7 research outputs found

    Matrix Metalloproteinase-2 and -9 Secreted by Leukemic Cells Increase the Permeability of Blood-Brain Barrier by Disrupting Tight Junction Proteins

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    Central nervous system (CNS) involvement remains an important cause of morbidity and mortality in acute leukemia, the mechanisms of leukemic cell infiltration into the CNS have not yet been elucidated. The blood-brain barrier (BBB) makes CNS become a refugee to leukemic cells and serves as a resource of cells that seed extraneural sites. How can the leukemic cells disrupt this barrier and invasive the CNS, even if many of the currently available chemotherapies can not cross the BBB? Tight junction in endothelial cells occupies a central role in the function of the BBB. Except the well known role of degrading extracellular matrix in metastasis of cancer cells, here we show matrix metalloproteinase (MMP)-2 and -9, secreted by leukemic cells, mediate the BBB opening by disrupting tight junction proteins in the CNS leukemia. We demonstrated that leukemic cells impaired tight junction proteins ZO-1, claudin-5 and occludin resulting in increased permeability of the BBB. However, these alterations reduced when MMP-2 and -9 activities were inhibited by RNA interference strategy or by MMP inhibitor GM6001 in an in vitro BBB model. We also found that the disruption of the BBB in company with the down-regulation of ZO-1, claudin-5 and occludin and the up-regulation of MMP-2 and -9 in mouse brain tissues with leukemic cell infiltration by confocal imaging and the assay of in situ gelatin zymography. Besides, GM6001 protected all mice against CNS leukemia. Our findings suggest that the degradation of tight junction proteins ZO-1, claudin-5 and occludin by MMP-2 and -9 secreted by leukemic cells constitutes an important mechanism in the BBB breakdown which contributes to the invasion of leukemic cells to the CNS in acute leukemia

    Surreptitious manipulation of the human host by Helicobacter pylori

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    Microbial pathogens contribute to the development of more than 1 million cases of cancer per year. Gastric adenocarcinoma is the second leading cause of cancer-related death in the world, and gastritis induced by Helicobacter pylori is the strongest known risk factor for this malignancy. H. pylori colonizes the stomach for years, not days or weeks, as is usually the case for bacterial pathogens, and it always induces inflammation; however, only a fraction of colonized individuals ever develop disease. Identification of mechanisms through which H. pylori co-opts host defenses to facilitate its own persistence will not only improve diagnostic and therapeutic modalities, but may also provide insights into other diseases that arise within the context of long-term pathogen-initiated inflammatory states, such as chronic viral hepatitis and hepatocellular carcinoma

    The role of epithelial tight junctions involved in pathogen infections

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    Functional Morphology of the Gastrointestinal Tract

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    Virulence Mechanisms and Persistence Strategies of the Human Gastric Pathogen Helicobacter pylori

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