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Beatrice Nico

Publications and source records attributed to Beatrice Nico.

At least 19 recordsLinked to original sources
PubMed2006

Cutting edge: IL-1beta mediates the proangiogenic activity of osteopontin-activated human monocytes.

Inflammation plays an important role in the onset of angiogenesis. In the present study, we show that osteopontin (OPN), a proinflammatory mediator involved in tissue repair, induces IL-1beta up-regulation in human monocytes. This was accompanied by the enhanced production of TNF-alpha, IL-8, and IL-6, a decreased release of IL-10, and increased p38 phosphorylation. The supernatants of OPN-treated monocytes were highly angiogenic when delivered on the chick embryo chorioallantoic membrane. The angiogenic response was completely abrogated by a neutralizing anti-IL-1 Ab, thus indicating that this cytokine represents the major proangiogenic factor expressed by OPN-activated monocytes. Accordingly, rIL-1beta mimicked the proangiogenic activity of OPN-treated monocyte supernatants, and IL-1R (type I) was found to be expressed in the chorioallantoic membrane. In conclusion, OPN-activated monocytes may contribute to the onset of angiogenesis through a mechanism mediated by IL-1beta.

Animals↗
PubMed2006

Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis.

BACKGROUND: Bortezomib is a selective and reversible inhibitor of the 26S proteasome that shows potent antitumor activity in vitro and in vivo against several human cancers of adulthood. No data are available on bortezomib activity against human pediatric neuroblastoma. METHODS: Ten neuroblastoma cell lines and suspensions of primary neuroblastoma cells from three patients were tested for sensitivity to bortezomib. Colony formation, cell proliferation, cell cycle progression, and apoptosis were evaluated by a clonogenic assay and by measuring 3H-thymidine incorporation, bromodeoxyuridine uptake, DNA fragmentation, and phosphatidylserine exposure and propidium iodide staining, respectively. Angiogenesis was assessed by the chick embryo chorioallantoic membrane (CAM) assay. Two mouse xenograft models that mimic the growth and spread of neuroblastoma in humans were used to examine in vivo sensitivity of neuroblastoma to bortezomib. All statistical tests were two-sided. RESULTS: Bortezomib inhibited proliferation and colony formation of neuroblastoma cell lines in a time- and dose-dependent manner. The mean bortezomib concentration that caused 50% inhibition of growth was 6.1 nM (95% confidence interval [CI] = 0.9 to 11.3 nM) at 72 hours. Bortezomib-treated neuroblastoma cells were arrested at G2/M and underwent apoptosis (mean percentage of apoptotic cells in four neuroblastoma cell lines treated with 20 nM bortezomib for 24 hours ranged from 20% to 35%, and caspases were activated by two- to fivefold with respect to untreated cells). Similar results were obtained for primary neuroblastoma cells exposed to bortezomib. Bortezomib inhibited angiogenesis in CAMs stimulated by conditioned medium from neuroblastoma cell lines, by neuroblastoma xenografts, and by primary neuroblastoma biopsy specimens (microvessel area: 2.9 x 10(-2) mm2, 95% CI = 1.8 x 10(-2) to 3.8 x 10(-2) mm2 in CAMs treated with biopsy specimens alone and 1.3 x 10(-2) mm2, 95% CI = 1 x 10(-2) to 1.5 x 10(-2) mm2 in CAMs treated with biopsy specimens plus bortezomib, P = .024). In both mouse models, mice treated with bortezomib lived statistically significantly longer than control mice (mean survival time in the pseudometastatic model: 74.2 versus 50.3 days, P<.001; mean survival time in the orthotopic model: 72.3 versus 50.6 days, P<.001). CONCLUSIONS: Bortezomib is an effective inhibitor of neuroblastoma cell growth and angiogenesis. These findings provide the rationale for further clinical investigation of bortezomib in pediatric neuroblastoma.

Animals↗
PubMed2006

The structure of the vascular network of tumors.

Tumor blood vessels display many structural and functional abnormalities. Their unusual leakiness, potential for rapid growth and remodeling, and expression of distinctive surface molecules mediate the dissemination of tumor cells in the bloodstream and maintain the tumor microenvironment. Like normal blood vessels, they consist of endothelial cells, mural cells and their enveloping basement membrane. Common features, irrespective of their origin, size and growth pattern, are absent hierarchy, formation of large-caliber sinusoidal vessels and markedly heterogeneous density. This review will focus on the factors influencing this heterogeneity.

Animals↗
PubMed2006

Angiogenesis and anti-angiogenesis in hepatocellular carcinoma.

Experimental and clinical data indicate that in human hepatocellular carcinoma (HCC) tumor progression is associated with angiogenesis and that an increase in microvascular density is associated with a poor prognosis. This review summarizes the literature concerning the relationship between angiogenesis and progression in HCC. It is becoming increasingly evident that agents which interfere with blood vessel formation also block tumor progression. Accordingly, anti-angiogenic tumor therapy has gained much interest in preclinical and clinical assessments. The recent applications of anti-angiogenic agents which interfere or block HCC progression are reviewed.

Angiogenesis Inhibitors↗
PubMed2006

In vitro and in vivo proposal of an artificial esophagus.

Artificial materials and autologous tissues used for esophageal reconstruction often induce complications like stenosis and leakage at long-term follow-up. This study evaluates the possibility to obtain in vitro an implantable tissue-engineered esophagus composed of homologous esophageal acellular matrix and autologous smooth muscle cells (SMCs). Acellular matrices obtained by detergent-enzymatic method did not present any major histocompatibility complex marker and expressed bFGF as protein, showing angiogenic activity in vivo on the chick embryo chorioallantoic membrane (CAM). Moreover, they supported cell adhesion, and inasmuch as just after 24 h from seeding, the scaffold appeared completely covered by SMCs. To verify the biocompatibility of our constructs, defects created in the porcine esophageal wall were covered using homologous acellular matrices with and without cultures of autologous SMCs. At 3 week from surgery, the patches composed of only acellular matrices showed a more severe inflammatory response and were negative for alpha-smooth muscle actin immunostaining. In contrast, the cell-matrix implants presented ingrowth of SMCs, showing an early organization into small fascicules. Collectively, these results suggest that patches composed of homologous esophageal acellular matrix and autologous SMCs may represent a promising tissue-engineering approach for the repair of esophageal injuries.

Animals↗
PubMed2006

First evaluation of the potential effectiveness in muscular dystrophy of a novel chimeric compound, BN 82270, acting as calpain-inhibitor and anti-oxidant.

BN 82270 is a membrane-permeable prodrug of a chimeric compound (BN 82204) dually acting as calpain inhibitor and anti-oxidant. Acute in vivo injection of dystrophic mdx mice (30 mg/kg, s.c.) fully counteracted calpain overactivity in diaphragm. A chronic 4-6 weeks administration significantly prevented in vivo the fore limb force drop occurring in mdx mice exercised on treadmill. Ex vivo electrophysiological recordings showed that BN 82270 treatment contrasted the decrease in chloride channel function (gCl) in diaphragm, an index of spontaneous degeneration, while it was less effective on both exercise-impaired gCl and calcium-dependent mechanical threshold of the hind limb extensor digitorum longus (EDL) muscle fibres. The BN 82270 treated mdx mice showed a marked reduction of plasma creatine kinase and of the pro-fibrotic cytokine TGF-beta1 in both hind limb muscles and diaphragm; however, the histopathological profile of gastrocnemious muscle was poorly ameliorated. In hind limb muscles of treated mice, the active form was detected by HPLC in the low therapeutic concentration range. In vitro exposure to 100 microM BN 82270 led to higher active form in diaphragm than in EDL muscle. This is the first demonstration that this class of chimeric compounds, dually targeting pathology-related events, exerts beneficial effects in muscular dystrophy. The drug/prodrug system may require posology adjustment to produce wider beneficial effects on all muscle types.

Animals↗
PubMed2006

Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells.

Bone marrow angiogenesis plays an important role in the pathogenesis and progression in multiple myeloma. Recent studies have shown that proteasome inhibitor bortezomib (Velcade, formerly PS-341) can overcome conventional drug resistance in vitro and in vivo; however, its antiangiogenic activity in the bone marrow milieu has not yet been defined. In the present study, we examined the effects of bortezomib on the angiogenic phenotype of multiple myeloma patient-derived endothelial cells (MMEC). At clinically achievable concentrations, bortezomib inhibited the proliferation of MMECs and human umbilical vein endothelial cells in a dose-dependent and time-dependent manner. In functional assays of angiogenesis, including chemotaxis, adhesion to fibronectin, capillary formation on Matrigel, and chick embryo chorioallantoic membrane assay, bortezomib induced a dose-dependent inhibition of angiogenesis. Importantly, binding of MM.1S cells to MMECs triggered multiple myeloma cell proliferation, which was also abrogated by bortezomib in a dose-dependent fashion. Bortezomib triggered a dose-dependent inhibition of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) secretion by the MMECs, and reverse transcriptase-PCR confirmed drug-related down-regulation of VEGF, IL-6, insulin-like growth factor-I, Angiopoietin 1 (Ang1), and Ang2 transcription. These data, therefore, delineate the mechanisms of the antiangiogenic effects of bortezomib on multiple myeloma cells in the bone marrow milieu.

Angiogenesis Inhibitors↗
PubMed2006

In vivo administered reserpine increases piecemeal degranulation in rat adrenal chromaffin cells.

The effects of the amine-depletory agent reserpine have been evaluated by transmission electron microscopy in chromaffin cells of the rat adrenal glands. The drug has been injected intraperitoneally in the animals at a dose of 0.5 mg/kg body weight in two administrations at 24-hr interval. The observed ultrastructural changes closely reminded of piecemeal degranulation (PMD), a slow and long-lasting secretory process previously described in normal and tumor pheochromocytes. Both adrenaline- and noradrenaline-storing cells presented the following microscopic features: high granule polymorphism, due to coexistence in the same cell of normal resting granules, granules with partially mobilized components, and large empty containers; absence of granule fusion; characteristic "haloed" pattern of residual secretory contents; great amount of 30-150 nm diameter, membrane-bound, electron-dense and -lucent vesicles, free in the cytoplasm or attached to granules; and multiple vesicles budding from the granule-limiting membranes. Morphometric analysis revealed that the frequency of all these microscopic parameters was found to be significantly increased in adrenal chromaffin cells from reserpinized rats in comparison to cells from control animals. These data suggest that reserpine, besides blocking the inward transport of catecholamines in chromaffin granules, might also stimulate a complex secretory reaction, which shares many common passages with bona fide PMD.

Adrenal Medulla↗
PubMed2006

Development of the blood-brain barrier: a historical point of view.

Although there has been considerable controversy since the observation by Ehrlich more than 100 years ago that the brain did not take up dyes from the vascular system, the concept of an endothelial blood-brain barrier (BBB) was confirmed by the unequivocal demonstration that the passage of molecules from blood to brain and vice versa was prevented by endothelial tight junctions (TJs). There are three major functions implicated in the term "BBB": protection of the brain from the blood milieu, selective transport, and metabolism or modification of blood- or brain-borne substances. The BBB phenotype develops under the influence of associated brain cells, especially astrocytic glia, and consists of complex TJs and a number of specific transport and enzyme systems that regulate molecular traffic across the endothelial cells. The development of the BBB is a complex process that leads to endothelial cells with unique permeability characteristics due to high electrical resistance and the expression of specific transporters and metabolic pathways. This review article summarizes the historical background underlying our current knowledge of the cellular and molecular mechanisms involved in the development and maintenance of the BBB.

Anatomy↗
PubMed2006

An image analysis of the spatial distribution of perivascular mast cells in human melanoma.

A mutual spatial and functional relationship occurs between mast cells (MCs) and endothelial cells and the density of MCs is highly correlated with the extent of tumor angiogenesis. The aim of this study was to investigate the pattern of MCs around the blood vessels in melanoma samples by means of an approach derived from spatial statistics, based on the analysis of the distribution of the distances of MCs from vessels to objectively establish if the two structures (MCs and vessels) are distributed independently over the studied area or if they displayed any kind of spatial association. Results showed that a higher number of vessels and MCs can be observed in melanoma as compared with samples from common acquired nevi (control group). The percent of area covered by vessel profiles was significantly higher in the melanoma group than the control group and the MC density was also significantly different; the melanoma group showing a number of MCs per unit area twice as high as the number measured in the control group. Furthermore, in the melanoma group, MCs were closer to each other and to the vessels. In fact, both the mean distance from vessels and the mean distance from the nearest cell profile were significantly lower than in the control group. This close association between MCs and the endothelium does not necessarily imply a participation of MCs in angiogenic processes, but might rather indicate that MCs are involved in the maintenance reaction necessary for the long lasting functional integrity of the endothelium.

Adult↗
PubMed2006

Dense-core granules in neuroendocrine cells and neurons release their secretory constituents by piecemeal degranulation (review).

The term piecemeal degranulation (PMD) refers to a slow releasing process mediated by vesicular transport of stored secretory granule contents. This form of cell secretion was first proposed for basophils, mast cells and eosinophils, but evidence has begun to accumulate that PMD also occurs in dense-core granules of neuroendocrine cells and neurons. This review summarizes the electron-microscopic evidence that has been gathered in support of this view and also discusses the possible physiological significance of PMD in this class of secretory organelles in comparison with 'full fusion' and 'kiss-and-run' exocytosis.

Animals↗
PubMed2006

Urotensin-II and its receptor (UT-R) are expressed in rat brain endothelial cells, and urotensin-II via UT-R stimulates angiogenesis in vivo and in vitro.

Urotensin-II (UII), along its receptor UT-R, is widely expressed in the cardiovascular system, where it exerts regulatory actions under both physiological and pathological conditions. Real-time PCR and immunocytochemistry demonstrated the expression of UII and UT-R as mRNA and protein in rat neuromicrovascular endothelial cells (NECs). UII did not affect the proliferation rate of cultured NECs, but exerted a strong angiogenic action in both an in vitro assay on Matrigel and an in vivo assay on chorioallantoic membrane. The angiogenic effect of UII was similar to that of FGF-2, and was abolished by the UT-R antagonist Palosuran. Collectively, our findings allow us to include UII in the group of cytokines (e.g. endothelin-1 and adrenomedullin), which are expressed in endothelial cells and exert a pro-angiogenic effect acting in an autocrine-paracrine manner.

Animals↗
PubMed2005

Synergistic inhibition of human neuroblastoma-related angiogenesis by vinblastine and rapamycin.

The aim of this study was to evaluate the synergistic antiangiogenic effect of low dose of vinblastine (VBL) and rapamycin (RAP) in neuroblastoma (NB). Both in vitro (endothelial cells proliferation assay; TUNEL assay; phosphatidylserine exposure and cell cycle analysis) and in vivo (chick embryo chorioallantoic membrane, CAM) assays were used. Each compound alone was able to induce a significant dose- and time-response inhibition of in vitro endothelial cells (EC) growth. Interaction index evaluation indicates that a synergistic effect was found when both drugs were combined at very low doses. Comparable effects were obtained when EC were preincubated with conditioned medium (CM) derived from the human NB cell line HTLA-230. Morphological changes were induced by each drug, and their combination resulted in a clear and stronger effect. Apoptosis was demonstrated by the TUNEL assay and confirmed by Annexin V-FITC staining of EC treated with VBL, showing an increase in the percentage of cells with a G2-M and sub-G1 DNA content, whereas in those treated with RAP a block in the G1 cell fraction and inhibition of progression to the S phase were observed. Here too, the combination resulted in a synergistic cell cycle arrest and induction of apoptosis. Similar results were obtained in vivo with the CAM assay. The angiogenic responses induced by HTLA-230-derived CM, NB tumor xenografts, and human NB biopsy specimens were inhibited by each drug and more significantly by their combination. The observation that these well-known drugs display synergistic effects as antiangiogenics when administered frequently at very low dose may be of significance in the designing of new ways of treating NB.

Animals↗
PubMed2005

Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma.

PURPOSE: To study the antiangiogenic effect of thalidomide. PATIENTS AND METHODS: The expression of key angiogenic genes was studied in bone marrow endothelial cells (ECs) of patients with active and nonactive multiple myeloma (MM), monoclonal gammopathies unattributed/unassociated (MG[u]), diffuse large B-cell non-Hodgkin's lymphoma, in a Kaposi's sarcoma (KS) cell line, and in healthy human umbilical vein ECs (HUVECs) following exposure to therapeutic doses of thalidomide. RESULTS: Thalidomide markedly downregulates the genes in a dose-dependent fashion in active MMECs and KS cell line, but upregulates them or is ineffective in nonactive MMECs, MG(u)ECs, NHL-ECs, and in HUVECs. Secretion of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and hepatocyte growth factor also diminishes according to the dose in culture conditioned media (CM) of active MMECs and KS, whereas it does not change in the other CM. CONCLUSION: Inhibition by thalidomide is probably confined to the genes of active MMECs and KS. This would account for its higher efficacy in these diseases.

Adult↗
PubMed2005

The role of adrenomedullin in angiogenesis.

Adrenomedullin (AM) is a 52 amino acid peptide originally isolated from human pheochromocytoma. It was initially demonstrated to have profound effects in vascular cell biology, since AM protects endothelial cells from apoptosis, promotes angiogenesis and affects vascular tone and permeability. This review article summarizes the literature data concerning the relationship between AM and angiogenesis and describes the relationship between vascular endothelial growth factor, hypoxia and AM and tumor angiogenesis. Finally, the role of AM as a potential target of antiangiogenic therapy is discussed.

Adrenomedullin↗
PubMed2005

Neovascularization and mast cells with tryptase activity increase simultaneously with pathologic progression in human endometrial cancer.

OBJECTIVE: In vitro and in vivo studies have linked mast cell (MC) degranulation and activation with angiogenesis and neovascularization. This assumption is partially supported by the close anatomic association between MC and the vasculature and the recruitment of these cells during tumor growth. The aim of this study was to correlate the extent of angiogenesis with the number of MC expressing tryptase in human endometrial adenocarcinoma. STUDY DESIGN: Tissues from human endometrial hyperplasia and endometrial adenocarcinoma were investigated immunohistochemically, using 2 murine monoclonal antibodies against the endothelial cell marker CD31 and the MC marker tryptase. RESULTS: Angiogenesis, measured as microvessel counts, was highly correlated with MC tryptase-positive cell counts and that these parameters increase in agreement with tumor progression. CONCLUSION: These results suggest that angiogenesis in endometrial cancer increases with tumor progression and that angiogenic tryptase secreted by host MC cooperate in its induction.

Adenocarcinoma↗