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Lipid accumulation and oxidative stress in the liver of mice following binge alcohol administration. Mice were administered a single dose of alcohol (6 g/kg body weight) or equal amounts of PBS (control group) and were euthanized 12 h post-treatment. (A) Representative images of liver sections stained with oil red O. Lipid droplets are stained red. For oil red O staining, n=11 in WT and SHP-KO control groups and n=15 in WT and SHP-KO alcohol groups. Levels of (B) TG, (C) malondialdehyde formation and (D) total ROS levels in the liver extracts were determined. For TG, malondialdehyde lipid peroxidation and total ROS assays, n=3 in WT and SHP-KO control groups and n=5 in WT and SHP-KO alcohol groups. Data are presented as the mean ± standard error of the mean. Comparisons between groups are indicated by lowercase letters and groups not sharing a common letter are significantly different to one another at a threshold of P<0.05. TG, triglyceride; ROS, reactive oxygen species; WT, wild-type; SHP, small heterodimer partner; KO, knockout; TBARS, thiobarbituric acid reactive substances; ns, not significant.
Source publication
Binge drinking among alcohol consumers is a common occurrence, and may result in the development of numerous diseases, including liver disorders. It has previously been reported that natural killer T (NKT) cells induce alcohol‑associated liver injury by promoting neutrophil infiltration. In the present study, the role of the orphan nuclear receptor...
Citations
... NR0B2 expression is lacking in human cancer samples; 2 reports have noted that NR0B2 is downregulated in liver cancer (27) and renal cancer (28). NR0B2 has been reported to suppress inflammation and innate immunity to hepatocyte injury (29)(30)(31)(32). Given that inflammatory responses and immune cells have distinct functions in immune escape and antitumor immunity (30,33), the clinical significance of NR0B2 expression in relation to tumor immunity requires more research. ...
Background:
Tumor metabolism and immune response can affect the biological behavior of tumor cells. There is an obvious relationship between glycolysis and immune response. However, the association between metabolism and immune response and prognosis in lung adenocarcinoma (LUAD) has not yet been examined in a comprehensive and detailed manner. The establishment of reliable models for predicting the prognosis of LUAD based on glycolysis ability and immune status is still highly anticipated.
Methods:
The expression of genes were obtained from online databases, and the differentially expressed genes in LUAD tissues and adjacent tissues were identified. We used LUAD samples in The Cancer Genome Atlas (TCGA) database as training set and the Gene Expression Omnibus (GEO) databases as validation sets. The best predictive model was constructed using least absolute selection and shrinkage operator (LASSO) regression and Cox regression. The receiver operator characteristic (ROC) curve is used to verify the accuracy of the model. The expression status of the Glycolysis-related genes (GRGs) and the status of the immune cells in LUCD patients were further analyzed. The protein levels of the 3 identified genes were then tested in LUAD patients.
Results:
We identified 3 GRGs and immune-related genes (i.e., fibroblast growth factor 2, hyaluronan-mediated motor receptor, and nuclear receptor 0B2) and constructed a stable comprehensive index of glycolysis and immunity (CIGI) prediction model. The validation results for this CIGI model were quite stable across different datasets and patient subgroups and the CIGI score can be included as an independent prognostic factor for LUAD patients. The area under the curve (AUC) values of 1-, 3- and 5-year of the finally established nomogram model are 0.767, 0.735 and 0.769. Further analysis showed that LUAD patients in the low-risk group had lower levels of glycolytic gene expression than those in the high-risk group and exhibited an immunosuppressed state. Finally, hyaluronan-mediated motor receptor may play a role in inhibiting cancer, while fibroblast growth factor 2 and nuclear receptor 0B2 may play roles in promoting cancer.
Conclusions:
In this study, we established a new prognostic prediction model for LUAD patients that combines glycolysis ability and immune status.
... Recently, we and others reported that NR0B2 expression suppressed inflammation (13,34,35) and innate immune response (36). We, therefore, analyzed the correlation between NR0B2 expression and tumor-infiltrating lymphocytes using the TIMER database. ...
... Tumor-infiltrating immune cells are the major parts of the tumor microenvironment associated with disease progress, immunotherapy response, and patient survival (49,50). We and others reported that NR0B2 has a unique function in suppressing inflammation and innate immunity in response to liver cell injury (13,21,35,36). This study discovered a negative correlation of NR0B2 expression with tumor-infiltrating lymphocytes, The Gene module on the Tumor Immune Estimation Resource (TIMER) platform was used to visualize the correlation between NR0B2 gene expression and immune infiltration levels in liver cancer tissues (16,17). ...
Background
Liver cancer is a leading cause of cancer death worldwide, and novel prognostic factor is needed for early detection and therapeutic responsiveness monitoring. The orphan nuclear receptor NR0B2 was reported to suppress liver cancer development in a mouse model, and its expression levels were reduced in liver cancer tissues and cell lines due to hypermethylation within its promoter region. However, it is not clear if NR0B2 expression is associated with cancer survival or disease progression and how NR0B2 gene expression is regulated at the molecular level.
Methods
Multiple cancer databases were utilized to explore NR0B2 gene expression profiles crossing a variety of human cancers, including liver cancers, on several publicly assessable bioinformatics platforms. NR0B2 gene expression with or without kinase inhibitor treatment was analyzed using the qPCR technique, and NR0B2 protein expression was assessed in western blot assays. Two human hepatocellular carcinoma cell lines HepG2 and Huh7, were used in these experiments. NR0B2 gene activation was evaluated using NR0B2 promoter-driven luciferase reporter assays.
Results
NR0B2 gene is predominantly expressed in liver tissue crossing human major organs or tissues, but it is significantly downregulated in liver cancers. NR0B2 expression is mostly downregulated in most common cancers but also upregulated in a few intestinal cancers. NR0B2 gene expression significantly correlated with patient overall survival status in multiple human malignancies, including lung, kidney, breast, urinary bladder, thyroid, colon, and head-neck cancers, as well as liposarcoma and B-cell lymphoma. In liver cancer patients, higher NR0B2 expression is associated with favorite relapse-free and progression-free survival, especially in Asian male patients with viral infection history. In addition, NR0B2 expression negatively correlated with immune infiltration and PIK3CA and PIK3CG gene expression in liver cancer tissues. In HepG2 and Huh7 cells, NR0B2 expression at the transcription level was drastically reduced after MAPK inhibition but was significantly enhanced after PI3K inhibition.
Conclusion
NR0B2 gene expression is altered mainly in most human malignancies and significantly reduced in liver cancers. NR0B2 is a prognosis factor for patient survival in liver cancers. MAPK and PI3K oppositely modulate NR0B2 expression, and NR0B2 gene upregulation might serve as a therapeutic responsiveness factor in anti-PI3K therapy for liver cancer.
... There are also many studies that indicate the health, social and economic burdens of high-risk drinking in different ways for Korea [9][10][11]. Some studies demonstrate that Koreans who identify as heavy drinkers during college or earlier were at higher risk of premature cardiovascular disease [12], liver disease [13] and gastrointestinal disease [14]. A cross-sectional study of Korean violent crimes from 2007 to 2009, reveals that about one third of all homicides, violent assaults and sexual assaults were alcohol related [15]. ...
This study examines Korean college students’ rates and the severity of various negative consequences resulting from the frequency and quantity of alcohol consumption and the unique factors that are affecting this problem in the Korean context in comparison to other countries. It assesses how much gender, age and other associated respondent characteristics mediate alcohol use and the resulting negative consequences among the population. A stratified representative sample of 4803 valid student respondents attending 82 colleges participated in the alcohol consumption survey, of which 95% reported drinking in past 12 months. Drinking is measured by the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) screening tool. Based on this test, composite scores for each participant were computed and students were grouped into four risk groups: (a) nondrinkers, (b) light drinkers, (c) moderate drinkers and (d) heavy drinkers. Outcome measures include 21 validated items evaluating self-reported alcohol-related negative consequences. Rates of negative consequences are reported for each drinking risk group stratified by gender. Descriptive statistics, stepwise regression, multivariate linear regression and MANOVA tests were used to analyze the data. The study found that female respondents in the sample who consumed alcohol in the past 12 months drank 11.5 percent less than males (AUDIT-C score μ = 6.0 and 6.7, respectively), and there was a greater proportion of females (5.1 percent) who were nondrinkers than males (4.6 percent). Yet, when females drank, they experienced 11.8 percent more negative consequences on average than males (μ = 1.9 and 1.7, respectively). The study attempts to explain this apparent contradiction. The self-reported rates for many individual negative consequences also varied discernibly by gender. The study concludes with suggestions for how alcohol prevention on Korean college campuses would benefit from targeting females and males differently.
Background & Aims
We recently analyzed and reported the features of the microbiome under hepatitis C virus (HCV) infection, but the effect of HCV infection on bile acid (BA) metabolism in the gut-liver axis remains poorly understood. The aim of this study was to clarify the characteristics of the gut-liver axis in HCV-infected patients.
Methods
The fecal BAs composition and gut microbiota from 100 chronic hepatitis C (CHC) patients were compared with those from 23 healthy individuals. For transcriptional analysis of the liver, 22 mild CHC (fibrosis stages [F] 0–2) and 42 advanced CHC (F3–4) cases were compared with 12 healthy individuals. The findings were confirmed using chimeric mice with human hepatocytes infected with HCV HCR6.
Results
CHC patients, even at earlier disease stages, showed BA profiles distinct from healthy individuals, in which fecal deoxycholic acid (DCA) was significantly reduced and lithocholic acid or ursodeoxycholic acid became dominant. The decrease of fecal DCA was correlated with reduction of commensal Clostridiales and increase of oral Lactobacillales. Impaired biosynthesis of cholic acid (CA) was observed as a reduction of the transcription level of cytochrome P450 8B1 (CYP8B1), a key enzyme in CA biosynthesis. The reductions of fecal DCA and liver CYP8B1 were also observed in HCV-infected chimeric mice.
Conclusions
CHC alters the intestinal BA profile, in association with the imbalance of BA biosynthesis, which differs from the pattern in NAFLD. These imbalances appear to drive disease progression through the gut-microbiome-liver axis.
Liver injury can result in different hepatic diseases such as fatty liver, liver fibrosis, hepatitis, and liver failure, which are mainly responsible for global mortality and morbidity. Early diagnosis is critical for the treatment of liver diseases. Herein we report luminescence imaging of neutrophil-mediated acute liver injury, including alcoholic liver injury (ALI) and acute liver failure (ALF). To this purpose, a biodegradable luminescent material was developed by chemical functionalization of a cyclic oligosaccharide, which can be produced into nanoprobes (defined as LaCD NP). Luminescence of LaCD NP was dependent on the level of reactive oxygen species and myeloperoxidase (MPO). Correspondingly, activated neutrophils could be specifically imaged by LaCD NP, and the luminescent signal was positively associated with the neutrophil count. In mouse models of ALI and ALF, LaCD NP enabled precise quantification and tracking of neutrophils in livers. In both cases, changes in the luminescence intensity are consistent with time-dependent profiles of neutrophils, MPO, and other parameters relevant to the pathogenesis of liver injury. Moreover, luminescence imaging capacity of LaCD NP can be additionally improved by surface functionalization with a neutrophil-targeting peptide. In addition, preliminary in vitro and in vivo studies demonstrated good safety of LaCD NP. Consequently, LaCD NP can be further developed as an effective and biocompatible luminescent nanoprobe for in vivo dynamic detection of the development of neutrophil-mediated acute liver injury. It is also promising for diagnosis of other neutrophil-associated liver diseases.
Recently, we reported that orphan nuclear receptor small heterodimer partner (SHP) is involved in neutrophil recruitment through the regulation of C-X-C motif chemokine ligand 2 (CXCL2) expression in a concanavalin A (ConA)-induced hepatitis model. In the present study, we examined the mechanisms underlying CXCL2 regulation by SHP and the cell types involved in liver inflammation. To this end, either Shp knockout (KO) or wild-type (WT) bone marrow cells were transferred into sublethally-irradiated WT (KO → WT or WT → WT) or Shp KO (KO → KO or WT → KO) recipients, followed by intravenous injection of ConA (20–30 mg/kg) 8 weeks later. The KO recipient groups showed higher ConA-induced lethality than the WT recipient groups. Accordingly, plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and inflammatory cytokine expressions were significantly higher in the KO recipients than in the WT recipients regardless of donor genotype. Massively increased hepatocyte death in KO recipients, as determined by H&E and TUNEL staining, was observed after ConA challenge. Bone marrow chimera experiments and in vitro chemotaxis assay also showed that SHP-deficient hepatocytes have an enhanced ability to recruit neutrophils to the injured liver. In vitro promoter assays showed that SHP is a negative regulator of Cxcl2 transcription by interfering with c-Jun binding to the AP-1 site within the Cxcl2 promoter. Collectively, SHP regulates Cxcl2 transcription in hepatocytes, playing a pivotal role in the recruitment of neutrophils. SHP-targeting strategies may represent alternative approaches to control fulminant hepatitis.
