Microbial Intervention as a Novel Target in Treatment of Non-Alcoholic Fatty Liver Disease Progression

Background/Aims: Emerging evidence suggests a close link between gut microbiota and non-alcoholic fatty liver disease (NAFLD). In this study, we aimed to investigate the association between gut microbiota and the DNA methylation of adiponectin (an adipocyte-specific adipocytokine) in rats, following diet-induced NAFLD. Methods: 50 male SD rats were randomly divided into five groups with or without a high fat diet (HFD), antibiotics, and probiotics, in order to establish an imbalanced gut microbiota and probiotic treatment model in NAFLD rats. After 13 weeks of treatment, blood, liver, and cecal tissue samples were collected. Serum lipids, liver function indexes by biochemical analyzers, and changes in liver pathology with hematoxylin-eosin (HE) and masson staining were detected. Furthermore, the serum adiponectin by enzyme-linked immunosorbent assay (ELISA) and liver adiponectin methylation levels in the promoter regions by pyrophosphate sequencing were determined. High throughput Illumina sequencing targeted microbial 16S genes, bioinformatics and statistical analysis identified cecal-associated gut microbiota. Results: HFD with antibiotic exposure showed the most severe steatohepatitis and a severe gut microbiota alteration. Reduced bacterial diversity was also seen and the abundances of Firmicutes, Lactobacillus, Cyanobacteria, Acidobacteria, Chlamydiae, Chlamydiales, Rubrobacteria, Verrucomicrobia, Blautia, Shewanella, Bacteroides, Bacteroides acidifaciens, and Bacteroides uniformis, were shown to be partly reversed by probiotic treatment. Decreased serum adiponectin levels and increased DNA methylation levels of adiponectin promoter regions were also markedly associated with the NAFLD progression during gut microbiota alteration. Conclusion: Our results suggested that both gut microbiota alteration and adiponectin variability may be drivers of NAFLD progression and that targeting the gut microbiota, such as via administration of a probiotic, may delay NAFLD progression via adiponectin

Incidence and Etiology of Drug-Induced Liver Injury in Mainland China

Background & Aims: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China.Methods: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n=29,478) according to the Roussel Uclaf Causality Assessment Method.Results: Most cases of DILI presented with hepatocellular injury (51.39%; 95% CI, 50.76–52.03), followed by mixed injury (28.30%; 95% CI, 27.73–28.87) and cholestatic injury (20.31%; 95% CI, 19.80–20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and anti-tuberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy’s Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI, 20.86–26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher.Conclusions: In a retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons—higher than that reported from western countries. Traditional Chinese medicines, herbal and dietary supplements, and anti-tuberculosis drugs were the leading causes of DILI in mainland Chin

Bioinformatics analysis of hedgehog interacting protein in colorectal cancer: a study based on GEO data and TCGA data

Abstract Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide. Hedgehog Interacting Protein (HHIP) is evolutionarily conserved protein, which are important morphogens for a wide range of developmental processes,However, the specific role and mechanism of HHIP in CRC remains not fully understood. In this study, we first performed pan-cancer analysis for HHIP’s expression via The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) data and found that HHIP might be a potential anti-oncogene for CRC. Subsequently, non-coding RNAs (ncRNAs) contributing to down-regulated HHIP expression were identified through a combination of a series of in silico analyses, including expression and correlation analysis. Finally, the LINC02381/miR-577 complex was identified as the top potential upstream regulator of HHIP in CRC. In addition, HHIP expression level was significantly correlated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. Overall, our findings clarified ncRNAs-mediated down-regulation of HHIP which was associated with poor prognosis and tumor immune infiltration in CRC

Microbial Metabolites in Colorectal Cancer: Basic and Clinical Implications

Colorectal cancer (CRC) is one of the leading cancers that cause cancer-related deaths worldwide. The gut microbiota has been proved to show relevance with colorectal tumorigenesis through microbial metabolites. By decomposing various dietary residues in the intestinal tract, gut microbiota harvest energy and produce a variety of metabolites to affect the host physiology. However, some of these metabolites are oncogenic factors for CRC. With the advent of metabolomics technology, studies profiling microbiota-derived metabolites have greatly accelerated the progress in our understanding of the host-microbiota metabolism interactions in CRC. In this review, we briefly summarize the present metabolomics techniques in microbial metabolites researches and the mechanisms of microbial metabolites in CRC pathogenesis, furthermore, we discuss the potential clinical applications of microbial metabolites in cancer diagnosis and treatment

Synthesis, Characterization and Anticancer Efficacy Studies of Iridium (III) Polypyridyl Complexes against Colon Cancer HCT116 Cells

In this paper, two new iridium (III) complexes, [Ir(ppy)2(ipbp)](PF6) (Ir1) (ppy = 2-phenylpyridine, ipbp = 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2yl)-4H-chromen-4-one) and [Ir(bzq)2(ipbp)](PF6) (Ir2) (bzq = benzo[h]quinolone), were synthesized and characterized. The cytotoxicity of the complexes against human colon cancer HCT116 and normal LO2 cells was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The complexes Ir1 and Ir2 show high cytotoxic efficacy toward HCT116 cells with a low IC50 value of 1.75 ± 0.10 and 6.12 ± 0.2 µM. Interestingly, Ir1 only kills cancer cells, not normal LO2 cells (IC50 > 200 µM). The inhibition of cell proliferation and migration were investigated by multiple tumor spheroid (3D) and wound healing experiments. The cellular uptake was explored under a fluorescence microscope. The intracellular reactive oxygen species (ROS), change of mitochondrial membrane potential, glutathione (GSH) and adenine nucleoside triphosphate (ATP) were studied. Apoptosis and cell cycle arrest were performed by flow cytometry. The results show that the complexes induce early apoptosis and inhibit the cell proliferation at the G0/G1 phase. Additionally, the apoptotic mechanism was researched by Western blot analysis. The results obtained demonstrate that the complexes cause apoptosis in HCT116 cells through ROS-mediated mitochondrial dysfunction and the inhibition of PI3K/AKT signaling pathways

Lack of PPARβ/δ-Inactivated SGK-1 Is Implicated in Liver Carcinogenesis.

ObjectiveThe present study examined the role of PPARβ/δ in hepatocellular carcinoma (HCC).MethodsThe effect of PPARβ/δ on HCC development was analyzed using PPARβ/δ-overexpressed liver cancer cells and PPARβ/δ-knockout mouse models.ResultsPPARβ/δ (-/-) mice were susceptible to diethylnitrosamine- (DEN-) induced HCC (87.5% vs. 37.5%, p < 0.05). In addition, PPARβ/δ-overexpressed HepG2 cells had reduced proliferation, migration, and invasion capabilities accompanied by increased apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, differential gene expression profiling uncovered that the levels of serine/threonine-protein kinase (SGK-1) mRNA and its encoded protein were reduced in PPARβ/δ-overexpressed HepG2 cells. Consistently, elevated SGK-1 levels were found in PPARβ/δ (-/-) mouse livers as well as PPARβ/δ-knockdown human SMMC-7721 HCC cells. Chromatin immunoprecipitation (ChIP) assays followed by real-time quantitative polymerase chain reaction (qPCR) assays further revealed the binding of PPARβ/δ to the SGK-1 regulatory region in HepG2 cells.ConclusionsDue to the known tumor-promoting effect of SGK1, the present data suggest that PPARβ/δ-deactivated SGK1 is a novel pathway for inhibiting liver carcinogenesis

The clinical features of infantile hypertrophic pyloric stenosis in Chinese Han population: analysis from 1998 to 2010.

OBJECTIVE: To investigate clinical features of infantile hypertrophic pyloric stenosis (IHPS) in Chinese Han population. METHODS: Three hundred and sixteen hospitalized patients with IHPS from January 1998 to February 2010 were retrospectively reviewed, and data including patient's sex, onset age, other coexisting congenital defects, pyloric circular muscle thickness evaluated by ultrasonograph, serum electrolytes concentration, and results of arterial blood gas analysis on admission were collected. The patients were divided into two groups: the duration between first onset and admission less than or equal to 10 days (early onset group), and more than 10 days (late onset group). The results of arterial blood gas and serum electrolyte concentration were compared between the two groups. RESULTS: There were 271 males and 45 females in 316 patients; the onset age ranged between 1 and 351 (26.5±26.6) days. The birth weight ranged between 1.6 and 4.5 (3.23±0.44) kilograms; coexisting congenital defects were found in 65 cases (20.6%). Pyloric circular muscle thickness was 4-8 (5.4±1.0) millimetres (mm). For the early onset group, the rates of hypokalemia, hypochloraemia and hypercapnia were significantly lower than those in the late onset group (18.67% VS 50%, P<0.0001; 46.03% VS 71.01%, P = 0.003; 56.58% VS 83.44%, P = 2.17×10(-5); respectively). CONCLUSIONS: The symptom duration in Chinese Han population was longer than that in other populations. And as the prolongation of symptom duration, the incidence of acid-base imbalance increased significantly. Infants with persistent vomiting at the age of 3∼5 weeks after birth should be considered IHPS, and go to hospital as soon as possible in order to reduce the incidence of hypokalemia, hypochloraemia and hypercapnia, and avoid deterioration

Transcriptome Reveals 1400-Fold Upregulation of APOA4-APOC3 and 1100-Fold Downregulation of GIF in the Patients with Polycythemia-Induced Gastric Injury.

High-altitude polycythemia (HAPC) inducing gastric mucosal lesion (GML) is still out of control and molecular mechanisms remain widely unknown. To address the issues, endoscopy and histopathological analyses were performed. Meanwhile, microarray-based transcriptome profiling was conducted in the gastric mucosa from 3 pairs of healthy subjects and HAPC-induced GML patients. HAPC caused morphological changes and pathological damages of the gastric mucosa of GML patients. A total of 10304 differentially expressed genes (DEGs) were identified, including 4941 up-regulated and 5363 down-regulated DEGs in gastric mucosa of GML patients compared with healthy controls (fold change ≥2, P<0.01 and FDR <0.01). Particularly, apolipoprotein genes APOA4 and APOC3 were 1473-fold and 1468-fold up-regulated in GML patients compared with the controls. In contrast, gastric intrinsic factor (GIF) was 1102-fold down-regulated in GML patients compared with the controls. APOA4 (chr11:116691770-116691711), APOC3 (chr11:116703530-116703589) and GIF (chr11:59603362-59603303) genes are all located on chromosome 11. APOA4 and APOC3 act as an inhibitor of gastric acid secretion while gastric acid promotes ulceration. GIF deficiency activates a program of acute anemia, which may antagonize polycythemia while polycythemia raises the risk of GML. Therefore, the present findings reveal that HAPC-induced GML inspires the protection responses by up-regulating APOA4 and APOC3, and down-regulating GIF. These results may offer the basic information for the treatment of HAPC-induced gastric lesion in the future

Lack of PPARβ/δ-Inactivated SGK-1 Is Implicated in Liver Carcinogenesis

Objective. The present study examined the role of PPARβ/δ in hepatocellular carcinoma (HCC). Methods. The effect of PPARβ/δ on HCC development was analyzed using PPARβ/δ-overexpressed liver cancer cells and PPARβ/δ-knockout mouse models. Results. PPARβ/δ(-/-) mice were susceptible to diethylnitrosamine- (DEN-) induced HCC (87.5% vs. 37.5%, p<0.05). In addition, PPARβ/δ-overexpressed HepG2 cells had reduced proliferation, migration, and invasion capabilities accompanied by increased apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, differential gene expression profiling uncovered that the levels of serine/threonine-protein kinase (SGK-1) mRNA and its encoded protein were reduced in PPARβ/δ-overexpressed HepG2 cells. Consistently, elevated SGK-1 levels were found in PPARβ/δ(-/-) mouse livers as well as PPARβ/δ-knockdown human SMMC-7721 HCC cells. Chromatin immunoprecipitation (ChIP) assays followed by real-time quantitative polymerase chain reaction (qPCR) assays further revealed the binding of PPARβ/δ to the SGK-1 regulatory region in HepG2 cells. Conclusions. Due to the known tumor-promoting effect of SGK1, the present data suggest that PPARβ/δ-deactivated SGK1 is a novel pathway for inhibiting liver carcinogenesis