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Jurasz P.,St. Michaels Hospital | Jurasz P.,University of Alberta | Yurkova N.,Institute of Cardiovascular science | Kirshenbaum L.,Institute of Cardiovascular science | And 4 more authors.
Angiogenesis | Year: 2011

Hypoxia results in the apoptotic death of myocytes, neurons, and epithelial cells, through the actions of Bcl-2 and Nineteen kilodalton Interacting Protein-3 (BNIP3). On the contrary, endothelial cells are especially adept at surviving conditions of oxygen deprivation via up-regulation of vascular endothelial growth factor (VEGF) the most potent endothelial survival factor. Both VEGF and BNIP3 expression are transcriptionally regulated by hypoxia inducible factor and may antagonize each other's affects in endothelial cells (ECs). Since factors that promote and inhibit apoptosis may be expressed at the same time in endothelial cells under hypoxic conditions, we decided to investigate whether VEGF and BNIP3 have opposing actions in endothelial cells. Human microvascular endothelial cells were exposed to hypoxic conditions in a Billups-Rothenburg chamber. Under hypoxic conditions BNIP3 expression by endothelial cells increased as measured by real-time PCR and immunoblot. After 48 h of hypoxia, EC apoptosis was assessed by flow cytometry and was lower than in corresponding normoxia serum starved controls. The increase in EC survival under hypoxic conditions corresponded with an increase in the expression of VEGF. Under normoxic conditions adenoviral BNIP3 over-expression promoted apoptosis of ECs; however, recombinant VEGF (100 pg/ml) antagonized the BNIP3 apoptosis promoting affects. SiRNA knockdown of VEGF expression by hypoxic ECs resulted in increased apoptosis with a concomitant increase in BNIP3 expression. SiRNA knockdown of BNIP3 expression by hypoxic ECs reduced the increase in EC apoptosis as a result of VEGF knockdown. We conclude that under hypoxic conditions VEGF counteracts and masks the apoptosis promoting affects of BNIP3. © 2010 Springer Science+Business Media B.V.

Wang C.,University of Toronto | Wang C.,Tianjin Institute of Urological Surgery | Tao W.,Harbin Medical University | Wang Y.,University of Toronto | And 9 more authors.
European Urology | Year: 2010

Background: Prostate cancer (PCa) is the most common malignancy in males in Western countries. Despite improvements in standard treatments such as surgery, radiotherapy, and chemotherapy, many patients still progress to advanced stages. Recent clinical trials have shown encouraging results regarding the application of angiogenic inhibitors in the treatment of angiogenesis-dependent diseases, paving the way for novel PCa therapies. Objective: To identify new antiangiogenic compounds and examine their therapeutic potential in models of PCa. Design, setting, and participants: We performed a chemical genetic screen in developing zebrafish embryos to identify small molecules inhibiting zebrafish angiogenesis. Transgenic Tg(flk1:EGFP) zebrafish embryos were used in the screening of the Spectrum Collection compound library. Subsequently, the antiangiogenic mechanism of an identified lead compound, rosuvastatin, was studied by conducting endothelial cell function assays and examining antitumor efficacy in a PCa xenograft mouse model. Measurements, results and limitations: Seven lead compounds, including isorotenone, dihydromunduletone, aristolochic acid, simvastatin, mevastatin, lovastatin, and rosuvastatin, were identified to inhibit the growth of the zebrafish intersegmental vessels. Of these seven leads, rosuvastatin was further evaluated for its antiangiogenic mechanism and anticancer efficacy. Rosuvastatin decreased the viability of the human umbilical endothelial cells (HUVECs) (one-half inhibitory concentration: 5.87 μM) by inducing G1 phase arrest and promoting apoptosis. Moreover, rosuvastatin remarkably inhibited the migration of HUVECs and dose-dependently inhibited the HUVEC capillary-like tube formation in vitro. Furthermore, we demonstrated that rosuvastatin suppressed xenografted PPC-1 prostate tumors in nonobese diabetic severe combined immunodeficiency (NOD-SCID) mice associated with decreased microvessel density (MVD) and tumor cell apoptosis. Conclusions: Collectively, our data suggest that rosuvastatin possesses antiangiogenic and antitumor activities and has therapeutic potential for the treatment of PCa. This study represents the first zebrafish antiangiogenic chemical genetic screen to identify a lead compound that targets cancer angiogenesis. © 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Jurasz P.,St. Michaels Hospital | Courtman D.,St. Michaels Hospital | Courtman D.,University of Toronto | Babaie S.,The Terrence Donnelley Heart Center | And 5 more authors.
Pharmacology and Therapeutics | Year: 2010

Pulmonary arterial hypertension (PAH) is a progressive and lethal disease that has a strong female predominance, often affecting the young. Current therapies are mostly vasodilator agents, and while mainly addressing the endothelial dysfunction that has been widely reported in this disease, they may be less effective in treating arterial remodeling. The lung pathology of PAH is characterized by medial hypertrophy and intimal hyperplasia of muscular arteries as well as plexiform lesions, that lead to a widespread narrowing or obliteration of the pulmonary arteriolar bed. However, the pathogenesis of the functional and structural abnormalities of the lung microcirculation in PAH is poorly understood. Perhaps the greatest advancement in the last decade has been the discovery of the "PAH gene," bone morphogenetic receptor 2 (Bmpr2), however how the loss-of-function mutations in Bmpr2 lead to PAH is unclear. The BMPR2 pathway has recently been shown to mediate survival signaling in endothelial cells (EC), and thus the reduced activity will favor endothelial apoptosis, likely increasing the susceptibility to endothelial injury in response to various environmental triggers. EC apoptosis has been implicated as an initiating event in experimental PAH, leading either directly to the degeneration of pre-capillary arterioles or to the selection of hyperproliferative, apoptosis-resistant ECs that may contribute to "angioproliferative" plexiform lesions. The idea that EC apoptosis may play a central role in the initiation and progression of PAH suggests that therapeutic strategies aimed at endothelial repair and regeneration of ECs may be uniquely effective in the treatment of this disease. Preclinical evaluation and validation on the use of endothelial progenitor cells (EPCs) for the prevention and reversal of experimental PAH is reviewed and the design of a "first in man" clinical trial to assess the safety and efficacy of a combined EPC and endothelial NO-synthase gene therapy for patients that are refractory to standard therapies is discussed. © 2010 Elsevier Inc. All rights reserved.

Turnbull H.,University of Alberta | Conroy A.,University of Toronto | Opoka R.O.,Makerere University | Namasopo S.,Jinja Regional Referral Hospital | And 6 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2016

Setting: A resource-limited paediatric hospital in Uganda. OBJECTIVE: Pneumonia is a leading cause of child mortality worldwide. Access to life-saving oxygen therapy is limited in many areas. We designed and implemented a solar-powered oxygen delivery system for the treatment of paediatric pneumonia. DESIGN: Proof-of-concept pilot study. A solar-powered oxygen delivery system was designed and piloted in a cohort of children with hypoxaemic illness. RESULT S: The system consisted of 25 × 80 W photovoltaic solar panels (daily output 7.5 kWh [range 3.8-9.7kWh]), × 3 220 Ah batteries and a 300 W oxygen concentrator (output up to 5 l/min oxygen at 88% [±2%] purity). A series of 28 patients with hypoxaemia were treated with solar-powered oxygen. Immediate improvement in peripheral blood oxygen saturation was documented (median change12% [range 5-15%], P < 0.0001). Tachypnoea, tachycardia and composite illness severity score improved over the first 24 h of hospitalisation (P < 0.01 for all comparisons). The case fatality rate was 6/28 (21%). The median recovery times to sit, eat, wean oxygen and hospital discharge were respectively 7.5 h, 9.8 h, 44 h and 4 days. CONCLUS ION: Solar energy can be used to concentrate oxygen from ambient air and oxygenate children with respiratory distress and hypoxaemia in a resourcelimited setting. © 2016 The Union.

Nyende S.,Jinja Regional Referral Hospital | Conroy A.,University of Toronto | Opoka R.O.,Makerere University | Namasopo S.,Jinja Regional Referral Hospital | And 8 more authors.
Trials | Year: 2015

Background: Pneumonia is a leading cause of childhood mortality globally. Oxygen therapy improves survival in children with pneumonia, yet its availability remains limited in many resource-constrained settings where most deaths occur. Solar-powered oxygen delivery could be a sustainable method to improve oxygen delivery in remote areas with restricted access to a supply chain of compressed oxygen cylinders and reliable electrical power. Methods/Design: This study is a randomized controlled trial (RCT). Solar-powered oxygen delivery systems will be compared to a conventional method (oxygen from cylinders) in patients with hypoxemic respiratory illness. Enrollment will occur at two sites in Uganda: Jinja Regional Referral Hospital and Kambuga District Hospital. The primary outcome will be the length of hospital stay. Secondary study endpoints will be mortality, duration of supplemental oxygen therapy (time to wean oxygen), proportion of patients successfully oxygenated, delivery system failure, cost, system maintenance and convenience. Discussion: The RCT will provide useful data on the feasibility and noninferiority of solar-powered oxygen delivery. This technological innovation uses freely available inputs, the sun and the air, to oxygenate children with pneumonia, and can be applied "off the grid" in remote and/or resource-constrained settings where most pneumonia deaths occur. If proven successful, solar-powered oxygen delivery systems could be scaled up and widely implemented for impact on global child mortality. Trial registration: Clinicaltrials.gov registration number NCT0210086. (date of registration: 27 March, 2014). © 2015 Nyende et al.

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