MicroRNAs (miRNA) have received considerable attention as potential biomarkers for drug‐induced liver injury. We recently reported that the plasma levels of miR‐143‐3p and miR‐218a‐5p increased in severe cholestasis in rats. This study aimed to investigate whether these miRNAs increase in a severity‐dependent manner and to elucidate their pathophysiological roles in cholestasis. Male Sprague–Dawley rats were orally administered different doses of α‐naphthylisothiocyanate or 4,4‐methylenedianiline to induce acute cholestasis. They were also orally administered acetaminophen or thioacetamide to induce hepatocellular injury. We found that plasma miR‐143‐3p and miR‐218a‐5p levels increased in a dose‐dependent manner in cholestatic rats but not in hepatocellular injury. Bioinformatic analysis provided putative target genes of hsa‐miR‐218‐5p, rno‐miR‐218a‐5p, and mmu‐miR‐218‐5p, among which GNAI2, PPP1CB, and PPP2R5A were experimentally validated as their direct target genes in human cholangiocyte line MMNK‐1. Proliferation of MMNK‐1 cells was significantly suppressed after overexpression of miR‐218‐5p and transduction of siRNAs for GNAI2, PPP1CB, and PPP2R5A. In the cholestatic livers of rats, Ppp1cb and Ppp2r5a expression levels decreased, whereas Gnai2 expression levels increased compared with those in vehicle‐treated rats, suggesting that Ppp1cb and Ppp2r5a may be under the control of miR‐218a‐5p in vivo. In conclusion, our data suggest that miR‐218(a)‐5p is involved in the suppression of cholangiocyte proliferation by inhibiting the expression of PPP1CB and PPP2R5A, thereby contributing to the pathogenesis of cholestasis; and miR‐218a‐5p leaks into the plasma probably from damaged cholangiocytes in a severity‐dependent manner in rats. Therefore, miR‐218a‐5p overexpression could be one of the underlying mechanisms of acute cholestatic liver injury in rats.
Solgel synthesis of TiO 2 /SiO 2 multilayers was studied for application to structural color materials. The purpose of this study is to achieve crack-free thick films, which are indispensable for high reflectance and color vividness. We investigated the effect of polymer additives and heating conditions on the fracture of TiO 2 gel films. The critical cracking thickness increased more than three-fold at maximum by adding poly(vinyl pyrrolidone) (PVP) to precursor sols and by using a low heating rate. From stress measurement based on Stoney's model, we found that the addition of PVP extensively reduced residual stress, proving the mechanism suggested so far that PVP hinders the evolution of the TiO network and reduces drying stress. Under the restriction of the critical thickness, TiO 2 /SiO 2 multilayered films and flakes were prepared as a feasibility test of structural coloration. A high-order interference condition was used for the optical design, which allows us to obtain narrow spectral peaks and the primary colors of light. Theoretically expected reflection spectra that corresponded to blue and green colors were attained for five-layered films.
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