Molecular and Cellular Aspects of Cirrhosis and How an Adenosine Derivative Could Revert Fibrosis

Abstract

Hepatic fibrosis occurs in response to persistent liver damage and is characterized by an excessive accumulation of extracellular matrix. When the damage is prolonged, there is a chronic inflammation and persistent hepatic fibrosis eventually leads to cirrhosis, where in addition to the scar, there is an important vascular remodeling associated with portal hypertension and, if decompensated, leads to death or can develop hepatocellular carcinoma. We have been studying the pharmacologic functions of adenosine, finding that a derivative of this nucleoside, IFC-305, shows hepatoprotective effects in a CCl 4-induced rat cirrhosis model where it reverses liver fibrosis through modulation of fibrosis-related genes and by ameliorating hepatic function. Furthermore, this compound has the property to rescue cell cycle inhibition in vivo, prevents hepatic stellate cell activation, modulates antiinflammatory macrophage polarization, and favors a chromatin context that could decrease the genomic instability and characteristics of cirrhosis, enabling the recovery of gene expression profile. Here we show results that contribute to the comprehension of molecular and cellular mechanism of cirrhosis, give the opportunity to suggest biomarkers to the early diagnostic of this pathology, and constitute the fundaments to suggest IFC-305 as a coadjuvant for treatment of this disease.

Molecular Mechanism Contributing to Malnutrition and Sarcopenia in Patients with Liver Cirrhosis

“…In Germany, more than 62,000 patients with chronic liver diseases were admitted to hospital in 2016 [ 5 ] showing an increasing trend and imposing a high medical and economic burden. Liver cirrhosis is the late and irreversible stage of hepatic fibrosis [ 6 ], pathologically representing a hepatic tissue remodeling with the formation of fibrotic interconnected septa that distort the liver tissue, divide the parenchyma in nodules and alter vascular architecture and resistance resulting in altered blood flow and portal hypertension [ 7 ]. The most common underlying etiologies of liver cirrhosis are alcohol abuse, chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, as well as non-alcoholic steatohepatitis (NASH) [ 8 ].…”

The Hepatic Sinusoid in Aging and Disease: Update and Advances From the 20th Liver Sinusoid Meeting

“…This group reported that IFC-305 reduced cell survival in HCC cell lines but did not impair survival of a human hepatic progenitor cell line. (34)…”

Genome-wide 5-hydroxymethylcytosine (5hmC) emerges at early stage of in vitro hepatocyte differentiation

“…An adenosine derivative, IFC-305 (UNAM Patent 207422), administered in a cirrhotic rat model has previously been able to recover SAM levels abrogated in cirrhosis which triggers the re-establishment of 5mC and 5hmC in this condition . IFC-305 also has several hepatoprotective properties (reviewed in [Rodríguez-Aguilera et al, 2019]), such as, reduction of fibrosis and amelioration of liver function through regulation of transcriptome , promotion of cell cycle recovery in the liver [Chagoya de Sanchez et al, 2012], antiinflammatory effects during cirrhosis , prevention of hepatic stellate cells (HSCs) activation , and anti-carcinogenic effects [Velasco-Loyden et al, 2017].…”