Pregnane X Receptor agonist Increases the Expression Levels of the Plasma Membrane Monoamine Transporter

We evaluated the effect of the pregnane X receptor agonist, pregnenolone 16 alpha-carbonitrile (PCN) on the expression levels of plasma monoamine transporter (PMAT) in the intestine. Male C57/BL6 mice were divided into two 2 groups: mice in the PCN group (n=3) were administered PCN once a day for 4 days, while those in the control group (n=3) received the same volume of vehicle once a day for 4 days. After the mice were killed 24 h after administration of the last dose of PCN or vehicle, and the expression levels of PMAT in the intestine tissues were isolated and measured the expression level of PMAT using immunohistochemical and western blotting analyses. The expression level of PMAT expression levels in the small intestine increased after PCN treatment. These results suggest that the induction of PMAT may play a clinically significant role by increasing intestinal absorption of PMAT substrates such as metformin.

Protein Expression Profiles in a Rat Cirrhotic Model Induced by Thioacetamide / 대한간학회지

BACKGROUND/AIMS: The reactive oxygen species from thioacetamide (TAA) induces rat liver cirrhosis that resembles the human disease, and it can serve as a suitable animal model for studying human liver cirrhosis. The aim of this study was to identify the molecular protein signatures via a proteomics approach with using a rat model with TAA-induced liver cirrhosis. METHODS: Male Wistar rats were treated with 0.3 g/L TAA in their drinking water. The animals were then sacrificed at 9 and 30 weeks after TAA administration. The development of liver cirrhosis was observed with histological study. The livers were processed for proteins extraction and the proteins were analyzed by 2-dimensional electrophoresis. The proteins were identified by matrix-assisted laser desorption ionizing time-of-flight mass spectrometry and this was validated by immunohistochemical staining. RESULTS: On the proteomics analysis of the liver tissues, a total of 88 proteins showed significant change in their expression between the controls and the cirrhotic rats. When the proteins were categorized by their function, they included ECM/cellular skeleton, cell proliferation/death signal, metabolism, DNA damage/stress and immune response related proteins. The level of expression gradually increased up to 30 weeks for interleukin-6 (IL-6) precursor, transforming growth factor-beta (TGF-beta) induced protein, TIMP-1 and MMP-9. Cytochrome P450 2B, which is required for the metabolic activation of TAA, also showed the same increasing pattern. In contrast, the expression level of the proteins did not show a significant change at 9 weeks, but this increased to 3-fold at 30 weeks for carbonic anhydrase VII, ras related protein Rab 6, Annexin A2, neurofibromatosis type 2 and aldehyde dehydrogenase. CONCLUSIONS: This study showed that there is a repertoire of proteins during the development of liver cirrhosis via TAA. In this model, IL-6, TGF-beta, MMP-9 and TIMP-1 were reconfirmed as the molecular signatures during the development of TAA-induced liver cirrhosis.