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Biomedical subjects

Enrico Crivellato

Publications and source records attributed to Enrico Crivellato.

At least 37 records · Page 2Linked to original sources
PubMed2005

Angiogenic response induced by acellular femoral matrix in vivo.

We investigated the angiogenic response induced by acellular femoral matrices implanted in vivo on to the chick embryo chorioallantoic membrane (CAM), a useful model for such investigation. The results showed that acellular matrices were able to induce a strong angiogenic response, comparable with that of fibroblast growth factor-2 (FGF-2), a well-known angiogenic cytokine. The angiogenic response was further increased when exogenous FGF-2 or transforming growth factor beta-1 (TGF-beta1) was added to the matrices and inhibited by the addition of anti-FGF-2 or anti-TGF-beta1 antibodies. The response may be considered to be dependent on a direct angiogenic effect exerted by the matrices, and also in part by the presence of FGF-2 and TGF-beta1 in the acellular matrices.

Angiogenesis Inducing Agents↗
PubMed2005

Involvement of mast cells in angiogenesis and chronic inflammation.

Mast cells (MC) are granulated secretory cells that have long been recognized as a rich source of biologically highly active mediators such as biogenic amines, prostaglandins, leukotrienes, proteases, cytokines and chemokines. Most of their biological functions however has been rather elusive. There are now emerging data assigning these cells a relevant role in orchestrating angiogenesis, both in normal and pathological conditions. MC indeed synthesize and release a large array of proangiogenic factors upon different stimulation pathways. In addition, MC have been recognized as key cells in mediating host innate and adaptive immune responses. This review summarizes the most recent acquisitions concerning MC involvement in angiogenic processes and chronic inflammatory reactions.

Animals↗
PubMed2004

Toxicity of Hypericum perforatum (St. John's wort) administered during pregnancy and lactation in rats.

The popularity of St. John's wort (Hypericum perforatum) for the treatment of depression is increasing and, in recent years, concerns about its use during pregnancy and breastfeeding have emerged. The purpose of this study was to investigate, in Wistar rats, the effects of a treatment with hypericum administered prenatally and during breastfeeding (from 2 weeks before mating to 21 days after delivery). Two doses of the extract were chosen, 100 mg/kg per day, which, based on surface area, is comparable to the dose administered to humans, and 1000 mg/kg per day. A microscopical analysis of livers, kidneys, hearts, lungs, brains, and small bowels was performed. A severe damage was observed in the livers and kidneys of animals euthanized postnatally on days 0 and 21. The lesions were more severe with the higher dose and in animals that were breastfed for 21 days; however, an important renal and hepatic damage was evident also with the dose of 100 mg/kg per day. In addition, similar serious hepatic and renal lesions were evident also in animals that were exposed to hypericum only during breastfeeding. In particular, a focal hepatic damage, with vacuolization, lobular fibrosis, and disorganization of hepatic arrays was evident; in the kidney, a reduction in glomerular size, disappearance of Bowman's space, and hyaline tubular degeneration were found. The results obtained in this study indicate that further, appropriate histological studies should be performed in other animal species to better evaluate the safety of hypericum extracts taken during pregnancy and breastfeeding.

Animals↗
PubMed2004

Chromaffin granules in the rat adrenal medulla release their secretory content in a particulate fashion.

Exocytosis is considered the main route of granule discharge in chromaffin cells. We recently provided ultrastructural evidence suggesting that piecemeal degranulation (PMD) occurs in mouse adrenal chromaffin cells. In the present study, we processed rat adrenal glands for transmission electron microscopy (TEM), and examined chromaffin cells for changes characteristic of PMD. Both adrenaline (A)- and noradrenaline (NA)-storing cells express ultrastructural features suggestive of a slow and particulate mode of granule discharge. In adrenaline-containing cells, some granules present enlarged dimensions accompanied by eroded or dissolved matrices. Likewise, a number of granules in NA-releasing cells show content reduction with variably expanded granule chambers. Dilated, empty granule containers are recognizable in the cytoplasm of both cell types. Characteristically, altered granules and empty containers are seen intermingled with normal, resting granules. In addition, chromaffin granules often show irregular profiles, with budding or tail-like projections of their limiting membranes. Thirty 150-nm-diameter membrane-bound vesicles with a moderately electron-dense or -lucent internal structure are observable in the cytoplasm of both cell types. These vesicles are seen among the granules and some of them are fused with the perigranule membranes in the process of attachment to or budding from the granules. These data add further support to the concept that PMD may be an alternative secretory pathway in adrenal chromaffin cells.

Adrenal Medulla↗
PubMed2004

Desmin-positive pericytes in the chick embryo chorioallantoic membrane in response to fibroblast growth factor-2.

Pericytes stabilize vessel wall, participate in the regulation of blood flow microcirculation and influence endothelial proliferation, survival, migration and maturation. Pericytes are commonly identified by molecular markers, such as desmin. The aim of this study was to analyze the pattern of distribution of desmin in the chick embryo chorioallantoic membrane (CAM) vasculature in normal condition and in response to an angiogenic cytokine, such as fibroblast growth factor-2 (FGF-2) by using conventional immunohistochemistry and confocal laser scanning microscopy. Results indicate that, in normal condition, the desmin-positive pericytes are located around the endothelial cells of the capillary plexus and of larger vessels in the intermediate mesenchyme. In response to FGF-2 numerous desmin-positive and alpha smooth muscle actin-negative cells are located in the mesenchyme and numerous blood vessels positive to factor VIII and desmin are recognizable near to the gelatin sponge soaked with FGF-2. These data suggest that pericytes in normal condition intervene to stabilize the wall of newly formed blood vessel, while in response to FGF-2, they detach from the wall of parental vessels and migrate, as extramural fibroblast-like desmin-positive cells, in the surrounding mesenchyme, where they modulate the angiogenic response.

Actins↗
PubMed2004

Hematopoietic cancer and angiogenesis.

The growth of solid tumors is certainly angiogenesis dependent. However, the role of angiogenesis in the growth and survival of leukemias and other hematological malignancies has only been rendered evident since 1994 in a series of demonstrations showing that the progression of several forms is clearly related to their degree of angiogenesis. Here, we present an overview of the literature concerning the relationship between angiogenesis and disease progression in several hematological malignancies and the recent advances in antiangiogenesis in these diseases and we describe the most important active substances, preclinical and clinical data, and future perspectives.

Angiogenesis Inhibitors↗
PubMed2004

Bodipy-FL-verapamil: a fluorescent probe for the study of multidrug resistance proteins.

Most of the substances used as fluorescent probes to study drug transport and the effect of efflux blockers in multidrug resistant cells have many drawbacks, such as toxicity, unspecific background, accumulation in mitochondria. New fluorescent compounds, among which Bodipy-FL-verapamil (BV), have been therefore proposed as more useful tools. The uptake of BV has been evaluated by cytofluorimetry and fluorescence microscopy using cell lines that overexpress P-glycoprotein (P388/ADR and LLC-PK(1)/ADR) or MRP (multidrug resistance-related protein) (PANC-1) and clinical specimens from patients. The effect of specific inhibitors for P-glycoprotein (verapamil and vinblastine) or MRP (MK571 and probenecid) has been also studied. BV intracellular concentrations were significantly lower in the two P-glycoprotein overexpressing cell lines in comparison with the parental lines. In addition, verapamil and vinblastine increased the intracellular concentrations of the dye; MK571 and probenecid, two MRP inhibitors, increased BV levels in PANC-1 cells, that express this protein. These findings were confirmed in clinical specimens from patients. Fluorescence microscopy revealed a faint fluorescence emission in P-glycoprotein or MRP expressing cell lines; however, treatment with specific inhibitors significantly increased the fluorescence. BV is a useful tool for studying multidrug resistance proteins with different techniques such as cytofluorimetry and fluorescence microscopy, but does not discriminate between P-glycoprotein and MRP. In comparison with other classic fluorescent probes, the assay with this dye is extremely rapid, simple, not toxic for cells, devoid of fluorescent background, and can be useful in the clinical settings.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Ultrastructural morphology of adrenal chromaffin cells indicative of a process of piecemeal degranulation.

Chromaffin cells of the mouse adrenal medulla were found by transmission electron microscopy (TEM) to exhibit ultrastructural changes suggestive of piecemeal degranulation (PMD), a unique model of cell secretion characterized by the slow release of granule materials without granules opening to the cell exterior. The expression of PMD was recognized in both adrenaline- and noradrenaline-containing cells. Ultrastructural changes included specific granule and cytoplasmic morphologies. In adrenaline-releasing cells the granule content was loosely packed or condensed, and surrounded by a clear halo. In noradrenaline-storing cells, the granule material appeared asymmetrically arranged and exhibited characteristic "semilunar" electron-dense domains within the granule chambers. Notably, altered granules did not fuse with each other or with the plasma membrane, and were intermingled with normal, resting granules. Large, empty cytoplasmic containers or vacuoles filled with partially dissolved matrices were frequently observed. In addition, both adrenaline- and noradrenaline-storing cells presented a rich supply of membrane-bound, smooth vesicles (50-200 nm diameter) that were either free in the cytoplasm or attached to granules. The finding of ultrastructural features characteristic of PMD in adrenal chromaffin cells suggests that such a secretory model may be an alternative secretory pathway to regulated exocytosis. Moreover, these results support the hypothesis that PMD may be a general degranulation pattern in cells involved in paracrine-endocrine secretion.

Adrenal Medulla↗
PubMed2003

Piecemeal degranulation as a general secretory mechanism?

In this article we review the ultrastructural findings, functional aspects, and biological significance of piecemeal degranulation (PMD), a unique secretory pathway that has been described in basophils, mast cells, and eosinophils. Recent ultrastructural data suggestive of PMD in enteroendocrine cells of the gastrointestinal tract and chromaffin cells of the adrenal medulla are also presented and discussed. Further research on PMD in secretory cells of the endocrine and exocrine glands, as well as in neurons, is recommended, since the current data indicate that PMD has a broader spectrum of expression than was hitherto reported. The identification of the PMD phenotype in different cell types (e.g., basophils, mast cells, eosinophils, enteroendocrine cells, and adrenal chromaffin cells) suggests that PMD is a unique degranulation model for paracrine and endocrine secretion. Further investigation will clarify whether PMD can be considered as a general mechanism for the slow release of bioactive stored materials by granulated secretory cells.

Animals↗
PubMed2003

In vivo time-course of the angiogenic response induced by multiple myeloma plasma cells in the chick embryo chorioallantoic membrane.

In this study, we set out to make a fine characterization of the angiogenic response induced by plasma cells obtained from patients with active-multiple myeloma (MM), in comparison with cells obtained from patients with non-active MM and benign lesions such as monoclonal gammopathy of undetermined significance (MGUS), in the chick embryo chorioallantoic membrane (CAM) assay. To achieve this we investigated the time-course of the angiogenic response induced by gelatin sponges soaked in the cell suspensions and implanted on the CAM surface from day 8 to day 12 of incubation by evaluating the number of vessels, of the vessel bifurcation and the intervascular distance at 24, 48, 72 and 96 h after the implants. The results show that plasma cell suspensions obtained from patients with active MM induce a vasoproliferative response that was significantly higher than that induced by cell suspensions obtained from patients with non-active MM or with MGUS, which is also a function of the day of implantation. In fact, implants made from day 8 to day 10 induce a strong angiogenic response, whereas those made from day 11 to day 12 do not. This finding might depend on the fact that CAM endothelium exhibits an intrinsically high mitotic rate until day 10. Thereafter, the endothelial mitotic index declines rapidly, and consequently cell suspensions implanted on the CAM of successively older embryos are not able to induce a vasoproliferative response in parallel with the reduced rates of growth of the CAM's endothelial cells.

Allantoin↗
PubMed2003

Ultrastructural analysis of mast cell recovery after secretion by piecemeal degranulation in B-cell non-Hodgkin's lymphoma.

Mast cells (MC) are critical for a number of pathological conditions, including acute and chronic inflammation and tumor angiogenesis. We have previously demonstrated in B-cell non-Hodgkin's lymphoma (B-NHL) the presence of an heterogeneous population of MC characterized by granules with a morphological semilunar appearance, or piecemeal partial degranulation (PMD), and containing scrolls. With the aim to further elucidate the morphological features of MC in B-NHL, in the present study an ultrastructural analysis of MC recovery after secretion by PMD in B-NHL samples has been carried out. Results indicate that PMD is identified by the presence of partially or completely empty granule containers in the cytoplasm, considered as the morphological endpoint of secretion by PMD. Granule refilling after PMD implies condensation of dense granule matrix material leading to the highly characteristics morphological patterns described in this paper. After the recovery from secretion by PMD in B-NHL, mature MC with full complement of granules displaying crystal, particle, scroll, and mixed patterns are recognizable. We believe that the images presented here, in the absence of MC mitosis, support the possibility that in B-NHL, MC after PMD, refill empty granule containers in situ, as seen in MC during the angiogenic phase of wound-healing, and that both events, PMD and recovery of MC after their degranulation, occur during biological processes in which MC and angiogenesis are strictly interconnected.

Cytoplasmic Granules↗
PubMed2003

B-cell non-Hodgkin's lymphomas express heterogeneous patterns of neovascularization.

BACKGROUND AND OBJECTIVES: The role of angiogenesis in the growth and survival of hematologic malignancies was not clear until recently. We have previously demonstrated in beta-cell non Hodgkin's lymphomas (B-NHL), that neoplastic progression, as defined by its increasing malignancy grades, is clearly related to the degree of angiogenesis. DESIGN AND METHODS: In the present study we used transmission electron microscopy to examine the ultrastructural patterns of neovascularization in both low and high grade B-NHL). In low grade B-NHL the vessel lumen was formed either by endothelial cell body curving or, more frequently, by the fusion of intracellular vacuoles in poorly differentiated endothelial cells. In high grade B-NHL, on the other hand, the predominant neo-angiogenic pattern was the formation of a slit-like lumen. A remarkable ultrastructural feature in high-grade B-NHL was the intimate relationship between endothelial and tumor cells. Both low and high grade B-NHL exhibited development of transluminal bridges in larger vessels, leading to the division of the vessel. INTERPRETATION AND CONCLUSIONS: These in situ data suggest that the intrinsic process of endothelial cell proliferation and vessel formation in the stroma of B-NHL varies according to the grade of tumor malignancy and point to the important role played by the specific organ microenvironment, which determines the extent of cancer cell proliferation, angiogenesis and invasion. In fact, the microenvironment has an important influence on vascular architecture, i.e., the properties of tumor cells can also determine the outcome of the angiogenic response. Taken together our findings, which provide quantitative data on different vascular patterns in B-NHL, have potential implications for vascular targeting and cancer therapy.

Endothelium, Vascular↗
PubMed2002

Granule changes of human and murine endocrine cells in the gastrointestinal epithelia are characteristic of piecemeal degranulation.

Piecemeal degranulation is a unique pattern of cell secretion that consists of a slow release of granule contents from cytoplasmic secretory granules, which leaves empty chambers that do not fuse with each other or with the plasma membrane. To our knowledge, no cell types other than mast cells, basophils, and eosinophils have been reported in the literature to show morphological features of piecemeal degranulation. In the present study we provide evidence for ultrastructural morphologies characteristic of piecemeal degranulation in entero-endocrine cells of the human and murine gastrointestinal epithelia. Human biopsy samples were taken from the mucosa of the distal duodenum, proximal jejunum, and colon in 10 patients undergoing endoscopic examination for malabsorption, diarrhea, and/or abdominal pain. Murine gastrointestinal samples were obtained from 10 adult C57 mice. All specimens were prepared for transmission electron microscopy (TEM) according to standard protocols. Results showed that different types of gastrointestinal entero-endocrine cells, in both humans and mice, were recognizable with ultrastructural features diagnostic for piecemeal degranulation, including specific granule and cytoplasmic changes. In the granules, the content was found to be loosely packed or diminished. Notably, altered granules did not fuse with each other or with the plasma membrane, and were characteristically intermingled with normal, resting granules. At times, the release events transformed the granules into enlarged, empty containers. Numerous entero-endocrine cells presented a rich supply of membrane-bound vesicles (50-200 nm in diameter) that were free in the cytoplasm or attached to granules. This finding of piecemeal degranulation in gastrointestinal entero-endocrine cells suggests that such a secretory model might be a general degranulation pattern in cells involved in paracrine-endocrine secretion.

Adolescent↗
PubMed2002

Toxicologic and pharmacokinetic study of low doses of verapamil combined with doxorubicin.

The effect of a chronic treatment with low oral doses of verapamil, a calcium channel blocker commonly employed in cardiovascular therapy, on doxorubicin toxicity, was evaluated in CD1 mice. Verapamil, administered at a dosage corresponding to a typical cardiovascular posology in humans, significantly increased doxorubicin toxicity. In particular the mortality was significantly higher and earlier and histological analysis revealed an increase in the severity of lesions in the liver, kidney and small bowel of verapamil pretreated animals. The pharmacokinetic profiles revealed that verapamil treated group had higher doxorubicin peak plasma and tissue levels and AUCs. This study shows that verapamil, administered at low doses, dramatically increases doxorubicin toxicity, probably through an interaction between the two drugs, both P-glycoprotein substrates, on the protein expressed in normal tissues, and suggests caution in the use of the calcium channel blocker for cardiovascular pathologies in patients who have to be treated with antineoplastic agents, substrates of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗