Anti-angiogenic effects of pterogynidine alkaloid isolated from Alchornea glandulosa

<p>Abstract</p> <p>Background</p> <p>Angiogenesis, a complex multistep process that comprehends proliferation, migration and anastomosis of endothelial cells (EC), has a major role in the development of pathologic conditions such as inflammatory diseases, tumor growth and metastasis. Brazilian flora, the most diverse in the world, is an interesting spot to prospect for new chemical leads, being an important source of new anticancer drugs. Plant-derived alkaloids have traditionally been of interest due to their pronounced physiological activities. We investigated the anti-angiogenic potential of the naturally occurring guanidine alkaloid pterogynidine (Pt) isolated from the Brazilian plant <it>Alchornea glandulosa</it>. The purpose of this study was to examine which features of the angiogenic process could be disturbed by Pt.</p> <p>Methods</p> <p>Human umbilical vein endothelial cells (HUVEC) were incubated with 8 μM Pt and cell viability, proliferation, apoptosis, invasion and capillary-like structures formation were addressed. Nuclear factor κB (NFκB), a transcription factor implicated in these processes, was also evaluated in HUVEC incubated with Pt. Quantifications were expressed as mean ± SD of five independent experiments and one-way analysis of variance (ANOVA) followed by the Dunnet test was used.</p> <p>Results</p> <p>A significant decrease in proliferation and invasion capacity and an effective increase in apoptosis as assessed by bromodeoxyuridine (BrdU), double-chamber and terminal transferase dUTP nick end labeling (TUNEL) assay, respectively, have been found. Pt also led to a drastic reduction in the number of capillary-like structures formation when HUVEC were cultured on growth factor reduced-Matrigel (GFR-Matrigel) coated plates. In addition, incubation of HUVEC with Pt resulted in reduced NFκB activity.</p> <p>Conclusion</p> <p>These findings emphasize the potential use of Pt against pathological situations where angiogenesis is stimulated as tumor development.</p

Phthiocerol Dimycocerosates of M. tuberculosis Participate in Macrophage Invasion by Inducing Changes in the Organization of Plasma Membrane Lipids

Phthiocerol dimycocerosates (DIM) are major virulence factors of Mycobacterium tuberculosis (Mtb), in particular during the early step of infection when bacilli encounter their host macrophages. However, their cellular and molecular mechanisms of action remain unknown. Using Mtb mutants deleted for genes involved in DIM biosynthesis, we demonstrated that DIM participate both in the receptor-dependent phagocytosis of Mtb and the prevention of phagosomal acidification. The effects of DIM required a state of the membrane fluidity as demonstrated by experiments conducted with cholesterol-depleting drugs that abolished the differences in phagocytosis efficiency and phagosome acidification observed between wild-type and mutant strains. The insertion of a new cholesterol-pyrene probe in living cells demonstrated that the polarity of the membrane hydrophobic core changed upon contact with Mtb whereas the lateral diffusion of cholesterol was unaffected. This effect was dependent on DIM and was consistent with the effect observed following DIM insertion in model membrane. Therefore, we propose that DIM control the invasion of macrophages by Mtb by targeting lipid organisation in the host membrane, thereby modifying its biophysical properties. The DIM-induced changes in lipid ordering favour the efficiency of receptor-mediated phagocytosis of Mtb and contribute to the control of phagosomal pH driving bacilli in a protective niche

A review of outcome following valve surgery for rheumatic heart disease in Australia

Background: Globally, rheumatic heart disease (RHD) remains an important cause of heart disease. In Australia it particularly affects younger Indigenous and older non-Indigenous Australians. Despite its impact there is limited understanding of the factors influencing outcome following surgery for RHD. Methods: The Australian and New Zealand Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database was analysed to assess outcomes following surgical procedures for RHD and non-RHD valvular disease. The association with demographics, co-morbidities, pre-operative status, valve(s) affected and operative procedure was evaluated. Results: Outcome of 1384 RHD and 15843 non-RHD valve procedures was analysed. RHD patients had longer ventilation, experienced fewer strokes and had more readmissions to hospital and anticoagulant complications. Mortality following RHD surgery at 30 days was 3.1 % (95 % CI 2.2 – 4.3), 5 years 15.3 % (11.7 – 19.5) and 10 years 25.0 % (10.7 – 44.9). Mortality following non-RHD surgery at 30 days was 4.3 % (95 % CI 3.9 - 4.6), 5 years 17.6 % (16.4 - 18.9) and 10 years 39.4 % (33.0 - 46.1). Factors independently associated with poorer longer term survival following RHD surgery included older age (OR1.03/additional year, 95 % CI 1.01 – 1.05), concomitant diabetes (OR 1.7, 95 % CI 1.1 – 2.5) and chronic kidney disease (1.9, 1.2 – 2.9), longer invasive ventilation time (OR 1.7 if greater than median value, 1.1– 2.9) and prolonged stay in hospital (1.02/additional day, 1.01 – 1.03). Survival in Indigenous Australians was comparable to that seen in non-Indigenous Australians.Conclusion: In a large prospective cohort study we have demonstrated survival following RHD valve surgery in Australia is comparable to earlier studies. Patients with diabetes and chronic kidney disease, were at particular risk of poorer long-term survival. Unlike earlier studies we did not find pre-existing atrial fibrillation, being an Indigenous Australian or the nature of the underlying valve lesion were independent predictors of survival