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1.
Nat Metab ; 2(5): 413-431, 2020 05.
Article de Anglais | MEDLINE | ID: mdl-32478287

RÉSUMÉ

Non-alcoholic fatty liver disease and steatohepatitis are highly associated with obesity and type 2 diabetes mellitus. Cotadutide, a GLP-1R/GcgR agonist, was shown to reduce blood glycemia, body weight and hepatic steatosis in patients with T2DM. Here, we demonstrate that the effects of Cotadutide to reduce body weight, food intake and improve glucose control are predominantly mediated through the GLP-1 signaling, while, its action on the liver to reduce lipid content, drive glycogen flux and improve mitochondrial turnover and function are directly mediated through Gcg signaling. This was confirmed by the identification of phosphorylation sites on key lipogenic and glucose metabolism enzymes in liver of mice treated with Cotadutide. Complementary metabolomic and transcriptomic analyses implicated lipogenic, fibrotic and inflammatory pathways, which are consistent with a unique therapeutic contribution of GcgR agonism by Cotadutide in vivo. Significantly, Cotadutide also alleviated fibrosis to a greater extent than Liraglutide or Obeticholic acid (OCA), despite adjusting dose to achieve similar weight loss in 2 preclinical mouse models of NASH. Thus Cotadutide, via direct hepatic (GcgR) and extra-hepatic (GLP-1R) effects, exerts multi-factorial improvement in liver function and is a promising therapeutic option for the treatment of steatohepatitis.


Sujet(s)
Récepteur du peptide-1 similaire au glucagon/agonistes , Lipogenèse/effets des médicaments et des substances chimiques , Cirrhose du foie/traitement médicamenteux , Mitochondries/effets des médicaments et des substances chimiques , Stéatose hépatique non alcoolique/traitement médicamenteux , Peptides/usage thérapeutique , Animaux , Glycémie/métabolisme , Poids , Diabète de type 2/complications , Récepteur du peptide-1 similaire au glucagon/génétique , Glycogène/métabolisme , Foie/effets des médicaments et des substances chimiques , Foie/enzymologie , Foie/métabolisme , Cirrhose du foie/métabolisme , Mâle , Souris , Souris knockout , Mitochondries/métabolisme , Stéatose hépatique non alcoolique/métabolisme , Protéomique
2.
Neurotoxicology ; 45: 192-200, 2014 Dec.
Article de Anglais | MEDLINE | ID: mdl-25454721

RÉSUMÉ

Human primary neural tissue is a vital component for the quick and simple determination of chemical compound neurotoxicity in vitro. In particular, such tissue would be ideal for high-throughput screens that can be used to identify novel neurotoxic or neurotherapeutic compounds. We have previously established a high-throughput screening platform using human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) and neurons. In this study, we conducted a 2000 compound screen with human NSCs and rat cortical cells to identify compounds that are selectively toxic to each group. Approximately 100 of the tested compounds showed specific toxicity to human NSCs. A secondary screen of a small subset of compounds from the primary screen on human iPSCs, NSC-derived neurons, and fetal astrocytes validated the results from >80% of these compounds with some showing cell specific toxicity. Amongst those compounds were several cardiac glycosides, all of which were selectively toxic to the human cells. As the screen was able to reliably identify neurotoxicants, many with species and cell-type specificity, this study demonstrates the feasibility of this NSC-driven platform for higher-throughput neurotoxicity screens.


Sujet(s)
Astrocytes/effets des médicaments et des substances chimiques , Cortex cérébral/effets des médicaments et des substances chimiques , Tests de criblage à haut débit/méthodes , Cellules souches neurales/effets des médicaments et des substances chimiques , Tests de toxicité/méthodes , Animaux , Mort cellulaire/effets des médicaments et des substances chimiques , Cellules cultivées , Relation dose-effet des médicaments , Humains , Rats
3.
J Gen Virol ; 94(Pt 7): 1468-1476, 2013 Jul.
Article de Anglais | MEDLINE | ID: mdl-23515023

RÉSUMÉ

Hepatitis E virus (genus Hepevirus, family Hepeviridae) is one of the most important causes of acute hepatitis in adults, particularly among pregnant women, throughout Asia and Africa where mortality rates can be 20-30 %. Hepatitis E virus has a single-stranded positive-sense RNA genome that contains three translated ORFs. The two 3' ORFs are translated from a subgenomic RNA. Functional RNA elements have been identified in and adjacent to the genomic 5' and 3' UTRs and in and around the intergenic region. Here we describe an additional RNA element that is located in a central region of ORF2. The RNA element is predicted to fold into two highly conserved stem-loop structures, ISL1 and ISL2. Mutations that disrupt the predicted structures, without altering the encoded amino acid sequence, result in a drastic reduction in capsid protein synthesis. This indicates that the RNA element plays an important role in one of the early steps of virus replication. The structures were further investigated using a replicon that expresses Gaussia luciferase in place of the capsid protein. Single mutations in ISL2 severely reduced luciferase expression, but a pair of compensatory mutations that were predicted to restore the ISL2 structure, restored luciferase expression to near-WT levels, thus lending experimental support to the predicted structure. Nonetheless the precise role of the ISL1+ISL2 element remains unknown.


Sujet(s)
Virus de l'hépatite E/génétique , ARN viral/génétique , Protéines virales/génétique , Réplication virale , Animaux , Séquence nucléotidique , Capside/métabolisme , Protéines de capside/composition chimique , Protéines de capside/génétique , Protéines de capside/métabolisme , Génome viral/génétique , Virus de l'hépatite E/métabolisme , Virus de l'hépatite E/physiologie , Humains , Données de séquences moléculaires , Mutation , Protéines virales/composition chimique
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