BackgroundAugmenter of liver regeneration (ALR) exerts strong hepatoprotective properties in various animal models of liver injury, but its protective mechanisms have not yet been explored. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of this study was to test the hypothesis that ALR may protect against acute liver injury through the autophagic pathway.MethodsThe level and role of ALR in liver injury were studied in a mouse model of acute liver injury induced by carbon tetrachloride (CCl4). The effect of ALR on autophagy was analyzed in vitro and in vivo. After autophagy was inhibited by 3-methyladenine (3-MA), apoptosis and proliferation were detected in the mouse model with acute liver injury. The ALR and autophagic levels were measured in patients with liver cirrhosis (LC) and acute liver failure (ALF), respectively.ResultsDuring the progression of acute liver injury, the ALR levels increased slightly in early stage and significantly decreased in late stage in mice Treatment with an ALR plasmid via tail vein injection protected mice against acute liver injury. The protective effect of ALR relied on the induction of autophagy, which was supported by the following evidence: (1) ALR overexpression directly induced autophagy flux in vitro and in vivo; and (2) ALR treatment suppressed apoptosis and promoted proliferation in mice exposed to CCl4, but the inhibition of autophagy reversed these effects. More importantly, the ALR levels decreased in patients with LC and ALF compared with normal controls.ConclusionWe demonstrated that ALR ameliorated liver injury via an autophagic mechanism, which indicates a potential therapeutic application for liver injury.

Background The prevalence of primary biliary cholangitis (PBC), which is an autoimmune liver disease, has increased over time. PBC often leads to severe consequences, such as liver failure and death. Stratification tools using biochemical liver tests are needed to assess and predict the progression of this disease at the time of PBC diagnosis. Methods We searched PubMed, Cochrane Library, Web of Science, and Embase for studies focused on the relationship between positive rates of Gp210 antibodies and poor prognosis of PBC. The primary end point was the number of PBC patients with poor outcome in the Gp210 antibody (+) and Gp210 antibody (−) groups. The secondary end point was the basic serum level of alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL), and IgM in the two groups. The age and number of female patients were also measured. Results A total of 5 studies, comprising 737 patients, were included in this analysis. A positive rate of Gp210 antibodies was positively correlated with poor outcomes and with many types of progression in PBC, especially liver failure. Mortality was also higher in the Gp210 antibody (+) group. Furthermore, the serum levels of ALP and IgM were associated with the positive rate of Gp210 antibodies, while the serum levels of ALT and TBIL were not. The age and number of female patients were also not associated with the positive rate of Gp210 antibodies. Conclusion PBC-specific Gp120 antibodies are optimal predictors of PBC prognosis at the time of diagnosis. Some other liver function indicators, such as ALP and IgM, can be used as predictors to complement Gp210 antibodies to establish a stratification tool to predict the prognosis of PBC at the time of diagnosis.

Many categories of drugs can induce hepatotoxicity, so improving the prediction of toxic drugs is important. In vitro models using human hepatocytes are more accurate than in vivo animal models. Good in vitro models require an abundance of metabolic enzyme activities and normal cellular polarity. However, none of the in vitro models can completely simulate hepatocytes in the human body. There are two ways to overcome this limitation: enhancing the metabolic function of hepatocytes and changing the cultural environment. In this review, we summarize the current state of research, including the main characteristics of in vitro models and their limitations, as well as improved technology and developmental prospects. We hope that this review provides some new ideas for hepatotoxicity research.

Background:The prognosis of primary bile cholangitis (PBC) is linked to gut microbiota dysbiosis. This study investigated the association between the gut microbiome and elevated total bilirubin (TB) level in PBC patients treated with ursodeoxycholic acid (UCDA). Methods: A total of 47 PBC patients with 12 months of UCDA treatment were enrolled. Patients were divided into the TB (+) (TB>1× upper limit of the normal range [ULN]; n = 20) and TB(−) (TB≤1× ULN; n = 27) groups. Stool and serum specimens were collected, and microbiota composition and functional characteristics in the 2 groups were evaluated by 16S RNA gene sequencing and bioinformatic analysis.Results: Bacterial diversity was lower in the TB(+) group than in the TB(−) group, although there was no significant difference in bacterial community profile. The phylum Saccharibacteria showed differential abundance in the 2 groups. Meanwhile, the TB(−) group had lower abundance of the Gemmiger, Blautia, Anaerostipes and Coprococcus genera than the TB(+) group, whereas Holdemania was absent. The abundance of Gemmiger formicillis and Coprococcus eutactus was positively correlated with that of Faecalibacterium prausnitzii, while Blautia, Anaerostipes and Coprococcus were negatively correlated with total bile acid level. Conclusion:TB level in PBC patients treated for 12 months with UCDA is associated with a distinct gut microbiome profile.

Tumors tend to metastasize to the liver. Premetastatic niche formation is a vital step in liver metastasis. Tumor-derived exosomes can influence premetastatic niche formation from three aspects: vascular leakiness and angiogenesis, recruitment of nonresident cells, and changes in local resident cells. Exosomes from other tissues, such as mesenchymal stem cell-derived exosomes and engineered exosomes, also have therapeutic potential, but further research on these exosomes is required.Based on the mechanism of premetastatic niche formation, we summarize the therapeutic and diagnostic potential of exosomes in inhibiting liver metastases in this review in an attempt to provide new avenues for the prevention and treatment of liver metastases. K E Y W O R D S liver metastasis tumor, premetastatic niche formation, tumor-derived exosomes

Background: Hepatitis B virus (HBV) infection has been reported to affect the bacterial characteristics in the host. We aimed to elucidate the compositional and functional characteristics of the microbiota in southern Chinese patients with coexistent HBV infection, non-alcoholic fatty liver disease (NAFLD), and type-2 diabetes mellitus (T2DM).Methods: Healthy controls (HCs) and patients with coexistent NAFLD and T2DM were enrolled. Patients were divided into two groups: N1 (without HBV infection) and N2 (with HBV infection). Stool samples were collected for 16s RNA gene sequencing and untargeted metabolomics analysis.Results: Bacterial diversity was decreased in the N2 group. There was a significantly lower abundance of bacteria of Faecalibacterium, Gemmiger, and Clostridium_XIVA genera, but a higher abundance of Megamonas and Phascolarctobacterium genera in the N2 group. Compared with the N1 group, the abundance of Gemmiger species was even lower, and alterations in the abundance of Phascolarctobacterium and Clostridium_XIVA genera only occurred in the N2 group. There were significantly different fecal metabolic features, which were enriched in glucose and lipid metabolic pathways (e.g., fatty acid and glycerophospholipid metabolism) between the N2 and HC groups. Metabolites in glycerophospholipid metabolism, such as Sn-3-o-(geranylgeranyl)glycerol1-phosphate, were even higher in the N2 group than in the N1 group. The decreased Faecalibacterium and Gemmiger contributed to the increased level of Sn-3-o-(geranylgeranyl) glycerol1-phosphate, palmitoylcarnitine, and serum triglycerides. Clostridium_XIVA species were positively correlated to 15(s)-hpete. Megamonas species were positively correlated with the serum level of glucose indirectly.Conclusions: The distinct gut-microbiome profile associated with HBV infection has a role in lipid metabolism and glucose metabolism in patients with coexistent NAFLD and T2DM.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03525769.

Aim: Malnutrition is one of the most common complications in patients with liver cirrhosis. Abnormal energy substrate metabolism may contribute to aggravation of malnutrition. Late evening snack (LESs) supplementation has been recommended as an intervention to reduce starvation time and improve nutritional status. Published studies have analyzed the effect of LESs on the branched-chain amino acid (BCAA)/tyrosine ratio (BTR) and oxidation rate of fat and carbohydrate in patients with liver cirrhosis. Methods: We searched PubMed, Cochrane Library, Web of Science and Embase for relevant research from January 2000 to October 2018. The primary outcome for this analysis was changes in BTR and fat and carbohydrate oxidation in patients with liver cirrhosis. Results: A total of 9 articles, containing 211 patients, were included in this analysis. The results supported that supplementation with BCAA-enriched LESs improved BTR, and long-term supplementation with BCAAs (>1 month) may be more beneficial than short-term supplementation (<1 month) in patients with liver cirrhosis. In addition, supplementation with BCAAs may increase the oxidation rate of carbohydrates and decrease the oxidation rate of fat. Furthermore, compared with liquid-enriched LESs, BCAA was a better choice for increasing the oxidation of carbohydrates and decreasing the rate of fat oxidation. Conclusion: BCAA-enriched LES supplementation is an appropriate nutritional intervention to improve abnormal energy substrate metabolism, which may improve malnutrition in patients with liver cirrhosis. Further research is needed on the long-term benefit and improved survival in patients with liver cirrhosis.

Minimal hepatic encephalopathy (MHE), which shows mild cognitive impairment, is a subtle complication of cirrhosis that has been shown to affect daily functioning and quality of life. However, until 2014, relevant guidelines do not give much attention to the diagnosis and treatment of MHE, resulting in patients being ignored and denied the benefits of treatment. In this review, we summarize recent cognition-based research about (1) alteration of nerve cells, including astrocytes, microglial cells and neurons, in mild cognitive impairment in MHE; (2) comparison of methods in detecting cognitive impairment in MHE; and (3) comparison of methods for therapy of cognitive impairment in MHE. We hope to provide information about diagnosis and treatment of cognitive impairment in patients with MHE.