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1.
Cancer Biol Ther ; 21(1): 81-94, 2020.
Article in English | MEDLINE | ID: mdl-31552788

ABSTRACT

S-adenosylmethionine (SAM), biosynthesis from methionine and ATP, is markedly decreased in hepatocellularular carcinoma (HCC) for a diminution in ATP levels, and the down regulation of the liver specific MAT1a enzyme. Its metabolic activity is very important in the transmethylation reactions, the methionine cycle, the biosynthesis of glutathione (GSH) and the polyamine pathway, which are markedly affected in the HCC. The chemo-preventive effect of IFC305 in HCC induced by DEN, and the increase of ATP and SAM in CCl4-induced cirrhosis have been previously demonstrated. The aim of this work was to test whether this chemo-preventive effect is mediated by the induction of SAM biosynthesis and its metabolic flow. SAM hepatic levels and the methionine cycle were recovered with IFC305 treatment, restoring transmethylation and transsulfuration activities. IFC305 treatment, increased MAT1a levels and decrease MAT2a levels through modulation of their post-transcriptional regulation. This occurred through the binding of the AUF1 (binding factor 1 AU-rich sites) and HuR (human antigen R) ribonucleoproteins to Mat1a and Mat2a messenger RNAs, which maintained their nuclear localization. Finally, the compound inhibited the polyamine pathway favoring the recuperation of the normal methionine and one carbon cycle recuperating the metabolic flow of methionine, which probably facilitated its HCC chemo-preventive effect.


Subject(s)
Adenosine/analogs & derivatives , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Methionine Adenosyltransferase/metabolism , RNA-Binding Proteins/metabolism , S-Adenosylmethionine/metabolism , Adenosine/pharmacology , Animals , Apoptosis , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Proliferation , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Methionine Adenosyltransferase/genetics , RNA-Binding Proteins/genetics , Rats , Rats, Wistar , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
2.
Int J Hepatol ; 2012: 212530, 2012.
Article in English | MEDLINE | ID: mdl-23056951

ABSTRACT

Introduction. Cirrhosis is a chronic degenerative illness characterized by changes in normal liver architecture, failure of hepatic function, and impairment of proliferative activity. The aim of this study is to know how IFC-305 compound induces proliferation of the liver during reversion of cirrhosis. Methods. Once cirrhosis has been installed by CCl(4) treatment for 10 weeks in male Wistar rats, they were divided into four groups: two received saline and two received the compound; all were euthanized at 5 and 10 weeks of treatment. Liver homogenate, mitochondria, and nucleus were used to measure cyclins, CDKs, and cell cycle regulatory proteins PCNA, pRb, p53, E2F, p21, p27, HGF, liver ATP, and mitochondrial function. Results. Diminution and small changes were observed in the studied proteins in the cirrhotic animals without treatment. The IFC-305-treated rats showed a clear increase in most of the proteins studied mainly in PCNA and CDK6, and a marked increased in ATP and mitochondrial function. Discussion/Conclusion. IFC-305 induces a recovery of the cell cycle inhibition promoting recovery of DNA damage through the action of PCNA and p53. The increase in energy and preservation of mitochondrial function contribute to recovering the proliferative function.

3.
Biochem Pharmacol ; 80(11): 1690-9, 2010 Dec 01.
Article in English | MEDLINE | ID: mdl-20813095

ABSTRACT

We have previously shown that adenosine and the aspartate salt of adenosine (IFC305) reverse pre-established CCl(4)-induced cirrhosis in rats. However, their molecular mechanism of action is not clearly understood. Hepatic stellate cells (HSC) play a pivotal role in liver fibrogenesis leading to cirrhosis, mainly through their activation, changing from a quiescent adipogenic state to a proliferative myofibrogenic condition. Therefore, we decided to investigate the effect of IFC305 on primary cultured rat HSC. Our results reveal that this compound suppressed the activation of HSC, as demonstrated by the maintenance of a quiescent cell morphology, including lipid droplets content, inhibition of α-smooth muscle actin (α-SMA) and collagen α1(I) expression, and up-regulation of MMP-13, Smad7, and PPARγ expression, three key antifibrogenic genes. Furthermore, IFC305 was able to repress the platelet-derived growth factor (PDGF)-induced proliferation of HSC. This inhibition was independent of adenosine receptors stimulation; instead, IFC305 was incorporated into cells by adenosine transporters and converted to AMP by adenosine kinase. On the other hand, addition of pyrimidine ribonucleoside as uridine reversed the suppressive effect of IFC305 on the proliferation and activation of HSC, suggesting that intracellular pyrimidine starvation would be involved in the molecular mechanism of action of IFC305. In conclusion, IFC305 inhibits HSC activation and maintains their quiescence in vitro; these results could explain in part the antifibrotic liver beneficial effect previously described for this compound on the animal model.


Subject(s)
Adenosine/analogs & derivatives , Growth Inhibitors/pharmacology , Hepatic Stellate Cells/drug effects , Hepatic Stellate Cells/metabolism , Adenosine/pharmacology , Animals , Cell Proliferation/drug effects , Cells, Cultured , Male , Rats , Rats, Wistar , Up-Regulation/drug effects , Up-Regulation/physiology
4.
Int J Biochem Cell Biol ; 42(2): 287-96, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19914391

ABSTRACT

Cirrhosis is a complex process that involves a dynamic modification of liver cell phenotype associated to gene expression changes. This study investigates the reversing capacity of an adenosine derivative compound (IFC305) on a rat model of liver cirrhosis and gene expression changes associated with it. Rats were treated with IFC305 or saline for 5 or 10 weeks after cirrhosis induction (CCl(4) treatment for 10 weeks). Fibrosis score, collagenase activity and amount of hepatic stellate cells (HSC, activated and with a lipid-storing phenotype) were measured in livers. In addition, gene expression analysis was performed using 5K DNA microarrays and quantitative RT-PCR. Treatment of cirrhotic rats with IFC305 for 5 or 10 weeks compared to saline control, induced: (1) reduction of fibrosis (50-70%) and of collagen, of alpha-SMA and desmin proteins, as well as of activated HSCs in liver, (2) increased collagenase activity and cell number of lipid-storing HSC, (3) improved serum parameters of liver function, such as reduced activity of aminotransferases and bilirubin. Expression of 413 differential genes, deregulated in cirrhotic samples, tended to be normalized by IFC305 treatment. Some genes modulated at transcript level by IFC305 were Tgfb1, Fn1, Col1a1, C9, Apoa1, Ass1, Cps1, and Pparg. The present study shows that IFC305 reverses liver fibrosis through modulation of adipogenic and fibrosis-related genes and by ameliorating hepatic function. Thus, understanding of the anti-cirrhotic effect of IFC305 might have therapeutical potential in patients with cirrhosis.


Subject(s)
Adenosine/analogs & derivatives , Adenosine/pharmacology , Carbon Tetrachloride/pharmacology , Gene Expression Regulation/drug effects , Liver Cirrhosis/chemically induced , Liver Cirrhosis/drug therapy , Adenosine/therapeutic use , Animals , Aspartic Acid/analogs & derivatives , Gene Expression Profiling , Hepatic Stellate Cells/drug effects , Hepatic Stellate Cells/metabolism , In Vitro Techniques , Kinetics , Lipid Metabolism/drug effects , Liver/drug effects , Liver/enzymology , Liver/metabolism , Liver/physiopathology , Liver Cirrhosis/metabolism , Liver Cirrhosis/physiopathology , Male , Rats , Rats, Wistar , Recovery of Function/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Urea/metabolism
5.
Exp Biol Med (Maywood) ; 233(7): 827-39, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18445764

ABSTRACT

Hepatic fibrosis underlies most types of chronic liver diseases and is characterized by excessive deposition of extracellular matrix (ECM), altered liver architecture, and impaired hepatocyte proliferation; however, the fibrotic liver can still regenerate after partial hepatectomy (PH). Therefore, the present study was aimed at addressing whether a PH-induced regeneration normalizes ECM turnover and the possible involvement of hepatic stellate cells (HSC) during resolution of a pre-established fibrosis. Male Wistar rats were rendered fibrotic by intraperitoneal administration of swine serum for 9 weeks and subjected afterwards to 70% PH or sham-operation. Histological and morphometric analyses were performed, and parameters indicative of cell proliferation, collagen synthesis and degradation, and activation of HSC were determined. Liver collagen content was reduced to 75% after PH in cirrhotic rats when compared with sham-operated cirrhotic rats. The regenerating fibrotic liver oxidized actively free proline and had diminished transcripts for alpha-1 (I) collagen mRNA, resulting in decreased collagen synthesis. PH also increased collagenase activity, accounted for by higher amounts of pro-MMP-9, MMP-2, and MMP-13, which largely coincided with a lower expression of TIMP-1 and TIMP-2. Therefore, an early decreased collagen synthesis, mild ECM degradation, and active liver regeneration were followed by higher collagenolysis and limited deposition of ECM, probably associated with increased mitochondrial activity. Activated HSC readily increased during liver fibrosis and remained activated after liver regeneration, even during fibrosis resolution. In conclusion, stimulation of liver regeneration through PH restores the balance in ECM synthesis/degradation, leading to ECM remodeling and to an almost complete resolution of liver fibrosis. As a response to the regenerative stimulus, activated HSC seem to play a controlling role on ECM remodeling during experimental cirrhosis in rats. Therefore, pharmacological approaches for the resolution of liver fibrosis by blocking HSC activation should also evaluate possible effects on liver cell proliferation.


Subject(s)
Hepatectomy , Hepatocytes/pathology , Liver Cirrhosis/pathology , Liver Cirrhosis/physiopathology , Liver Regeneration/physiology , Animals , Cell Proliferation , Collagen/metabolism , Extracellular Matrix/metabolism , Liver/metabolism , Liver/pathology , Male , Matrix Metalloproteinase 13/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , RNA, Messenger/metabolism , Rats , Rats, Wistar , Tissue Inhibitor of Metalloproteinase-1/metabolism , Tissue Inhibitor of Metalloproteinase-2/metabolism
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