Ajoene, a garlic compound, inhibits protein prenylation and arterial smooth muscle cell proliferation

1) Ajoene is a garlic compound with anti-platelet properties and, in addition, was shown to inhibit cholesterol biosynthesis by affecting 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and late enzymatic steps of the mevalonate (MVA) pathway. (2) MVA constitutes the precursor not only of cholesterol, but also of a number of non-sterol isoprenoids, such as farnesyl and geranylgeranyl groups. Covalent attachment of these MVA-derived isoprenoid groups (prenylation) is a required function of several proteins that regulate cell proliferation. We investigated the effect of ajoene on rat aortic smooth muscle cell proliferation as related to protein prenylation. (3) Cell counting, DNA synthesis, and cell cycle analysis showed that ajoene (1-50 micro M) interfered with the progression of the G1 phase of the cell cycle, and inhibited rat SMC proliferation. (4) Similar to the HMG-CoA reductase inhibitor simvastatin, ajoene inhibited cholesterol biosynthesis. However, in contrast to simvastatin, the antiproliferative effect of ajoene was not prevented by the addition of MVA, farnesol (FOH), and geranylgeraniol (GGOH). Labelling of smooth muscle cell cellular proteins with [3H]-FOH and [3H]-GGOH was significantly inhibited by ajoene. (5) In vitro assays for protein farnesyltransferase (PFTase) and protein geranylgeranyltransferase type I (PGGTase-I) confirmed that ajoene inhibits protein prenylation. High performance liquid chromatography (HPLC) and mass spectrometry analyses also demonstrated that ajoene causes a covalent modification of the cysteine SH group of a peptide substrate for protein PGGTase-I. (6) Altogether, our results provide evidence that ajoene interferes with the protein prenylation reaction, an effect that may contribute to its inhibition of SMC proliferatio

Assessing the Conditions for Multilateral Interventions or Non-Interventions: Intervention and Non-Intervention in the Asia Pacific Region

The focus of this thesis has been on the identification of the primary conditions that attract or deter multilateral interventions into internal conflicts in the Asia Pacific region. This thesis develops a framework which is applied to four cases of internal conflict to see what roles twenty-two structural and perceptual conditions have played in determining why multilateral intervention was initiated in two of the cases, and why multilateral intervention failed to be initiated in the other two cases. The research found that multilateral organizations will accept risks and costs associated with intervention if certain structural and perceptual conditions make intervention an attractive option. These conditions are, a favourable or significant international environment or international event(s), the consent of a sovereign state (even if it is induced), sustained and critical regional and international media coverage, a complete collapse of the state in conflict tainting it with the term 'failed state', a high probability of success, potential economic benefits, a humanitarian crisis (in respect of Unregulated Population Movements and genocide/politicide), the possibility of a clear exit strategy, and a self-interested Member State who can greatly subsidize an intervention. Multilateral non-interventions, on the contrary, are driven by a combination of a lack of sustained and critically analyzed media coverage on conflict issues and consequences, generally positive tactics and strategies adopted by disputants, conflicts of a long duration, the international environment, economic factors unfavourable to intervention, resistance levels to intervention or a failure to call for intervention, lack of any clear exit points, and an escalation phase. The importance of these conditions suggest that multilateral organizations are reluctant to take risks and costs when political will, for the collective and self, are not provoked. Consequently, particular structural and perceptual conditions trigger or influence political will. The analysis of four case studies (East Timor, Solomon Islands, Philippines (Moros), and West Papua) concludes that multilateral interventions will be the exception to the rule in the foreseeable future given the obvious selection bias evident in these policies, and the project questions the ad hoc determinants of current multilateral intervention policies

Metal-macrofauna interactions determine microbial community structure and function in copper contaminated sediments

Peer reviewedPublisher PD

Biventricular structural and functional responses to aortic constriction in a rabbit model of chronic right ventricular pressure overload

Objectives: Chronic right ventricular (RV) pressure overload results in pathologic RV hypertrophy and diminished RV function. Although aortic constriction has been shown to improve systolic function in acute RV failure, its effect on RV responses to chronic pressure overload is unknown. Methods: Adjustable vascular banding devices were placed on the main pulmonary artery and descending aorta. In 5 animals (sham group), neither band was inflated. In 9 animals (PAB group), only the pulmonary arterial band was inflated, with adjustments on a weekly basis to generate systemic or suprasystemic RV pressure at 28 days. In 9 animals, both pulmonary arterial and aortic devices were inflated (PAB+AO group), the pulmonary arterial band as for the PAB group and the aortic band adjusted to increase proximal systolic blood pressure by approximately 20 mm Hg. Effects on the functional performance were assessed 5 weeks after surgery by conductance catheters, followed by histologic and molecular assessment. Results: Contractile performance was significantly improved in the PAB+AO group versus the PAB group for both ventricles. Relative to sham-operated animals, both banding groups showed significant differences in myocardial histologic and molecular responses. Relative to the PAB group, the PAB+AO group showed significantly decreased RV cardiomyocyte diameter, decreased RV collagen content, and reduced RV expression of endothelin receptor type B, matrix metalloproteinase 9, and transforming growth factor beta genes. Conclusions: Aortic constriction in an experimental model of chronic RV pressure overload not only resulted in improved biventricular systolic function but also improved myocardial remodeling. These data suggest that chronically increased left ventricular afterload leads to a more physiologically hypertrophic response in the pressure-overloaded RV. (J Thorac Cardiovasc Surg 2012;144:1494-501)Deutsche Herzstiftung e.V., Frankfurt, German

Science-Policy Interactions in MPA Site Selection in the Dutch Part of the North Sea

At the 7th conference of the parties to the Convention on Biological Diversity (CBD-COP7, Kuala Lumpur, 2004) it was agreed to establish a global network of marine and coastal protected areas by 2012. The defined objectives of this MPA-network are based on the ecosystem approach: to protect biodiversity and other ecological values, and to ensure sustainable use. The (inter)national policy guidelines state that the selection of MPAs should be based on scientific information and ecological criteria only. As a signatory to the Convention, the Netherlands is now faced with meeting this obligation, and the process of designating the first Marine Protected Areas (MPAs) in the Dutch part of the North Sea is currently in progress. We focus on the science–policy interactions that are part of this Dutch MPA selection process. By taking a closer look at the contemporary site selection process as well as its historical background, we show that ecological, socio-economic and political considerations cannot always be easily separated. Uncertainty is high and the ultimate selection and delimitation of candidate sites rather seems to be the result of a balancing act between ecological, socio-economic and political interests, in which scientific and policy guiding procedures blend with ad-hoc political decision making, and with expert judgment in cases where data is lacking. As such, this paper presents an example of present-day environmental policy making in action

Effect of garlic on cardiovascular disorders: a review

Garlic and its preparations have been widely recognized as agents for prevention and treatment of cardiovascular and other metabolic diseases, atherosclerosis, hyperlipidemia, thrombosis, hypertension and diabetes. Effectiveness of garlic in cardiovascular diseases was more encouraging in experimental studies, which prompted several clinical trials. Though many clinical trials showed a positive effect of garlic on almost all cardiovascular conditions mentioned above, however a number of negative studies have recently cast doubt on the efficary of garlic specially its cholesterol lowering effect of garlic. It is a great challenge for scientists all over the world to make a proper use of garlic and enjoy its maximum beneficial effect as it is the cheapest way to prevent cardiovascular disease. This review has attempted to make a bridge the gap between experimental and clinical study and to discuss the possible mechanisms of such therapeutic actions of garlic

3D Real-Time Echocardiography Combined with Mini Pressure Wire Generate Reliable Pressure-Volume Loops in Small Hearts

BACKGROUND: Pressure-volume loops (PVL) provide vital information regarding ventricular performance and pathophysiology in cardiac disease. Unfortunately, acquisition of PVL by conductance technology is not feasible in neonates and small children due to the available human catheter size and resulting invasiveness. The aim of the study was to validate the accuracy of PVL in small hearts using volume data obtained by real-time three-dimensional echocardiography (3DE) and simultaneously acquired pressure data. METHODS: In 17 piglets (weight range: 3.6–8.0 kg) left ventricular PVL were generated by 3DE and simultaneous recordings of ventricular pressure using a mini pressure wire (PVL3D). PVL3D were compared to conductance catheter measurements (PVLCond) under various hemodynamic conditions (baseline, alpha-adrenergic stimulation with phenylephrine, beta-adrenoreceptor-blockage using esmolol). In order to validate the accuracy of 3D volumetric data, cardiac magnetic resonance imaging (CMR) was performed in another 8 piglets. RESULTS: Correlation between CMR- and 3DE-derived volumes was good (enddiastolic volume: mean bias -0.03ml ±1.34ml). Computation of PVL3D in small hearts was feasible and comparable to results obtained by conductance technology. Bland-Altman analysis showed a low bias between PVL3D and PVLCond. Systolic and diastolic parameters were closely associated (Intraclass-Correlation Coefficient for: systolic myocardial elastance 0.95, arterial elastance 0.93, diastolic relaxation constant tau 0.90, indexed end-diastolic volume 0.98). Hemodynamic changes under different conditions were well detected by both methods (ICC 0.82 to 0.98). Inter- and intra-observer coefficients of variation were below 5% for all parameters. CONCLUSIONS: PVL3D generated from 3DE combined with mini pressure wire represent a novel, feasible and reliable method to assess different hemodynamic conditions of cardiac function in hearts comparable to neonate and infant size. This methodology may be integrated into clinical practice and cardiac catheterization programs and has the capability to contribute to clinical decision making even in small hearts

rst Transcriptional Activity Influences kirre mRNA Concentration in the Drosophila Pupal Retina during the Final Steps of Ommatidial Patterning

Background: Drosophila retinal architecture is laid down between 24-48 hours after puparium formation, when some of the still uncommitted interommatidial cells (IOCs) are recruited to become secondary and tertiary pigment cells while the remaining ones undergo apoptosis. This choice between survival and death requires the product of the roughest (rst) gene, an immunoglobulin superfamily transmembrane glycoprotein involved in a wide range of developmental processes. Both temporal misexpression of Rst and truncation of the protein intracytoplasmic domain, lead to severe defects in which IOCs either remain mostly undifferentiated and die late and erratically or, instead, differentiate into extra pigment cells. Intriguingly, mutants not expressing wild type protein often have normal or very mild rough eyes. Methodology/Principal Findings: By using quantitative real time PCR to examine rst transcriptional dynamics in the pupal retina, both in wild type and mutant alleles we showed that tightly regulated temporal changes in rst transcriptional rate underlie its proper function during the final steps of eye patterning. Furthermore we demonstrated that the unexpected wild type eye phenotype of mutants with low or no rst expression correlates with an upregulation in the mRNA levels of the rst paralogue kin-of-irre (kirre), which seems able to substitute for rst function in this process, similarly to their role in myoblast fusion. This compensatory upregulation of kirre mRNA levels could be directly induced in wild type pupa upon RNAi-mediated silencing of rst, indicating that expression of both genes is also coordinately regulated in physiological conditions. Conclusions/Significance: These findings suggest a general mechanism by which rst and kirre expression could be fine tuned to optimize their redundant roles during development and provide a clearer picture of how the specification of survival and apoptotic fates by differential cell adhesion during the final steps of retinal morphogenesis in insects are controlled at the transcriptional level