure (SBP) were seen after 8 weeks treatment with tripeptide-containing products compared to control product. Plant sterols did not enhance this effect. Two differently produced tripeptide powders produced a similar attenuating effect on SBP in SHR. In mildly hypertensive subjects, a single administration of tripeptide- and plant sterol-containing fermented milk product decreased both SBP and diastolic blood pressure (DBP) over a period of 8 hours. Protective effect of tripeptides Ile-Pro-Pro and Val-Pro-Pro and fermented milk products containing them on vascular function was demonstrated in in vitro studies and long-term experimental studies. The effect was shown to be endothelium-dependent and possibly involving endothelium-derived hyperpolarizing factor (EDHF). In the clinical study, single administration of tripeptide-containing fermented milk product did not affect measures of arterial stiffness. Long-term treatment with fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro inhibited angiotensin-converting enzyme (ACE) and decreased aldosterone levels thus showing beneficial effects on the renin-angiotensin system (RAS) in SHR and GK. No changes in the components of RAS were observed by the single administration of the same product in mildly hypertensive subjects. Increased levels of cGMP, NOx and citrulline suggest increased nitric oxide (NO) production by the tripeptides. Taken together, Ile-Pro-Pro and Val-Pro-Pro -containing products attenuate the development of hypertension after long-term treatment in experimental models of hypertension and possess an acute antihypertensive effect in mildly hypertensive subjects. In addition, these tripeptides show endothelium-mediated beneficial effects on vascular function. Attenuation of blood pressure increase by the tripeptides in experimental animals involves RAS, but its role in the antihypertensive effect in humans remains to be elucidated.

High pressure induced crystallization of rapidly solidified Al---Fe and Al---Mn quasi-crystalline alloysstar

The presence of phases showing icosahedral point symmetry was reported by Shechtman, Blech, Gratias and Cahn in rapidly quenched alloys of Al---Mn, Al---Fe and Al---Cr, and subsequently many other splat-cooled alloys with the i phase have been reported. In this paper we present the first results of high pressure experiments carried out on Al---Fe and Al---Mn quasi-crystals. The experiments performed at room temperature showed irreversible quasi-crystal-to-crystal transitions in Al---Mn and Al---Fe alloys. The transition pressures are 49 kbar for Al78Mn22, 93 kbar for Al86Mn14, 79 kbar for Al86Fe14, 54 kbar for Al82Fe18 and 108 kbar for Al75Fe25. The high pressure phases are found to be the equilibrium phases.

Electrical transport in layered crystalline semiconductors GeS doped with Ag, P impurities at high pressure

A study of the transport properties of layered crystalline semiconductors GeS (undoped and doped with Ag, P impurity) under quasihydrostatic pressure using Bridgman anvil system is made for the first time. Pressure-induced effects in undoped crystals reveal initial rise in resistivity followed by two broad peaks at higher pressures. Silver doping induces only minor changes in the behaviour except removing the second peak. Phosphorous impurity is found to have drastic effect on the transport properties. Temperature dependence of the resistivity exhibits two activation energies having opposite pressure coefficients. Results are discussed in the light of intrinsic features of the layered semiconductors.

Pressure induced effects in bulk amorphous n-type semiconductors(GeSe3.5)100âxBix

The effect of pressure on the electrical resistivity of amorphous n-type (GeSe3.5)100�xBix been studied in a Bridgeman anvil system up to a pressure of 90 kbar down to liquid nitrogen temperature. A continuous amorphous semiconductor to metal-like solid transition in the undoped GeSe3.5 is observed at room temperature. Incorporation of Bi in the GeSe3.5 network is found to significantly disturb the behaviour of the resistivity with pressure. With increasing Bi concentration a much broader variation in resistivity with pressure is observed. The temperature dependence of the resistivity and activation energy at different pressures is also measured and they are found to be composition dependent. Results are discussed in the light of the Phillips Model of ordered clusters in chalcogenide semiconductors.

Early growth and adult health: focus on blood pressure, glucose tolerance status and body composition

Theory of developmental origins of adult health and disease proposes that experiences during critical periods of early development may have consequences on health throughout a lifespan. Thesis studies aimed to characterize associations between early growth and some components of the metabolic syndrome cluster. Participants belong to two epidemiological cohorts with data on birth measurements and, for the younger cohort, on serial recordings of weight and height during childhood. They were born as singletons between 1924-33 and 1934-44 in the Helsinki University Central Hospital, and 500 and 2003 of them, respectively, attended clinical studies at the age of 65-75 and 56-70 years, respectively. In the 65-75 year old men and women, the well-known inverse relationship between birth weight and systolic blood pressure (SBP) was confined to people who had established hypertension. Among them a 1-kg increase in birth weight was associated with a 6.4-mmHg (95% CI: 1.0 to 11.9) decrease in SBP. This relationship was further confined to people with the prevailing Pro12Pro polymorphism of the peroxisome proliferator-activated receptor-γ2 (PPARγ2) gene. People with low birth weight were more likely to receive angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEI/ARB, p=0.03), and, again, this relationship was confined to the carriers of the Pro12Pro (p=0.01 for interaction). These results suggest that the inverse association between birth weight and systolic BP becomes focused in hypertensive people because pathological features of BP regulation, associated with slow fetal growth, become self-perpetuating in adult life. Insulin resistance of the Pro12Pro carriers with low birth weight may interact with the renin-angiotensin system leading to raised BP levels. Habitual physical activity protected men and women who were small at birth, and thus at increased risk for the development of type 2 diabetes, against glucose intolerance more strongly. Among subjects with birth weight ≤3000 g, the odds ratio (OR) for glucose intolerance was 5.2 (95% CI: 2.1 to 13) in those who exercised less than 3 times per week compared to regular exercisers; in those who scored their exercise light compared with moderate exercisers (defined as comparable to brisk walking) the OR was 3.5 (1.5 to 8.2). In the 56-70 year old men a 1 kg increase in birth weight corresponded to a 4.1 kg (95% CI: 3.1 to 5.1) and in women to a 2.9 kg (2.1 to 3.6) increase in adult lean mass. Rapid gain in body mass index (BMI), i.e. crossing from an original BMI percentile to a higher one, before the age of 2 years increased adult lean mass index (LMI, lean mass/height squared) without excess fat accumulation whereas rapid gain in BMI during later childhood, despite the concurrent rise in LMI, resulted in a relatively higher increase in adult body fat mass. These findings illustrate how genes, the environment and their interactions, early growth patterns, and adult lifestyle modify adult health risks which originate from early life.

Generation of rotationally dominated galaxies by mergers of pressure-supported progenitors

Through the analysis of a set of numerical simulations of major mergers between initially non-rotating, pressure-supported progenitor galaxies with a range of central mass concentrations, we have shown that: (1) it is possible to generate elliptical-like galaxies, with outside one effective radius, as a result of the conversion of orbital- into internal-angular momentum; (2) the outer regions acquire part of the angular momentum first; (3) both the baryonic and the dark matter components of the remnant galaxy acquire part of the angular momentum, the relative fractions depending on the initial concentration of the merging galaxies. For this conversion to occur the initial baryonic component must be sufficiently dense and/or the encounter should take place on an orbit with high angular momentum. Systems with these hybrid properties have recently been observed through a combination of stellar absorption lines and planetary nebulae for kinematic studies of early-type galaxies. Our results are in qualitative agreement with these observations and demonstrate that even mergers composed of non rotating, pressure-supported progenitor galaxies can produce early-type galaxies with significant rotation at large radii.

Study of effects of dopants on structure of vitreous semiconductors (GeSe3.5)100-xMx (M = Bi, Sb) using high pressure techniques

An investigation of the problem of controlled doping of amorphous chalcogenide semiconductors utilizing a Bridgman anvil high pressure technique, has been undertaken. Bulk amorphous semiconducting materials (GeSe3.5)100-x doped with M = Bi (x = 2, 4, 10) and M = Sb (x = 10) respectively are studied up to a pressure of 100 kbar down to liquid nitrogen temperature, with a view to observe the impurity induced modifications. Measurement of the electrical conductivity of the doped samples under quasi-hydrostatic pressure reveals that the pressure induced effects in lightly doped (2 at % Bi) and heavily doped (x = 4, 10) semiconductors are markedly different. The pressure effects in Sb-doped semiconductors are quite different from those in Bi-doped material.

Soil carbon stock in the tropical rangelands of Australia: Effects of soil type and grazing pressure, and determination of sampling requirement.

On-going, high-profile public debate about climate change has focussed attention on how to monitor the soil organic carbon stock (C(s)) of rangelands (savannas). Unfortunately, optimal sampling of the rangelands for baseline C(s) - the critical first step towards efficient monitoring - has received relatively little attention to date. Moreover, in the rangelands of tropical Australia relatively little is known about how C(s) is influenced by the practice of cattle grazing. To address these issues we used linear mixed models to: (i) unravel how grazing pressure (over a 12-year period) and soil type have affected C(s) and the stable carbon isotope ratio of soil organic carbon (delta(13)C) (a measure of the relative contributions of C(3) and C(4) vegetation to C(s)); (ii) examine the spatial covariation of C(s) and delta(13)C; and, (iii) explore the amount of soil sampling required to adequately determine baseline C(s). Modelling was done in the context of the material coordinate system for the soil profile, therefore the depths reported, while conventional, are only nominal. Linear mixed models revealed that soil type and grazing pressure interacted to influence C(s) to a depth of 0.3 m in the profile. At a depth of 0.5 m there was no effect of grazing on C(s), but the soil type effect on C(s) was significant. Soil type influenced delta(13)C to a soil depth of 0.5 m but there was no effect of grazing at any depth examined. The linear mixed model also revealed the strong negative correlation of C(s) with delta(13)C, particularly to a depth of 0.1 m in the soil profile. This suggested that increased C(s) at the study site was associated with increased input of C from C(3) trees and shrubs relative to the C(4) perennial grasses; as the latter form the bulk of the cattle diet, we contend that C sequestration may be negatively correlated with forage production. Our baseline C(s) sampling recommendation for cattle-grazing properties of the tropical rangelands of Australia is to: (i) divide the property into units of apparently uniform soil type and grazing management; (ii) use stratified simple random sampling to spread at least 25 soil sampling locations about each unit, with at least two samples collected per stratum. This will be adequate to accurately estimate baseline mean C(s) to within 20% of the true mean, to a nominal depth of 0.3 m in the profile.

Intracellular effects of atmospheric-pressure plasmas on melanoma cancer cells

Gas discharge plasmas formed at atmospheric pressure and near room temperature have recently been shown as a promising tool for cancer treatment. The mechanism of the plasma action is attributed to generation of reactive oxygen and nitrogen species, electric fields, charges, and photons. The relative importance of different modes of action of atmospheric-pressure plasmas depends on the process parameters and specific treatment objects. Hence, an in-depth understanding of biological mechanisms that underpin plasma-induced death in cancer cells is required to optimise plasma processing conditions. Here, the intracellular factors involved in the observed anti-cancer activity in melanoma Mel007 cells are studied, focusing on the effect of the plasma treatment dose on the expression of tumour suppressor protein TP73. Over-expression of TP73 causes cell growth arrest and/or apoptosis, and hence can potentially be targeted to enhance killing efficacy and selectivity of the plasma treatment. It is shown that the plasma treatment induces dose-dependent up-regulation of TP73 gene expression, resulting in significantly elevated levels of TP73 RNA and protein in plasma-treated melanoma cells. Silencing of TP73 expression by means of RNA interference inhibited the anticancer effects of the plasma, similar to the effect of caspase inhibitor z-VAD or ROS scavenger N-acetyl cysteine. These results confirm the role of TP73 protein in dose-dependent regulation of anticancer activity of atmospheric-pressure plasmas.

Pro-apoptotic NOXA is implicated in atmospheric-pressure plasma-induced melanoma cell death

Atmospheric-pressure plasma (APP) has been successfully used to treat several types of cancers in vivo and in vitro, with the effect being primarily attributed to the generation of reactive oxygen species (ROS). However, the mechanisms by which APP induces apoptosis in cancer cells require further elucidation. In this study, the effects of APP on the expression of 500 genes in melanoma Mel007 cancer cells were examined. Pro-apoptotic phorbol-12-myristate-13-acetate-induced protein (PMAIP1), also known as NOXA, was highly expressed as a result of APP treatment in a dose-dependent manner. Blocking of ROS using scavenger NAC or silencing of NOXA gene by RNA interference inhibited the APP-induced NOXA genes upregulation and impaired caspases 3/7 mediated apoptosis, confirming the important role plasma-generated ROS species and pro-apoptotic NOXA play in APP-induced cancer cell death.