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Biomedical subjects

M Fontaine

Publications and source records attributed to M Fontaine.

At least 73 records · Page 4Linked to original sources
PubMed1993

Preliminary studies about novel strategies to reverse chemoresistance to adriamycin regarding glutathione metabolism, peroxisomal and extraperoxisomal hydroperoxide and valproic acid metabolic pathways.

The present work was aimed at defining novel strategies to reverse chemoresistance to anticancer drugs, especially by interfering with cellular glutathione metabolism, peroxisomal and/or extraperoxisomal hydroperoxide metabolic pathways. Preliminary results are presented about molecules we demonstrated to be capable of interfering with hydrogen peroxide metabolism in cells. Prior to describing these molecules, a short overview of glutathione and free radical metabolic pathways is presented as well as a rapid presentation of the characteristics of chemo-sensitivity and -resistance towards the anticancer drug adriamycin, with special emphasis on hydrogen peroxide metabolism. The strategies currently developed to reverse chemoresistance are further presented in subsequent sections, our own strategy to achieve inhibition of hydrogen peroxide breakdown and stimulation of peroxisomal hydrogen peroxide production is illustrated on the basis of molecular modelling studies and biochemical investigations on extraperoxisomal and peroxisomal metabolic pathways. Preliminary studies on cultured cells have been initiated. The perspective for future studies is presented as well as other possible models of chemoresistance as target for the design of hydrogen peroxide metabolism-interfering pharmacomolecules.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Local and systemic activation of the whole complement cascade in human leukocytoclastic cutaneous vasculitis; C3d,g and terminal complement complex as sensitive markers.

We have studied complement activation both in plasma samples and in lesional skin from patients with leukocytoclastic cutaneous vasculitis (LCV). Enzyme immunoassay (EIA) quantification of the complement activation markers, C3d,g and the terminal complement complex (TCC) in plasma, showed that their levels were significantly increased in 66% and 55% of the patients, respectively (n = 29) compared with healthy controls, whereas the standard measurements of C3, factor B, C1q, C4 and C2 were generally within normal range. Elevations of C3d,g and TCC levels in plasma were significantly correlated. Importantly, a significant correlation was found between the severity of the vasculitis and both C3d,g and TCC plasma levels. Immunofluorescence studies of skin biopsy specimens demonstrated simultaneous presence of perivascular dermal deposits of C3d,g and TCC in lesional skin from 96% and 80% respectively of the patients (n = 25). There was a significant correlation between the intensity of the deposits of both markers. Clusterin, a TCC inhibitory protein, was always found at the same sites of perivascular TCC deposits. Immunofluorescence studies at the epidermal basement membrane zone (BMZ) revealed in each case deposits of C3d,g which were accompanied by TCC deposits in 52% of the biopsy specimens. These data demonstrate that there is a local and systemic activation of the whole complement cascade in human LCV. The presence of both C3d,g and clusterin-associated TCC perivascular deposits suggests an intervention of a regulatory mechanism of local complement activation in LCV. Finally, measurement of plasma C3d,g and TCC appears to be a sensitive indicator of systemic complement activation and disease severity in LCV.

Aged↗
PubMed1992

Expression of complement components of the alternative pathway by glioma cell lines.

Glioma cell lines express proteins of the complement alternative pathway, namely C3, factor B, factor H, and factor I. Secretion of these proteins was shown by a sensitive and specific ELISA. C3 and factor H were rapidly secreted by glioma cell line CB193 and reached a concentration of 140 ng/ml/10(6) cells after 72 h of culture. Factor B and factor I were secreted at a lower rate and reached concentrations of 25 and 15 ng/ml/10(6) cells, respectively. Western blot and immunoprecipitation experiments showed that secreted proteins were identical to the corresponding plasma proteins. For factor H, besides the well known 150-kDa species, an additional polypeptide of 45 kDa with factor H immunoreactivity was observed. This species corresponded to the N-terminal truncated form found in plasma. In preliminary experiments, we observed control of these syntheses by cytokines. IL-1 beta significantly increased C3 secretion, with no effect on factor H. Secretion of factor H was enhanced by IFN-gamma. These results show that a glioma cell line could be a useful tool to study complement biosynthesis by glial cells in humans.

Complement C3↗
PubMed1992

In vitro biosynthesis of complement factor I by human endothelial cells.

We have studied the secretion of the complement regulatory protein factor I by human umbilical vein endothelial cells (HUVEC). Northern and Western blot analysis and biosynthetic labeling experiments indicate that HUVEC secrete factor I at very low levels in basal conditions and that this secretion is significantly enhanced by interferon-gamma. Analysis of the proteolytic inactivation of C3b by HUVEC supernatants show that factor I is secreted in a functional form and can promote the specific proteolytic inactivation of C3b to iC3b. Together with previous studies establishing the secretion of complement factor H by HUVEC, this work demonstrates that the endothelial cell is able to secrete in its environment two complement regulatory proteins, factor I and factor H, which can mediate the degradation of C3b to iC3b. The secretion of factor I by HUVEC provides a useful in vitro model to analyze the modulation of this secretion and may be relevant to the local deposition of iC3b at the surface of the endothelium during the inflammatory reaction.

Cells, Cultured↗
PubMed1992

Differential modulation by glucocorticoids of alternative complement protein secretion in cells of the monocyte/macrophage lineage.

The effect of the synthetic glucocorticoid dexamethasone (DXM) on the secretion by human monocytes of alternative complement proteins C3, factor B and factor H was investigated. Results indicated that DXM modulates this secretion in a direction which would be consistent with its anti-inflammatory properties. DXM, at therapeutic concentrations, had a suppressive effect on C3 and factor B secretion and a stimulatory effect on factor H secretion by monocytes. This differential modulation on C3, factor B and factor H secretion was similar in mature macrophages. Together with previous studies showing that DXM had a suppressive effect on C3 and factor B secretion and a stimulatory effect on factor H secretion by human endothelial cells, our results indicate that DXM appears to have the general property of regulating local production of complement components so as to control complement activation.

Cell Differentiation↗
PubMed1992

[Efficacy and tolerance of a dietary iron supplement (Bio-fer) in pregnancy anemia].

Fifty pregnant women with a hemoglobin between > 10 and < or = 12 g/100 ml during the second three months of pregnancy participated in a non-comparative clinical trial intended to evaluate, during a one month treatment period, the acceptability and effectiveness of an iron supplement (Bio-fer), combined with a high iron diet. Gastric discomfort regressed (present in 11 and 3 women before and after treatment) (p < 0.05), the same applying to constipation (p < 0.05) (present in 17 and 8 women before and after treatment). Reasons for abandoning treatment were nausea (n = 2) and vertigo (n = 1). Anemia or deficiency, evaluated on the basis of hemoglobin and iron-binding capacity levels, improved or stabilised in 34 patients out of 47 (72.3%). Hemoglobin increased (p < 0.0001) on average from 11.4 +/- 0.6 to 11.7 +/- 0.8 g/100 ml.

Adult↗
PubMed1991

Evidence for an active hydrophobic form of factor H that is able to induce secretion of interleukin 1-beta or by human monocytes.

We studied the capacity of human factor H to promote the secretion of a lymphocyte-activating factor (LAF) by human monocytes cultured under serum-free conditions. Presence of LAF in the culture supernatants was assessed with the mouse thymocyte assay. Highly purified factor H alone had no effect on thymocyte proliferation. When monocytes were cultured with factor H for 24 h, a significant secretion of LAF was observed. The effect was dose dependent over a range of factor H concentrations from 1 to 15 micrograms/ml. Polymyxin B did not abrogate the capacity of factor H to induce LAF secretion. Adsorption of factor H preparations onto anti-factor H-Sepharose completely suppressed the phenomenon. Conversely, the activity was recovered in the acidic eluate. Furthermore, factor H subpopulation phi 2, that was able to bind to phenyl-Sepharose, was a stronger inducer of LAF secretion by monocytes than the subpopulation phi 1 (which did not bind to phenyl-Sepharose). Using a specific radioimmunoassay for interleukin 1-beta (IL 1 beta), we observed a good correlation between the LAF activity and the amount of IL 1 beta secreted by human monocytes stimulated with factor H. We have shown previously that factor H (phi 2) bound specifically on Raji cells whereas factor H (phi 1) did not. These results argue for the participation of the interaction of factor H with its receptor to stimulate the secretion of IL 1 by monocytes and that the phi 2 form of factor H is a ligand for the human factor H receptor.

Cells, Cultured↗
PubMed1990

Expression of complement alternative pathway proteins by endothelial cells. Differential regulation by interleukin 1 and glucocorticoids.

We have studied the secretion of proteins of the alternative pathway of complement C3, factor B and factor H by human umbilical vein endothelial cells (HUVEC). Results showed that factor H and factor B are quantitatively secreted in abundance whereas C3 could only be detected when the cells are maintained in culture during long periods of time. Interferon-gamma stimulated factor H, factor B and, to a lesser extent, C3 secretions. Interleukin (IL) 1 had a differential effect on spontaneous C3, factor B and factor H secretions. In the presence of IL 1, there was a significant secretion of C3 occurring within a short period of culture. IL 1 also stimulated factor B secretion. There was a synergistic stimulating effect between IL 1 and interferon-gamma to bring C3 and factor B productions by HUVEC to very high levels. In contrast, factor H secretion was consistently inhibited by IL 1. Local increase in C3 and factor B secretions by endothelial cells in the presence of IL 1 may have important implications in the inflammatory reaction. In striking contrast, the glucocorticoid dexamethasone (DXM) had modulatory effects which are consistent with its anti-inflammatory properties. DXM, at therapeutic concentrations, decreased C3 and factor B secretions and increased factor H secretion. Local modulation of complement protein secretion by DXM appears to be a new mechanism by which this glucocorticoid may control inflammation.

Complement C3b Inactivator Proteins↗
PubMed1990

Comparison of two techniques to isolate microvascular endothelial cells from the omentum.

The purpose of the study was to compare two different techniques for isolation of omental microvascular endothelial cells (ECs). Segments of unreinforced polytetrafluorethylene (PTFE) grafts, 9 cm long and 6 mm in diameter, were implanted in 22 dogs as an aortic interposition. Fourteen grafts were seeded with a mean of 7 x 10(5) viable ECs, derived from the microvessels of the omentum: eight grafts (group A) were seeded with ECs obtained by collagenase digestion and by filtration through a pore mesh; six grafts (group B) were seeded with ECs obtained by collagenase digestion and by Percoll gradient separation. In eight grafts (group C), the ECs were not added to the preclot mixture and served as a control. Animals were sacrificed 5 weeks after surgery. The percentage of thrombus-free area was 65 +/- 22% for group A grafts and 74 +/- 15% for group B grafts (NS). The subendothelial layer was 280 +/- 60 microns thick in group A and 220 +/- 30 microns thick in group B (P less than 0.05). Seeded grafts showed a higher production of 6-keto-PGF1 alpha after addition of sodium arachidonate than control grafts. Percoll gradient separation allows isolation of a more purified suspension of ECs. Refinements in omental EC procurement are still required to minimize contamination with other types of cells.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

[Study of the complement system. General principles and perspectives].

Measurement of complement in clinical medicine is traditionally based on the determination of CH50 and immunochemical and/or functional measurement of complement proteins C1q, factor B, C3 and C4. The interpretation of these measurements, as far as complement activation is concerned, can however be difficult as these tests do not allow to discriminate between consumption due to activation, hereditary deficiency, increased rate of synthesis or even hyposynthesis. This explains why their use as markers of evolutivity in diseases where complement activation is occurring has given variable results. New tests for complement activation have been more recently introduced. These are mainly the measurements of the anaphytotoxins, the degradation products of C3 and the membrane attack complex. As these tests reflect more directly complement activation, they may be more reliable markers. The immunochemical and functional measurements of C1-inhibitor are of special interest as they are the tests which allow definitive diagnosis of the hereditary angio-oedema. General principles for the interpretation of the different tests used to evaluate the complement system are presented and discussed.

Anaphylatoxins↗