Novel nanoscale therapeutic approaches to treat liver diseases

[eng] Chronic liver diseases are one of the most prevalent diseases worldwide. The study of the signaling pathways involved in the fibrogenic process as well as the evaluation of novel therapies such as nanoparticles (NPs) could be useful to mitigate their progression. In this context, the first objective of this doctoral thesis was to evaluate the role of PTTG1/DLK1 in the profibrogenic process. The expression of PTTG1 and DLK1 was selectively increased in the cirrhotic rat and human liver. Besides, fibrotic mice lacking Pttg1 showed a significant decrease in intrahepatic collagen deposition and the hepatic expression of genes involved in extracellular matrix remodeling in comparison with fibrotic wild type mice. Finally, hepatic Pttg1 interference results in fibrosis attenuation, reduced portal hypertension and diminished transcription of Dlk1 and profibrogenic genes in rats with fibrosis. In conclusion, PTTG1/DLK1 signaling pathway is a promising therapeutic target to mitigate liver fibrosis progression. The second objective of this doctoral thesis was to investigate the potential therapeutic effect of CeO2NPs in experimental hepatocarcinoma. Once administrated in rats with hepatocarcinoma CeO2NPs mainly accumulate in the liver, where they decrease inflammation and cellular proliferation. Besides, CeO2NPs modify the phosphorylation of proteins related to cellular adhesion and RNA splicing. Moreover, the treatment with CeO2NPs results in decreased alpha-fetoprotein serum concentration and increase in animal survival. Finally, the human liver is able to uptake CeO2NPs, which are found free in the cytoplasm and inside endosome-like organelles. In conclusion, CeO2NPs treatment mitigate hepatocarcinoma progression. The third objective was to assess the potential therapeutic effect of a liver-targeted nitric oxide (NO) donor in portal hypertension and liver function in cirrhotic rats with ascites. The targeted NO donor significantly reduces portal hypertension, without modifying mean arterial pressure or cardiac ...