Biomedical subjects

S Antonaci

Publications and source records attributed to S Antonaci.

At least 37 records · Page 2Linked to original sources

PubMed2000

Regulatory role of extracellular matrix proteins in neutrophil respiratory burst during aging.

Neutrophil respiratory burst was assessed on plates coated with fibronectin (FN) or laminin (LM), both used at dosages inhibiting polystyrene-triggered cell activation in young healthy volunteers. Under these conditions, a low, yet significant, spontaneous superoxide anion (O(2)(-)) production, matching with enhanced levels of basal adherence, was detected in FN-plated neutrophils of elderly donors. In contrast, although neutrophil stimulation with tumor necrosis factor (TNF)-alpha, granulocyte macrophage-colony stimulating factor (GM-CSF), fMLP or phorbol myristate acetate (PMA) gave rise to a massive and prolonged FN-primed O(2)(-) release, a significant impairment of oxidative response occurred in the aged group as a result of GM-CSF or fMLP cell challenge. Such an effect was not associated to an age-related imbalance of stimulant-triggered neutrophil adhesiveness to FN, even though a larger contribution of CD18-dependent versus CD18-independent pathways was observed in old as compared to young individuals. Notably, within the aged group, anti-CD18 monoclonal antibody cell pretreatment resulted in a higher suppression of FN-primed O(2)(-) release following TNF-alpha with respect to GM-CSF stimulation, thus implying that an agonist-related defect of the coupling between beta2 integrin-dependent adhesive and oxidative events is likely to occur as a feature of age. All physiological mediators failed to activate the respiratory burst of neutrophils plated on LM-coated wells in both young and aged donors. This effect appears to be the result of an active process, since neutrophils from either group of subjects adhered to LM-coated surfaces and LM inhibited in a dose-dependent manner the FN-priming effect on neutrophil O(2)(-) production. All together the findings provide additional evidence for an imbalance of neutrophil-mediated functions in the elderly.

Aged↗

PubMed2000

Transforming growth factor beta1 and soluble Fas serum levels in hepatocellular carcinoma.

In this study we assessed the usefulness of serum Transforming Growth Factor-beta1 (TGF-beta1) and soluble Fas (sFas) in distinguishing liver cirrhosis (LC) with and without hepatocellular carcinoma (HCC) as compared with alpha-fetoprotein (AFP). Serum TGF-beta1 and sFas levels were measured by ELISA in 51 LC patients, 54 patients with HCC and 30 healthy donors. Considering as a cut-off limit (mean+1SD of controls) 74 pg/ml and 637 pg/ml for TGF-beta1 and sFas, respectively, we computed serum concentrations of TGF-beta1 and sFas as a score (mean+/-SD). The positive frequency of serum TGF-beta1 levels in HCC patients (54%) was greater than in LC patients (26%) and healthy donors (3%). TGF-beta1 levels were higher in HCC (1.6+/-0.5) than in LC (1.1+/-0.2) (P<0.0001) and healthy donors (0.6+/-0.2). Using a cut-off limit of 82 pg/ml (mean+2SD), the positive frequency of TGF-beta1 was 20% in HCC patients. None of the controls and LC patients had TGF-beta1 levels higher than 82 pg/ml. The positive frequency of serum sFas levels was 100% in HCC patients, 98% in LC patients and 3% in healthy controls. Serum sFas levels were higher in HCC (2.5+/-0.7) than in LC (1.9+/-0.5) (P<0. 001) and healthy donors (0.6+/-0.3). No significant change of positive frequency was obtained by setting sFas cut-off at higher levels. sFas values did not correlate with TGF-beta1 levels. No relationship was found between TGF-beta1 amounts and AFP levels. However, in the 23% of HCC patients, with normal AFP values TGF-beta1 levels were higher than the cut off. These findings suggest the potential usefulness for TGF-beta1 assay in AFP-negative HCC.

Adult↗

PubMed2000

Correlation between shape and electronic states in nanostructures

We show how the electronic states of quantum wires and quantum dots can be evaluated exactly starting from the profile of the nanostructure observed by transmission electron microscopy, scanning tunneling microscopy and atomic force microscopy. The calculated quantization energies reproduce the energy position of the luminescence resonances in the optical spectra of different samples, without fitting parameters.

Journal Article↗

PubMed2000

Relationship between interferon-gamma, interleukin-10, and interleukin-12 production in chronic hepatitis C and in vitro effects of interferon-alpha.

In the current study, increased interferon (IFN)-gamma, interleukin (IL)-10, and IL-12 p40 serum levels were observed in patients with chronic hepatitis C (CHC) compared to controls. Patients also displayed an increased spontaneous IFN-gamma release but a deficient peripheral blood mononuclear cells (PBMC) IFN-gamma production following stimulation with Staphylococcus aureus Cowan I strain (SAC). No difference was found with reference to spontaneous or phytohaemagglutinin (PHA)-induced IL-10 release between patients and controls, whereas a higher IL-12 p70 and IL-12 p40 secretion triggered by SAC was observed in patients. Moreover, IL-12 p40/p70 ratio following SAC stimulation was higher in patients compared to controls and a negative correlation was found between this ratio and IFN-gamma amounts. Recombinant IL-12 (rIL-12) as well as neutralizing anti-IL-10 monoclonal antibodies (mAbs) were able to restore the compromised IFN-gamma production. Of note, anti-IL-10 supplementation induced a lower IL-12 p40/p70 ratio in HCV subjects as compared to controls. Finally, IFN-alpha upregulated in vitro IFN-gamma, IL-10, and IL-12 p70 release but not IL-12 p40 secretion, this giving rise to a normalization of IL-12 p40/p70 ratio. The data suggest the occurrence of an enhanced responsiveness to IL-10 modulating effects, likely mediated by an imbalance of IL-12 p40/p70 ratio, in chronic HCV infection. Cytokine balance restoration might thus contribute to achieve therapeutical results in chronic hepatitis C.

Adult↗

PubMed2000

Biological and clinical relevance of Laminin-5 in cancer.

The occurrence of metastases is the hallmark of cancer. Development of metastasis severely affects prognosis and survival. It limits or discourages therapeutic interventions since no therapies are available to block or prevent cancer invasion. In order to invade, epithelial cancer cells need to penetrate through the basement membrane (BM) and remove extra-cellular matrix (ECM) tissue boundaries. In this context, proteases play a key role since they can either degrade or process the ECM components and thereby support cancer cell invasion. Laminin-5 (Ln-5) is an ECM protein, expressed predominantly in the BM structure, that promotes static adhesion and hemidesmosome formation. However, it also stimulates cell migration and/or invasion after having been cleaved by matrix metalloproteinases (MMPs) such as MMP-2 and MT1-MMP. Based on its dual functions, it would be intriguing to elucidate the role that Ln-5 plays in cancer cell motility and metastasis. One possibility is that MMPs, secreted by cancer cells or by neighbouring stromal cells, can cleave the gamma2 chain of Ln-5 deposited along the advancing edge of tumors. Ln-5, and in particular its gamma2 chain, has been found to be preferentially expressed in the cytoplasm of epithelial human cancer cells located at the advancing edge of the tumor. Such a distribution, which is restricted only to malignancies, suggests that the gamma2 chain may be implicated in epithelial cancer growth and invasion. Although the clinical significance of this finding is not yet clear, it seems often to be associated with a more aggressive and invasive cancer phenotype. This article will review the current body of evidence implicating the Ln-5 molecule, and in particular its gamma2 chain, as an important player in the tumor cascade and progression to metastatic disease. This will then be followed by a discussion of the presented data and its limitations. Finally, suggestions will be provided to improve the current state of knowledge in the field and future implications will be briefly discussed.

Cell Adhesion Molecules↗

PubMed2000

Hepatitis C virus infection: immune responsiveness and interferon-alpha treatment.

Hepatitis C virus (HCV) is responsible for most cases of posttransfusion hepatitis and sporadic or community-acquired non-A, non-B hepatitis. Different generations of enzyme-linked immunosorbent assay have been generated for detecting antibodies to HCV epitopes. HCV-RNA quantitative analysis has been developed by means of polymerase chain reaction technique. This approach is the only reliable method for HCV-RNA tissue localization, being helpful in early diagnosis. HCV infected liver is characterized by an inflammatory infiltrate including CD4+, CD8+, and B lymphocytes. Evidence has been provided that in HCV patients CD8+ cell response is associated with low level of viraemia and higher level of disease activity. CD4+ T cells exhibit specificity for the core antigen, also correlating with disease activity and viraemia. Costimulatory molecules, cytokines, oxygen radicals, the complex Fas/Fas-ligand and soluble class I HLA structures are discussed as putative cofactors involved in disease evolution. Various forms of interferon (IFN)-alpha have been evaluated for the treatment of patients with HCV infection. Initial enthusiasm has been attenuated by the evidence of a low sustained virological response rate and the constant side effects of IFN-alpha therapy in patients with chronic HCV disease. Among possible markers for predicting therapeutic outcome in HCV-positive individuals, anti-core antibodies correlate positively with response to IFN-alpha administration, as well as reduction of interleukin-2 serum levels has been detected in patients with a good therapeutic response. Association between HCV infection and autoimmune phenomena, also in relation to IFN-alpha therapy has been reported. Finally, results of the combined treatment with IFN-alpha/ribavirin are illustrated.

Arachidonic Acid↗

PubMed2000

sICAM-1, sCD95 and sCD95L levels in chronic liver diseases of different etiology.

The release of soluble circulating molecules represents a prominent feature during the course of immune-mediated clinical conditions. To further assess the relationship between serum concentrations of adhesion or apoptotic-related soluble structures and liver diseases, we evaluated the levels of intercellular adhesion molecule-1 (sICAM-1), Fas receptor (CD95) and Fas ligand (sCD95L) in a group of patients affected by Hepatitis C Virus (HCV)-induced chronic hepatitis (CH-C), HCV-positive liver cirrhosis with superimposed hepatocellular carcinoma (HCC), autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and alcoholic liver cirrhosis (ALC). Results show that sICAM-1 values were in all instances significantly elevated when compared to those seen in healthy donors. Similar findings were noted in subjects with liver diseases in terms of sCD95 concentrations, even if to a different degree of statistical significance. Finally, sCD95L amounts were augmented in AIH, PBC, ALC and CH-C in comparison to controls, while in the HCC counterpart sCD95L levels fell within normal range. All together, these findings emphasize the occurrence of circulating soluble molecules in patients with various chronic liver diseases, likely reflecting the involvement of several pathogenetic mechanisms.

Adult↗

PubMed1999

Age-related effects of oxidative metabolism and cyclic AMP signaling on neutrophil apoptosis.

Spontaneous as well as Fas-induced polymorphonuclear cell apoptosis is unchanged in the elderly. However, a weak responsiveness to antiapoptotic signals elicited by proinflammatory molecules has been reported in neutrophils isolated from aged humans. To gain insight into this field, here we have evaluated the role of oxidative metabolism and cyclic AMP (cAMP) signaling on age-related neutrophil apoptotic cell death. Results show that although superoxide dismutase (SOD), added exogenously to cell cultures, is able to prolong neutrophil survival in both young and aged individuals, high amounts of the enzyme are further effective in cell cultures of young donors only. Notably, the addition of catalase gives rise to a more striking, yet comparable, inhibition of neutrophil-programmed cell death in both groups of subjects. Furthermore, even low amounts of catalase are enough to restore a normal apoptotic outcome in SOD-treated cell cultures of old donors. Unlike the oxidative metabolism, cAMP signaling activation does not reveal any difference in the apoptotic response of neutrophils isolated from young and aged donors. Thus, supplementation of cell cultures with prostaglandin E2, dibutyryl cAMP or, to a lesser degree, forskolin results in a dose-dependent inhibition of DNA cleavage product appearance in both groups of subjects. The data outline that an impairment of neutrophil antioxidant shield, leading to an augmented cell oxidative load, is likely to occur as a feature of age. This may increase the apoptotic rate of stimulated cells, which may in turn account for the increased susceptibility of elderly individuals to life-threatening infections.

Adult↗

PubMed1999

Soluble HLA class I antigens in chronic hepatitis C: a disease-associated manifestation or molecules modulating immunoresponsiveness?

The occurrence of high levels of soluble human leukocyte class I antigens (sHLA-I) represents an usual finding during the course of different clinical conditions, such as viral infections and autoimmune disorders. On the other hand, the well known property of sHLA-I to modulate T cell responsiveness could be taken as an advantage to improve long-term allograft acceptance. Recent data have pointed out that subjects with chronic hepatitis C virus (HCV) infection exhibit high amounts of sHLA-I, a pattern which has also been used for monitoring host responsiveness to interferon alpha (IFN-alpha) therapy. However, the lack of correlation between lymphocyte infiltration at liver site and disease biological activity suggests a potential role for sHLA-I in T cell dysfunction during chronic hepatitis C. sHLA-I antigens may, in fact, either interact with T cell receptor delivering an inhibitory signal or trigger cytotoxic T lymphocyte apoptosis by inducing CD95 ligand expression. Both events seem to favour HCV replication and liver tissue damage progression. Alltogether, these findings indicate that, besides viral variant generation and HCV core-mediated immunosuppression, sHLA-I may contribute to the imbalance of immunoresponsiveness during chronic HCV infection.

Animals↗

PubMed1999

Helicobacter pylori infection and host cell responses.

It is well known that Helicobacter pylori is able to colonize the gastric mucosa, causing a chronic and persistent infection with complications, such as peptic ulcer and gastric cancer. This review places emphasis on some epidemiological aspects of Helicobacter pylori infection and its mode of transmission. At the same time, invasive and non-invasive methods of diagnosis of Helicobacter pylori infection are illustrated. More space is devoted to the host response following invasion of the stomach. In this respect, the role played by different growth factors and polyamines in the course of Helicobacter pylori disease is discussed also in relation to the result of eradicating treatment. On the other hand, an accurate description of the host immune responses against Helicobacter pylori organism and/or their components (e.g. lipopolysaccharides) is reported. Finally, since Helicobacter pylori has been classified as a class I carcinogen, current researches are focussed on the Helicobacter pylori-induced carcinogenesis.

Animals↗

PubMed1999

Liver tissue expression of CD80 and CD95 antigens in chronic hepatitis C: relationship with biological and histological disease activities.

The well known discrepancy between cytotoxic T lymphocyte (CTL) infiltration in the liver and disease biological activity, as assessed by alanine aminotransferase (ALT) levels, during the course of chronic hepatitis C virus (HCV) infection, suggests the possible failure of cytotoxic mechanisms devoted to virus clearance. To further investigate the biological events involved in CTL-mediated lysis, i.e. B7/CD28 costimulatory and Fas/Fas-ligand pathways, the CD80 and CD95 antigen expression in liver tissue specimens from chronically HCV-infected patients was evaluated. The results were analysed in relation to serum ALT values and the histological activity (HAI) of liver disease. The data provide evidence for a strong and comparable hepatocyte CD80 and C95 structure expression in chronically HCV-infected livers. CD80- and CD95-carrying liver cells were more frequently distributed at the periportal region of the hepatic lobule, above all near piecemeal necrosis areas, among infiltrating CTL. On the other hand, a negative correlation was found between liver tissue expression of both antigens and serum ALT activity. The relationship with HAI was not statistically significant. The results imply that HCV infection triggers CD80 and CD95 molecule expression on hepatocytes. Further studies are required to clarify the relevance of such a finding in the context of virus-host interactions.

Adult↗

PubMed1999

[Autoimmune hemolytic anemia in chronic hepatitis C virus infection treated with alpha-interferon: a therapy-related event or extra-hepatic immunologic manifestation?].

We report a case of Coombs' positive autoimmune haemolytic anaemia occurring in a patient with chronic hepatitis C virus infection, after five months of alpha-interferon administration. Prednisolone treatment induced a complete remission of both clinical and hematological findings after two months, while Coombs' tests became negative after three months. This points out the possibility of an additional unusual extrahepatic autoimmune feature during the course of hepatitis C virus infection.

Anemia, Hemolytic, Autoimmune↗

PubMed1998

Spontaneous and Fas-induced apoptotic cell death in aged neutrophils.

On the basis of the strict analogies between polymorphonuclear cell (PMN) alterations in the aging and depressed functional capacities displayed by apoptotic PMN, we investigated the possible occurrence of age-associated changes in neutrophil apoptosis, either spontaneous or induced by Fas antigen (CD95) activation. In both cases, old subjects exhibited a time course kinetics of neutrophil apoptosis, as assessed by morphologic and quantitative DNA fragmentation analysis, which overlapped that observed in the young. These findings were confirmed by DNA ladder analysis, showing a progressive increase in DNA cleavage products in cells cultured in medium alone or added with agonistic anti-Fas IgM (CH-11) monoclonal antibodies (mAbs), after 12 and 6 hr of incubation, respectively. Aged purified neutrophils constitutively expressed CD95, at levels similar to those observed in the young. Moreover, although we failed to detect Fas ligand expression on PMN surface, treatment of cell cultures with antagonistic anti-Fas IgG1 (ZB4) mAbs determined a significant inhibition of spontaneous apoptosis in neutrophils from both groups of subjects, thus suggesting that the Fas/Fas ligand system is in fact involved in such an event. The results indicate that the overall intrinsic mechanisms regulating neutrophil cell death are not affected by age. Yet aged neutrophils showed a diminished capacity to be rescued by proinflammatory mediators, such as granulocyte-monocyte colony-stimulating factor, granulocyte colony-stimulating factor, and bacterial lipopolysaccharide, following Fas activation. This may hamper the accumulation of functionally active cells in inflammatory areas in vivo, thus contributing to the increased susceptibility of elderly individuals to life-threatening infections.

Aged↗

PubMed1998

Effects of granulocyte-macrophage colony-stimulating factor and cyclic AMP interaction on human neutrophil apoptosis.

The current study was undertaken to evaluate the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and cyclic AMP (cAMP) signaling interaction on human neutrophil apoptosis, either occurring spontaneously or induced by Fas antigen activation. Results show that GM-CSF, dibutyryl cAMP (a cAMP analog) and forskolin (an adenylate cyclase activator) are all able to suppress spontaneous neutrophil cell death. Of note however, when GM-CSF is used in combination with cAMP-elevating agents, an additive effect on neutrophil survival is observed with dibutyryl cAMP only, whereas supplementation of cell cultures with GM-CSF and forskolin results in a progressive reduction of antiapoptotic effects exerted by the single compounds. Moreover, although dibutyryl cAMP and forskolin do not affect Fas-triggered apoptotic events, they are still able to modulate the GM-CSF capacity to prolong neutrophil survival following anti-Fas IgM cell challenge, with effects similar to those respectively exerted on spontaneous neutrophil apoptosis. The data indicate that GM-CSF may negatively modulate the cAMP-mediated antiapoptotic pathway in human neutrophils, likely via the inhibition of adenylate cyclase activity. This would prevent an abnormal neutrophil survival as a result of cAMP signaling stimulation, which provides a novel insight into the role of GM-CSF as a physiological regulator of myeloid cell turnover.

Apoptosis↗

PubMed1998

Costimulatory molecules and cytotoxic T cells in chronic hepatitis C: defence mechanisms devoted to host integrity or harmful events favouring liver injury progression? A review.

The recruitment of antigen-specific lymphocytes at liver site represents a prominent feature in patients chronically infected with hepatitis C virus (HCV). However, despite the strong and multispecific response, chronic infection leads in a significant number of cases to the development of cirrhosis and hepatocellular carcinoma. The finding that the expression of CD80 structure positively correlates with disease histological worsening points out a role for the costimulatory pathway in the progression of liver cell injury. On the other hand, the demonstration of CD95 and CD95-ligand positive cells in the context of periportal areas, a pattern which is not strictly associated to HCV tissue distribution, indicates the occurrence of either virus-infected or innocent bystander hepatocyte killing. Nonetheless, the persistence of HCV, in spite of cytotoxic T lymphocyte (CTL) liver recruitment, suggests a possible in-situ imbalance of cytotoxic activities, above all referred to perforin-granzyme-dependent necrosis. Altogether, these findings outline that several factors might be involved in HCV-driven immunopathogenesis. Therefore, the fully clarification of these mechanisms may offer a suitable therapeutical approach for the improvement of clinical outcome in chronic hepatitis C.

Antigens, CD↗

PubMed1998

Soluble (s) CD14 and plasmatic lipopolysaccharides (LPS) in patients with chronic hepatitis C before and after treatment with interferon (IFN)-alpha.

CDI4 is a monocyte/polymorphonuclear cell receptor for lipopolysaccharide (LPS)-LPS Binding Protein (LBP), which mediates most of the toxic effects exerted by such a bacterial component in the host. Here, we provide evidence that sCD14 and interferon (IFN)-gamma serum levels are significantly higher in chronic hepatitis C (CH-C) patients than those detected in normal donors. On the other hand, CD4+/CD8+ antibacterial activity is depressed, thus facilitating entry of bacteria into the host. Of note, all these immune parameters are not modified by in vivo IFN-alpha administration over a period of one year. Finally, after 12 months of IFN-alpha treatment number of CH-C patients with detectable levels of plasmatic LPS increased, thus indicating a continuous release of LPS into the host and also suggesting a putative pathogenetic role for sCD14 LPS-LBP complex in subjects affected by CH-C virus infection.

Adult↗

PubMed1998

Immunoresponsiveness in chronic hepatitis C patients: correlation between tissue and serum findings.

In the present study, intrahepatic CD8+ lymphocyte infiltrates as well as HLA class I and CD54 (ICAM-1) antigen expression at both tissue and serum levels were evaluated in 54 untreated patients with chronic hepatitis C stratified on the basis of histological diagnosis (Chronic Persistent Hepatitis/Chronic Lobular Hepatitis -CPH/CLH- and Chronic Active Hepatitis -CAH-: 22 and 32 subjects, respectively). The relationships between soluble HLA-I (sHLA-I) and ICAM-1 (sICAM-1) serum levels and their membrane-bound counterparts, CD8+ liver infiltration and serum alanine aminotransferase (ALT) were also studied. A strong HLA-I and CD54 tissue expression, associated to the presence of CD8+ cell infiltrates in necro-inflammatory areas, and elevated sHLA-I and sICAM-1 serum amounts were observed in all patients. At the same time, no difference was found at tissue level between the two groups of patients with respect to the mean scores of HLA-I and CD54 expression, while CAH subjects displayed a significantly higher CD8 periportal and lobular reactivity in comparison to the other subset. Serological assays outlined higher values of circulating HLA-I molecules in CPH/CLH patients and higher sICAM-1 levels in the CAH group. Finally, a negative correlation was found between sHLA-I and ALT in CAH subjects while, in all patients, sICAM-1 positively correlated with both CD8 tissue infiltration and ALT. Our findings confirm the occurrence of an immune activation status during chronic hepatitis C and suggest that sHLA-I molecules might play a down-modulating role on immunoresponsiveness of these patients.

Adult↗

PubMed1998

Modulation of cytoskeleton assembly capacity and oxidative response in aged neutrophils.

Several reports have emphasized that aged polymorphonuclear cells (PMN) exhibit an impairment of superoxide anion (O2-) generation when triggered with formyl-methionyl-leucine-phenylalanine (FMLP) in comparison to the younger counterpart. Since microfilaments and microtubules are involved in PMN-mediated functions, in a group of old donors we assessed the effects of either actin stabilizing and disrupting agents, i.e. phalloidin and cytochalasin B, or microtubule stabilization or disruption by taxol and colchicine, respectively, on FMLP-triggered neutrophil oxidative responsiveness. Results show that phalloidin treatment, at a concentration ranging from 10(-6) to 10(-8) M, gave rise to an inhibition of O2- release by aged PMN, while the same effect was seen in similarly treated young cells at a concentration of 10(-7) M only. On the contrary, cytochalasin B pretreatment led to an enhancement of O2- generation in both young and aged neutrophils, even if to a lower extent in the latter group. At the same time, taxol at 10(-8) M strength inhibited young cell responsiveness, while no effects were induced by colchicine treatment. Quite interestingly, elderly neutrophil function was negatively modulated by both microtubule affecting compounds. Altogether, these findings suggest the possible relevance of cytoskeletal affecting compounds in the modulation of FMLP-stimulated O2- release during senescence.

Actins↗