An adenosine derivative compound, IFC305, reverses fibrosis and alters gene expression in a pre-established CCl4-induced rat cirrhosis

The hepatic phosphatidylcholine (PC) transporter ATP-binding cassette (ABC) B4 flops PC from hepatocytes into bile, and its dysfunction causes chronic cholestasis and fibrosis. Because a nuclear receptor-dependent PC pathway has been determined to exert antidiabetic effects, we now analyzed the role of ABCB4 in glucose metabolism. We bred congenic Abcb4-knockout (Abcb4(-/-)) mice on the fibrosis-susceptible BALB/cJ background. Knockout mice and wild-type controls were phenotyped by measuring plasma glucose concentrations, intraperitoneal glucose tolerance, hepatic RNA expression profiles, and liver histology. In addition, 4 procholestatic ABCB4 gene variants were correlated with blood glucose levels in 682 individuals from 2 independent European cohorts. Systemic glucose levels differ significantly between Abcb4(-/-) mice and wild-type controls, and knockout mice display improved glucose tolerance with significantly lower area under the curve values on intraperitoneal glucose challenge. Of note, hepatic expression of the antidiabetic nuclear receptor 5A2 (LRH-1) is induced consistently in Abcb4(-/-) mice, and its specific rare PC ligands are detected in liver by mass spectrometry imaging. In humans, serum glucose levels are associated significantly with the common ABCB4 variant c.711A>T. In summary, ABCB4 might play a critical role in glucose homeostasis in mice and humans. We speculate that the effects could be mediated via LRH-1-dependent PC pathways.

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“…35), carbamoyl‐phosphate synthetase 1 ( Cps1 ; ref. 36), hemolytic complement factor 5 ( Hc ; ref. 23), decorin ( Dcn ; ref.…”

Section: Resultsmentioning

confidence: 99%

The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis

et al. 2012

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“…On the other hand, there are observations which show that ADO has a protective role in liver fibrosis, since the systemic administration of the nucleoside protects against the CCl 4 -induced fibrosis [134,135]. In this context, renal fibrosis (RF) induced by UUO exacerbated the expression of EMT induction markers and fibrosis indicators in knockout mice; accordingly, ADORA2A activation with the agonist CGS21680 reduced EMT and the onset of renal fibrosis in wild-type littermates with the UUO model.…”

Section: Purinergic Signaling Emt and Fibrosismentioning

confidence: 99%

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Martinez-Ramirez

Dı́az-Muñoz

Butanda-Ochoa

et al. 2016

Purinergic Signalling

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The epithelium-mesenchymal transition (EMT) is an important process of cell plasticity, consisting in the loss of epithelial identity and the gain of mesenchymal characteristics through the coordinated activity of a highly regulated informational program. Although it was originally described in the embryonic development, an important body of information supports its role in pathology, mainly in cancerous and fibrotic processes. The purinergic system of inter-cellular communication, mainly based in ATP and adenosine acting throughout their specific receptors, has emerged as a potent regulator of the EMT in several pathological entities. In this context, cellular signaling associated to purines is opening the understanding of a new element in the complex regulatory network of this phenotypical differentiation process. In this review, we have summarized recent information about the role of ATP and adenosine in EMT, as a growing field with high therapeutic potential.Keywords P2 receptors . P1 receptors . Purinergic signaling . Cell migration . EMTThe purinergic system of intercellular communication General aspects The term purine (from: pure urine) was created more than 130 years ago by Emil Fischer after detailed analytical characterization of the uric acid molecule [1]. Purine molecular structure is the result of fusing pyrimidine and imidazole rings, and it exists as four N-H tautomeric forms [2]. Tautomerism of purine bases in DNA is one of the earliest reasons for mutations [3][4][5]. The interconversion of the different adenine or guanine tautomers produced mispairing with pyrimidines (which also show tautomeric forms) that may lead to changes in DNA sequence [6].Purine molecules appeared very early in the history of our planet, in the period known as Borganic evolution^, before the establishment of living systems. It has been postulated that purines could be formed by a eutectic (denoting a mixture of substances in fixed proportions that melts and freezes at a single temperature that is lower than the melting points of any of the separate constituents) concentration of HCN at extremely low temperature over a period of dozens of years [7]. Purine molecules, such as adenine and guanine, are components of the genetic material (DNA and RNA) of all living beings. Purine and pyrimidine tautomeric equilibria in nucleic acids was postulated to be significant in events such as DNA replication and repair as well as in the occurrence of point mutations [8].As nucleosides and nucleotides, purines play other highly strategic roles, acting as energy intermediates, allosteric regulators of key metabolic activities, redox molecules, and chemical messengers for signal transduction events. The two most important purines serving as extracellular ligands for paracrine and autocrine signaling are ATP and its dephosphorylated form, adenosine (ADO). ATP and ADO act as intracellular intermediate metabolites, and their presence in the

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“…Its metabolism is very active resulting in a short half-life of the nucleoside but with an action as metabolic modulator. The derivative IFC-305 has a longer half-life in the liver potentiating the beneficial effects of adenosine on CCl 4 -induced cirrhosis in rats [10]. Adenosine presents interesting effects in hepatic metabolism: it increases the energy charge of the hepatocyte, augments the synthesis of hepatic glycogen, and inhibits fatty acid oxidation [11–13]; it also modulates the redox state of the cell through maintaining the structure and function of the mitochondria [14].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we have demonstrated that adenosine administration accelerates progression of the cell cycle during liver regeneration in rats subjected to one-third hepatectomy [19]. Some of these effects, such as prevention of collagen accumulation and increase in DNA synthesis, have been reproduced with the IFC-305 [5, 10]. Moreover, microarray studies showed that 414 genes modified in cirrhosis are decreased to 263 with IFC-305 treatment and the downregulated or upregulated genes showed a tendency to normalize with the compound treatment, among them there are 24 genes involved in the cell cycle [10].…”

Section: Introductionmentioning

confidence: 99%

“…Some of these effects, such as prevention of collagen accumulation and increase in DNA synthesis, have been reproduced with the IFC-305 [5, 10]. Moreover, microarray studies showed that 414 genes modified in cirrhosis are decreased to 263 with IFC-305 treatment and the downregulated or upregulated genes showed a tendency to normalize with the compound treatment, among them there are 24 genes involved in the cell cycle [10]. On the other hand, it has been shown that the cell cycle-related molecules play essential roles in hepatocyte proliferation.…”

Section: Introductionmentioning

confidence: 99%

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Recovery of the Cell Cycle Inhibition inCCl4-Induced Cirrhosis by the Adenosine Derivative IFC-305

Sánchez

Martínez-Pérez

Hernández‐Muñoz

et al. 2012

International Journal of Hepatology

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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 CCl4 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.

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An adenosine derivative compound, IFC305, reverses fibrosis and alters gene expression in a pre-established CCl4-induced rat cirrhosis

Cited by 22 publications

References 45 publications

The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis

The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Recovery of the Cell Cycle Inhibition inCCl4-Induced Cirrhosis by the Adenosine Derivative IFC-305

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