Biomedical subjects

F Novelli

Publications and source records attributed to F Novelli.

At least 37 records · Page 2Linked to original sources

PubMed1998

Beta-galactoside-binding protein (beta GBP) alters the cell cycle, up-regulates expression of the alpha- and beta-chains of the IFN-gamma receptor, and triggers IFN-gamma-mediated apoptosis of activated human T lymphocytes.

In this paper, the effects of beta-galactoside binding protein (beta GBP), the LGALS1 gene product, on the cell cycle progression and expansion of activated human T lymphocytes were studied. Beta GBP drastically inhibits the IL-2 induced proliferation of PHA-activated T lymphocytes as well as the IL-2 independent proliferation of malignant T lymphocytes by arresting them in the S and G2/M phases of the cell cycle. In addition, beta GBP up-regulates the expression of both the alpha- and the beta-chains of the IFN-gamma R on activated T lymphocyte membrane. None of these effects depend on sugar binding: saturating amounts of lactose do not affect the cell cycle block nor IFN-gamma R up-modulation. The increased expression of both chains renders beta GBP-treated T lymphoblasts sensitive to IFN-y-induced apoptosis. Taken as a whole, these findings suggest that beta GBP plays an important immunoregulatory role by switching off T lymphocyte effector functions. They also provide the first evidence of up-modulation of IFN-gamma R expression on T lymphocytes by a negative cell growth regulator.

Apoptosis↗

PubMed1998

Synthesis and biological activity of gold and tin compounds in ovarian cancer cells.

We have investigated the patterns of in vitro cytotoxicity, induced by six newly synthesized gold and tin compounds, in three human ovarian cancer cell lines (SW 626, IGROV 1 and OVCAR-3). Four gold compounds, i.e. gold(I)lupinylsulfide hydrochloride [1] (containing a naked gold atom), triethylphosphinogold(I)lupinylsulfide hydrochloride [2], triphenyl-phosphinogold(I)lupinylsulfide hydrochloride [3] and 1 ,2-bis(diphenylphosphino)ethane bis[gold(I)lupinylsulfide] dihydrochloride [4] (all containing a gold atom coordinated with different phosphines), were prepared. Moreover, the triethylphosphinogold(I)(2-diethylamino)ethylsulfide hydrochloride [5] in which the simple diethylaminoethylthiol replaced the bulky lupinylthiol was synthesized. The tin compound, triethyltin(IV)lupinylsulfide hydrochlorlde [6], was also studied. Comparative tests with cisplatin, the most widely used antitumor agent in ovarian cancer, were carried out in biological Investigations. In vitro cytotoxicity, by MTT assay, showed that compound [4] and compound [6] exhibited interesting antiproliferative activity in all the three cell lines (mean IC50=1.3 and 0.7 microM, respectively) compared to cisplatin (mean IC50=4.8 microM). In addition, the PA-1 cell line, more sensitive to cisplatin (IC50=0.6 microM), was included as a comparison in the study. Cell count assays confirmed the cytotoxic properties of compounds [4] and [6] against the four cell lines, reporting higher growth Inhibition potency than cisplatin, with IC50 values in the sub-micromolar range.

Antineoplastic Agents↗

PubMed1997

Expression and role in apoptosis of the alpha- and beta-chains of the IFN-gamma receptor on human Th1 and Th2 clones.

The mRNA and protein expression of the alpha- and beta-chains of IFN-gammaR were evaluated on a panel of human Th1 and Th2 clones. When cultured in IL-2-conditioned medium, both types of clones expressed mRNA for the alpha- and beta-chains, and both chains were present in the cytoplasm. Membrane expression of the alpha-chain was higher on Th2 than on Th1, whereas the beta-chain was poorly expressed on both types but increased following IL-2 withdrawal or PHA stimulation. In addition, both types of clones overexpressed MHC class I glycoproteins following IFN-gammaR triggering by exogenous IFN-gamma, although the kinetics was slower in Th1, and this exposure induced mRNA for IRF-1. When their TCR was triggered in the absence of APC, Th1 only underwent apoptosis. This activation-induced apoptosis was prevented by blocking of the alpha-chain or by IFN-gamma neutralization. Addition of IFN-gamma triggered the apoptosis of Th2 clones. Apoptosis of both types of clones was mediated by autocrine or exogenous IFN-gamma through the up-regulation of Fas-L expression, since anti-IFN-gammaR alpha mAb inhibited its expression on Th1 and exogenous IFN-gamma increased its expression on Th2. These results indicate that activated human Th1 and Th2 lymphocytes express IFN-gammaR alpha- and beta-chains and are both sensitive to signals provided by IFN-gamma. Data also suggest that IFN-gamma is critical for switching off their responses.

Apoptosis↗

PubMed1997

Antiblastic chemotherapy drugs up-modulate interferon-gamma receptor expression on human malignant T cells.

We have previously shown that the contrasting ability of interferon-gamma (IFN-gamma) either to stimulate the proliferation of malignant T cells or to induce their apoptosis is determined by the low and high intensity of IFN-gamma receptor (IFN-gamma R) expression, respectively. High IFN-gamma R expression is a marker for the T cell stress that precedes apoptosis. In this paper, we show that a 12- to 24-h culture of three human malignant T-cell lines displaying distinct differentiation stages (ST4, PF382, and Jurkat) in medium supplemented with four chemotherapy drugs (etoposide, cisplatin, cytarabine, and daunomycin) up-modulates their IFN-gamma R expression followed by their apoptosis after 24-48 h later. Increased IFN-gamma R expression (by at least an order of magnitude) was observed in 30 to 90% of cells during exposure to pharmacologic drug concentrations. Timely combination of chemotherapy drugs with IFN-gamma may thus provide a more effective way of inhibiting the progress of human malignant T cells through synergistic induction of their apoptosis.

Antineoplastic Agents↗

PubMed1996

Switching on of the proliferation or apoptosis of activated human T lymphocytes by IFN-gamma is correlated with the differential expression of the alpha- and beta-chains of its receptor.

To find out how physiologically secreted IFN-gamma controls either the proliferation or the apoptosis of human T lymphocytes, the kinetics of expression of the alpha- and beta-chains of its receptor (IFN-gamma R) were sequentially followed on T lymphocytes first activated with PHA and then cultured in the presence of IL-2, and related to the kinetics of expression of Fas, Bcl-2, and IL-2R p55 chain. Both IFN-gamma R chains were poorly expressed on the membrane of resting T lymphocytes. Following their stimulation with PHA, IFN-gamma R alpha but not IFN gamma R beta-chain up-modulated before T lymphocyte entry into the S phase, and then IFN-gamma R alpha down-modulated when they passed through the S and G2/M. The ensuing proliferative response was inhibited by an anti-IFN-gamma R alpha mAb that impeded the binding of IFN-gamma. When PHA-activated T lymphoblasts were cultured for 16 days with IL-2, IFN-gamma R alpha expression increased, whereas that of the beta-chain remained barely detectable. Fas and Bcl-2 were both highly expressed. When these T lymphoblasts were restimulated by PHA, OKT3, or Staphylococcus enterotoxin beta-pokeweed mitogen, both chains up-modulated and most cells underwent apoptosis in a way apparently independent of Bcl-2, but not of Fas. This apoptosis, too, was prevented by the anti-IFN-gamma R alpha mAb. Physiologically secreted IFN-gamma is thus involved in the activation of resting T lymphocytes and in the apoptosis of reactivated lymphoblasts. However, high expression of IFN-gamma R beta took place when IFN-gamma induced apoptosis, but not when it induced proliferation. In conclusion, a correlation exists between differential expression of the IFN-gamma R beta-chain and the delivery by IFN-gamma of proliferative or apoptotic signals.

Antibodies, Monoclonal↗

PubMed1996

Adriamycin-induced proteinuria in nude mice: an immune-system-mediated toxic effect.

BACKGROUND: The renal minimal lesion disease induced in rats by adriamycin (ADR) is generally thought to be consequent to a direct cytotoxic effect of this drug on glomerular epithelial cells. Only recently an altered synthesis of mediators, including reactive oxygen species and monocyte-macrophage cytokines, has been hypothesized. METHODS: A mouse strain (nude) bearing a congenital thymic aplasia is a suitable experimental animal to evaluate the role of immune reactions in the development of the ADR nephropathy, provided mouse susceptibility to its toxic effect. Therefore, experimental mice were divided into three groups (G) each receiving adriamycin 7.5 mg/kg b.w.: GA (15 heterozygous nu/O mice with normal immune system); GB (15 homozygous nu/nu athymic mice); GC (15 homozygous nu/nu mice which were also splenectomized, irradiated, and treated with anti-asialo Gm1 antibody to abolish NK and decrease macrophage activity). All animals were maintained under pathogen-free conditions. Urinary proteins, albumin and TNF-alpha excretion were measured. RESULTS: After 14 days the proteinuria was 43.8+/-1.7 microg/min in GA, 30.2+/-2.9 microg/min in GB (P<0.05) and 12.2+/-2.8 microg/min in GC (GA vs GC, P<0.0001; GB vs GC, P<0.05). Albuminuria gave a similar profile. TNG-alpha urinary excretion was significantly higher in GA (17.3+/-3.2 mU/min) than in GB (5+/-0.6 mU/min, P<0.001) and GC (3.2+/-0.9 mU/min, P<0.001). A significant correlation was found in GA between urinary TNF-alpha and protein losses (r2=0.63 P<0.0001). Kidney tissue homogenates failed to show in each experimental group any evidence of mRNA encoding for TNF-alpha, which was detectable in peripheral mononuclear cells from GA and GB, but undetectable in GC mice. Segmental effacements of glomerular epithelial cell foot process were observed by electron-microscopy in GA only, while they were minimal in GB and absent in GC. Iron colloidal staining for anionic sites on frozen sections always showed a normal pattern. CONCLUSIONS: Nude mice bearing cellular immunity deficiency are protected from proteinuria following ADR toxicity. An impaired synthesis and release of lymphomonocyte mediators including TNF-alpha could be envisaged.

Animals↗

PubMed1995

Inhibitory properties of triethylphosphine goldlupinylsulfide in adjuvant-induced arthritis in rats.

A new gold coordination compound (triethylphosphine goldlupinylsulfide: TP-Au-LS) was tested in adjuvant-induced arthritis in the rat, by oral administration at doses of 5, 10 and 20 mg/kg/day of gold for 17 consecutive days, in comparison with auranofin and betamethasone. TP-Au-LS produced a dose dependent reduction of both the injected and uninjected hind paw volume. Gold levels in serum (measured on day 18 by inductively coupled plasma atomic emission spectrometry) were also found to be dose related. At the dose of 10 mg/kg, TP-Au-LS and auranofin induced superimposable reductions of the injected paw volume; however the first drug produced higher serum gold concentrations than those achieved with the latter.

Animals↗

PubMed1995

Human PBMC proliferative response to Leishmania infantum promastigotes is inhibited by anti-IFN-gamma mAb gamma 123.

PBMC from individuals both exposed and non-exposed to leishmaniae proliferative and produce interferon-gamma (IFN-gamma) following stimulation with Leishmania antigens. We studied the kinetics of the proliferative response of PBMC from non-exposed individuals and from patients recovering from visceral leishmaniasis due to Leishmania infantum, using heat-killed stationary-phase promastigotes of L. infantum as stimulating agent. The kinetics of both groups followed a similar temporal pattern, with higher values in the patient's group. Moreover, we observed that in both groups the activation was dose-dependently inhibited following the addition of gamma 123 anti-IFN-gamma monoclonal antibody. These results indicate the need for IFN-gamma in the activation process of PBMC induced by Leishmania antigens and stress the role of IFN-gamma in the immune response to leishmaniasis. The relevance of the elucidation of the immune response mechanism in human leishmaniasis for therapy and vaccination is briefly discussed.

Animals↗

PubMed1994

An efficient Th2-type memory follows CD8+ lymphocyte-driven and eosinophil-mediated rejection of a spontaneous mouse mammary adenocarcinoma engineered to release IL-4.

A retroviral infection was used to introduce the cDNA coding for mouse IL-4 into the parental cells of a spontaneous adenocarcinoma of BALB/c mice (TS/A-pc). Four clones releasing between 5 to 40 U of IL-4 (10(5) cells) in 48 h culture were selected. The secretion of IL-4 does not affect their in vitro growth, whereas their ability to form tumor in vivo inversely correlates with the amount of IL-4 secreted. Although morphologic observation suggested that the rejection of clone D5.40 cells (releasing 40 U of IL-4) depends on eosinophil cytolysis, lymphocyte depletion experiments showed that this required CD8+ lymphocyte guidance. Mice that had rejected D5.40 cells were immune to a subsequent challenge with TS/A-pc. This memory rests on the interaction between noncytotoxic lymphocytes, eosinophils, and IgG1 and IgE anti-TS/A Abs. Comparison of these memory mechanisms with those elicited by IL-2 gene-transduced TS/A cells shows that the kind of cytokine released by the tumor cells determines the type of response. This Th2 memory seems to be more efficient in protecting against a subsequent challenge of TS/A-pc than the Th1-type memory elicited by IL-2 gene-transduced TS/A cells.

Adenocarcinoma↗

PubMed1994

Environmental signals influencing expression of the IFN-gamma receptor on human T cells control whether IFN-gamma promotes proliferation or apoptosis.

IFN-gamma R expression is subject to contrasting modulation on human T cells. IFN-gamma R constitutive expression is low on three human malignant T cells (ST4, PF382, and Jurkat) growing in medium supplemented with serum. The addition of IFN-gamma down-modulates IFN-gamma R expression and increases both proliferation and MHC class I Ag expression. By contrast, when malignant T cells are cultured in medium without serum, IFN-gamma R expression dramatically increases and the cells undergo a slow apoptotic death. The addition of IFN-gamma enhances apoptosis and inhibits cell rescue in serum-supplemented medium. This opposite ability of IFN-gamma to stimulate malignant T cell proliferation or death correlates with the intensity of IFN-gamma R cell expression, high expression being a marker for cell apoptosis. IFN-gamma R up-modulation also occurs on malignant T cells undergoing apoptosis after treatment with dexamethasone, on irradiated normal CD3+ PBL, and on cultured normal CD3+ thymocytes. Moreover, the ability of IFN-gamma to augment apoptosis of highly IFN-gamma R-positive thymocytes suggests that its role in promoting T cell apoptosis is also important in physiologic conditions.

Apoptosis↗

PubMed1994

Quinolizidine derivatives with antitubercular activity.

By reacting lupinylmagnesium chloride with suitable aromatic ketones, several lupinyldiarylcarbinols were obtained, whose dehydration gave the corresponding lupinylidenediarylmethanes. By reduction of three of these unsaturated compounds, the corresponding lupinyldiarylmethanes were also obtained. Direct condensation of lupinine with fluorene gave the 9-epi-lupinylfluorene. The quinolizidine derivatives obtained were tested against Mycobacterium tuberculosis H37RV. Nine compounds resulted endowed with good antitubercular activity with MIC < 8 micrograms/ml, while the remaining were only moderately active. Most interesting was the lupinylidene derivative 13 with MIC > 0.1 < 0.5 micrograms/ml.

Antitubercular Agents↗

PubMed1994

Proliferative response of human T cells to stimulation with Leishmania infantum and L. major promastigotes in logarithmic and stationary growth phase.

T cells from healthy donors, non-exposed to Leishmania, proliferative and produce lymphokines when cultured in the presence of killed Leishmania promastigotes. We compared the stimulative activity of L. major and L. infantum promastigotes harvested in logarithmic and stationary growth phase on human T cells by performing a proliferation kinetics during the first 5 days of culture. Stationary-phase promastigotes induced a good response at the 4th-5th day, whereas the effect of logarithmic-phase promastigotes was almost undetectable. Both species gave a similar pattern. The implications of these findings in the current model of immunologic reaction to leishmaniasis are discussed.

Animals↗

PubMed1993

Modulation of interferon-gamma receptor during human T lymphocyte alloactivation.

Previous work has shown that neutralization of physiologically secreted interferon(IFN)-gamma or blockade of its receptor during T lymphocyte activation inhibits both proliferation and cytotoxic T lymphocyte generation, suggesting that IFN-gamma plays a crucial role in T lymphocyte induction and differentiation. In this study, the kinetics of the surface expression of the 90-kDa IFN-gamma receptor (IFN-gamma R) was followed during human mixed lymphocyte reaction (MLR) to alloantigens. IFN-gamma R mRNA is constitutively expressed on resting peripheral blood lymphocytes emerging from nylon wood column (NW-PBL) and its expression increases two- to threefold on alloactivated NW-PBL. IFN-gamma R protein is poorly expressed on the membrane of resting CD3+ cells, but up-modulates after 3-day MLR and sharply down-modulates at day 6. Both the p55 and the p75 chains of interleukin-2 receptor (IL-2R) were shown to up-modulate in parallel with IFN-gamma R, whereas they were still highly expressed at day 6. After alloactivation, IFN-gamma and IL-2 secretion starts at 24 h, peaks at day 3 and decreases just when IFN-gamma R and IL-2R begin to up-modulate. Proliferation peaks at day 6. Lastly, stimulation with distinct cell populations showed that the intensity of lymphocyte proliferation, IFN-gamma R membrane up-modulation, and IFN-gamma and IL-2 secretion are regulated in a parallel manner, thus suggesting that they are interrelated. Taken as whole these results demonstrate that increased expression of IFN-gamma R on T lymphocytes can be a critical event during their activation, and strongly support the hypothesis that IFN-gamma/IFN-gamma R interaction provides a signal for its progression.

Cell Line↗

PubMed1993

Thiolupinine and some derivatives of pharmacological interest.

The (quinolizidin-1 alpha-yl)methanthiol (thiolupinine) was prepared and, utilizing the thiol group reactivity, several S-substituted derivatives were obtained among which was a group of 3-[(lupinylthio)methyl]indoles. Eight of the prepared compounds were subjected to a broad pharmacological screening that evidentiated for many of them good level of the following activities in vivo and in vitro: antiarrhythmic, local anesthetic, negative chronotropic on isolated atria, calcium antagonism on ileum and atria, inhibition of spontaneous contraction of isolated trachea, inhibition of guinea pig ileum contractions induced by angiotensin I and II, bradykinin and cholecystokinin, inhibition of platelet aggregation induced by PAF and ADP. Single compounds were remarkable for additional antagonistic activities: 4 against P1-purine receptor, 8 against substance P, 12 against methacholine and 13 strongly inhibited arachidonate induced platelet aggregation. Very peculiar was the ability of compound 6 to protect mice from PAF induced mortality.

Anesthetics, Local↗

PubMed1992

Distribution of interferon-gamma receptor in human tissues.

Interferon-gamma (IFN-gamma) is produced by activated T lymphocytes and plays a regulatory role in immune responses. The nature and location of cells that express the IFN-gamma receptor (R) and respond to this lymphokine are not well documented. The distribution of human IFN-gamma-R (HuIFN-gamma-R) was, therefore, investigated in situ by immunohistochemistry, using affinity-purified rabbit polyclonal antibodies directed against the extracellular domain of the receptor. In lymphoid organs, IFN-gamma-R expression is restricted to the B cell areas of lymph nodes, adult and fetal spleen, tonsils, appendix, and mucosa-associated lymphoid tissue of the small bowel. Macrophages and other reticular cells in lymphoid tissues and other organs are strongly positive for IFN-gamma-R, whereas its expression was consistently negative in the cortical and medullary thymocytes. Two-color flow cytofluorometric analysis of blood, lymph node, tonsil, spleen and thymus cells confirms that most B lymphocytes are IFN-gamma-R positive, whereas T lymphocytes are negative. However, after in vitro activation, peripheral blood T cells become IFN-gamma-R+. In non-lymphoid organs, IFN-gamma-R is expressed on endothelial cells of the medium- and small-size vessels. In epithelial tissues, high expression of IFN-gamma-R is detected on trophoblastic epithelium, glandular cells of stomach, ileum and colon, lung alveolar cells, salivary duct cells, renal tubular cells, and endometrial mucosa cells. Hepatocytes are weakly positive, while squamous epithelial cells are negative. The distribution of the HuIFN-gamma-R is discussed in view of the known functions of IFN-gamma.

Animals↗

PubMed1991

Blockade of physiologically secreted IFN-gamma inhibits human T lymphocyte and natural killer cell activation.

The role of physiologically secreted human IFN-gamma in T lymphocyte and NK cell activation has been probed with a panel of mouse mAb directed against various epitopes of the human IFN-gamma molecule, or human IFN-gamma R. Addition to the culture medium of those mAb that neutralize the antiviral activity of IFN-gamma or interact with its receptor inhibited proliferative and cytotoxic responses elicited in PBL by HLA alloantigens, anti-CD3 mAb, and IL-2, but not the proliferative response to PHA. The IFN-gamma blockade also inhibited IFN-gamma, IL-2, and TNF-alpha release during MLC. Kinetic experiments showed that reduction of proliferative and cytotoxic responses to HLA alloantigens is maximal when IFN-gamma is blocked within the first 48 h. Exogenous rIFN-gamma restored the proliferative response only when added at the beginning. Moreover, when IFN-gamma was blocked, T lymphocytes recovered from 6-day MLC displayed a profound decrease in their expression of p55 and p75 chains of the IL-2R, as well as in the number of high-affinity IL-2 binding sites. These findings strongly suggest that IFN-gamma is required in the early phases of induction of the oligo- and polyclonal proliferative and cytotoxic responses of lymphocytes.

Antibodies, Monoclonal↗

PubMed1989

[Preparation and pharmacologic activity of amido- derivatives of 3-methyl-3,4-dihydro benzo- and pyrido-1,2,4-triazin-3-acetic acids].

Thirteen amidoderivatives of 3-methyl-3,4-dihydro-6-R-benzo-1,2,4-triazin-3-yl-acetic acids and of 3-methyl-3,4-dihydro-pyrido [3,2-e]/[3,4-e]-1,2,4-triazin- 3-yl-acetic acids were prepared and submitted to a wide pharmacological screening. The dihydrobenzotriazine and dihydropyridotriazine moieties were endowed with a wide pharmacogenic capacity; in fact, several compounds exhibited high antiinflammatory [(I c), (I d), (II d), (V f), (VI f)], diuretic [(I f), (I g), (I h)] and antihypertensive activities [(I d), (III d)], as well as minor effects on the C.N.S.

Acetates↗

PubMed1988

Single kidney function: effect of acute protein and water loading on microalbuminuria.

The hyperfiltration induced by an acute response to an oral protein and water load was investigated to ascertain whether it can modify the urinary albumin excretion (UAE) in the microalbuminuric range by further increasing the glomerular filter permeability. To this end, six patients with a single kidney selected as having microalbuminuria on a regular diet without the clinical or laboratory data of overt renal disease and eight healthy subjects received a short-term protein and water load (150 g of meat-derived protein and 1 liter of water). In patients with one kidney, mean basal UAE values were significantly higher than in control subjects (p less than 0.006), whereas endogenous creatinine clearance values were only slightly lower (p greater than 0.05). One hour after the protein and water load, an abrupt increase in microalbuminuria levels was found in patients with one kidney and mean UAE values were significantly higher than in control subjects (p less than 0.002), whereas mean creatinine clearance values were significantly lower in patients than in control subjects (p less than 0.01). High UAE (p less than 0.002) and low creatinine clearance (p less than 0.002) values were maintained over the following four hours in patients with one kidney. These data suggest that in the single kidney with reduced renal functional reserve, an oral protein and water load magnifies the pre-existing loss of glomerular permselective properties due to chronic hyperfiltration as manifested by a further increase in microalbuminuria.

Adult↗