A Small-Molecule Inhibitor of Factor Inhibiting HIF Binding to a Tyrosine-flip Pocket for the Treatment of Obesity.

In animals limiting oxygen upregulates hypoxia-inducible factor (HIF) promoting a metabolic shift towards glycolysis. Factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that regulates HIF function by reducing its interaction with histone acetyl transferases. HIF levels are negatively regulated by the HIF prolyl hydroxylases (PHDs), which like FIH, are 2-oxoglutarate(2OG) oxygenases. Genetic loss of FIH promotes both glycolysis and aerobic metabolism. FIH has multiple non-HIF substrates making it challenging to connect its biochemistry with physiology. A structure-mechanism guided approach identified a highly potent in vivo active FIH inhibitor, ZG-2291, binding of which promotes a conformational flip of a catalytically important tyrosine, enabling selective inhibition of FIH over other JmjC subfamily 2OG oxygenases. Consistent with genetic studies, ZG-2291 promotes thermogenesis and ameliorates symptoms of obesity and metabolic dysfunction in ob/ob mice. The results reveal ZG-2291 as a useful probe for the physiological functions of FIH and identify FIH inhibition as a promising strategy for obesity treatment.

Quality of Health Economic Evaluations in Mainland China: A Comparison of Peer-Reviewed Articles in Chinese and in English.

OBJECTIVE: Our objective was to assess the incidence and quality of reporting of published health economic evaluations in mainland China and compare the quality of peer-reviewed articles in Chinese and English. METHODS: A comprehensive search was conducted for economic evaluations pertaining to China published from 2006 to 2015 using the PubMed, CBM, CMCC, CNKI, VIP, and Wanfang databases. All studies in English that met the inclusion criteria were included. For studies in Chinese, 200 sampled studies were included according to the random seeds method, and the same number of the most-cited studies in Chinese as those in English were included according to the number of citations and journal grades. Researchers independently assessed the quality of the studies using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: After literature search and screening, a total of 310 studies were identified. The majority of these studies were cost-effectiveness studies (82.26%). Scores among different CHEERS items varied greatly. There was a gap between the average quality scores of the studies published in Chinese and those published in English (49.78 ± 9.31 vs. 82.48 ± 17.69) and between the average quality scores of the included most-cited studies in Chinese and English, which was slightly smaller (54.08 ± 10.27 vs. 82.48 ± 17.69). The methods, results, and discussion sections of studies published in Chinese were of low quality. CONCLUSION: The quality of reporting of health economic evaluations in mainland China has developed slowly. Most of the included studies were incomplete in the presentation of content, making the results less reliable. It is important to standardize and improve the quality of Chinese health economic research.

Annexin A3 upregulates the infiltrated neutrophil-lymphocyte ratio to remodel the immune microenvironment in hepatocellular carcinoma.

Accumulating evidence has indicated that inflammation is required for the initiation and progression of hepatocellular carcinoma (HCC). The annexin family protein, which has a highly similar structure, has been demonstrated to participate in pro- or anti-inflammatory regulation in the developing of tumours. However, the potential effects of ANXA3 in the immune microenvironment of HCC remain unknown. In present study, we found that increased ANXA3 expression is associated with a higher infiltrated neutrophil-lymphocyte ratio (iNLR) in HCC. Moreover, HCC patients with a high iNLR and high ANXA3 expression confer the highest risk of death. ANXA3 can be detected in both cell lysates and culture supernatants. However, the secretory ANXA3 did not directly regulate the iNLR. Further study demonstrated that ANXA3 upregulated the iNLR by inducing chemokine CXCL8 and CCL25 release from HCC cells. We further confirmed that ANXA3 promotes tumourigenesis and detected the same associations between ANXA3 and the iNLR or chemokines in vivo. Our findings indicate that ANXA3 regulates the chemokine to remodel the iNLR and promotes tumourigenicity in HCC. These results further expanded our understanding of ANXA3 in the microenvironment of HCC and might provide novel targets for the investigation of molecular treatments for HCC patients.

Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3ß signalling pathway in renal cell carcinoma.

BACKGROUND: Clinically, the median survival in patients with metastatic renal cell carcinoma (RCC) was only 6-12 months and a 5-year survival rate of less than 20%. Therefore, an in-depth study of the molecular mechanisms involved in RCC is of great significance for improving the survival of patients with advanced RCC. Acylglycerol kinase (AGK) is a newly discovered lipid kinase that has been reported to be a potent oncogene that may be involved in the regulation of malignant progression in a variety of tumours. However, the expression and biological characteristics of the AGK gene in RCC remain unclear. METHODS: AGK expression was quantified by quantitative real-time PCR, Western blotting and immunohistochemistry in RCC cell lines and paired patient tissues. Kaplan-Meier method and Cox proportional hazards models were used to evaluate the prognostic value of AGK in human RCC tissue samples. Chi-squared test was performed to analyse the correlation between AGK expression and the clinicopathological features. Stable overexpression and knockdown of AGK in RCC cells was constructed with lentivirus. The oncogenic effects of AGK in human RCC progression were investigated using assays of colony formation, anchorage-independent growth, EdU assay, cell cycle analysis, wound-healing, trans-well analysis and xenograft tumour model. GSEA and KEGG analysis were conducted to detect the potential pathway of AGK involved in RCC. These results were further confirmed using the luciferase reporter assays, immunofluorescence and in vivo experiments. RESULTS: AGK expression is significantly elevated in RCC and closely related to the malignant development and poor prognosis in RCC patients. By in vitro and in vivo experiments, AGK was shown to enhance the proliferation of RCC cells by promoting the transition from the G1 phase to the S phase in the cell cycle and to enhance the migration and invasion by promoting epithelial-mesenchymal transition. By activating the PI3K/AKT/GSK3ß signalling pathway in RCC, AGK can increase nuclear accumulation of ß-catenin, which further upregulated TCF/LEF transcription factor activity. CONCLUSIONS: AGK promotes the progression of RCC via activating the PI3K/AKT/GSK3ß signalling pathway and might be a potential target for the further research of RCC.

Large-scale analyses identify a cluster of novel long noncoding RNAs as potential competitive endogenous RNAs in progression of hepatocellular carcinoma.

The abnormal expression of noncoding RNAs has attracted increasing interest in the field of hepatocellular carcinoma progression. However, the underlying molecular mechanisms mediated by noncoding RNAs in these processes are unclear. Here, we obtained the expression profiles of long noncoding RNAs, microRNAs, and mRNAs from the Gene Expression Omnibus database and identified hepatocarcinogenesis-specific differentially expressed transcripts. Next, we identified significant Gene Ontology and pathway terms that the differentially expressed transcripts involved in. Using functional analysis and target prediction, we constructed a hepatocellular carcinoma-associated deregulated competitive endogenous RNA network to reveal the potential mechanisms underlying tumor progression. By analyzing The Cancer Genome Atlas dataset, six key long noncoding RNAs showed significant association with overall survival as well as strong correlation with some microRNAs and mRNAs in the competitive endogenous RNA network. We further validated the above results and determined their diagnostic and prognostic value in clinical samples. Importantly, by large-scale analyses, we identified a cluster of long noncoding RNAs, GBAP1, MCM3AP-AS1, SLC16A1-AS1, C3P1, DIO3OS, and HNF4A-AS1 as candidate biomarkers for the diagnosis and prognosis of hepatocellular carcinoma, which will improve our understanding of competitive endogenous RNA-mediated regulatory mechanisms underlying hepatocellular carcinoma development and will provide novel therapeutic targets in the future.