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1.
Biochem Biophys Res Commun ; 682: 207-215, 2023 11 19.
Article in English | MEDLINE | ID: mdl-37826944

ABSTRACT

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is known to be linked with metabolic associated fatty liver disease and type 2 diabetes, but few studies assessed this relationship in prediabetes, especially among women, who are at greater risk of CVD. We aimed to evaluate cardiac alterations and its relationship with hepatic lipid metabolism in prediabetic female rats submitted to high-fat-high-sucrose diet (HFS). METHODS AND RESULTS: Wistar female rats were divided into 2 groups fed for 5 months with standard or HFS diet. We analyzed cardiac morphology, function, perfusion and fibrosis by Magnetic Resonance Imaging. Hepatic lipid contents along with inflammation and lipid metabolism gene expression were assessed. Five months of HFS diet induced glucose intolerance (p < 0.05), cardiac remodeling characterized by increased left-ventricular volume, wall thickness and mass (p < 0.05). No significant differences were found in left-ventricular ejection fraction and cardiac fibrosis but increased myocardial perfusion (p < 0.01) and reduced cardiac index (p < 0.05) were shown. HFS diet induced hepatic lipid accumulation with increased total lipid mass (p < 0.001) and triglyceride contents (p < 0.05), but also increased mitochondrial (CPT1a, MCAD; (p < 0.001; p < 0.05) and peroxisomal (ACO, LCAD; (p < 0.05; p < 0.001) ß-oxidation gene expression. Myocardial wall thickness and perfusion were correlated with hepatic ß-oxidation genes expression. Furthermore, myocardial perfusion was also correlated with hepatic lipid content and glucose intolerance. CONCLUSION: This study brings new insights on the relationship between cardiac sub-clinical alterations and hepatic metabolism in female prediabetic rats. Further studies are warranted to explore its involvement in the higher CVD risk observed among prediabetic women.


Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Glucose Intolerance , Prediabetic State , Humans , Rats , Female , Animals , Prediabetic State/metabolism , Sucrose/adverse effects , Sucrose/metabolism , Lipid Metabolism , Glucose Intolerance/metabolism , Diabetes Mellitus, Type 2/metabolism , Ventricular Remodeling , Stroke Volume , Rats, Wistar , Ventricular Function, Left , Liver/metabolism , Fibrosis , Perfusion , Cardiovascular Diseases/metabolism , Lipids , Diet, High-Fat/adverse effects
2.
Cardiovasc Diabetol ; 20(1): 57, 2021 03 01.
Article in English | MEDLINE | ID: mdl-33648515

ABSTRACT

BACKGROUND: Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has demonstrated cardiovascular and renal protection in patients with type 2 diabetes (T2D). We hypothesized that empaglifozin (EMPA) could modulate ectopic fat stores and myocardial energetics in high-fat-high-sucrose (HFHS) diet mice and in type 2 diabetics (T2D). METHODS: C57BL/6 HFHS mice (n = 24) and T2D subjects (n = 56) were randomly assigned to 12 weeks of treatment with EMPA (30 mg/kg in mice, 10 mg/day in humans) or with placebo. A 4.7 T or 3 T MRI with 1H-MRS evaluation-myocardial fat (primary endpoint) and liver fat content (LFC)-were performed at baseline and at 12 weeks. In humans, standard cardiac MRI was coupled with myocardial energetics (PCr/ATP) measured with 31P-MRS. Subcutaneous (SAT) abdominal, visceral (VAT), epicardial and pancreatic fat were also evaluated. The primary efficacy endpoint was the change in epicardial fat volume between EMPA and placebo from baseline to 12 weeks. Secondary endpoints were the differences in PCr/ATP ratio, myocardial, liver and pancreatic fat content, SAT and VAT between groups at 12 weeks. RESULTS: In mice fed HFHS, EMPA significantly improved glucose tolerance and increased blood ketone bodies (KB) and ß-hydroxybutyrate levels (p < 0.05) compared to placebo. Mice fed HFHS had increased myocardial and liver fat content compared to standard diet mice. EMPA significantly attenuated liver fat content by 55%, (p < 0.001) but had no effect on myocardial fat. In the human study, all the 56 patients had normal LV function with mean LVEF = 63.4 ± 7.9%. Compared to placebo, T2D patients treated with EMPA significantly lost weight (- 2.6 kg [- 1.2; - 3.7]) and improved their HbA1c by 0.88 ± 0.74%. Hematocrit and EPO levels were significantly increased in the EMPA group compared to placebo (p < 0.0001, p = 0.041). EMPA significantly increased glycosuria and plasma KB levels compared to placebo (p < 0.0001, p = 0.012, respectively), and significantly reduced liver fat content (- 27 ± 23 vs. - 2 ± 24%, p = 0.0005) and visceral fat (- 7.8% [- 15.3; - 5.6] vs. - 0.1% [- 1.1;6.5], p = 0.043), but had no effect on myocardial or epicardial fat. At 12 weeks, no significant change was observed in the myocardial PCr/ATP (p = 0.57 between groups). CONCLUSIONS: EMPA effectively reduced liver fat in mice and humans without changing epicardial, myocardial fat or myocardial energetics, rebutting the thrifty substrate hypothesis for cardiovascular protection of SGLT2 inhibitors. Trial registration NCT, NCT03118336. Registered 18 April 2017, https://clinicaltrials.gov/ct2/show/NCT03118336.


Subject(s)
Adipose Tissue/drug effects , Benzhydryl Compounds/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Energy Metabolism/drug effects , Glucosides/therapeutic use , Liver/drug effects , Myocardium/metabolism , Non-alcoholic Fatty Liver Disease/prevention & control , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Adipose Tissue/metabolism , Adipose Tissue/pathology , Animals , Benzhydryl Compounds/adverse effects , Biomarkers/blood , Blood Glucose/drug effects , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Disease Models, Animal , Double-Blind Method , France , Glucosides/adverse effects , Glycated Hemoglobin/metabolism , Humans , Liver/metabolism , Liver/pathology , Mice, Inbred C57BL , Myocardium/pathology , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Proton Magnetic Resonance Spectroscopy , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Time Factors , Treatment Outcome , Weight Loss/drug effects
3.
J Med Vasc ; 43(3): 182-192, 2018 May.
Article in French | MEDLINE | ID: mdl-29754728

ABSTRACT

OBJECTIVE: The purpose of this study was to enhance awareness among healthcare professionals about the application of guidelines relating to the management of venous thromboembolism (VTE) in cancer patients. METHODS: This collective approach involved: the Regional Health Agency (ARS), the Unions of Representatives of Healthcare Professionals (URPS), the Observatory of Drugs, the Medical Devices and Therapeutic Innovation agency (OMEDIT), the regional Oncology Network and specialist physicians. Performance indicators were defined to evaluate the actions performed. RESULTS: Multidisciplinary information meetings were organized. A standardized patient's folder was proposed in all healthcare institutions dealing with cancer, as a link between healthcare professionals and patients. Information brochures were prepared for healthcare professionals and patients. Web-based surveys were taken among healthcare professionals to evaluate changes in their knowledge and practices before and after the first actions taken. CONCLUSION: This collective approach improved the awareness of health professionals about care practices for VTE in cancer patients.


Subject(s)
Clinical Competence , Health Knowledge, Attitudes, Practice , Neoplasms/complications , Private Practice , Venous Thromboembolism/complications , Venous Thromboembolism/therapy , Anticoagulants/therapeutic use , Awareness , France , Humans , Practice Guidelines as Topic , Surveys and Questionnaires
4.
Genetics ; 158(1): 65-75, 2001 May.
Article in English | MEDLINE | ID: mdl-11333218

ABSTRACT

The msh6 mismatch repair gene of Schizosaccharomyces pombe was cloned, sequenced, and inactivated. Strains bearing all combinations of inactivated msh6, msh2, and swi4 (the S. pombe MSH3 ortholog) alleles were tested for their defects in mitotic and meiotic mismatch repair. Mitotic mutation rates were similarly increased in msh6 and msh2 mutants, both for reversion of a base-base substitution as well as of an insertion of one nucleotide in a mononucleotide run. Tetrad analysis and intragenic two-factor crosses revealed that meiotic mismatch repair was affected in msh6 to the same extent as in msh2 background. In contrast, loss of Swi4 likely did not cause a defect in mismatch repair, but rather resulted in reduced recombination frequency. Consistently, a mutated swi4 caused a two- to threefold reduction of recombinants in intergenic crosses, while msh2 and msh6 mutants were not significantly different from wild type. In summary, our study showed that Msh6 plays the same important role as Msh2 in the major mismatch repair pathway of S. pombe, while Swi4 rather functions in recombination.


Subject(s)
Base Pair Mismatch , DNA Repair/physiology , Fungal Proteins/physiology , Schizosaccharomyces/genetics , Amino Acid Sequence , Base Sequence , DNA Primers , DNA Repair/genetics , Fungal Proteins/chemistry , Fungal Proteins/genetics , Molecular Sequence Data , Recombination, Genetic , Sequence Homology, Amino Acid
5.
Curr Opin Genet Dev ; 7(4): 519-23, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9309184

ABSTRACT

All vertebrates develop with a distinct, invariant, left-right (L-R) body asymmetry. Recently, a number of molecules have been shown to be expressed asymmetrically with respect to the L-R axis during early embryogenesis. The temporal expression patterns of these molecules, in combination with embryo manipulation and genetic experiments, indicate that they may represent elements of a conserved pathway governing embryonic handedness.


Subject(s)
Vertebrates/embryology , Animals , Body Patterning/genetics , Gene Expression Regulation, Developmental , Heart/embryology , Signal Transduction/genetics , Vertebrates/genetics
6.
Development ; 124(5): 1033-44, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9056778

ABSTRACT

Mouse nodal, a member of the TGFbeta family of secreted growth factors is essential for gastrulation. We recently generated a nodal(lacZ) reporter allele by homologous recombination in ES cells. In the present study, beta-galactosidase staining in the perigastrulation-stage embryo has demonstrated the site of highest nodal expression is localised to the prospective posterior region of the epiblast marking the site of primitive streak formation. We also documented transient nodal.lacZ expression in the visceral endoderm prior to and during early streak formation. A mosaic analysis using wild-type ES cells to rescue nodal-deficient embryos allowed us to document functionally distinct nodal activities in the embryonic ectodermal and primitive endodermal cell lineages. nodal signaling in the ectoderm is necessary for primitive streak formation as the gastrulation defect of nodal-deficient embryos can be rescued by the inclusion of small numbers of wild-type cells. In addition, we show that chimeric embryos composed of nodal-deficient primitive endoderm fail to develop rostral neural structures. Thus we conclude that the action of nodal, a TGFbeta-related growth factor expressed in the primitive endoderm, is critical for patterning of the anterior aspects of the A-P axis.


Subject(s)
Endoderm/cytology , Gastrula/cytology , Proteins/physiology , Transforming Growth Factor beta , Alleles , Animals , Central Nervous System/embryology , Chimera , Genotype , Mice , Nodal Protein , Wnt Proteins
8.
Proc Natl Acad Sci U S A ; 93(19): 10156-61, 1996 Sep 17.
Article in English | MEDLINE | ID: mdl-8816768

ABSTRACT

In Xenopus egg extracts, DNA strand breaks (nicks) located 3' or 5' to a mismatch cause an overall 3-fold stimulation of the repair of the mismatch in circular heteroduplex DNA molecules. The increase in mismatch repair is almost entirely due to an increase in repair of the nicked strand, which is stimulated 5-fold. Repair synthesis is centered to the mismatch site, decreases symmetrically on both sides, and its position is not significantly altered by the presence of the nick. Therefore, it appears that in the Xenopus germ cells, the mismatch repair system utilizes nicks as signals for the induction and direction of mismatch repair, but not as the start or end point for excision and resynthesis.


Subject(s)
Bacterial Proteins , DNA Damage , DNA Repair , DNA/biosynthesis , Nucleic Acid Heteroduplexes/biosynthesis , Oocytes/physiology , Animals , Base Composition , DNA, Circular/biosynthesis , Deoxyribonucleases, Type II Site-Specific , Female , Kinetics , Restriction Mapping , Tissue Extracts , Xenopus laevis
9.
Nature ; 381(6578): 155-8, 1996 May 09.
Article in English | MEDLINE | ID: mdl-8610012

ABSTRACT

Growth factors related to TGF-beta provide important signals for patterning the vertebrate body plan. One such family member, nodal, is required for formation of the primitive streak during mouse gastrulation. Here we have used a nodal-lacZ reporter allele to demonstrate asymmetric nodal expression in the mouse node, a structure thought to be the functional equivalent of the frog and chick 'organizer', and in lateral place mesoderm cells. We have also identified two additional genes acting with nodal in a pathway determining the left-right body axis. Thus we observe in inv mutant embryos that the sidedness of nodal expression correlates with the direction of heart looping and embryonic turning. In contrast, HNF3-beta(+/-) nodal(lacZ/+) double-heterozygous embryos display LacZ staining on both left and right sides, and frequently exhibit defects in body situs. Taken together, these experiments, along with similar findings in chick, demonstrate that elements of the genetic pathway that establish the left-right body axis are conserved in vertebrates.


Subject(s)
Embryonic and Fetal Development/physiology , Protein Biosynthesis , Trans-Activators , Transcription Factors , Transforming Growth Factor beta , Animals , Base Sequence , DNA Primers , DNA-Binding Proteins/genetics , DNA-Binding Proteins/physiology , Embryonic and Fetal Development/genetics , Female , Gastrula/physiology , Gene Expression Regulation, Developmental , Hedgehog Proteins , Hepatocyte Nuclear Factor 3-beta , Lac Operon , Male , Mesoderm/physiology , Mice , Molecular Sequence Data , Mutagenesis, Insertional , Mutation , Nodal Protein , Nuclear Proteins/genetics , Nuclear Proteins/physiology , Proteins/physiology
10.
Nucleic Acids Res ; 22(25): 5723-8, 1994 Dec 25.
Article in English | MEDLINE | ID: mdl-7838728

ABSTRACT

Bacterial MutS protein and its yeast and human homologs MSH2 trigger the mismatch repair process by their initial binding to mispaired and unpaired bases in DNA. We describe the cloning and sequencing of genes from Xenopus laevis and Mus musculus encoding the homolog of the Saccharomyces cerevisiae MSH2 (the major DNA mismatch binding protein). Mutations in the human homolog of this gene have recently been implicated in microsatellite instability and DNA mismatch repair deficiency in tumour cells from patients with the most common hereditary predisposition to cancer (Lynch syndrome, or hereditary non-polyposis colorectal cancer, HNPCC), as well as in a significant percentage of sporadic tumours. Expression of the amphibian and murine Msh2 gene in different tissues appears to be ubiquitous. The Xenopus gene is highly expressed in eggs, a model system for the biochemistry of DNA mismatch repair. Expression of the murine gene is low in all tissues examined, and is relatively high in a rapidly dividing cell line. These data are suggestive of a role for MSH2 during DNA replication.


Subject(s)
DNA Repair , DNA-Binding Proteins , Fungal Proteins/genetics , Saccharomyces cerevisiae Proteins , Animals , Base Sequence , Cloning, Molecular , DNA Primers/chemistry , Gene Expression , Genes , Helix-Loop-Helix Motifs , Mice , Molecular Sequence Data , MutS Homolog 2 Protein , Polymerase Chain Reaction , RNA, Messenger/genetics , Sequence Alignment , Sequence Homology, Amino Acid , Tissue Distribution , Xenopus laevis
11.
Exp Cell Res ; 196(2): 314-22, 1991 Oct.
Article in English | MEDLINE | ID: mdl-1893942

ABSTRACT

Human Xeroderma pigmentosum "normal" fibroblasts AS16 (XP4 VI) were transformed after transfection with a recombinant v-myb clone. In this clone (pKXA 3457) derived from avian myeloblastosis virus (AMV), the expression of the oncogene sequences is driven by the AMV U-5 LTR promoter. The transformed cells (ASKXA), which have integrated a rearranged v-myb oncogene, grow in agar, are not tumorigenic in nude mice, and express a 45-kDa v-myb protein. The HMW DNA of these cells transform chicken embryo fibroblasts. The c-Ha-ras oncogene is overexpressed in the ASKXA cells but not in the parental "normal" AS16 cells and a revertant clone (ASKXA Cl 1.1 G). Our results lead to the conclusion that the XP fibroblasts are phenotypically transformed by the presence of the transfected v-myb oncogene, which is able to induce an overexpression of the c-Ha-ras gene.


Subject(s)
Cell Transformation, Neoplastic , DNA Replication , Oncogenes , Animals , Avian Myeloblastosis Virus/genetics , Cell Line , Chick Embryo , Cloning, Molecular , DNA Repair , DNA Replication/drug effects , Genes, ras , Humans , Phenotype , Promoter Regions, Genetic , Repetitive Sequences, Nucleic Acid , Transfection , Ultraviolet Rays , Xeroderma Pigmentosum
12.
Proc Natl Acad Sci U S A ; 87(20): 7883-7, 1990 Oct.
Article in English | MEDLINE | ID: mdl-2236005

ABSTRACT

Repair of all 12 single base-pair mismatches by Xenopus egg extracts was measured by a physical assay with a sequence containing four overlapping restriction sites. The heteroduplex substrates, derivatives of M13 phage DNA, differed in sequence at the mismatch position only and permitted measurement of repair to both strands. The efficiency of repair varied about 4-fold between the most and least effectively repaired mismatches. Repair was most active with C/A and T/C mismatches but the efficiency varied depending on the orientation of the mismatch. Mismatch-specific DNA repair synthesis was also observed but the extent of repair was not always predictive of the extent of synthesis, suggesting the presence of different repair systems or different modes of mismatch recognition.


Subject(s)
Base Composition , DNA Repair , DNA Replication , Oocytes/metabolism , Animals , Base Sequence , Female , Kinetics , Molecular Sequence Data , Nucleic Acid Heteroduplexes/metabolism , Restriction Mapping , Xenopus laevis
13.
Biochimie ; 70(7): 969-73, 1988 Jul.
Article in English | MEDLINE | ID: mdl-3145029

ABSTRACT

Oncogenes capable of transforming 3T3-Vill cells were not detected in 'normal' Xeroderma pigmentosum (XP) fibroblasts but were detected in two out of six XP epitheliomas. Preliminary results concerning the transfection of 'normal' XP fibroblasts with activated ras genes seem to indicate that these cells are as resistant as the healthy controls to the transforming action of the group II oncogenes. However, after transfection with v-myb oncogene in XP fibroblasts several cellular clones have been isolated showing some new phenotypic characteristics.


Subject(s)
Cell Transformation, Neoplastic , Oncogenes , Transfection , Xeroderma Pigmentosum/genetics , Cell Line , Cloning, Molecular , DNA, Neoplasm/genetics , Gene Expression Regulation , Humans , Skin Neoplasms/genetics
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