Cerium oxide nanoparticles improve liver regeneration after acetaminophen-induced liver injury and partial hepatectomy in rats

Bernat Córdoba-Jover,Guillermo Fernández-Varo,Jordi Ribera,Wladimiro Jiménez,Altamira Arce-Cerezo,Eudald Casals,Montse Pauta,Manuel Morales-Ruiz,Victor Puntes,Gregori Casals,Denise Oró

doi:10.1186/s12951-019-0544-5

Abstract

Background and aimsCerium oxide nanoparticles are effective scavengers of reactive oxygen species and have been proposed as a treatment for oxidative stress-related diseases. Consequently, we aimed to investigate the effect of these nanoparticles on hepatic regeneration after liver injury by partial hepatectomy and acetaminophen overdose.MethodsAll the in vitro experiments were performed in HepG2 cells. For the acetaminophen and partial hepatectomy experimental models, male Wistar rats were divided into three groups: (1) nanoparticles group, which received 0.1 mg/kg cerium nanoparticles i.v. twice a week for 2 weeks before 1 g/kg acetaminophen treatment, (2) N-acetyl-cysteine group, which received 300 mg/kg of N-acetyl-cysteine i.p. 1 h after APAP treatment and (3) partial hepatectomy group, which received the same nanoparticles treatment before partial hepatectomy. Each group was matched with vehicle-controlled rats.ResultsIn the partial hepatectomy model, rats treated with cerium oxide nanoparticles showed a significant increase in liver regeneration, compared with control rats. In the acetaminophen experimental model, nanoparticles and N-acetyl-cysteine treatments decreased early liver damage in hepatic tissue. However, only the effect of cerium oxide nanoparticles was associated with a significant increment in hepatocellular proliferation. This treatment also reduced stress markers and increased cell cycle progression in hepatocytes and the activation of the transcription factor NF-κB in vitro and in vivo.ConclusionsOur results demonstrate that the nanomaterial cerium oxide, besides their known antioxidant capacities, can enhance hepatocellular proliferation in experimental models of liver regeneration and drug-induced hepatotoxicity.

Highlights

Background and aimsCerium oxide nanoparticles are effective scavengers of reactive oxygen species and have been proposed as a treatment for oxidative stress-related diseases
To test our hypothesis we studied the hepatic regenerative process using two different rat experimental models of liver regeneration that are commonly associated with reactive oxygen species (ROS) production: partial hepatectomy (PHx) [35, 36] and drug-induced liver injury (DILI) caused by acetaminophen (APAP) overdose
The X-ray diffraction pattern of the cerium oxide nanoparticles (CeO2NPs) showed pure CeO2NPs with the typical peak broadening characteristic of nanosize particles (Fig. 1d)

Summary

Introduction

Cerium oxide nanoparticles are effective scavengers of reactive oxygen species and have been proposed as a treatment for oxidative stress-related diseases. There are some clinical situations in which the liver shows poor regenerative capacity, such as in the case of liver cirrhosis and severe drug-induced liver injury (DILI) [3, 4]. One pathological process that is common to these two clinical conditions is oxidative stress, which is caused by the excessive formation of reactive oxygen species (ROS). The presence of oxidative stress has been described in most of the clinical conditions associated with chronic liver injury (i.e.: nonalcoholic steatohepatitis, hepatitis C viral infection, alcoholic liver cirrhosis) [5, 6]. One of the reasons that explain this ROS effect is that ROS modulates the expression of a variety of regulators that play major roles in liver regeneration, including growth factors, transcription factors and cell cycle proteins such as β-catenin [13], cyclin D [14], p53 [15], Nrf2 [16] and JNK/p38 mitogen activated kinases [17]

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