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R Fantozzi

Publications and source records attributed to R Fantozzi.

At least 19 recordsLinked to original sources
PubMed2005

A preliminary in vitro and in vivo study of the effects of new anthraquinones on neutrophils and bone remodeling.

Osteolysis, that is, progressive periprosthetic bone loss, is responsible for approximately 70% of aseptic loosening and implant failure. Usually, it is due to a granulomatous reaction wear-induced, leading to macrophage and osteoclast-mediated bone resorption. At present, there is no established prophylaxis or treatment for this process. For this purpose, as a preliminary investigation, we aimed to study the effects in two directions, inhibition of proinflammatory signals, and bone remodeling activity, of two newly synthesized anthraquinone molecules [N,N'-Diethylamino-2,6-anthraquinone-disulfonamide (GR375) and N,N'-(p-ethoxyphenyl)-2,6-anthraquinone-disulfon amide (GR377)]. Among the pro-inflammatory signals, the ability of the two anthraquinones to interfere with the production of superoxide anion (O(2) (-)), which was assumed as a marker of reactive oxygen species (ROS), was evaluated in an in vitro cell model by testing phagocytes, such as human neutrophils, challenged by the chemotactic agent N-formylmethionyl-leucyl-phenylalanine (FMLP). Both compounds inhibited O(2) (-) production, in a dose-dependent way, without exerting scavenger effects. An in vivo model was applied to investigate their effect on bone remodeling. Fifty-four female Wistar rats were divided into eight groups of six animals each, and a 4-week treatment was applied in two phases. A 25 mg/kg/os dose in the first phase and 12.5-6.25 mg/kg/os doses in the second one were employed. The tibia trabecular bone at the secondary spongiosa level was analyzed, and trabecular bone volume (%TBV), trabecular thickness (TbTh), and apatite lattice parameters were measured. At the highest doses of GR375 and GR377 the %TBV and the TbTh increased by 33.2, 34.6%, and 3.6 and 9.1%, respectively, whereas crystallographic parameters were not significantly different from the untreated group. Our results suggest a simultaneous antiinflammatory and antiosteoclastic activity of both drugs that encourages to perform further research. If it will be confirmed, they could be proposed in a variety of bone diseases, in particular, when acute inflammation is associated to osteolytic processes and, eventually, in the prevention and treatment of periprosthetic osteolysis.

Animals↗
PubMed2001

Characterization of ionotropic glutamate receptors in human lymphocytes.

The effect of L-glutamate (Glu) on human lymphocyte function was studied by measuring anti-CD(3) monoclonal antibody (mAb) or phytohaemagglutinin (PHA)-induced intracellular Ca(2+) ([Ca(2+)](i)) rise (Fura-2 method), and cell proliferation (MTT assay). Glu (0.001 - 100 microM) did not modify basal lymphocyte [Ca(2+)](i), but significantly potentiated the effects of anti-CD(3) mAb or PHA. Maximal [Ca(2+)](i) rises over resting cells were: 165+/-8 and 247+/-10 nM at 3.0x10(-2) mg ml(-1) anti-CD(3) mAb; 201+/-4 and 266+/-9 nM at 5.0x10(-2) mg ml(-1) PHA, in the absence or presence of 1 microM Glu, respectively. The Glu effect showed a bell-shape concentration-dependent relationship, with a maximum (+90+/-3% for anti-CD(3) mAb and +57+/-2% for PHA over Glu-untreated cells) at 1 microM. Non-NMDA receptor agonists (1 microM) showed a greater efficacy (+76+/-2% for (S)-AMPA; +78+/-4% for KA), if compared to NMDA (+46+/-2%), or Glu itself. Ionotropic Glu receptor antagonists completely inhibited the effects of the corresponding specific receptor agonists (1 microM). The IC(50) values calculated were: 0.9 microM for D-AP5; 0.6 microM for (+)-MK801; 0.3 microM for NBQX. Both NBQX and KYNA were able to abolish Glu effect. The IC(50s) calculated were: 3.4 microM for NBQX; 0.4 microM for KYNA. Glu (0.1 - 1 mM) did not change the resting cell proliferation, whereas Glu (1 mM) significant inhibited (-27+/-4%) PHA (1.0x10(-2) mg ml(-1))-induced lymphocyte proliferation at 72 h. In conclusion, human lymphocytes express ionotropic Glu receptors functionally operating as modulators of cell activation.

2-Amino-5-phosphonovalerate↗
PubMed2001

Priming effects of substance P on calcium changes evoked by interleukin-8 in human neutrophils.

The neurokinin (NK) substance P (SP), which is a mediator of neurogenic inflammation, has been reported to prime human polymorphonuclear neutrophils (PMNs). The priming effects of SP on PMNs activated by recombinant interleukin-8 (rIL-8) were investigated. SP enhanced, in a dose- and time-dependent way, the rise in cytosolic free-calcium concentration, [Ca(2+)]i, evoked by the chemokine. The priming effects of SP were abolished by exposing PMNs to a calcium-free medium supplemented with EGTA. The C-terminal peptides SP(4-11) and SP(6-11) but not the N-terminal peptide SP(1-7) shared the priming effects of SP. The selective NK-1 receptor agonist [Sar-9, MetO2-11]SP mimicked the effects of SP, which were not reproduced by the selective NK-2 receptor agonist [betaAla-8]-NKA(4-10) or the selective NK-3 agonist senktide. Two selective NK-1 antagonists, CP96,345 and L703,606, dose dependently inhibited SP priming effects. These results demonstrated that SP primes PMNs exposed to rIL-8 and suggested that SP priming effects are receptor mediated.

Adult↗
PubMed1999

Autoimmunity in multiple sclerosis: study of a wide spectrum of autoantibodies.

The aim of this study was to assess the frequency of organ- and nonorgan-specific autoantibodies in MS patients and evaluate whether the presence of autoantibodies is an indicator of disease activity and/or a prognosis factor. One hundred and five definite MS patients in different stages and with different course and 75 blood donors were tested for the autoantibodies TgA, TMA/TPO-A, PCA, ANA, aCl, SMA, AMA and ANCA. All patients were screened for the LAC. Autoantibodies to at least one autoantigen were found in 66.6% MS patients and in 13.3% controls (P < 0.001). The frequency of TgA, TMA/TPO-A, ANA, aCl and SMA was statistically higher in patients than in controls. Circulating ANCAs were found in seven MS, a never reported finding. An early onset of MS (< 20 years) was associated with a lower autoantibody frequency (P < 0.01) Primary and secondary progressive MS had a higher antibody frequency than relapsing-remitting (P < 0.05) or benign (P < 0.001) MS. Up to 86% of patients were autoantibody-positive during the acute stage, but only 30% of them remained positive during the remission stage (P < 0.001). A generalised immune dysregulation occurs in MS patients, mostly during the acute stages and in the progressive courses, involving activation of both autoreactive Th1-cells (mainly linked to CNS lesions) and B-cells via Th2 cells.

Adolescent↗
PubMed1998

GAS6 inhibits granulocyte adhesion to endothelial cells.

GAS6 is a ligand for the tyrosine kinase receptors Rse, Axl, and Mer, but its function is poorly understood. Previous studies reported that both GAS6 and Axl are expressed by vascular endothelial cells (EC), which play a key role in leukocyte extravasation into tissues during inflammation through adhesive interactions with these cells. The aim of this work was to evaluate the GAS6 effect on the adhesive function of EC. Treatment of EC with GAS6 significantly inhibited adhesion of polymorphonuclear cells (PMN) induced by phorbol 12-myristate 13-acetate (PMA), platelet-activating factor (PAF), thrombin, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), but not that induced by FMLP and IL-8. GAS6 did not affect adhesion to resting EC. Titration experiments showed that high concentrations of GAS6 were needed to inhibit PMN adhesion and that inhibition was dose-dependent at the concentration range of 0.1 to 1 microg/mL. One possibility was that high concentrations were needed to overwhelm the effect of endogenous GAS6 produced by EC. In line with this possibility, treatment of resting EC with soluble Axl significantly potentiated PMN adhesion. Analysis of localization of GAS6 by confocal microscopy and cytofluorimetric analysis showed that it is concentrated along the plasma membrane in resting EC and treatment with PAF induces depletion and/or redistribution of the molecule. These data suggest that GAS6 functions as a physiologic antiinflammatory agent produced by resting EC and depleted when proinflammatory stimuli turn on the proadhesive machinery of EC.

Cell Adhesion↗
PubMed1996

Effect of 4-hydroxynonenal on superoxide anion production from primed human neutrophils.

HNE (4-hydroxy-2,3-trans-nonenal), and aldehydic product of lipid peroxidation, has been reported to modulate different functional parameters of human and rat neutrophils (PMNs), such as chemiluminescence, migration and some enzymatic activities, thus exerting effects that varied according to the concentration tested. Experiments were done to evaluate the effects of HNE on superoxide anion (O2-) production from human PMNs, isolated from healthy volunteers. After having tested that HNE by itself was not able to activate the cells, comparisons were made between its effects on PMNs, stimulated by either a single stimulus, N-formyl-methionyl-leucyl-phenylalanine (FMLP), or a combination of stimuli, such as FMLP and the neuropeptide substance P (SP; primed PMNs). In the concentration range tested (10(-12) - 10(-4) M), HNE inhibited FMLP-evoked O2- production with an IC50 of 11.6 +/- 1.5 x 10(-6) M; at concentrations < or = 10(-6) M, HNE enhanced O2- production elicited by FMLP + SP, while higher concentrations were inhibitory. There was a bell-shaped dose-response curve to the enhancing effects of HNE, depending on the incubation time being recorded after only short periods (< or = 5 min) of the exposure of the cells to HNE; this was not shown by structurally-related aldehydes, such as 2-nonenal and nonanal. These results suggest that low concentrations of HNE may participate in the evolution of the inflammatory process, by contributing to the activation of PMNs. The effects of high concentrations of the aldehyde may represent a mechanism which contributes to the regulation of the extent of the inflammatory response.

Aldehydes↗
PubMed1996

Tachykinin activation of human alveolar macrophages in tobacco smoke and sarcoidosis: a phenotypical and functional study.

Substance P (SP) and neurokinin A (NKA), which exert bronchoconstrictor effects on human airways, are known to interact with inflammatory and immune cells, including monocyte macrophages. We have evaluated the effects of SP, NKA and the NK2 selective agonist [beta-Ala8]-NKA(4-10) on alveolar macrophages (AM) isolated from 4 healthy smokers and 4 non-smoker active pulmonary sarcoid patients. An accumulation of activated mononuclear phagocytes, as well as elevated angiotensin-converting enzyme (ACE) activity, has been evidenced in both clinical conditions. The phenotype of AMs in the studied subjects was characterized by an elevated expression of CD68+, HLA-DR+ and CD14+, CD14+ being significantly less in sarcoidosis as compared to smokers. SP, NKA and the NK2 selective agonist evoked superoxide anion (O2-) production in AMs obtained from sarcoid patients or healthy smokers. While SP acted in a non-dose-dependent manner in both conditions, NKA and [beta-Ala8]-NKA(4-10) evoked a dose-dependent respiratory burst (ED50 = 0.25 and 0.26 nM, respectively) in smokers, but not in sarcoidosis. The more marked phenotypical expression correlated well with the ability of NK2 receptors to activate AMs in smoker subjects.

Adult↗
PubMed1996

Modulation by protein kinase C of the enhanced responsiveness to tachykinins in ovalbumin-sensitized guinea pig alveolar macrophages.

As previously reported, alveolar macrophages (AMs) from ovalbumin-sensitized guinea pigs present an enhanced responsiveness to tachykinins but not to N-formylmethionyl-leucyl-phenylalanine (fMLP). We have investigated the biochemical mechanisms underlying this varied responsiveness to tachykinins. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) induced a larger superoxide anion (O2-) production in AMs from sensitized guinea pigs, as did tachykinins. Pretreatment of AMs with pertussis toxin abolished tachykinin-evoked respiratory burst, had no effect on PMA-evoked O2- production and strongly inhibited fMLP-evoked one, with no appreciable variation between control or sensitized AMs. Staurosporine and its derivative cgp 41251, significantly decreased PMA- and tachykinin-evoked O2- production in both populations, being more potent in control AMs, but exerted little effects against fMLP. Pretreatment of AMs with PMA significantly inhibited fMLP-, PMA- and tachykinin-evoked O2- production in both control and sensitized AMs. fMLP, substance P (SP), neurokinin A (NKA) and the NK2 agonist [beta-Ala8]-NKA(4-10) dose-dependently increased [3H] phorbol 12, 13 dibutyrate (PDBu) binding to control and sensitized AMs. While fMLP exerted similar effects in both populations, dose-response curves for SP1 NKA and the NK2 receptor agonist were shifted leftwards (1, 4 and 3 orders of magnitude, respectively) in sensitized AMs. These results indicate a possible PKC involvement in the enhanced responsiveness to tachykinins in actively sensitized AMs.

Animals↗
PubMed1994

Adenosine modulation of primed human neutrophils.

Human neutrophils have been demonstrated to possess both adenosine A1 and A2 receptors: activation of adenosine A2 receptors inhibits the respiratory burst, assayed as superoxide anion production (O-2) from cells stimulated by the bacterial peptide N-formylmethionyl-leucyl-phenylalanine (FMLP). Exposure of neutrophils to different combinations of stimuli results in synergistic or primed responses. These responses can be measured by challenging the cells either with a combination of FMLP and platelet activating factor (PAF), or with a combination of PAF and the neuropeptide substance P, which by itself does not induce O-2 production. In order to evaluate the ability of adenosine receptor agonists to inhibit O-2 production by primed or synergistically stimulated neutrophils, a non-selective adenosine receptor agonist, 2-chloroadenosine, was tested in comparison with reportedly selective ligands of adenosine A1 and A2 receptor types, N6-cyclopentyladenosine (CPA) and 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethyl-carboxamido adenosine (CGS 21680). The order of activity CGS 21680 > 2-chloroadenosine > CPA indicates that adenosine A2 receptors mediate the inhibition of the respiratory burst even when neutrophils are primed or synergistically activated. 8-Phenyltheophylline antagonized the effects of these adenosine receptor agonists in a competitive way.

2-Chloroadenosine↗
PubMed1994

Effects of heparin and its desulfated derivatives on leukocyte-endothelial adhesion.

The effect of heparin and partially desulfated heparin derivatives on thrombin and PAF-induced adhesion of PMNs to the endothelium was studied either by a fluorescence image analysis or by 111In-labeled PMNs. The results observed with these two techniques consistently indicated that heparin and O-des-heparin inhibited PMN adhesion in a dose-dependent manner. Moreover, N-des-Hep and N-O-des-Hep, even if less effective, also inhibited the adhesion of PMNs when used at high concentrations. The effect of heparin and heparin derivatives was not directed to endothelial cells but rather to PMNs, as shown by the absence of inhibitory effects, when heparins were preincubated with endothelium.

Cell Adhesion↗
PubMed1994

Effects of bisphosphonate derivatives on macrophage function.

The effects of three bisphosphonates (BPs), designated 4-amino-1-hydroxybutylidene-1, 1-bisphosphonate (AHBuBP), 6-amino-1-hydroxylidene-1, 1-bisphosphonate (AHHexBP) and chloromethylenebisphosphonate (Cl2MBP), were evaluated on the basis of their effect on the phagocytic activity, lysosomal enzyme release and superoxide anion production in the rat peritoneal macrophage (M phi). AHBuBP was found to inhibit in a concentration-dependent manner the phagocytosis of sheep red blood cells (SRBC). The same activity was seen with the phagocytosis of latex beads, although this effect was independent of calcium concentration. Conversely, AHHexBP and Cl2MBP were weak inhibitors of phagocytosis of both SRBC and latex beads. Inhibition studies on the phorbol myristate acetate-stimulated production of superoxide anion have shown all three BPs to be active. When compared with Cl2MBP, AHBuBP and AHHexBP were shown to be substantially active in inhibiting the release of beta-glucuronidase from ionophore A23187-stimulated rat peritoneal M phi.

Alendronate↗
PubMed1993

Synthesis and study of the anti-inflammatory properties of some pyrazolo[1,5-a]pyrimidine derivatives.

A series of pyrazolo[1,5-a]pyrimidin-7-ones (1c-17c) were synthesized to evaluate in vivo and in vitro effects induced by structural modifications at the 2 position of 4,7-dihydro-4-ethyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-one (FPP028). This substance, which has been previously studied, is a weak inhibitor of prostaglandin biosynthesis and a nonacid analgesic and anti-inflammatory agent devoid of ulcerogenic properties. To gain more insight into the mechanism of action of this class of compounds, several in vivo tests were carried out, such as carrageenan-induced rat paw edema and pleurisy. In vitro tests include some studies of leukocyte functions, such as superoxide production and myeloperoxidase release. In vitro effects on arachidonic acid-, adenosine 5'-diphosphate-, and platelet-activating factor-induced platelet aggregation were also studied. Different anti-inflammatory activities were observed, depending on the nature of substituents at the 2 position; these differences are probably linked to the capacity of these compounds to inhibit leukotrienes and/or prostaglandin biosynthesis with different selectivity. 4,7-Dihydro-4-ethyl-2(2-thienyl)pyrazolo[1,5-a]pyrimidin-7-one (7c) proved to be the most interesting compound of the novel synthesized series, showing powerful pharmacological activity in vivo as well as in vitro, together with very weak acute toxicity.

Animals↗
PubMed1992

Evidence for tachykinin NK-2B-like receptors in guinea-pig alveolar macrophages.

Mammalian tachykinins dose-dependently activate guinea-pig alveolar macrophages, by interacting with tachykinin NK-2 receptors, mainly. By evaluating the effects of different NK-2 tachykinin receptor antagonists, we now provide evidence that tachykinin NK-2 receptors in guinea-pig alveolar macrophages meet the pharmacological criteria used to define the NK-2B subtype.

Amino Acid Sequence↗
PubMed1992

Enhanced responsiveness of ovalbumin-sensitized guinea-pig alveolar macrophages to tachykinins.

1. We have evaluated the ability of substance P (SP), neurokinin A (NKA) and the selective NK2 receptor agonist [beta-Ala8]-NKA(4-10) to induce superoxide anion (O2-) production and prostanoid (prostaglandin E2, thromboxane B2) release from alveolar macrophages (AMs) isolated from control or actively sensitized guinea-pigs. 2. The dose-response curves for NKA and SP were shifted to the left (three orders and one order of magnitude, respectively) in AMs isolated from sensitized animals, with no variation in maximal effects. 3. By evaluating the effects of [beta-Ala8]-NKA(4-10), we observed that not only was the concentration-response curve shifted to the left in both the functional parameters examined, but also maximal effects were significantly enhanced in AMs isolated from sensitized guinea-pigs. 4. This varied responsiveness seems to be specific for tachykinins, as it was not reproduced by another AM stimulant, the bacterial peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). 5. Only small amounts of beta-glucuronidase were released following tachykinin or ovalbumin stimulation both in control and sensitized AMs. 6. These results indicate that AMs isolated from sensitized guinea-pigs show an increased responsiveness to NK2 receptor stimulation and further stress the role played by AMs in allergic lung diseases.

Animals↗
PubMed1992

Potential role of heterologous collagen in promoting cutaneous wound repair in rats.

The effect of native bovine tendon type-I collagen sponges (CONDRESS) on wound repair was evaluated by employing an experimental animal (rat) model which utilized subcutaneously implanted collagen and polyurethane sponges. Lesions were also created in the control groups with the exception that implants were omitted. The fusion of the hypodermal layer was selected as the index of wound repair expressed as % healing. In order to assess the extent of the healing process, parameters of clinical evaluation such as exudate volume, number of polymorphonuclears (PMNs) and macrophages (MOs) were also determined. All studies were effected at time intervals of 24, 48 and 72 h post wounding and implantation. The collagen-treated groups showed a greater healing capacity as compared to the polyurethane sponge-treated and control groups. Likewise, the exudate volume, number of leukocytes and mononuclear-type cells were all significantly higher for the collagen-treated animals than those of the polyurethane sponge-treated and control ones. Furthermore, the healthier appearance of the artificially produced wounds in the collagen sponge-treated groups (when compared to the others after 24 h) further confirmed collagen's validity in the treatment of wounds.

Animals↗
PubMed1991

Temperature dependence of [3H]PAF binding to washed human platelets.

Our results indicate that the binding of [3H]PAF to a single class of high affinity sites on human platelets is endothermic and largely entropy-driven. The increase in entropy can be attributed to the disorganization of water molecules bound to both receptor and ligand during the binding process.

Blood Platelets↗
PubMed1991

Priming effects of mammalian tachykinins on human neutrophils.

The undecapeptide substance P (SP) is known to activate different cell types involved in inflammatory and immune processes. By evaluating primed stimulation of human neutrophils, we now demonstrate that SP (10 nM-0.1 mM) dose-dependently enhances superoxide anion production from cells stimulated by the phospholipid mediator Platelet Activating Factor (PAF). We also provide evidence that neurokinin A (NKA), which is released, as well as SP, from C fibers of sensory nerves, potentiates PAF-evoked superoxide anion generation, while neurokinin B (NKB) is ineffective.

Dose-Response Relationship, Drug↗