Plos One
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Cilengitide is a high-affinity cyclic pentapeptdic alphaV integrin antagonist previously reported to suppress angiogenesis by inducing anoikis of endothelial cells adhering through alphaVbeta3/alphaVbeta5 integrins. Angiogenic endothelial cells express multiple integrins, in particular those of the beta1 family, and little is known on the effect of cilengitide on endothelial cells expressing alphaVbeta3 but adhering through beta1 integrins. Through morphological, biochemical, pharmacological and functional approaches we investigated the effect of cilengitide on alphaVbeta3-expressing human umbilical vein endothelial cells (HUVEC) cultured on the beta1 ligands fibronectin and collagen I. ⋯ Pharmacological inhibition of Src kinase activity fully prevented cilengitide-induced phosphorylation of Src, FAK and VE-cadherin, and redistribution of alphaVbeta3 and VE-cadherin and partially prevented increased permeability, but did not prevent HUVEC detachment from low-density matrices. Taken together, these observations reveal a previously unreported effect of cilengitide on endothelial cells namely its ability to elicit signaling events disrupting VE-cadherin localization at cellular contacts and to increase endothelial monolayer permeability. These effects are potentially relevant to the clinical use of cilengitide as anticancer agent.
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Emerging infectious diseases in wildlife are major threats for both human health and biodiversity conservation. Infectious diseases can have serious consequences for the genetic diversity of populations, which could enhance the species' extinction probability. The Ebola epizootic in western and central Africa induced more than 90% mortality in Western lowland gorilla population. Although mortality rates are very high, the impacts of Ebola on genetic diversity of Western lowland gorilla have never been assessed. ⋯ Immigration and short time elapsed since outbreaks could explain the conservation of genetic diversity after the demographic crash. Temporal changes in allele frequencies could not be explained by genetic drift or random sampling. Immigration from genetically differentiated populations and a non random mortality induced by Ebola, i.e., selective pressure and cost of sociality, are alternative hypotheses. Understanding the influence of Ebola on gorilla genetic dynamics is of paramount importance for human health, primate evolution and conservation biology.
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Norepinephrine (NE) modulates the responsiveness of macrophages to proinflammatory stimuli through the activation of adrenergic receptors (ARs). Being part of the stress response, early increases of NE in sepsis sustain adverse systemic inflammatory responses. The intestine is an important source of NE release in the early stage of cecal ligation and puncture (CLP)-induced sepsis in rats, which then stimulates TNF-alpha production in Kupffer cells (KCs) through the activation of the alpha(2)-AR. It is important to know which of the three alpha(2)-AR subtypes (i.e., alpha(2A), alpha(2B) or alpha(2C)) is responsible for the upregulation of TNF-alpha production. The aim of this study was to determine the contribution of alpha(2A)-AR in this process. ⋯ Our novel finding is that hyperresponsiveness to alpha(2)-AR stimulation observed in sepsis is primarily due to an increase in alpha(2A)-AR expression in KCs. This appears to be in part responsible for the increased proinflammatory response and ensuing organ injury in sepsis. These findings provide important feasibility information for further developing the alpha(2A)-AR antagonist as a new therapy for sepsis.
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Loss of vascular barrier function causes leak of fluid and proteins into tissues, extensive leak leads to shock and death. Barriers are largely formed by endothelial cell-cell contacts built up by VE-cadherin and are under the control of RhoGTPases. Here we show that a natural plasmin digest product of fibrin, peptide Bbeta15-42 (also called FX06), significantly reduces vascular leak and mortality in animal models for Dengue shock syndrome. ⋯ Our results demonstrate a novel function for Bbeta15-42. Formerly mainly considered as a degradation product occurring after fibrin inactivation, it has now to be considered as a signaling molecule. It stabilizes endothelial barriers and thus could be an attractive adjuvant in the treatment of shock.
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Nitric oxide (NO) can induce acute pain in humans and plays an important role in pain sensitization caused by inflammation and injury in animal models. There is evidence that NO acts both in the central nervous system via a cyclic GMP pathway and in the periphery on sensory neurons through unknown mechanisms. It has recently been suggested that TRPV1 and TRPA1, two polymodal ion channels that sense noxious stimuli impinging on peripheral nociceptors, are activated by NO in heterologous systems. ⋯ We show that BH4-induced calcium influx is ablated in DRG neurons from TRPA1/TRPV1 double knockout mice, suggesting that production of endogenous levels of NO can activate these ion channels. In behavioral assays, peripheral NO-induced nociception is compromised when TRPV1 and TRPA1 are both ablated. These results provide genetic evidence that the peripheral nociceptive action of NO is mediated by both TRPV1 and TRPA1.