Project description:C57BL/6 mice were fed ad libitum for the first 5 days of the experiments with high fat high cholesterol (HFC) diet only. The next 7 days of the experiments mice were continuously fed on a HFC diet and simultaneously vehicle (control group), fenofibrate (100 mg/kg) or lovastatin (30 mg/kg) were orally daily administered. At the end of the experiment (day 12) fenofibrate and lovastatin significantly decreased plasma LDL levels, while plasma cholesterol levels were significantly decreased by lovastatin only. Gene expression analysis of hyperlipidemic mouse liver revealed 391 significantly modulated genes when compared to standard diet fed mice. KEGG pathways related to modulated genes were identified and the most significant were biosynthesis of steroids, metabolism of xenobiotics by cytochrome P450 and linoleic acid metabolism. These pathways were modulated in a way, which increased the clearance of lipids and decreased endogenous synthesis of fatty acids and cholesterol. Additionally, genes involved in the regulation of detoxification pathways were significantly upregulated. The hepatic gene expression profiles of fenofibrate and lovastatin-treated HFC diet fed mice were compared to the vehicle-treated HFC diet fed mice. In the fenofibrate-treated group 124 genes and in the lovastatin-treated group 38 genes were significantly modulated. In the fenofibrate-treated group the top three significantly modulated pathways are fatty acid metabolism, propanoate metabolism and ascorbate and aldarate metabolism. While in the lovastatin-treated group the top three significantly modulated pathways are glycosphingolipid biosynthesis, tyrosine metabolism and metabolism of xenobiotics by cytochrome P450. Expert based classification revealed that both fenofibrate an lovastatin significantly down-regulated genes encoding sterol-C4-methyl oxidase like and 7-dehydrocholesterol reductase. Additionally, the regulation of cholesterol at the transcriptional level was also significantly augmented by fenofibrate and lovastatin, as judged by increased expression of -1 and decreased expression of INSIG-2. Keywords: Drug treatment

Project description:C57BL/6 mice were fed ad libitum for the first 5 days of the experiments with high fat high cholesterol (HFC) diet only. The next 7 days of the experiments mice were continuously fed on a HFC diet and simultaneously vehicle (control group), fenofibrate (100 mg/kg) or lovastatin (30 mg/kg) were orally daily administered. At the end of the experiment (day 12) fenofibrate and lovastatin significantly decreased plasma LDL levels, while plasma cholesterol levels were significantly decreased by lovastatin only. Gene expression analysis of hyperlipidemic mouse liver revealed 391 significantly modulated genes when compared to standard diet fed mice. KEGG pathways related to modulated genes were identified and the most significant were biosynthesis of steroids, metabolism of xenobiotics by cytochrome P450 and linoleic acid metabolism. These pathways were modulated in a way, which increased the clearance of lipids and decreased endogenous synthesis of fatty acids and cholesterol. Additionally, genes involved in the regulation of detoxification pathways were significantly upregulated. The hepatic gene expression profiles of fenofibrate and lovastatin-treated HFC diet fed mice were compared to the vehicle-treated HFC diet fed mice. In the fenofibrate-treated group 124 genes and in the lovastatin-treated group 38 genes were significantly modulated. In the fenofibrate-treated group the top three significantly modulated pathways are fatty acid metabolism, propanoate metabolism and ascorbate and aldarate metabolism. While in the lovastatin-treated group the top three significantly modulated pathways are glycosphingolipid biosynthesis, tyrosine metabolism and metabolism of xenobiotics by cytochrome P450. Expert based classification revealed that both fenofibrate an lovastatin significantly down-regulated genes encoding sterol-C4-methyl oxidase like and 7-dehydrocholesterol reductase. Additionally, the regulation of cholesterol at the transcriptional level was also significantly augmented by fenofibrate and lovastatin, as judged by increased expression of -1 and decreased expression of INSIG-2. Experiment Overall Design: 24 seven week old mice were randomly divided in four experimental groups. Control group (n = 6) was fed on a standard chow diet (diet 3430, Provimi Kliba AG, Kaiseraugst, Switzerland) and treated orally once daily with vehicle for 12 days. Remaining 18 mice were fed on HFC diet for 12 days. On day five HFC diet fed mice were treated orally once daily either with vehicle (HFC group, n=6), lovastatin (HFC lovastatin group, 30mg/kg, n=6) or fenofibrate (HFC fenofibrate group, 100mg/kg, n=6). Doses of lovastatin and fenofibrate were choosen according to the literature review. On day 12 liver were excised and immediately frozen in liquid nitrogen and stored at -80Â°C for the subsequent transriptome analyses

Project description:Hepatocellular carcinoma (HCC) is the second prominent cause of cancer-associated death worldwide. Usually, HCC is diagnosed in advanced stages, where sorafenib, a multiple target ty-rosine kinase inhibitor, is used as the first line of treatment. Unfortunately, resistance to sorafenib is usually encountered within six months of the treatment. Therefore, there is a critical need to identify the underlying reasons for drug resistance. In the present study, we investigated the proteomic and metabolomics alterations accompanying to sorafenib resistance in hepatocellular carcinoma Hep3B cells by employing ultra-high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). The Bruker Human Metabolome Database (HMDB) library was used to identify the differentially abundant metabolites through MetaboScape 4.0 software (Bruker). For protein annotation and identification, the Uniprot proteome for Homo sapiens (Human) da-tabase was utilised through MaxQuant. The results revealed that 27 metabolites and 18 proteins were significantly dysregulated due to sorafenib resistance in Hep3B cells compared to the parental phenotype. D-alanine, L-proline, o-tyrosine, succinic acid and phosphatidylcholine (PC, 16:0/16:0) were among the significantly altered metabolites. Ubiquitin carboxyl-terminal hydrolase isozyme L1, mitochondrial superoxide dismutase, UDP-glucose-6-dehydrogenase, sorbitol dehydrogenase and calpain small subunit 1 were among the significantly altered proteins. The findings revealed that resistant Hep3B cells demonstrated significant alterations in amino acid and nucleotide met-abolic pathways, energy production pathways and other pathways related to cancer aggressive-ness, migration, proliferation, and drug-resistance. Joint pathway enrichment analysis unveiled unique pathways, including the antifolate resistance pathway and other important pathways that maintain cancer cells' survival, growth, and proliferation. Collectively, the results identified po-tential biomarkers for sorafenib-resistant HCC and gave insights into their role in chemotherapeutic drug resistance, cancer initiation, progression, and aggressiveness, which may contribute to better prognosis and chemotherapeutic outcomes.

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