Publications (10)29.81 Total impact
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Article: Cancer and diabetes: two pathological conditions in which adrenomedullin may be involved.
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ABSTRACT: Adrenomedullin (AM) is a regulatory peptide involved in several physiological processes. Among them, AM has been implicated in the regulation of growth, both with mitogenic and antiproliferative activities on normal cells. AM is widely expressed during embryogenesis and may have a significant role in the proliferation and differentiation processes associated with development. AM is also expressed by cancer cell lines and tumors and has been implicated in the growth of malignant cells. Some additional activities associated with AM (antiapoptotic capabilities, angiogenic potential, and upregulation in hypoxic conditions), together with its wide distribution in cancer, suggest that AM may be an important factor in carcinogenesis. Besides its implication in growth, embryogenesis and tumor biology, AM is also involved in pancreatic regulation and diabetes. AM regulates insulin secretion and is overexpressed in the plasma of diabetic patients. Several findings indicate that AM may participate in the pathogenesis and/or clinical complications of this disease.Peptides 12/2001; 22(11):1719-29. · 2.43 Impact Factor -
Article: Expression of the adrenomedullin binding protein, complement factor H, in the pancreas and its physiological impact on insulin secretion.
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ABSTRACT: Adrenomedullin (AM) is a ubiquitous peptide hormone which, among other functional roles, reduces insulin secretion in the pancreas. Recently we have described the interaction between AM and the complement regulator protein factor H, which results in mutual modulation of their respective functions. Here we identify the expression of factor H in the beta cells of the rat pancreatic islets by immunohistochemistry and multiple immunofluorescence followed by confocal microscopy. In addition, double immunogold staining under the electron microscope showed coexistence of insulin and factor H immunoreactivities within the same secretory granules; interestingly, factor H staining was found in the electron-lucent haloes whereas the insulin antibody labeled preferentially the dense cores. The existence of factor H mRNA in the pancreas was confirmed by RT-PCR and in situ hybridization. The function of factor H in the pancreas was investigated with an insulin secretion assay. Addition of factor H to freshly isolated islets in the presence of AM resulted in a further reduction in insulin secretion with a concomitant elevation of cAMP, suggesting that factor H increases AM function in glucose homeostasis. The expression of factor H in the pancreas may play other important roles such as protection against complement-mediated cell lysis.Journal of Endocrinology 10/2001; 170(3):503-11. · 3.55 Impact Factor -
Article: Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis.
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ABSTRACT: Little is known about the molecular mechanisms that control adrenomedullin (AM) production in human cancers. We demonstrate here that the expression of AM mRNA in a variety of human tumor cell lines is highly induced in a time-dependent manner by reduced oxygen tension (1% O2) or exposure to hypoxia mimetics such as desferrioxamine mesylate (DFX) or CoCl2. This AM expression seems to be under hypoxia-inducible factor-1 (HIF-1) transcriptional regulation, since HIF-1alpha and HIF-1beta knockout mouse cell lines had an ablated or greatly reduced hypoxia AM mRNA induction. Similarly, inhibition or enhancement of HIF-1 activity in human tumor cells showed an analogous modulation of AM mRNA. Under hypoxic conditions, immunohistochemical analysis of tumor cell lines revealed elevated levels of AM and HIF-1alpha as compared with normoxia, and we also found an increase of immunoreactive AM in the conditioned medium of tumor cells analyzed by RIA. AM mRNA stabilization was shown to be partially responsible for the hypoxic up-regulated expression of AM. In addition, we have identified several putative hypoxia response elements (HREs) in the human AM gene, and reporter studies with selected HREs were capable of enhancing luciferase expression after exposure to DFX. Furthermore, transient coexpression of HIF-1alpha resulted in an augmented transactivation of the reporter gene after DFX treatment. Given that most solid human tumors have focal hypoxic areas and that AM functions as a mitogen, angiogenic factor, and apoptosis-survival factor, our findings implicate the HIF-1/AM link as a possible promotion mechanism of carcinogenesis.Molecular Endocrinology 07/2000; 14(6):848-62. · 4.54 Impact Factor -
Article: Is adrenomedullin a causal agent in some cases of type 2 diabetes?
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ABSTRACT: The study of two populations with a recent onset of type 2 diabetes showed that a subset of the patients had higher levels of adrenomedullin (AM) than the rest of the diabetics. In this subset, physiological elevations of AM might have triggered the disease in predisposed individuals. Diabetics showed higher levels of AM than healthy controls. In addition, glycemia was measured in diabetic rats after injection of saline, AM, or antiAM antibody. AM elevated glycemia, whereas the antibody reduced circulating glucose to normal. These results suggest that manipulation of AM levels could represent a new approach in the management of diabetes for the appropriate individuals.Peptides 01/2000; 20(12):1471-8. · 2.43 Impact Factor -
Article: Underlying disease stress augments plasma and tissue adrenomedullin (AM) responses to endotoxin: colocalized increases in AM and inducible nitric oxide synthase within pancreatic islets.
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ABSTRACT: Rapid onset metabolic impairments accompany the initiation of the acute phase response to many disease stresses, whereas more chronic metabolic perturbations may prolong the recovery period. In the present experiment the application of a mild endotoxin challenge [lipopolysaccharide (LPS)] alone or additive to a chronic subclinical parasitic infection (Sarcocystis cruzi; LPS + PI) in calves was used as a model to investigate and define a dynamic axis coordinated between adrenomedullin (AM) and nitric oxide in response to immune challenge. Plasma AM and NO2/NO3 concentration responses after LPS (0.45 microg/kg, iv) were rapid in onset and of higher magnitude and longer duration in PI + LPS calves than in those challenged with LPS alone. The post-LPS increase in plasma insulin was significantly greater in PI + LPS than in LPS; following refeeding of calves, insulin secretion was most blunted in PI + LPS calves, consistent with the inhibitory effects of NO and AM on insulin secretion. A more chronic response to the immune challenge (organ specific) was in evidence in tissues harvested 24 h after LPS challenge. Where lung and liver showed no immunostaining for inducible nitric oxide (iNOS), iNOS immunostaining was present in the pancreas, localized to islets only. The percentages of iNOS-immunopositive cells in islets were 1.7%, 21%, 6.7%, and 24% for control (C; saline infused), PI, LPS, and PI + LPS calves, respectively. AM immunostaining was not evident in the liver and was present, but not differentially affected by treatment, in airway epithelium in the lung. The number of islet cells with positive immunostaining for AM was increased in LPS, PI, and PI + LPS calves. The percentages ofAM-immunopositive cells in islets were 8%, 27%, 20%, and 33% for C, PI, LPS, and PI + LPS, respectively. Immunostaining for AM and iNOS was colocalized with cells positive for pancreatic polypeptide. By triple label confocal fluorescence immunocytochemistry, colocalization of intense AM and iNOS immunostaining was confirmed in peripheral islet cells. A weaker, more diffuse iNOS signal was also apparent in insulin-containing cells in PI + LPS. We conclude that chronic low level infection potentiates the severity of metabolic perturbations that arise with additive sudden onset immune challenge, as can occur with bacterial toxins. These metabolic disturbances are reflected in and possibly mediated by early onset increases in plasma tumor necrosis factor-alpha, insulin, and AM and up-regulated iNOS activity. These acute complications rapidly progress into a more chronic state characterized by diminished insulin response to feeding stimulus and colocalized increases in pancreatic islet AM and iNOS. The pancreatic responses in AM and iNOS may play a major role in mediating prolonged disturbances in nutrient use by tissues through their influences on temporal patterns of pancreatic hormone secretion during chronic illness.Endocrinology 12/1999; 140(11):5402-11. · 4.46 Impact Factor -
Article: Granule associated DNase in T4 and T8 lymphocytes from patients with autoimmune diseases.
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ABSTRACT: The presence of a DNase activity associated with secretion granules was detected in T4 and T8 lymphocytes from patients with autoimmune diseases. This activity was much higher in primary biliary cirrhosis (PBC) than in Graves' disease (GD) and multiple sclerosis (MS) or in healthy subjects. This granule associated DNase activity was Ca(2+)-dependent, inhibited by Zn2+, and higher at low pH; its molecular weight corresponded to 66kDa; it was more active with double-strand than single-strand DNA. Judging from its properties this enzyme differed from the three types of endonucleases described as involved in DNA fragmentation (DNase I, DNase II and NUC18). Flow cytometry analysis of T lymphocytes showed that DNase activity associated with CD4+ lymphocyte granules correlated with the ratio CD4+CD45RO+/CD4+CD45RA+ (memory and cytotoxic cells/naive cells, inducers of suppression). In contrast, T8 lymphocyte DNase activity correlated with the proportion of CD4+ lymphocytes with CD4+CD45RA- phenotype (helpers and inducers of cytotoxicity). The possible role of this DNase activity in the mechanisms of lysis or apoptosis mediated by CTL is discussed. We suggest that this DNase activity could be implicated in some of the alterations of the autoimmune response depending on cytotoxic T lymphocytes or T cell inducers of apoptosis.Biochimica et Biophysica Acta 03/1998; 1406(1):51-61. · 4.66 Impact Factor -
Article: Nitric oxide activates granule-associated DNase in human monocytes.
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ABSTRACT: Activated and differentiated human monocytes with a CD14+CD16+ phenotype were found to contain a DNase activity associated with secretion granules. Activated cells were obtained from patients with autoimmune diseases. Activation and differentiation of monocytes were also achieved after incubation of PBMC from healthy subjects with protein A (SpA) or immunopotentiating peptides. DNase activity corresponded to a 66-kDa protein, similar to that described in granules from T lymphocytes, active preferentially on double-strand DNA. DNA fragmentation activity increased when NO donors were present; the activity was higher in the presence of Ca2+, and at low pH values. The Ca2+-dependent activity was inhibited by Zn2+. NO-dependent activity was additive with that of Ca2+-dependent and it was not inhibited by Zn2+. Dithiothreitol did not modify the effect of NO on DNase activity. Incubation of PBMC in the presence of NMLA, an inhibitor of NO synthases, decreased this DNase activity. Data reported clearly suggest a regulatory role of NO in granule-associated DNase activity.Nitric Oxide 02/1998; 2(3):165-73. · 3.55 Impact Factor -
Article: Monocyte inducible nitric oxide synthase in multiple sclerosis: regulatory role of nitric oxide.
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ABSTRACT: Immunophenotypic analysis of peripheral blood leukocytes from patients with multiple sclerosis (MS) showed a profile reflecting a state of activation and differentiation of monocytes. A subset of CD16+ monocytes with high HLA-DR expression was more prominent in patients with MS than in healthy subjects. The presence of the inducible form of nitric oxide synthase (iNOS) in these differentiated and activated monocytes freshly obtained from patients with MS was demonstrated by immunocytochemistry and flow cytometry analysis with two different antibodies. Incubation of lymphomononuclear cells from healthy volunteers in the presence of an immunomodulating peptide (NVLGAPKKLNESQAV) led to stimulation and maturation of monocytes manifested by changes in phenotype and an increase in both iNOS mRNA and protein, as well as HLA-DR expression. In this case also iNOS was expressed mainly on subsets of CD16+ monocytes with high HLA-DR expression. NO produced by human monocytes seems to have a function in the upregulation of membrane HLA-DR. These results are suggestive of a role for monocytic iNOS in the autoimmune response underlying the pathogenesis of multiple sclerosis.Nitric Oxide 03/1997; 1(1):95-104. · 3.55 Impact Factor -
Article: [Adrenomedullin: a new peptide with many clinical implications].
Anales del sistema sanitario de Navarra 22(3):307-15. · 0.32 Impact Factor -
Article: [FICTION as a new tool to early lung cancer diagnosis].
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ABSTRACT: Lung cancer is one of the most frequent causes of cancer death in Western countries. Overall 5-year survival rate is lower than 15% mainly due to the late diagnosis of the disease. Primary prevention (reduction of tobacco consumption) and more effective methods for early detection are needed. Some studies have recently shown that low-dose spiral computed tomography (CT) is a useful technique to the detection of pulmonary malignant nodules in early stages. Studies are developing to evaluate its efficacy in series of high-risk patients. A new cytogenetic technique has been developed: the FICTION technique (Fluorescence Immunophenotyping and Interphase Cytogenetics as a Tool for the Investigation of Neoplasms). This technique allows the simultaneous study of immunophenotypic markers and genetic abnormalities present in tumour cells. The goal of our project is optimise this technique in sputum and bronchoalveolar lavage specimens from lung cancer patients. The overall goal of this project is evaluate the usefulness of this technique, together with the new radiological techniques, in early detection programs of lung cancer in high-risk patients. In the present study we review the cytogenetic studies on lung cancer carried out in the recent years. We also introduce the basic methodological aspects that will be developed in our project.Anales del sistema sanitario de Navarra 25(3):305-15. · 0.32 Impact Factor
Top co-authors
Top Journals
Institutions
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2000–2001
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National Institutes of Health
- Branch of Cancer Cell Biology
Bethesda, MD, USA -
National Cancer Institute (USA)
- Cell and Cancer Biology Branch
Bethesda, MD, USA
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1998–2001
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Universidad de Navarra
- Bioquímica
Pamplona, Navarre, Spain
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1999
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United States Department of Agriculture
- Agricultural Research Service (ARS)
Washington, D. C., DC, USA
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