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Biomedical subjects

B Nico

Publications and source records attributed to B Nico.

At least 19 recordsLinked to original sources
PubMed2007

In vivo inhibition of human hepatocellular carcinoma related angiogenesis by vinblastine and rapamycin.

This paper illustrates the use of the chick embryo chorioallantoic membrane (CAM) assay to determine the single and combined antiangiogenic effects of very low doses of vinblastine (VBL) and rapamycin (RAP) in human hepatocellular carcinoma (HCC). The angiogenic response induced by human HCC biopsy specimens was inhibited by each drug and sinergistically by their combination. Morever, immunohistochemical detection of microvessels with anti-CD31 mAB showed that their area was significantly lower in specimens treated with VBL and RAP in combination. Sinergy on the part of these well-known drugs when used in combination as antiangiogenics at very low doses may be of significance in the designing of new ways of treating HCC.

Angiogenesis Inhibitors↗
PubMed2006

A novel cell type-specific role of p38alpha in the control of autophagy and cell death in colorectal cancer cells.

Cancer develops when molecular pathways that control the fine balance between proliferation, differentiation, autophagy and cell death undergo genetic deregulation. The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of these pathways in tumor cells. In an effort to evaluate the impact of p38 signaling on colorectal cancer cell fate, we treated HT29, Caco2, Hct116, LS174T and SW480 cell lines with the inhibitor SB202190 specific for p38alpha/beta kinases. We report that p38alpha is required for colorectal cancer cell homeostasis as the inhibition of its kinase function by pharmacological blockade or genetic inactivation causes cell cycle arrest, autophagy and cell death in a cell type-specific manner. Deficiency of p38alpha activity induces a tissue-restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis. These data identify p38alpha as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38alpha pathway in the treatment of colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Neridronate inhibits angiogenesis in vitro and in vivo.

The effects of the amino-bisphosphonate neridronate on endothelial cell functions involved in angiogenesis, namely, proliferation and morphogenesis on Matrigel were tested in vitro, whereas its effects on angiogenesis were studied in vivo, by using the chick embryo chorioallantoic membrane (CAM) assay. In vitro, neridronate inhibited endothelial cell proliferation in a dose-dependent fashion, peaking at 30 microM. At the same concentration, neridronate inhibited fibroblast growth factor-2 (FGF-2)-induced capillary-like tube formation in the morphogenesis assay on Matrigel. In vivo, when tested in the CAM assay, neridronate again displayed the capability to inhibit FGF-2-induced angiogenesis. Overall, these results suggest that anti-angiogenesis by neridronate could be used to treat a wide spectrum of angiogenesis-dependent diseases, including certain chronic inflammatory diseases and cancer.

Angiogenesis Inhibitors↗
PubMed2006

The history of the angiogenic switch concept.

Spontaneously arising tumor cells are not usually angiogenic at first. The phenotypic switch to angiogenesis is usually accomplished by a substet that induces new capillaries that then converge toward the tumor. The switch clearly involves more than simple upregulation of angiogenic activity and is thought to be the result of a net balance of positive and negative regulators. Tumor growth is although to require disruption of this balance and hence this switch must turned on for cancer progression. Progenitor endothelial cells, the crosstalk between angiogenic factors and their receptors and the interaction between vasculogenesis and lymphangiogenesis are all factors that may contribute to the switch. Its promotion is also the outcome of genetic instability resulting in the emergence of tumor cell lines. This review describes the history of the angiogenic switch illustrated in the literature and with particular reference to the three transgenic mouse models, namely RIP1-TAG2, keratin-14 (K14) (human papilloma virus) HPV16 and papilloma virus, used for stage-specific assessment of the effects of antiangiogenic and antitumorigenic agents.

Animals↗
PubMed2006

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-gamma.

Tumour progression in neuroblastoma (NB) patients correlates with high vascular index. We have previously shown that the ACN NB cell line is tumorigenic and angiogenic in immunodeficient mice, and that interferon-gamma (IFN-gamma) gene transfer dampens ACN tumorigenicity. As IFN-gamma represses lymphocyte-induced tumour angiogenesis in various murine models and inhibits proliferation and migration of human endothelial cells, we have investigated the antiangiogenic activity of tumour-derived IFN-gamma and the underlying mechanism(s). In addition, we characterised the tumour vasculature of the ACN xenografts, using the chick embryo chorioallantoic membrane assay. We show that the ACN/IFN-gamma xenografts had a lower microvessel density and less in vivo angiogenic potential than the vector-transfected ACN/neo. The vascular channels of both xenografts were formed by a mixed endothelial cell population of murine and human origin, as assessed by the FICTION (fluorescence immunophenotyping and interphase cytogenetics) technique. With respect to ACN/neo, the ACN/IFN-gamma xenografts showed more terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling-positive human and murine endothelial cells, suggesting that inhibition of angiogenesis by IFN-gamma was dependent on the induction of apoptosis, likely mediated by nitric oxide. Once the dual origin of tumour vasculature is confirmed in NB patients, the xenograft model described here will prove useful in testing the efficacy of different antiangiogenic compounds.

Animals↗
PubMed2006

Increased matrix-metalloproteinase-2 and matrix-metalloproteinase-9 expression in the brain of dystrophic mdx mouse.

Brain edema and severe alterations of the glial and endothelial cells have recently been demonstrated in the dystrophin-deficient mdx mouse, an experimental model of Duchenne muscular dystrophy, and an increase in microvessel density in patients affected by Duchenne muscular dystrophy has also been shown. In order to further elucidate the mechanisms underlying the angiogenetic processes occurring in Duchenne muscular dystrophy, in this study we analyzed matrix-metalloproteinase-2 and -9 expression in the brain of 20-month-old mdx and control mice by means of immunohistochemistry, in situ hybridization, immunoblotting and gelatin zymography. Moreover, we studied vascular endothelial growth factor expression by means of Western blot and immunohistochemistry, and by dual immunofluorescence using anti-vascular endothelial growth factor and anti matrix-metalloproteinase-2 and-9 antibodies. Ultrastructural features of the brain choroidal plexuses were evaluated by electron microscopy. Spatial relationships between endothelium and astrocyte processes were studied by confocal laser microscopy, using an anti-CD31 antibody as a marker of endothelial cells, and anti-glial fibrillary acidic protein (GFAP) as a marker of glial cells. The results demonstrate that high expression of matrix-metalloproteinase-2 and matrix-metalloproteinase-9 protein content occurs in mdx brain and in choroidal plexuses where, by in situ hybridization, matrix-metalloproteinase-2 and matrix-metalloproteinase-9 mRNA was localized in the epithelial cells. Moreover, matrix-metalloproteinase-2 mRNA was found in both mdx perivascular astrocytes and blood vessels, while matrix-metalloproteinase-9 mRNA was localized in mdx vessels. Through zymography, increased expression of matrix-metalloproteinase-2 and matrix-metalloproteinase-9 was found in mdx brain compared with the controls. These enhanced matrix-metalloproteinase levels in mdx mice were found to be associated with increased vascular endothelial growth factor expression, as determined by immunoblotting and immunocytochemistry and with ultrastructural alterations of the mdx choroidal epithelial cells and brain vessels, as previously reported [Nico B, Frigeri A, Nicchia GP, Corsi P, Ribatti D, Quondamatteo F, Herken R, Girolamo F, Marzullo A, Svelto M, Roncali L (2003) Severe alterations of endothelial and glial cells in the blood-brain barrier of dystrophic mdx mice. Glia 42:235-251]. Indeed, in the mdx epithelial cells of the plexuses, the apical microvilli were located on the lateral membranes, whereas in the controls they were uniformly distributed over the free ventricular surface. Moreover, by dual immunofluorescence, a colocalization of vascular endothelial growth factor and matrix-metalloproteinase-2 and matrix-metalloproteinase-9 was found in the ependymal and epithelial cells of plexuses in mdx mice and, under confocal laser microscopy, mdx CD-31 positive vessels were enveloped by less GFAP-positive astrocyte processes than the controls. Overall, these data point to a specific pathogenetic role of matrix-metalloproteinase-2 and matrix-metalloproteinase-9 in neurological dysfunctions associated with Duchenne muscular dystrophy.

Animals↗
PubMed2006

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma.

Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in multiple myeloma (MM). The encouraging results of preclinical and clinical trials in which MM has been treated by targeting the tumor microenvironment are also discussed.

Animals↗
PubMed2005

Fine ultrastructure of chromaffin granules in rat adrenal medulla indicative of a vesicle-mediated secretory process.

Observation by transmission electron microscopy, coupled with morphometric analysis and estimation procedure, revealed unique ultrastructural features in 25.94% of noradrenaline (NA)-containing granules and 16.85% of adrenaline (A)-containing granules in the rat adrenal medulla. These consisted of evaginations of the granule limiting membrane to form budding structures having different morphology and extension. In 14.8% of NA granules and 12.0% of A granules, outpouches were relatively short, looked like small blebs emerging from the granule surface and generally contained electron-dense material. A proportion of 11.2% of NA granules and 4.9% of A granules revealed the most striking ultrastructural features. These secretory organelles presented thin, elongated, tail-like or stem-like appendages, which were variably filled by chromaffin substance and terminated with spherical expansions of different electron density. A cohort of vesicles of variable size (30-150 nm in diameter) and content was found either close to them or in the intergranular cytosol. Examination of adrenal medullary cells fixed by zinc iodide-osmium tetroxide (ZIO) revealed fine electron dense precipitates in chromaffin granules, budding structures as well as cytoplasmic vesicles. These data indicate that a common constituent is revealed by the ZIO histochemical reaction in chromaffin cells. As catecholic compounds are the main tissue targets of ZIO complexes, catecholamines are good candidates to be responsible for the observed ZIO reactivity. This study adds further to the hypothesis that release of secretory material from chromaffin granules may be accomplished by a vesiclular transport mechanism typical of piecemeal degranulation.

Adrenal Medulla↗
PubMed2005

Ultrastructural evidence of piecemeal degranulation in large dense-core vesicles of brain neurons.

Large dense-core vesicles (LDCV) are a group of neuronal secretory organelles with different size and characteristically condensed morphology. LDCV release their specific cargo by regulated exocytosis, either in the form of "full fusion" or "kiss-and-run" exocytosis. In this paper, we provide ultrastructural evidence indicative of a slow and particulate mode of secretion from LDCV, called piecemeal degranulation (PMD). A number of LDCV in the nerve boutons of mouse brain presented marked increase in their size accompanied by reduction and also disappearance of content material. Residual secretory constituents in altered LDCV displayed eroded marginated patterns, leading to eccentric "haloed" morphologies. Remarkably, altered LDCV never appeared to be fused with each other or with the nerve plasma membrane. Very small vesicles, empty or apparently loaded with the same material making-up the LDCV content, could be seen near or attached to LDCV and the plasma membrane. First described in basophils, mast cells and eosinophils, PMD has recently been recognized in various neuro-endocrine cells, like adrenal chromaffin cells and endocrine cells of the gastro-intestinal epithelia. Here we suggest that PMD may be a hitherto unrecognized pathway of neuron secretion. It would represent the morphological correlate of a long-lasting and low-level process of neuro-transmitter release. It extends the patterns of neuron secretion and possibly opens new perspectives in understanding neuron plasticity.

Animals↗
PubMed2005

Endothelial progenitor cells in health and disease.

There is currently great excitement and expectation in the stem cell community following the discovery that multipotent stem cells can be cultured from human fetal tissue and retain their ability to give rise to a variety of differentiated cell types found in all three embryonic germ layers. Although the earliest sites of hematopoietic cell and endothelial cell differentiation in the yolk sac blood islands were identified about 100 years ago, cells with hemangioblast properties have not yet been identified in vivo. Endothelial cells differentiate from angioblasts in the embryo and from endothelial progenitor cells, mesoangioblasts and multipotent adult progenitor cells in the adult bone marrow. Circulating endothelial progenitor cells (EPC) have been detected in the circulation after vascular injury and during tumor growth. The molecular and cellular mechanisms underlying EPC recruitment and differentiation are not yet understood, and remain as one of the central issues in stem cell biology. For many years, the prevailing dogma stated that the vessels in the embryo develop from endothelial progenitors, whereas sprouting of vessels in the adult results only from division of differentiated endothelial cells. Recent evidence, however, indicates that EPC contribute to vessel growth in the embryo and in ischemic, malignant or inflammed tissues in the adult, and can even be therapeutically used to stimulate vessel growth in ischemic tissues.

Animals↗
PubMed2004

The thymus is a site of mast cell development in chicken embryos.

Thymic mast cells were studied by light and transmission electron microscopy in chicken embryos during organogenesis. Mast cells made their first appearance at day 15. At days 16 and 17, there was a burst of mast cell development with a peak of 278 +/- 54 cells/mm(2) at day 16. Then, mast cell density decreased until hatching. During the whole embryonic period, about 80% of mast cells localized to the thymic medulla. In the cortex, they were less numerous, and some rare mast cells could be identified in the capsule and septa. Thymic mast cells could be recognized in association with hematopoietic foci, but frequently they grew independently from areas of hematopoiesis and appeared as single cells interspersed among thymocytes, thymic epithelial cells, and interdigitating cells. They were often recognized in close relationship with the scanty and delicate extracellular matrix of the developing gland. Viewed by electron microscopy, mast cells were relatively small cells, with a few secretory granules. Exocytosis was never seen, but, notably, granules emptied in a piecemeal degranulation fashion. This study demonstrates that the chicken thymus is a site of mast cell development during embryogenesis. The high mast cell density we found suggests a possible role for these cells during thymus organogenesis.

Animals↗
PubMed2004

A possible role of tryptase in angiogenesis in the brain of mdx mouse, a model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and affects the CNS. Dystrophin is absent in muscle and CNS of both DMD patients and mdx mouse, a model of DMD. While the involvement of vascular compartment in DMD was poorly investigated, some studies suggested a role for mast cells (MC). Tryptase, contained in the MC granules, stimulates angiogenesis in vitro and in vivo. We demonstrated for the first time a correlation between the extent of angiogenesis and the number of tryptase-positive neurons and microvessels and suggest that the tryptase contained in the neurons and in the endothelial cells of the mdx mouse brain may be involved in the regulation of angiogenesis taking place in mdx mouse.

Animals↗
PubMed2004

Altered blood-brain barrier development in dystrophic MDX mice.

In order to ascertain whether the alterations of the blood-brain barrier (BBB) seen in adult dystrophic mdx-mice [Glia 42 (2003) 235], a human model of Duchenne muscular dystrophy (DMD), are developmentally established and correlated with other dystrophin isoforms which are localized at the glial-vascular interface, we used immunocytochemistry to investigate the expression of dystrophin isoforms (Dp71) during BBB development in mdx fetuses and in adult mice. Parallelly, we used Western blot, immunocytochemistry and immunogold electron microscopy to analyze the expression of the zonula occludens (ZO-1), aquaporin-4 (AQP4) and glial fibrillary acidic (GFAP) proteins as endothelial and glial markers, and we evaluated the integrity of the mdx BBB by means of intravascular injection of horseradish peroxidase (HRP). The results show reduced dystrophin isoforms (Dp71) in the mdx mouse compared with the control, starting from early embryonic life. Endothelial ZO-1 expression was reduced, and the tight junctions were altered and unlabeled. AQP4 and GFAP glial proteins in mdx mice also showed modifications in developmental expression, the glial vascular processes being only lightly AQP4- and GFAP-labeled compared with the controls. Confocal microscopy and HRP assays confirmed the alteration in vessel glial investment, GFAP perivascular endfoot reactivity being strongly reduced and BBB permeability increasing. These results demonstrate that a reduction in dystrophin isoforms (Dp71) at glial endfeet leads to an altered development of the BBB, whose no-closure might contribute to the neurological dysfunctions associated with DMD.

Animals↗
PubMed2004

The role of aquaporin-4 in the blood-brain barrier development and integrity: studies in animal and cell culture models.

Aquaporin-4 (AQP4) is the major water channel expressed in brain perivascular astrocyte processes. Although the role of AQP4 in brain edema has been extensively investigated, little information exists regarding its functional role at the blood-brain barrier (BBB). The purpose of this work is to integrate previous and recent data regarding AQP4 expression during BBB formation and depending on BBB integrity, using several experimental models. Results from studies on the chick optic tectum, a well-established model of BBB development, and the effect of lipopolysaccharide on the BBB integrity and on perivascular AQP4 expression have been analyzed and discussed. Moreover, data on the BBB structure and AQP4 expression in murine models of Duchenne muscular dystrophy are reviewed. In particular, published results obtained from mdx(3cv) mice have been analyzed together with new data obtained from mdx mice in which all the dystrophin isoforms including DP71 are strongly reduced. Finally, the role of the endothelial component on AQP4 cellular expression and distribution has been investigated using rat primary astrocytes and brain capillary endothelial cell co-cultures as an in vitro model of BBB.

Animals↗
PubMed2004

Recombinant human erythropoietin induces intussusceptive microvascular growth in vivo.

The role of erythropoietin (Epo) in angiogenesis has not been completely clarified. Epo induces endothelial cell proliferation and migration and stimulates angiogenesis on rat aortic rings in vitro and in vivo in the chick embryo chorioallantoic membrane (CAM) assay. The aim of the present study was to evaluate the ultrastructural aspects of angiogenesis in the CAM vasculature after recombinant human Epo (rHuEpo) exposure. The results demonstrated that after rHuEpo stimulation, the generation of new blood vessels occurred more frequently following an intussusceptive microvascular growth (IMG) mechanism. We have performed our experiments between days 8 and 12 of incubation, that is, when in the normal condition the capillary network expands mainly by IMG, and because it is generally accepted that implants made from days 8 to 10 are strongly angiogenic. This response is peculiar of rHuEpo, because it is abolished when an Epo-blocking antibody was coadministered with Epo.

Animals↗
PubMed2003

Neovascularisation, expression of fibroblast growth factor-2, and mast cells with tryptase activity increase simultaneously with pathological progression in human malignant melanoma.

Tissues from 92 proliferative lesions of the melanocytic lineage defining distinct steps in tumour progression were investigated immunohistochemically for changes in angiogenesis, expression of fibroblast growth factor-2 (FGF-2) and density of total mast cells (MCs) and MCs expressing tryptase, an angiogenic-inducing molecule. Although the microvessel number was low in common nevi, it increased significantly in nevi with architectural disorder with varying degrees of melanocytic atypia (termed 'nevi with ADMA'), and these changes persisted during tumour development. Progression of primary melanomas was accompanied by a high microvessel number, and the progression to metastases by another significant increase in the microvessel counts. Expression of FGF-2, evaluated as percentages of positive lesions and positive cells per lesion was upregulated in the course of progression. Changes in expression were associated with nevi with ADMA, tumour changeover, penetration of the tumour into the dermis and metastases. A high correlation was demonstrated in all groups of tissues between the microvessel counts, percentages of FGF-2-positive tumour cells, and both total metachromatic and tryptase-reactive MCs. These results suggest that angiogenesis in human melanoma increases with tumour progression and that FGF-2 secreted by tumour cells and tryptase secreted by host MCs cooperate in its induction.

Adult↗