Activation of diacylglycerol kinase alpha is required for VEGF-induced angiogenic signaling in vitro.

Vascular endothelial growth factor-A (VEGF-A) promotes angiogenesis by stimulating migration, proliferation and organization of endothelium, through the activation of signaling pathways involving Src tyrosine kinase. As we had previously shown that Src-mediated activation of diacylglycerol kinase-alpha (Dgk-alpha) is required for hepatocytes growth factor-stimulated cell migration, we asked whether Dgk-alpha is involved in the transduction of angiogenic signaling. In PAE-KDR cells, an endothelial-derived cell line expressing VEGFR-2, VEGF-A165, stimulates the enzymatic activity of Dgk-alpha: activation is inhibited by R59949, an isoform-specific Dgk inhibitor, and is dependent on Src tyrosine kinase, with which Dgk-alpha forms a complex. Conversely in HUVEC, VEGF-A165-induced activation of Dgk is only partially sensitive to R59949, suggesting that also other isoforms may be activated, albeit still dependent on Src tyrosine kinase. Specific inhibition of Dgk-alpha, obtained in both cells by R59949 and in PAE-KDR by expression of Dgk-alpha dominant-negative mutant, impairs VEGF-A165-dependent chemotaxis, proliferation and in vitro angiogenesis. In addition, in HUVEC, specific downregulation of Dgk-alpha by siRNA impairs in vitro angiogenesis on matrigel, further suggesting the requirement for Dgk-alpha in angiogenic signaling in HUVEC. Thus, we propose that activation of Dgk-alpha generates a signal essential for both proliferative and migratory response to VEGF-A165, suggesting that it may constitute a novel pharmacological target for angiogenesis control.

A computational approach based on the colored Petri net formalism for studying multiple sclerosis

Multiple Sclerosis (MS) is an immune-mediated inflammatory disease of the Central Nervous System (CNS) which damages the myelin sheath enveloping nerve cells thus causing severe physical disability in patients. Relapsing Remitting Multiple Sclerosis (RRMS) is one of the most common form of MS in adults and is characterized by a series of neurologic symptoms, followed by periods of remission. Recently, many treatments were proposed and studied to contrast the RRMS progression. Among these drugs, daclizumab (commercial name Zinbryta), an antibody tailored against the Interleukin-2 receptor of T cells, exhibited promising results, but its efficacy was accompanied by an increased frequency of serious adverse events. Manifested side effects consisted of infections, encephalitis, and liver damages. Therefore daclizumab has been withdrawn from the market worldwide. Another interesting case of RRMS regards its progression in pregnant women where a smaller incidence of relapses until the delivery has been observed

Multiple sclerosis disease: A computational approach for investigating its drug interactions

Multiple Sclerosis (MS) is a chronic and potentially highly disabling disease that can cause permanent damage and deterioration of the central nervous system. In Europe it is the leading cause of non-traumatic disabilities in young adults, since more than 700,000 EU people suffer from MS. Although recent studies on MS pathophysiology have been performed, providing interesting results, MS remains a challenging disease. In this context, thanks to recent advances in software and hardware technologies, computational models and computer simulations are becoming appealing research tools to support scientists in the study of such disease. Motivated by this consideration, we propose in this paper a new model to study the evolution of MS in silico, and the effects of the administration of the daclizumab drug, taking into account also spatiality and temporality of the involved phenomena. Moreover, we show how the intrinsic symmetries of the model we have developed can be exploited to drastically reduce the complexity of its analysis

Plasma cytokines, glomerular filtration rate and adipose tissue cytokines gene expression in chronic kidney disease (CKD) patients

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