1,724,567 research outputs found
dph08_earlycopepodite_HA-3196
No full textTIFF sequence of interaction HA-3196 (8 days post-hatch fish targeting an early copepodite)
Astronomische Nachrichten, nos 3184-3196
No full textR. Astronomische Nachrichten, nos 3184-3196. In: Bulletin astronomique, tome 10, 1893. pp. 529-536
Astronomische Nachrichten, nos 3196-3206
No full textRadau Rodolphe. Astronomische Nachrichten, nos 3196-3206. In: Bulletin astronomique, tome 11, 1894. pp. 84-90
AN IMPROVED PROCESS FOR THE PREPARATION OF RESMETIROM (MGL-3196)
Get PDFAn improved process for the preparation of Resmetirom (MGL-3196) of Formula I
Railey, Rowland Greenup, 1868-1932 (SC 3196)
Get PDFFinding aid and scan (Click on Additional Files below) for Manuscripts Small Collection 3196. Notice, 10 July 1906, to David Pipkins from R. G. Railey, tax collector for Monroe County, Kentucky sheriff W. D. White, demanding remittance of unpaid taxes for 1904. The envelope bearing the name “Railey and Jackson’s Collecting Agency, Tompkinsville, Ky.” has been marked returned as unclaimed
Ad recensionem bullarii Romano-Sveogothici a nobil. a Celse editam, accessio, disputationibus academicis proposita ab Henrico Gabriele Porthan.
Get PDFPainovuosi oletettu väitöskirjojen painovuosien perusteella.Arkit: 1 arkintunnukseton lehti, A-B4, A-Q4 R2 S-T4 U1. - S. [2] tyhjä.S. [I]-XVI: Esipuhe. - S. [133-134]: Errata. - S. [135-150]: Index.Ilmestynyt myös 15 väitöskirjana 1797-1801, ks. Vallinkoski 3182-3196
Cell-Specific Transport and Thyroid Hormone Receptor Isoform Selectivity Account for Hepatocyte-Targeted Thyromimetic Action of MGL-3196
Get PDFThyroid hormones (THs) and TH receptor-beta (TRβ) reduce hepatic triglycerides, indicating a therapeutic potential for TH analogs in liver steatosis. To avoid adverse extrahepatic, especially TRα-mediated effects such as tachycardia and bone loss, TH analogs with combined TRβ and hepatocyte specificity are desired. MGL-3196 is a new TH analog that supposedly meets these criteria. Here, we characterize the thyromimetic potential of MGL-3196 in cell-based assays and address its cellular uptake requirements. We studied the contribution of liver-specific organic anion transporters (OATP)1B1 and 1B3 to MGL-3196 action. The TR isoform-specific efficacy of MGL-3196 compared with 3,5,3′-triiodothyronine (T3) was determined with luciferase assays and gene expression analysis in OATP1B1 and OATP1B3 and TRα- or TRβ-expressing cells and in primary murine hepatocytes (PMHs) from wild-type and TRβ knockout mice. We measured the oxygen consumption rate to compare the effects of MGL-3196 and T3 on mitochondrial respiration. We identified OATP1B1 as the primary transporter for MGL-3196. MGL-3196 had a high efficacy (90% that of T3) in activating TRβ, while the activation of TRα was only 25%. The treatment of PMHs with T3 and MGL-3196 at EC50 resulted in a similar induction of Dio1 and repression of Serpina7. In HEK293 cells stably expressing OATP1B1, MGL-3196 had comparable effects on mitochondrial respiration as T3. These data indicate that MGL-3196’s hepatic thyromimetic action, the basis for its therapeutic use, results from a combination of hepatocyte-specific transport by OATP1B1 and the selective activation of TRβ over TRα
Molecular Dynamic Simulation To Reveal the Mechanism Underlying MGL-3196 Resistance to Thyroxine Receptor Beta
No full textThyroxine receptor beta (TRβ) is a ligand-dependent
nuclear
receptor that participates in regulating multiple biological processes,
particularly playing an important role in lipid metabolism regulation.
TRβ is currently a popular therapeutic target for nonalcoholic
steatohepatitis (NASH), while no drugs have been approved to treat
this disease. MGL-3196 (Resmetirom) is the first TRβ agonist
that has succeeded in phase III clinical trials for the treatment
of NASH; therefore, studying its molecular mechanism of action is
of great significance. In this study, we employed molecular dynamic
simulation to investigate the interaction mode between MGL-3196 and
TRβ at the all-atom level. More importantly, by comparing the
binding patterns of MGL-3196 in several prevalent TRβ mutants,
it was identified that the mutations R243Q and H435R located, respectively,
around and within the ligand-binding pocket of TRβ cause TRβ
to be insensitive to MGL-3196. This indicates that patients with NASH
carrying these two mutations may exhibit resistance to the medication
of MGL-3196, thereby highlighting the potential impact of TRβ
mutations on TRβ-targeted treatment of NASH and beyond
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