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1.
Rev Med Suisse ; 9(396): 1594, 1596-8, 2013 Sep 04.
Article in French | MEDLINE | ID: mdl-24066468

ABSTRACT

The hepatitis E virus (HEV) is an RNA virus transmitted via the fecal-oral route or through uncooked animal meat products. Of the 4 known genotypes, genotype 3 is responsible for autochthonous infections in industrialized countries, with a seroprevalence in Switzerland estimated as high as 22%. The majority of infections is asymptomatic but a minority of patients, notably men over 50 or with underlying liver disease, can present with severe acute hepatitis. Chronic hepatitis E with HEV of genotype 3 has been observed in immunosuppressed patients, mostly transplant recipients. Serology is not sufficiently sensitive, especially in immunosuppressed patients, making PCR identification the preferred test for diagnosing active infection. Ribavirin or interferon-alpha can be used to treat chronic hepatitis E if reduction of immunosuppressive treatment does not result in viral elimination.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis E virus/isolation & purification , Hepatitis E/therapy , Immunocompromised Host , Adolescent , Adult , Age Factors , Female , Genotype , Hepatitis E/epidemiology , Hepatitis E/virology , Hepatitis E virus/genetics , Humans , Male , Middle Aged , Risk Factors , Seroepidemiologic Studies , Sex Factors , Switzerland/epidemiology , Young Adult
2.
J Viral Hepat ; 18(5): 305-15, 2011 May.
Article in English | MEDLINE | ID: mdl-21470343

ABSTRACT

Hepatitis C virus (HCV) nonstructural protein 3-4A (NS3-4A) is a complex composed of NS3 and its cofactor NS4A. It harbours serine protease as well as NTPase/RNA helicase activities and is essential for viral polyprotein processing, RNA replication and virion formation. Specific inhibitors of the NS3-4A protease significantly improve sustained virological response rates in patients with chronic hepatitis C when combined with pegylated interferon-α and ribavirin. The NS3-4A protease can also target selected cellular proteins, thereby blocking innate immune pathways and modulating growth factor signalling. Hence, NS3-4A is not only an essential component of the viral replication complex and prime target for antiviral intervention but also a key player in the persistence and pathogenesis of HCV. This review provides a concise update on the biochemical and structural aspects of NS3-4A, its role in the pathogenesis of chronic hepatitis C and the clinical development of NS3-4A protease inhibitors.


Subject(s)
Carrier Proteins/metabolism , Hepacivirus/metabolism , Hepatitis C, Chronic/virology , Viral Nonstructural Proteins/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Vesicular Transport/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/chemistry , Carrier Proteins/genetics , Drug Resistance, Viral/genetics , Hepacivirus/enzymology , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Humans , Intracellular Signaling Peptides and Proteins , Mitochondrial Proteins/antagonists & inhibitors , Mitochondrial Proteins/chemistry , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Mutation , Nucleoside-Triphosphatase/antagonists & inhibitors , Nucleoside-Triphosphatase/chemistry , Nucleoside-Triphosphatase/genetics , Nucleoside-Triphosphatase/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism , RNA Helicases/antagonists & inhibitors , RNA Helicases/chemistry , RNA Helicases/genetics , RNA Helicases/metabolism , Serine Proteases/chemistry , Serine Proteases/genetics , Serine Proteases/metabolism , Serine Proteinase Inhibitors/pharmacology , Serine Proteinase Inhibitors/therapeutic use , Signal Transduction , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Virus Replication
3.
Osteoarthritis Cartilage ; 14(7): 631-40, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16527498

ABSTRACT

OBJECTIVE: To determine the best protocol for the preparation of a tissue-engineered cartilage to investigate the potential anti-arthritic and/or anti-osteoarthritic effects of drugs. METHODS: Calf articular chondrocytes, seeded in collagen sponges were grown in culture for up to 1 month. At day 14 cultures received interleukin (IL)-1beta (ranging from 0.1 to 20 ng/ml) for 1 to 3 days. Analyses of gene expression for extracellular matrix proteins, collagen-binding integrins, matrix metalloproteinases (MMPs), aggrecanases, TIMPs, IL-1Ra and Ikappa-Balpha were carried out using real-time polymerase chain reaction (PCR). Metalloproteinase activities were analysed in the culture medium using both zymography and fluorogenic peptide substrates. RESULTS: We selected a culture for 15 or 17 days with collagen sponges seeded with 10(7) chondrocytes showing a minimal cell proliferation, a maximal sulphated glycosaminoglycan (sGAG) deposition and a high expression of COL2A1, aggrecan and the alpha10 integrin sub-unit and low expression of COL1A2 and the alpha11 integrin sub-unit. In the presence of 1 ng/ml IL-1beta, we observed at day 15 up-regulations of 450-fold for MMP-1, 60-fold for MMP-13, 54-fold for ADAMTS-4 and MMP-3 and 10-fold for ADAMTS-5 and IL-1Ra. Down-regulations of 2.5-fold for COL2A1 and aggrecan were observed only at day 17. At the protein level a dose-dependent increase of total MMP-1 and MMP-13 was noted with less than 15% in the active form. CONCLUSIONS: This in vitro model of chondrocyte culture in three dimensional (3D) seems well adapted to investigate the responses of these cells to inflammatory cytokines and to evaluate the potential anti-inflammatory effects of drugs.


Subject(s)
Cartilage, Articular/drug effects , Chondrocytes/drug effects , Interleukin-1/pharmacology , Tissue Engineering/methods , ADAM Proteins/biosynthesis , Aggrecans/metabolism , Animals , Cattle , Collagen/metabolism , Integrins/metabolism , Matrix Metalloproteinases/biosynthesis , Osteoarthritis/drug therapy , Tissue Inhibitor of Metalloproteinases/metabolism
4.
Biorheology ; 39(1-2): 247-58, 2002.
Article in English | MEDLINE | ID: mdl-12082287

ABSTRACT

Osteoarthritis (OA) is the most common of all joint diseases to affect mankind and is characterized by the degradation of articular cartilage. The low availability of normal and pathologic human cartilage and the inability to study the early stages of the disease in humans has led to the development of numerous animal models of OA. The aim of our study was to establish gene expression profiles during the progression of a rabbit model of OA induced by anterior cruciate ligament (ACL) section. Semiquantitative RT-PCR was used to follow expression of several relevant molecules (type II and X collagens, aggrecan, osteonectin, betaig-h3, BiP, TIMP-1, MMP-1, -3, -13, aggrecanase-1, -2) during development of OA in articular cartilage. In parallel, we monitored the activities of collagenase, caseinase, phospholipase A2 and glycosyltransferases (xylosyl-, galactosyl-, glucuronyl- and N-acetyl-galactosaminyl-transferase). Novel cDNA clones for rabbit type X collagen, aggrecanase-1 and -2, osteonectin and BiP were constructed to obtain species-specific primers. Ours result show that MMP-13 (collagenase-3) gene expression increased dramatically early after ACL surgery and remained high thereafter. An increase in MMP-1 (collagenase-1) and MMP-3 expression was also noted with an absence of variation for TIMP-1 expression. In addition, the global MMPs activities paralleled the MMP gene expression. These data together characterize at the molecular level the evolution of OA in this rabbit model. Furthermore, we have undertaken a search for identifying differentially expressed genes in normal and OA cartilage in this model, by differential display RT-PCR. We present here preliminary results with the determination of the best technical conditions to obtain reproducible electrophoresis patterns of differential display RT-PCR.


Subject(s)
Anterior Cruciate Ligament Injuries , Disease Models, Animal , Extracellular Matrix Proteins , Matrix Metalloproteinases/genetics , Osteoarthritis/genetics , Aggrecans , Amino Acid Sequence , Animals , Base Sequence , Collagen/genetics , Collagenases/genetics , Endopeptidases/genetics , Gene Expression Profiling , Hindlimb , Lectins, C-Type , Metalloendopeptidases/genetics , Molecular Sequence Data , Osteoarthritis/metabolism , Osteonectin/genetics , Proteoglycans/genetics , Rabbits , Reverse Transcriptase Polymerase Chain Reaction , Tissue Inhibitor of Metalloproteinases/genetics
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