Biomedical subjects

Véronique Barbu

Publications and source records attributed to Véronique Barbu.

8 recordsLinked to original sources

PubMed2005

Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome.

Silver-Russell syndrome (SRS, OMIM 180860) is a congenital disorder characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features and body asymmetry. SRS is genetically heterogenous with maternal uniparental disomy with respect to chromosome 7 occurring in approximately 10% of affected individuals. Given the crucial role of the 11p15 imprinted region in the control of fetal growth, we hypothesized that dysregulation of genes at 11p15 might be involved in syndromic intrauterine growth retardation. We identified an epimutation (demethylation) in the telomeric imprinting center region ICR1 of the 11p15 region in several individuals with clinically typical SRS. This epigenetic defect is associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 and downregulation of IGF2. These findings provide new insight into the pathogenesis of SRS and strongly suggest that the 11p15 imprinted region, in addition to those of 7p11.2-p13 and 7q31-qter, is involved in SRS.

CCCTC-Binding Factor↗

PubMed2005

Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis.

Epidermal growth factor receptor (EGFR) binds transforming growth factor alpha (TGF-alpha) which is mitogenic for hepatocytes. Diverse lines of evidence suggest that activation of the TGF-alpha /EGFR pathway contributes to hepatocellular carcinoma (HCC) formation. Herein, we developed an experimental model of cirrhosis giving rise to HCC and tested the antitumoral effect of gefitinib, a selective EGFR tyrosine kinase inhibitor, in this model. Rats received weekly intraperitoneal injections of diethylnitrosamine (DEN) followed by a 2-week wash-out period that caused cirrhosis in 14 weeks and multifocal HCC in 18 weeks. Hepatocyte proliferation was increased in diseased tissue at 14 weeks compared with control liver and at even higher levels in HCC nodules compared with surrounding diseased tissues at 18 weeks. Increased proliferation was paralleled by upregulation of TGF-alpha messenger RNA expression. A group of DEN-treated rats received daily intraperitoneal injections of gefitinib between weeks 12 and 18. In rats treated with gefitinib, the number of HCC nodules was significantly lower than in untreated rats (18.1 +/- 2.4 vs. 3.7 +/- 0.45; P < .05), while EGFR was activated to a lesser extent in the diseased and tumoral tissues of these animals compared with untreated rats. HCC nodules from both untreated and gefitinib-treated animals displayed insulin-like growth factor 2 overexpression that contributed to tumor formation in treated animals. In conclusion, the blockade of EGFR activity by gefitinib has an antitumoral effect on the development of HCC in DEN-exposed rats, suggesting that it may provide benefit for the chemoprevention of HCC.

Alkylating Agents↗

PubMed2005

VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium.

Vasoactive intestinal peptide receptor-1 (VPAC1) is the high-affinity receptor of vasoactive intestinal peptide (VIP), a major regulator of bile secretion. To better define the level at which VPAC1 stimulates bile secretion, we examined its expression in the different cell types participating in bile formation (i.e., hepatocytes, bile duct, and gallbladder epithelial cells). Because VPAC1 expression was previously shown to be regulated by nuclear receptors, we tested the hypothesis that it may be regulated by the farnesoid X receptor (FXR). Quantitative RT-PCR and immunoblot analyses of cell isolates indicated that VPAC1 is expressed in all three cell types lining the human biliary tree, with predominant expression in the gallbladder. In primary cultures of human gallbladder epithelial cells, VIP induced cAMP production and chloride secretion. Analysis of the VPAC1 gene revealed the presence of potential FXR response element sequences, and both FXR and RXRalpha expressions were detected in gallbladder epithelial cells. In these cells, the FXR pharmacological agonist GW4064 upregulated VPAC1 expression in a dose-dependent manner, and this effect was antagonized by the RXRalpha ligand, 9-cis retinoic acid. Chenodeoxycholate activated endogenous FXR in gallbladder epithelial cells, as ascertained by electromobility shift assay and upregulation of the FXR target gene, small heterodimer partner. Chenodeoxycholate also provoked an increase in VPAC1 mRNA and protein content in these cells. In conclusion, FXR agonists may increase gallbladder fluid secretion through transcriptional activation of VPAC1, which may contribute to the regulation of bile secretion by bile salts and to a protective effect of FXR pharmacological agonists in gallstone disease.

Base Sequence↗

PubMed2005

Adaptative bile duct proliferative response in experimental bile duct ischemia.

BACKGROUND/AIMS: A rat model of bile duct ischemia was established and used to examine the potential of bile duct proliferation to provide an adaptative response in cholestatic disorders. METHODS: Rats underwent partial or complete arterial deprivation of the liver. Serum biochemical tests, histological analyses and bile secretion measurements were performed at different time points up to 6 weeks after surgery. RESULTS: Rats developed biochemical signs of cholestasis exclusively after complete arterial deprivation. Within 4h, cholangiocytes in these rats showed morphological signs of cell damage. After 48h, they displayed VEGF expression and became proliferative. The proportion of Ki67-labeled cholangiocytes ( approximately 30%) was similar in interlobular bile ducts and periportal ductules. A ductular reaction made of well-formed bile ducts confined to portal tracts developed within 1 week. Bile flow which was initially decreased, was restored at 3 weeks, while the biochemical signs of cholestasis completely resolved at 6 weeks. At this time, the number of bile duct sections was maximal. Fibrosis intensity was also maximal, although moderate (<F2 METAVIR staging) as assessed by Sirius-red staining morphometry. CONCLUSIONS: In the present model of bile duct ischemia, ductular reaction derives from bile ducts of all anatomical compartments, and provides a poorly fibrogenic functional response to biliary dysfunction.

Animals↗

PubMed2004

Rapamycin inhibits cdk4 activation, p 21(WAF1/CIP1) expression and G1-phase progression in transformed mouse fibroblasts.

Rapamycin, a bacterial macrolide antibiotic, is a potent immunosuppressant agent that blocks cell proliferation by inhibiting the G1/S transition in several cell types. In sensitive cells, rapamycin inhibits the phosphorylation of p70 S6K and of Rb; however, the precise mechanisms involved have not been elucidated. In the mouse BP-A31 fibroblasts, synchronised in G0/G1 phase by serum starvation and induced to reinitiate the G1-phase progression, rapamycin inhibited the entry into S phase. The effect of rapamycin was situated in early G1 phase. The assembly of the cyclin D1/cdk4 complexes that phosphorylate Rb early in the G1 phase was not modified by the drug. Nevertheless, an inhibition of the activation of cyclin D1/cdk4 and cyclin E/cdk2 as well as of Rb phosphorylation accompanied the cell cycle arrest. Remarkably, rapamycin reduced the level of total p21(WAF1/CIP1) as well as that of p21(WAF1/CIP1) associated with the cyclin D1/cdk4 complexes. Besides its inhibitory activity toward cdk, p21(WAF1/CIP1) has been recently found to participate in the formation/stabilisation/nuclear translocation of cyclin D1/cdk4 complexes. We propose that the inhibition of the expression of p21(WAF1/CIP1) is a mechanism by which rapamycin inhibits the triggering of the cdk cascade in the BP-A31 cells.

3T3 Cells↗

PubMed2004

[Biliary function and its regulation].

Biliary function is essential for intestinal absorption of fat, homeostasis of cholesterol and elimination of diverse metabolic end-products. Bile is elaborated in hepatocyte canaliculi and modified by cholangiocytes through both secretion and absorption processes. The main determinant of bile formation is an osmotic filtration process resulting from active transport of bile acids and other osmotic solutes. Most of the membrane transporters ensuring bile formation have now been identified. The expression of these membrane transporters is regulated in particular through transcriptional mechanisms under the control of nuclear receptors activated by ligands, such as bile acids, which act as endogenous steroids synthesized from cholesterol in hepatocytes. Monogenic cholestatic diseases illustrate the key role of membrane transporters in biliary function. Bile acids are potent modulators of transporters and thus trigger an adaptative response to cholestasis. The extent of this adaptative response could explain the compelling phenotypic variability of cholestatic diseases in childhood and adults. The firstline medical treatment is currently ursodeoxycholic acid. In case of failure of this medical treatment, liver transplantation is required. Recent progress in the molecular pathogenesis of bile formation and cholestatic liver diseases is expected to provide the design for drugs targeted to the molecular abnormalities responsible of cholestatic diseases.

Animals↗

PubMed2003

Frequency of cytochrome P450 2C9 allelic variants in the Chinese and French populations.

Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme responsible for the metabolism of different drugs with low therapeutic index such as oral anticoagulants. CYP2C9*2 and CYP2C9*3 are two single nucleotide polymorphic allelic variants. The frequency of these alleles in different ethnic populations is extremely variable. In this study, we compared the frequencies of CYP2C9 allelic variants among 394 Chinese living in Shanghai to 151 French Caucasians living in Paris. The allelic frequencies of CYP2C9 variants of the Chinese and the French subjects were 0.963, 0.001, 0.036 and 0.77, 0.15, 0.08 for CYP2C9*1, CYP2C9*2, CYP2C9*3, respectively. Chinese CYP2C9*3 allelic frequency was twice as lower as the French subjects, but three times higher than Korean (0.036 vs. 0.011). The CYP2C9*2 allele could be detected in only one Chinese subject, whereas it represented the major allelic variant in French Caucasians. The low frequency of the CYP2C9*2 and CYP2C9*3 allelic variants in Chinese subjects does not justify their detection in clinical practice, unlike French Caucasians.

Adolescent↗

PubMed2003

The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis.

The origin of myofibroblasts and the factors promoting their differentiation during liver fibrogenesis remain uncertain. During biliary-type fibrogenesis, the proliferation and chemoattraction of hepatic stellate cells (HSC) toward bile ducts is mediated by platelet-derived growth factor (PDGF), while myofibroblastic conversion of peribiliary cells distinct from HSC also occurs. We herein examined the phenotype of these peribiliary myofibroblasts as compared with myofibroblastic HSC and tested whether their differentiation was affected by PDGF. Biliary-type liver fibrogenesis was induced by common bile duct ligation in rats. After 48 hours, periductular fibrosis in portal tracts colocalized with smooth muscle alpha-actin-immunoreactive myofibroblasts, the majority of which were desmin negative. Simultaneously, in sinusoids, desmin immunoreactivity was induced in a large number of HSC, which were smooth muscle alpha-actin negative. Cultures of peribiliary myofibroblasts were expanded from isolated bile duct segments and compared with myofibroblastic HSC. Peribiliary myofibroblasts outgrowing from bile duct segments expressed smooth muscle alpha-actin, alpha1 (I) collagen mRNA, and PDGF receptor-beta subunit. Desmin immunoreactivity gradually decreased in cultured peribiliary myofibroblasts, contrasting with constant labeling of all myofibroblastic HSC. In addition, IL-6 expression in peribiliary myofibroblasts was up to 100-fold lower than in myofibroblastic HSC, whereas the expression of the complement-activating protease P100 in both cell types showed little difference and that of the extracellular matrix component fibulin 2 was similar. The expression of smooth muscle alpha-actin protein in cultured peribiliary myofibroblasts was stimulated by PDGF-BB and inhibited by STI571, a PDGF receptor tyrosine kinase inhibitor, whereas in bile duct-ligated rats, the administration of STI571 caused a significant decrease in peribiliary smooth muscle alpha-actin immunoreactivity, and to a lesser extent, a decrease in peribiliary fibrosis. These results indicate that peribiliary cells distinct from HSC undergo a PDGF-mediated conversion into myofibroblasts expressing IL-6 at lower levels than myofibroblastic HSC and contribute to the initial formation of biliary-type liver fibrosis.

Actins↗