Interaction of Mitochondrial and Epigenetic Regulation in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a pathology preceded mainly by cirrhosis of diverse etiology and is associated with uncontrolled dedifferentiation and cell proliferation processes. Many cellular functions are dependent on mitochondrial function, among which we can mention the enzymatic activity of PARP-1 and sirtuin 1, epigenetic regulation of gene expression, apoptosis, and so on. Mitochondrial dysfunction is related to liver diseases including cirrhosis and HCC; the energetic demand is not properly supplied and mitochondrial morphologic changes have been observed, resulting in an altered metabolism. There is a strong relationship between epigenetics and mitochondrion since the first one is dependent on the correct function of the last one. There is an interest to improve or to maintain mitochondrial integrity in order to prevent or reverse HCC; such is the case of IFC-305 that has a beneficial effect on mitochondrial function in a sequential model of cirrhosis-HCC. In this model, IFC-305 downregulates the expression of PCNA, thymidylate synthase, HGF and its receptor c-Met and upregulates the cell cycle inhibitor p27, thereby decreasing cell proliferation. Both effects, improvement of mitochondria function and reduction of tumor proliferation, suggest its use as HCC chemoprevention or as an adjuvant in chemotherapy

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

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 CCl4-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 anti-inflammatory 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

Immunomodulatory effect of an adenosine derivative (IFC-305) in is oproterenol induced myocardial infarction

Cardiovascular diseases are the principal cause of decease in the world, 16.4% of the worldwide population dies every year as consequence of myocardial infarction (MI) (WHO, 2013).In the myocardium infarction a vascular occlusion originates isquemic necrosis and decrease of coronary flow. Several models had been developed to research this pathology, nonetheless not all models offer the possibility to evaluate each stage of MI, which limits the understanding of this phenomena. In 1956, Rona found that isoproterenol (ISO), a beta adrenergic agonist, is able to i nduce MI in rats. This model, characterized biochemical , histological and physiologically (Chagoya, 1997) allows the study of every stage of MI: pre- infarction, infarction (12 hours after ISO administration) and post-infarction. Correct inflammatory responses during the post infarction phase leads to the formation of a scar with enough force to prevent the extension of the infarct, which is necessary for an accurate h ealing process (Anzai, 2013).It has been reported that adenosine has a strong role in the inflammation process.(Haskó, 2004). In previous studies achieved in our laboratory it was observed that an adenosine derivative, IFC-305 favor the hepatic tissue remodeling , modulates the energetic state (Pérez-Carreón JI, 2010; Master thesis Pérez-Cabeza de Vaca, 2010) and immune response in hepatoxicity, this suggest a possible role of the IFC-305 against the injuries that take place during MI. EXPERIMENTAL MODEL: Male rats Wist ar of 200g receive a subcutaneous administration of ISO 67mg/kg, and one hour after they receive an IFC-305 intraperitoneal injection. We worked wi th the following groups: 1. Control (Saline solution), 2. ISO, 3.IFC and 4. ISO+IFC. Rats sacrifice was performed 6, 12, 24 or 96 hours after ISO administration. Hearts and plasma samples were recollected. We evaluated the levels of IL 1β, IL-6, INFγ, T NFα, and IL 10, in male Wist ar rat plasma and heart, through every stage of the infarction process induced by isoproterenol. The results s how alterations in the former cytokines levels as consequence of isoproterenol administration. Also, the restoration of the physiological levels of these cytokines was reached with the administration of an adenosine derivative: IFC-305. In conclusion, our results show evident alterations in cytokines levels as reflect of immune response that take place during the MI and that the IFC-305 is able to modulate this response in a favorable way. Still, there are necessary more studies about the immnunomodulatory role of the IFC-305 during MI

Investigación y desarrollo de un fármaco para el tratamiento de la cirrosis

La cirrosis es una de las causas más comunes de muerte en el mundo ya que la disfunción hepática conduce a una condición letal. Su etiología es diversa y no existe un tratamiento efectivo para prevenir o revertir esta patología, sin embargo, el riesgo de complicaciones como sepsis, peritonitis, sangrados e hipertensión y desarrollo de carcinoma hepático aumenta. En esta nota describimos brevemente las características estructurales y funcionales del tejido hepático normal comparándolas con los cambios que ocurren a lo largo del desarrollo de esta patología. Comentamos el trabajo que hemos realizado en el laboratorio en un modelo experimental de hepatotoxicidad aguda y crónica usando al nucleósido adenosina como hepatoprotector. A través de sus efectos antifibrogénicos en el metabolismo de colágena estimula su degradación al disminuir los inhibidores y favorece la recuperación de la función hepática, principalmente su capacidad de regeneración. También comentamos aspectos importantes y necesarios que permitan la aplicación de estos hallazgos de investigación básica a un modelo experimental de pacientes con este padecimiento y enumeramos una serie de estudios de tipo farmacológico que permitirán la aplicación de este compuesto a pacientes