Maria Distaso

Mario Negri Institute for Pharmacological Research, Milano, Lombardy, Italy

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Publications (7)27.34 Total impact

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    ABSTRACT: Patients with multiple myeloma (MM) are at relatively high risk of developing thromboembolic events such deep venous thrombosis (DVT) where thalidomide therapy has been identified to increase this risk. Defibrotide (DF), a polydisperse oligonucleotide, showed previously to counteract the alterations in endothelial cells (ECs) induced by lipopolysaccharide. It prompts us to investigate the impact of thalidomide on ECs and whether DF modulates changes in fibrinolysis induced by thalidomide. In this in vitro study, MM by itself alters the profibrinolytic potential of ECs decreasing the tissue plasminogen activator (t-PA) and increasing the plasminogen activator inhibitor 1 (PAI-1) levels which is potentiated by thalidomide. Defibrotide was able to counteract these effects. Additionally, DF upregulated the t-PA and downregulated PAI-1 gene expression modulated by thalidomide. Defibrotide also protects ECs from thalidomide-mediated cell death without interfering with its antitumor effects. These findings support DF clinical use for the prevention of DVT induced by immunomodulatory drugs.
    Clinical and Applied Thrombosis/Hemostasis 07/2011; 18(1):79-86. · 1.58 Impact Factor
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    ABSTRACT: Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation-related toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents. Further, given its antiadhesive properties, we evaluated whether defibrotide modulates the protection conferred to multiple myeloma cells by bone marrow stromal cells. Defibrotide lacks significant single-agent in vitro cytotoxicity on multiple myeloma or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including melphalan and cyclophosphamide. Importantly, defibrotide enhances in vivo chemosensitivity of multiple myeloma and mammary carcinoma xenografts in animal models. In cocultures of multiple myeloma cells with bone marrow stromal cells in vitro, defibrotide enhances the multiple myeloma cell sensitivity to melphalan and dexamethasone, and decreases multiple myeloma-bone marrow stromal cell adhesion and its sequelae, including nuclear factor-kappaB activation in multiple myeloma and bone marrow stromal cells, and associated cytokine production. Moreover, defibrotide inhibits expression and/or function of key mediators of multiple myeloma interaction with bone marrow stromal cell and endothelium, including heparanase, angiogenic cytokines, and adhesion molecules. Defibrotide's in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between bone marrow stromal cells and endothelia in the tumor microenvironment. These data support clinical studies of defibrotide in combination with conventional and novel therapies to potentially improve patient outcome in multiple myeloma and other malignancies.
    Clinical Cancer Research 03/2009; 15(4):1210-21. · 7.84 Impact Factor
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    ABSTRACT: Arterial hypertension is not only a major risk factor for cerebrovascular accidents, such as stroke and cerebral hemorrhage, but is also associated to milder forms of brain injury. One of the main causes of neurodegeneration is the increase in reactive oxygen species (ROS) that is also a common trait of hypertensive conditions, thus suggesting that such a mechanism could play a role even in the onset of hypertension-evoked brain injury. To investigate this issue, we have explored the effect of acute-induced hypertensive conditions on cerebral oxidative stress. To this aim, we have developed a mouse model of transverse aortic coarctation (TAC) between the two carotid arteries, which imposes acutely on the right brain hemisphere a dramatic increase in blood pressure. Our results show that hypertension acutely induced by aortic coarctation induces a breaking of the blood-brain barrier (BBB) and reactive astrocytosis through hyperperfusion, and evokes trigger factors of neurodegeneration such as oxidative stress and inflammation, similar to that observed in cerebral hypoperfusion. Moreover, the derived brain injury is mainly localized in selected brain areas controlling cognitive functions, such as the cortex and hippocampus, and could be a consequence of a defect in the BBB permeability. It is noteworthy to emphasize that, even if these latter events are not enough to produce ischemic/hemorrhagic injury, they are able to alter mechanisms fundamental for maintaining normal brain function, such as protein synthesis, which has a prominent role for memory formation and cortical plasticity.
    Journal of Cerebral Blood Flow & Metabolism 03/2006; 26(2):253-62. · 5.40 Impact Factor
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    ABSTRACT: Previous studies demonstrated that C1-inhibitor (C1-INH), a complement and contact-kinin systems inhibitor, is neuroprotective in cerebral ischemia. To investigate the mechanism of this action, we evaluated the expression of neurodegeneration and inflammation-related factors in mice subjected to 2-h ischemia and 2 or 46 h reperfusion. C1-INH significantly dampened the mRNA expression of the adhesion molecules P-selectin and ICAM-1 induced by the ischemic insult. It significantly decreased the pro-inflammatory cytokine (TNF alpha, IL-18) and increased the protective cytokine (IL-6, IL-10) gene expression. C1-INH treatment prevented the decrease of NFH gene, a marker of cellular integrity and counteracted the increase of pro-caspase 3, an apoptosis index. Furthermore, C1-INH markedly inhibited the activation and/or recruitment of microglia/macrophage, as shown by immunohistochemistry. In conclusion, C1-INH exerts an anti-inflammatory and anti-apoptotic action on ischemia-reperfusion injury. Our present and past data support a major effect of C1-INH on cell recruitment from the vasculature to the ischemic site.
    Neurobiology of Disease 08/2005; 19(1-2):10-7. · 5.62 Impact Factor
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    ABSTRACT: We investigated the effect of long-term, peripheral treatment with enoxaparin, a low molecular weight heparin, in transgenic mice overexpressing human amyloid precursor protein(751). Enoxaparin (6 IU per mouse intraperitoneally, three times a week for 6 months) significantly lowered the number and the area occupied by cortical beta-amyloid deposits and the total beta-amyloid (1-40) cortical concentration. Immunocytochemical analysis of glial fibrillary acid protein-positive cells showed that enoxaparin markedly reduced the number of activated astrocytes surrounding beta-amyloid deposits. In vitro, the drug dose-dependently attenuated the toxic effect of beta-amyloid on neuronal cells. Enoxaparin dose-dependently reduced the ability of beta-amyloid to activate complement and contact systems, two powerful effectors of inflammatory response in AD brain. By reducing the beta-amyloid load and cytotoxicity and proinflammatory activity, enoxaparin offers promise as a tool for slowing the progression of Alzheimer's disease.
    Journal of Neuroscience 05/2004; 24(17):4181-6. · 6.91 Impact Factor
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    ABSTRACT: Fucan sulfate are sulfated fucosylated polymers from brown algae cell wall that exhibit some heparin/heparan sulfate properties. They are among the most widely studied of all the sulphated polysaccharides of non–mammalian origin that exhibit biological activities in mammalian systems. Previously, we have shown that sulfated fucans with low molecular weight (14000-29000 Da) have anticoagulant and antithrombotic activities. Cathepsin G and Elastase are two serine proteinases contained in azurophil granules of polymorphonuclear leukocytes involved in thrombotic events. Cathepsin G act as a potent agonist of human platelet activation leading to their aggregation. While, Elastase degrades collagen, elastin and proteoglycans being implicated in tumor cell invasion and metastasis. The scope of this study was to evaluate whether the fucan sulfate (MW 12.5KDa) is able to modulate the catalytic activity of Cathepsin G and Elastase, in vitro assays.
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    ABSTRACT: The present study demonstrates that fucan sulphate is able to inhibit the activity of Cathepsin G and Elastase in the hydrolysis of the chromogenic substrates. These findings suggest the antithrombotic activity of fucan sulfate. Serin proteinases activity were evaluated with or without Fucan Sulfate using specific chromogenic substrate. Fucan Sulfate was able to significantly decrease the elastase activity with a range of concentrations of 1µg/ml to 80µg/ml (figure 1). The cathepsin G analysis showed that Fucan Sulfate at concentrations of 100ng/ml to 800ng/ml was already able to significantly decreased the activity of this enzyme in a dose dependent manner while, at higher concentrations (1µg/ml to 80µg/ml) the cathepsin G was dramatically inhibited (figure 2). Results Fucan sulfate are sulfated fucosylated polymers from brown algae cell wall that exhibit some heparin/heparan sulfate properties. They are among the most widely studied of all the sulphated polysaccharides of non–mammalian origin that exhibit biological activities in mammalian systems. Previously, we have shown that sulfated fucans with low molecular weight (14000-29000 Da) have anticoagulant and antithrombotic activities. Cathepsin G and Elastase are two serine proteinases contained in azurophil granules of polymorphonuclear leukocytes involved in thrombotic events. Cathepsin G act as a potent agonist of human platelet activation leading to their aggregation. While, Elastase degrades collagen, elastin and proteoglycans.