ABSTRACT
Using a composite model of the glucose homeostasis system, consisting of seven interconnected submodels, we enumerate the possible behaviours of the model in response to variation of liver insulin sensitivity and dietary glucose variability. The model can reproduce published experimental manipulations of the glucose homeostasis system and clearly illustrates several important properties of glucose homeostasis-boundedness in model parameters of the region of efficient homeostasis, existence of an insulin sensitivity that allows effective homeostatic control and the importance of transient and oscillatory behaviour in characterizing homeostatic failure. Bifurcation analysis shows that the appearance of a stable limit cycle can be identified.
Subject(s)
Glucose/metabolism , Liver/metabolism , Models, Biological , Activity Cycles/physiology , Blood Glucose/metabolism , Homeostasis , Humans , Insulin/metabolism , Insulin Resistance/physiology , Systems BiologyABSTRACT
Sirtuin 1 (Sirt1) and Sirtuin 2 (Sirt2) belong to the family of NAD+ (nicotinamide adenine dinucleotide-positive)-dependent class III histone deacetylases and are involved in regulating lifespan. As cancer is a disease of ageing, targeting Sirtuins is emerging as a promising antitumour strategy. Here we present Salermide (N-{3-[(2-hydroxy-naphthalen-1-ylmethylene)-amino]-phenyl}-2-phenyl-propionamide), a reverse amide with a strong in vitro inhibitory effect on Sirt1 and Sirt2. Salermide was well tolerated by mice at concentrations up to 100 muM and prompted tumour-specific cell death in a wide range of human cancer cell lines. The antitumour activity of Salermide was primarily because of a massive induction of apoptosis. This was independent of global tubulin and K16H4 acetylation, which ruled out a putative Sirt2-mediated apoptotic pathway and suggested an in vivo mechanism of action through Sirt1. Consistently with this, RNA interference-mediated knockdown of Sirt1, but not Sirt2, induced apoptosis in cancer cells. Although p53 has been reported to be a target of Sirt1, genetic p53 knockdowns showed that the Sirt1-dependent proapoptotic effect of Salermide is p53-independent. We were finally able to ascribe the apoptotic effect of Salermide to the reactivation of proapoptotic genes epigenetically repressed exclusively in cancer cells by Sirt1. Taken together, our results underline Salermide's promise as an anticancer drug and provide evidence for the molecular mechanism through which Sirt1 is involved in human tumorigenesis.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis , Naphthols/pharmacology , Neoplasms/drug therapy , Neoplasms/pathology , Phenylpropionates/pharmacology , Sirtuins/antagonists & inhibitors , Animals , Cell Line, Tumor , Female , Genes, p53 , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Naphthols/chemistry , Phenylpropionates/chemistry , Sirtuin 1 , Sirtuin 2 , Sirtuins/metabolism , Tumor Suppressor Protein p53/metabolismABSTRACT
The role of members of the mitogen-activated protein kinase (MAPK) family on tumor necrosis factor alpha (TNF-alpha)-mediated down-regulation of col1a1 gene was studied. TNF-alpha increased extracellular-regulated kinase and Jun-N-terminal kinase phosphorylation, but these effects were not related to its inhibitory effect on alpha1(I) procollagen (col1a1) mRNA levels. Phosphorylation of p38 MAPK was decreased in response to TNF-alpha, and the specific p38 MAPK inhibitor SB203580 mimicked the effect of TNF-alpha on col1a1 mRNA levels. Transforming growth factor beta (TGF-beta) increased p38 MAPK phosphorylation and SB203580 prevented the induction of col1a1 mRNA levels by TGF-beta. These results suggest that p38 MAPK plays an important role in regulating the expression of col1a1 in hepatic stellate cells in response to cytokines.
Subject(s)
Collagen Type I/genetics , Hepatocytes/drug effects , Hepatocytes/metabolism , Mitogen-Activated Protein Kinases/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transforming Growth Factor beta/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Animals , Apoptosis/drug effects , Base Sequence , Cell Line , Down-Regulation/drug effects , Enzyme Inhibitors/pharmacology , Hepatocytes/cytology , Imidazoles/pharmacology , JNK Mitogen-Activated Protein Kinases , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Phosphorylation , Pyridines/pharmacology , Rats , Sphingomyelin Phosphodiesterase/metabolism , Up-Regulation/drug effects , p38 Mitogen-Activated Protein KinasesABSTRACT
3,4-Methylenedioxymethamphetamine, MDMA ("Ecstasy"), has been previously shown to produce cell necrosis and fibrosis in the liver. Our aim was to study the effect of MDMA on the type I collagen production by a cell line of hepatic stellate cells (HSC), the cell type mainly responsible for collagen synthesis in the liver. We demonstrated that MDMA increases alpha1(I) procollagen mRNA levels and that this increase correlates with glutathione depletion and enhanced hydrogen peroxide production by HSC. Pre-treatment with either glutathione monoethyl ester or deferoxamine prevents the MDMA-induced alpha1(I) procollagen mRNA expression, indicating oxidative stress to be a mediator of this effect. Lipid peroxidation was not detected in MDMA-treated cells and therefore does not seem to be involved in the pro-fibrogenic action of MDMA on HSC.
