Macrophages Modulate Hepatic Injury Involving NLRP3 Inflammasome: The Example of Efavirenz

Drug-induced liver injury (DILI) constitutes a clinical challenge due to the incomplete characterization of the mechanisms involved and potential risk factors. Efavirenz, an anti-HIV drug, induces deleterious actions in hepatocytes that could underlie induction of the NLRP3 inflammasome, an important regulator of inflammatory responses during liver injury. We assessed the potential of efavirenz to modulate the inflammatory and fibrogenic responses of major liver cell types involved in DILI. The effects of efavirenz were evaluated both in vitro and in vivo. Efavirenz triggered inflammation in hepatocytes, in a process that involved NF-κB and the NLRP3 inflammasome, and activated hepatic stellate cells (HSCs), thereby enhancing expression of inflammatory and fibrogenic markers. The NLRP3 inflammasome was not altered in efavirenz-treated macrophages, but these cells polarized towards the anti-inflammatory M2 phenotype and displayed upregulated anti-inflammatory mediators. Conversely, no evidence of damage was observed in efavirenz-treated animals, except when macrophages were depleted, which resulted in the in vivo manifestation of the deleterious effects detected in hepatocytes and HSCs. Efavirenz elicits a cell-specific activation of the NLRP3 inflammasome in hepatocytes and HSCs, but macrophages appear to counteract efavirenz-induced liver injury. Our results highlight the dynamic nature of the interaction among liver cell populations and emphasize the potential of targeting macrophage polarization as a strategy to treat NLRP3 inflammasome-induced liver injury.

HBV enveloped particle secretion is positively regulated by GRP78 through direct interaction with preS1

Hepatitis B virus (HBV) infection is a common cause of liver diseases worldwide. Existing drugs do not effectively eliminate HBV from infected hepatocytes; thus, novel curative therapies are needed. Enveloped-particle secretion is a key but poorly studied aspect of the viral life cycle. Here, we report that GRP78 positively regulates HBV enveloped-particle secretion. GRP78 is the specific target of preS1 binding; HBV can upregulate GRP78 in liver cell lines and sera from chronic hepatitis B patients. GRP78 promoted intact HBV-particle secretion in liver cell lines and an HBV transgenic-mouse model. Some peptides screened from preS1 via phage display could inhibit viral-particle secretion by interacting with GRP78 via hydrogen bonds and hydrophobic interactions, thereby disturbing the interaction with HBV particles. These results provide insight into enveloped-particle secretion in the HBV life cycle. GRP78 might be a potential target for HBV-infection treatment via restricting GRP78–preS1 interactions to block viral-particle secretion.

A Magnetic Field Prevents Alcoholic Liver Disease by Reducing Oxidative Stress

The radical-pair recombination change will affect the generation of free radicals, which can be regulated by static magnetic fields (SMFs) in a SMF setting dependent way. It is well known that alcohol consumption leads to significantly increased free radical levels and health risks, which lacks effective treatment method besides alcohol abstinence. Here we compared different SMF settings and found that a downward SMF of ∼0.1 T with magnetic flux of ∼4.5×10−3 Wb could effectively alleviate alcohol-induced liver damage and lipid accumulation, and improve liver function. The inflammation, reactive oxygen species (ROS) level and oxidative stress were significantly reduced. EPR (electron paramagnetic resonance) experiments also confirmed the reduced amount of free radical by SMF treatment. Moreover, the lifespan of heavy alcohol drinking mice was also significantly changed due to the SMF effects on liver cell ROS level, DNA synthesis and liver cell regeneration. Our study shows that moderate SMFs with specific parameters have great promises to be developed into a physical method to reduce alcohol-induced liver damage in the future.

Histomorphometric study of rat liver during the treatment of the acute toxic injury

Introduction. There are a few effective therapies are available for acute liver injury at present. The aim of the study was to investigate histological and morphometric changes in the liver using models of toxic damage caused by carbon tetrachloride (CCl4 ) and acetaminophen during correction with Oxymethyluracil (OMU). Material and methods. A total of ninety rats were divided into 18 groups. The treatment of acute liver damage models caused by a single injection of CCl4 or acetaminophen was carried out using “Heptor”, “Mexidol”, and OMU. The correction was carried out twice (sacrificed 24 hours after intoxication) and four times (sacrificed 72 hours after intoxication). Liver tissues were processed using standard histological techniques (H&E). A semi-quantitative assessment was performed using a scale based on the severity of liver cell deaths. Results. Twenty-four hours after administration of CCl4 or 72 hours after administration of acetaminophen, the treatment with OMU led to a decrease in liver cell death compared to the group with administration of only CCl4 or acetaminophen. Seventy-two hours after CCl4 and 24 hours after acetaminophen intoxication, these groups with the OMU treatment did not differ from those of the carbon tetrachloride- or acetaminophen-induced liver injury groups, respectively. Conclusion. Thus, on the model of CCl4 liver injury, the treatment with OMU is more effective for 24 hours. In the case of acetaminophen intoxication, the effectiveness of treatment with OMU is better for 72 hours. The results obtained are possibly associated with a different mechanism of the damaging effect of the studied toxicants.

The Contribution of Sex Difference on Different Liver Histopathology Between Male and Female Mice After Oral Administration of Caffeine

Background : There are several studies reporting the effect of caffeine on liver histopathology, but it remains controversy. The laboratory animal used in those studies were predominantly male, whereas there is contribution of sex difference on different liver reaction to xenobiotic between male and female subject. Objective : It is necessary to conduct a study to explore the differences between the liver histopathology of male and female mice after oral administration of caffeine. Methods : This study used 36 mice (Mus musculus) that were divided into 4 groups: male & female untreated groups and male & female treated groups which were orally administered with caffeine 0.4 mg / 20 gramBW daily for 30 days. At the end of treatment, mice were euthanized and dissected. Histopathological examination was done to determine the percentage of liver cell death of each group. Results: The percentage of liver cell deathin female treated group was higher than male treated group (p = 0.0001). But there was no significant difference of liver cells death between male control and treated group and between female control and treated group. Conclusion : There was significant difference in liver histopathology between male and female mice after oral administration of caffeine.

Bone marrow mesenchymal stem cells stimulated by tumor necrosis factor-α can promote the repair of fatty liver cell oxidative stress injury and fatty liver ischemia-reperfusion injury

Mesenchymal stem cells (MSCs) have great prospects for the treatment of ischemia-reperfusion injury (IRI) after liver transplantation. At this stage, the main factor limiting MSCs in the treatment of fatty liver IRI of the donor liver is the residence time of stem cells at the site of inflammatory injury. This study investigated whether bone marrow mesenchymal stem cells (BMSCs) stimulated by tumor necrosis factor-α (TNF-α) can promote the repair of fatty liver cell oxidative stress injury and fatty liver IRI in rats. The results indicated the BMSCs treatment group stimulated by TNF-α had lower indexes and significantly improved oxidative stress damage in vitro through Transwell chamber co-culture experiment, compared with the control group. In vivo, compared with the PBS group and the BMSCs group, the indexes of the BMSCs treatment group stimulated by TNF-α were reduced, and the degree of tissue damage was significantly reduced. BMSCs can repair fatty liver cell oxidative stress injury and fatty liver IRI, however, BMSCs stimulated by TNF-α can promote the repair of tissues and cells.