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Biomedical subjects

M Foti

Publications and source records attributed to M Foti.

At least 19 recordsLinked to original sources
PubMed2006

Dendritic cell interactions and cytokine production.

The dendritic cell lineage comprises cells at various stages of functional maturation that are able to induce and regulate the immune response against antigens and thus function as initiators of protective immunity. The signals that determine the given dendritic cell functions depend mostly on the local microenvironment and on the interaction between dendritic cells and microorganisms. These interactions are complex and very different from one pathogen to another; nevertheless, both shared and unique responses have been observed using global genomic analyses. In this review, we have focused on the study of host-pathogen interactions using a genome-wide transcriptional approach with a focus on cytokine family members.

Animals↗
PubMed2004

[Thyroid-intestinal motility interactions summary].

Thyroid diseases may be related to gastrointestinal motility symptoms. Such symptoms can vary in degree and, sometimes, are the only clue of a thyroid disease or, at least, the first. The mechanism by which the thyroid hormones can influence gastrointestinal motility, even if not still completely elucidated, can be found in a synergism between a direct effect of the thyronins and an indirect effect mediated by cathecolamines on the muscle cell receptors. Neck discomfort and dysphagia are common findings in patients with thyroid diseases. Hyper- and hypothyroidism can impair esophageal motility, modifying pharyngo-esophageal structure and/or muscular function and interacting with the neuro-humoral regulation of the esophageal peristalsis. Oesophageal motility alterations, observed in patients affected by small non-toxic goiter, are less understandable. At the gastro-duodenal level, basic and postprandial electric rhythm alterations have been observed in hyperthyroid patients, often associated with delayed gastric emptying, too. In such patients, the autonomous nervous system dysfunction may even modify the neuro-hormonal mutual regulation (vagal influence decrease) of the gastro-duodenal myoelectric activity. Hypothyroidism may cause a delay of the gastric emptying too, but such pattern may also be related to an associated autoimmune disease or to an independent chronic modification of the gastric mucosa. Diarrhoea and malabsorption are common findings together with hyperthyroidism, whereas constipation is frequently observed in hypothyroidism. The clinically most demanding situation is certainly the secondary chronic intestinal pseudo-obstruction syndrome, which involves the bowel in most cases, but may also show up by means of a mega-small bowel or a mega-duodenum, or even all of the above. In conclusion it may be stated that: 1) thyroid diseases may be related to symptoms due to digestive motility dysfunction. 2) Any segment of the gastrointestinal trait may be involved. 3) The typical clinical manifestations of the thyroid illnesses may be borderline, missing or concealed by other intercurrent illnesses, especially in the elderly patients. 4) Motility-related digestive symptoms may conceal an underlying, easily misdetected, thyroid disease and must be therefore carefully analyzed.

Esophageal Motility Disorders↗
PubMed2002

An arginine to cysteine(252) mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events.

AIMS/HYPOTHESIS: We examined the properties of a mutant insulin receptor (IR) with an Arg(252) to Cys (IR(R252C)) substitution in the alpha-subunit originally identified in a patient with extreme insulin resistance and acanthosis nigricans. METHODS: We studied IR cell biology and signalling pathways in Chinese Hamster Ovary cells overexpressing this IR(R252C). RESULTS: Our investigation showed an impairment in insulin binding to IR(R252C) related mostly to a reduced affinity of the receptor for insulin and to a reduced rate of IR(R252C) maturation; an inhibition of IR(R252C)-mediated endocytosis resulting in a decreased insulin degradation and insulin-induced receptor down-regulation; a maintenance of IR(R252C) on microvilli even in the presence of insulin; a similar autophosphorylation of mutant IR(R252C) followed by IRS 1/IRS 2 phosphorylation, p85 association with IRS 1 and IRS 2 and Akt phosphorylation similar to those observed in cells expressing wild type IR (IRwt); and finally, a reduced insulin-induced Shc phosphorylation accompanied by decreased ERK1/2 phosphorylation and activity and of thymidine incorporation into DNA in cells expressing IR(R252C) as compared to cells expressing IRwt. CONCLUSION/INTERPRETATION: These observations suggest that: parameters other than tyrosine kinase activation participate in or control the first steps of IR internalisation or both; IR-mediated IRS 1/2 phosphorylation can be achieved from the cell surface and microvilli in particular; Shc phosphorylation and its subsequent signalling pathway might require IR internalisation; defective IR endocytosis correlates with an enhancement of some biological responses to insulin and attenuation of others.

Acanthosis Nigricans↗
PubMed2002

Detection and genetic characterization of canine distemper virus (CDV) from free-ranging red foxes in Italy.

Fragments of the genes encoding the haemoagglutinin (H) and the nucleocapsid protein (N) of a canine distemper (CDV)-like virus affecting a red fox (Vulpes vulpes) were sequenced and analysed. The CDV-like virus detected in the fox was found to be not dissimilar, in both the H and N gene, from other CDVs spreading in Italy, as well as all over the world, and phylogenetic analysis on the H protein-encoding gene allowed to include all the Italian CDVs in the H European genotype.

Animals↗
PubMed2001

Kinetic solvent effects on phenolic antioxidants determined by spectrophotometric measurements.

The effects of polar (acetonitrile and tert-butyl alcohol) and apolar (cyclohexane) solvents on the peroxyl-radical-trapping antioxidant activity of some flavonoids, catechol derivatives, hydroquinone, and monophenols have been studied. The inhibition rate constants k(inh) of the antioxidants have been determined by following the increase in absorbance at 234 nm of a dilute solution of linoleic acid at 50 degrees C containing small amounts of antioxidant and radical initiator. Despite the low concentration of linoleic acid, the peroxidation process has been confirmed to be a free radical chain reaction described by the classical kinetic laws for this process. However, in the evaluation of k(inh), a careful analysis of the peroxidation curve, absorbance versus time, must be done because the final oxidation products of phenols may absorb at 234 nm. Phenols with two ortho-hydroxyls are the most active antioxidants, with inhibition rate constants in the range of (3-15) x 10(5) M(-1) x s(-1) (in cyclohexane). Nevertheless, it has been observed that in tert-butyl alcohol (a strong hydrogen bond acceptor) the rate constants dramatically decline to values not detectable by the present kinetic method. In acetonitrile (a weaker hydrogen bond acceptor) instead, the phenols with two ortho-hydroxyls scavenge the peroxyl radicals with rate constants close to those in cyclohexane. From the kinetic solvent effect, the equilibrium constant of the first solvation step of hydroquinone with tert-butyl alcohol has been determined at 50 degrees C, K(1) = 2.5 +/- 0.5 M(-1).

Acetonitriles↗
PubMed2001

Sac1 lipid phosphatase and Stt4 phosphatidylinositol 4-kinase regulate a pool of phosphatidylinositol 4-phosphate that functions in the control of the actin cytoskeleton and vacuole morphology.

Synthesis and turnover of phosphoinositides are tightly regulated processes mediated by a set of recently identified kinases and phosphatases. We analyzed the primary role of the phosphoinositide phosphatase Sac1p in Saccharomyces cerevisiae with the use of a temperature-sensitive allele of this gene. Our analysis demonstrates that inactivation of Sac1p leads to a specific increase in the cellular levels of phosphatidylinositol 4-phosphate (PtdIns(4)P), accompanied by changes in vacuole morphology and an accumulation of lipid droplets. We have found that the majority of Sac1p localizes to the endoplasmic reticulum, and this localization is crucial for the efficient turnover of PtdIns(4)P. By generating double mutant strains harboring the sac1(ts) allele and one of two temperature-sensitive PtdIns 4-kinase genes, stt4(ts) or pik1(ts), we have demonstrated that the bulk of PtdIns(4)P that accumulates in sac1 mutant cells is generated by the Stt4 PtdIns 4-kinase, and not Pik1p. Consistent with these findings, inactivation of Sac1p partially rescued defects associated with stt4(ts) but not pik1(ts) mutant cells. To analyze potential overlapping functions between Sac1p and other homologous phosphoinositide phosphatases, sac1(ts) mutant cells lacking various other synaptojanin-like phosphatases were generated. These double and triple mutants exacerbated the accumulation of intracellular phosphoinositides and caused defects in Golgi function. Together, our results demonstrate that Sac1p primarily turns over Stt4p-generated PtdIns(4)P and that the membrane localization of Sac1p is important for its function in vivo. Regulation of this PtdIns(4)P pool appears to be crucial for the maintenance of vacuole morphology, regulation of lipid storage, Golgi function, and actin cytoskeleton organization.

1-Phosphatidylinositol 4-Kinase↗
PubMed2000

The gamma-2-herpesvirus bovine herpesvirus 4 causes apoptotic infection in permissive cell lines.

Increasing evidence suggests that regulation of apoptosis in infected cells is associated with several viral infections. The gammaherpesvirus bovine herpesvirus 4 (BHV-4) has been shown to harbor genes with antiapoptotic potentialities. However, here we have demonstrated that productive infection of adherent, permissive cell lines by BHV-4 resulted in a cytopathic effect characterized by induction of apoptosis. This phenomenon was confirmed using different techniques to detect apoptosis and using different virus strains and cell targets. Apoptosis induced by BHV-4 was inhibited by (1) treatment with doses of heparin, which completely inhibited virus attachment and infectivity; (2) UV treatment, which completely abrogated infectivity; and (3) treatment with a dose of phosphonoacetic acid, which blocked virus replication. Virus-induced apoptosis was associated with a down-regulation of Bcl-2 expression and was reduced by Z-VAD-FMK, but not by Z-DEVD-FMK (caspase-3-specific) caspase inhibitors. Inhibition of apoptosis by Z-VAD-FMK treatment during infection did not modify virus yield. Therefore, despite the presence of antiapoptotic genes in its genoma, BHV-4 could complete its cycle of productive infection while inducing apoptosis of infected cells. This finding might have implications for the pathobiology of BHV-4 and other gammaherpesviruses in vivo.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Distinct roles for the yeast phosphatidylinositol 4-kinases, Stt4p and Pik1p, in secretion, cell growth, and organelle membrane dynamics.

The yeast Saccharomyces cerevisiae possesses two genes that encode phosphatidylinositol (PtdIns) 4-kinases, STT4 and PIK1. Both gene products phosphorylate PtdIns at the D-4 position of the inositol ring to generate PtdIns(4)P, which plays an essential role in yeast viability because deletion of either STT4 or PIK1 is lethal. Furthermore, although both enzymes have the same biochemical activity, increased expression of either kinase cannot compensate for the loss of the other, suggesting that these kinases regulate distinct intracellular functions, each of which is required for yeast cell growth. By the construction of temperature-conditional single and double mutants, we have found that Stt4p activity is required for the maintenance of vacuole morphology, cell wall integrity, and actin cytoskeleton organization. In contrast, Pik1p is essential for normal secretion, Golgi and vacuole membrane dynamics, and endocytosis. Strikingly, pik1(ts) cells exhibit a rapid defect in secretion of Golgi-modified secretory pathway cargos, Hsp150p and invertase, whereas stt4(ts) cells exhibit no detectable secretory defects. Both single mutants reduce PtdIns(4)P by approximately 50%; however, stt4(ts)/pik1(ts) double mutant cells produce more than 10-fold less PtdIns(4)P as well as PtdIns(4,5)P(2). The aberrant Golgi morphology found in pik1(ts) mutants is strikingly similar to that found in cells lacking the function of Arf1p, a small GTPase that is known to regulate multiple membrane trafficking events throughout the cell. Consistent with this observation, arf1 mutants exhibit reduced PtdIns(4)P levels. In contrast, diminished levels of PtdIns(4)P observed in stt4(ts) cells at restrictive temperature result in a dramatic change in vacuole size compared with pik1(ts) cells and persistent actin delocalization. Based on these results, we propose that Stt4p and Pik1p act as the major, if not the only, PtdIns 4-kinases in yeast and produce distinct pools of PtdIns(4)P and PtdIns(4,5)P(2) that act on different intracellular membranes to recruit or activate as yet uncharacterized effector proteins.

1-Phosphatidylinositol 4-Kinase↗
PubMed1999

The HIV Nef protein alters Ca(2+) signaling in myelomonocytic cells through SH3-mediated protein-protein interactions.

Human immunodeficiency virus Nef plays an important role in AIDS pathogenesis. In addition to the well known down-regulation of cell surface receptors (CD4, MHCI), Nef is able to alter cellular signaling. Of particular interest for this study is the ability of Nef to bind with a very high affinity to SH3 domains of myelomonocyte-specific protein-tyrosine kinases of the Src family (Src-like PTK). We have therefore investigated Ca(2+) signaling in HL60 cells retrovirally transduced with wild type Nef or with a Nef mutant deficient in the SH3-interacting proline-rich motif (Nef((PXXP)4(-))). In differentiated HL60 cells, Nef markedly altered cellular Ca(2+) signaling; the amount of intracellularly stored Ca(2+) was increased, and as a consequence, store-operated Ca(2+)-influx was decreased. This effect was not observed in undifferentiated HL60 cells or in CEM T-lymphocytes and correlated with the differentiation-induced up-regulation of Src-like PTK. The Nef effect on Ca(2+) signaling depended entirely on the integrity of its PXXP motif. The Src-like PTK p56/59(hck) co-immunoprecipitated with both Nef and with the inositol 1,4,5-trisphosphate receptor, providing a possible mechanistic link between the viral protein and intracellular Ca(2+) stores of the host cell. Collectively, our results demonstrate that the human immunodeficiency virus 1 Nef protein manipulates intracellular Ca(2+) stores through SH3-mediated interactions in myelomonocytic cells.

Calcitriol↗
PubMed1999

Immunity to poliomyelitis, diphtheria and tetanus in pediatric patients before and after renal or liver transplantation.

Few studies have considered the safety, efficacy and appropriateness of vaccinations in pediatric patients before and after solid organ transplantation. The aim of this study was to evaluate the immune status after primary vaccination to diphtheria, tetanus and poliomyelitis in pediatric patients before and after hepatic transplantation and to poliomyelitis in pediatric patients before and after renal transplantation. All the patients had received a complete primary immunization schedule for diphtheria and tetanus and poliomyelitis. Immunity to the three polioviruses was evaluated in 56 patients with renal transplant, 27 on chronic dialysis and 33 controls and in 39 patients with hepatic transplant, 25 with chronic hepatic failure and their 36 controls. Immunity to diphtheria and tetanus was evaluated in 52 liver transplant patients, 29 children with chronic hepatic failure and 54 healthy children. Renal transplant patients were less protected and had lower antibody geometric mean titers than healthy controls for polioviruses 1 and 2. Whereas, protection in the children liver transplant patients was similar to that in their controls. Patients with chronic hepatic failure had higher antibody geometric mean titers to diphtheria and polioviruses 1 and 3 than their control group. Immunosuppression after transplantation has a negative influence on the immune status after primary vaccination in children with renal transplant. Whereas children with chronic hepatic failure have higher antibodies than a normal population. When possible, it could be advisable to individualize immunization schedules in patients at high risk.

Adolescent↗
PubMed1999

Nef-induced CD4 degradation: a diacidic-based motif in Nef functions as a lysosomal targeting signal through the binding of beta-COP in endosomes.

The Nef protein of primate lentiviruses downregulates the cell surface expression of CD4 through a two-step process. First, Nef connects the cytoplasmic tail of CD4 with adaptor protein complexes (AP), thereby inducing the formation of CD4-specific clathrin-coated pits that rapidly endocytose the viral receptor. Second, Nef targets internalized CD4 molecules for degradation. Here we show that Nef accomplishes this second task by acting as a connector between CD4 and the beta subunit of COPI coatomers in endosomes. A sequence encompassing a critical acidic dipeptide, located nearby but distinct from the AP-binding determinant of HIV-1 Nef, is responsible for beta-COP recruitment and for routing to lysosomes. A novel class of endosomal sorting motif, based on acidic residues, is thus revealed, and beta-COP is identified as its downstream partner.

Amino Acid Sequence↗
PubMed1999

Effects of nucleoside analog incorporation on DNA binding to the DNA binding domain of the GATA-1 erythroid transcription factor.

We investigate here the effects of the incorporation of the nucleoside analogs araC (1-beta-D-arabinofuranosylcytosine) and ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl] guanine) into the DNA binding recognition sequence for the GATA-1 erythroid transcription factor. A 10-fold decrease in binding affinity was observed for the ganciclovir-substituted DNA complex in comparison to an unmodified DNA of the same sequence composition. AraC substitution did not result in any changes in binding affinity. 1H-15N HSQC and NOESY NMR experiments revealed a number of chemical shift changes in both DNA and protein in the ganciclovir-modified DNA-protein complex when compared to the unmodified DNA-protein complex. These changes in chemical shift and binding affinity suggest a change in the binding mode of the complex when ganciclovir is incorporated into the GATA DNA binding site.

Animals↗
PubMed1999

Dendritic cells as natural adjuvants.

Dendritic cells (DCs) are professional antigen presenting cells that hold the key to the induction of T-cell responses. Therefore, the use of DCs for immunotherapy to stimulate immune responses has recently raised a great deal of interest. Many clinical trials using DCs have been initiated to stimulate immune responses against tumors or infectious agents. Several issues need to be considered before DCs can be used successfully as natural adjuvants: DCs have to be generated in sufficient numbers; they should display morphological, phenotypical, and functional properties of DCs; and they should be able to present antigens. In the present review we focus on methods for the purification of DCs from human bone marrow and peripheral blood and for the optimization of in vitro cell culture systems. Methods to generate growth factor-dependent mouse DC lines are also described.

Adjuvants, Immunologic↗
PubMed1999

Early events in dendritic cell maturation induced by LPS.

Immature dendritic cells (Dcs) are characterised by high antigen uptake ability and poor T-cell stimulatory function. In contrast, mature DCs have a high stimulatory function and poor antigen uptake ability. Inflammatory stimuli induce DC maturation and migration from nonlymphoid tissues to lymphoid organs. We investigated the effect of lipopolysaccharide (LPS) on DC antigen uptake and migratory function at early and late stimulation time points. We observed that the transition from the immature to the mature state is not a progressive itinerary, but it is characterised by precise functional stages. At early time points after LPS stimulation DCs significantly decrease their intrinsic migratory ability and increase the antigen uptake function. Later, around 4 h after LPS activation, DCs show recovery of migratory ability and start to progressively lose their antigen uptake function until the mature stage in which they show poor antigen uptake and migratory activity.

Animals↗
PubMed1999

Duration of immunity to diphtheria and tetanus in young kidney transplant patients.

A considerable proportion of patients with renal transplant, evaluated many years after transplant, lack protective diphtheria antibody levels, despite primary immunization, but maintain immunity to tetanus. These patients respond to a diphtheria and tetanus booster but the duration of the response is uncertain. This study was undertaken to assess if protective antibodies evoked by primary immunization are lost quickly after transplantation, and whether the extent of the immune response to a booster influences the persistence of protective antibodies. We studied 15 patients (group 1) immediately after renal transplant and 35 patients with renal transplant for 6 +/- 4 yr who received a diphtheria and tetanus booster (group 2). Six patients (40%) of group 1 lost protective diphtheria antibodies a median time of 6.5 months after transplant. Thirty-three patients of group 2 responded to the booster with normal diphtheria antibody titers (> 1 IU/mL) in 22 cases and with low titers in 11. Four of the latter lacked immunity to diphtheria at 12 months follow-up. All patients with normal immunity maintained protective levels of diphtheria antibodies. The low responders had a creatinine clearance of 50 +/- 20 mL/min/1.73 m2. Tetanus immunity was maintained in almost all patients of both groups. In conclusion, renal transplant patients had an accelerated loss of diphtheria antibodies in the early post-transplant period. Response to a diphtheria booster identified a group at particular risk, namely the low responders, who may require frequent booster doses. This group had significantly poorer renal function than the normal responders.

Adolescent↗
PubMed1999

Fibronectin-binding protein acts as Staphylococcus aureus invasin via fibronectin bridging to integrin alpha5beta1.

The ability of Staphylococcus aureus to invade mammalian cells may explain its capacity to colonize mucosa and to persist in tissues after bacteraemia. To date, the underlying molecular mechanisms of cellular invasion by S. aureus are unknown, despite its high prevalence and difficulties in treatment. Here, we show cellular invasion as a novel function for an S. aureus adhesin, previously implicated solely in attachment. S. aureus, but not S. epidermidis, invaded epithelial 293 cells in a temperature- and F-actin-dependent manner. Formaldehyde-fixed and live bacteria were equally invasive, suggesting that no active bacterial process was involved. All clinical S. aureus isolates analysed, but only a subset of laboratory strains, were invasive. Fibronectin-binding proteins (FnBPs) acted as S. aureus invasins, because: (i) FnBP deletion mutants of invasive laboratory strains lost invasiveness; (ii) expression of FnBPs in noninvasive strains conferred invasiveness; and (iii) the soluble isolated fibronectin-binding domain of FnBP (D1-D4) completely blocked invasion. Integrin alpha5beta1 served as host cell receptor, which interacted with staphylococcal FnBPs through cellular or soluble fibronectin. FnBP-deficient mutants lost invasiveness for epithelial cells, endothelial cells and fibroblasts. Thus, fibronectin-dependent bridging between S. aureus FnBPs and host cell integrin alpha5beta1 is a conserved mechanism for S. aureus invasion of human cells. This may prove useful in developing new therapeutic and vaccine strategies for S. aureus infections.

Adhesins, Bacterial↗
PubMed1999

Upon dendritic cell (DC) activation chemokines and chemokine receptor expression are rapidly regulated for recruitment and maintenance of DC at the inflammatory site.

Dendritic cells (DC) are highly motile antigen-presenting cells that are recruited to sites of infection and inflammation to antigen uptake and processing. Then, to initiate T cell-dependent immune responses, they migrate from non-lymphoid organs to lymph nodes and the spleen. Since chemokines have been involved in human DC recruitment, we investigated the role of chemokines on mouse DC migration using the mouse growth factor-dependent immature DC line (D1). In this study, we characterized receptor expression, responsiveness to chemoattractants and chemokine expression of D1 cells during the maturation process induced by lipopolysaccharide (LPS). MIP-1alpha and MIP-5 were found to be the most effective chemoattractants, CCR1 was the main receptor expressed and modulated during LPS treatment, and MIP-2, RANTES, IP-10 and MCP-1 were the chemokines modulated during DC maturation. Thus, murine DC respond to a unique set of CC and CXC chemokines, and the maturational stage determines the program of chemokine receptors and chemokines that are expressed. Since CCR1 is modulated during the early phases of DC maturation, our results indicate that the CCR1 receptor may participate in the recruitment and maintenance of DC at the inflammatory site.

Animals↗