Metabolomics demonstrate powerful diagnostic value in estimating HF-related metabolic disturbance. The profile of metabolites provides better prognostic value versus conventional biomarkers.

No abstract

The host cellular environment is a key determinant of pathogen infectivity. Viral gene expression and viral particle production of glucose-6-phosphate dehydrogenase (G6PD)-deficient and G6PD-knockdown cells were much higher than their counterparts when human coronavirus (HCoV) 229E was applied at 0.1 multiplicity of infection. These phenomena were correlated with increased oxidant production. Accordingly, ectopic expression of G6PD in G6PD-deficient cells or addition of antioxidant (such as alpha-lipoic acid) to G6PD-knockdown cells attenuated the increased susceptibility to HCoV 229E infection. All experimental data indicated that oxidative stress in host cells is an important factor in HCoV 229E infectivity.

Traditional serrated adenoma is one type of colorectal serrated neoplasm and a precursor of colorectal cancer. We evaluated the pathologic and molecular features of 60 traditional serrated adenomas with cytologic dysplasia and/or invasive carcinoma. On the basis of morphological features, 16 cases (27%) were categorized as traditional serrated adenoma with serrated dysplasia and 25 cases (42%) as traditional serrated adenoma with conventional adenomatous dysplasia. In addition, 19 cases (31%) showed an overall tubulovillous adenomatous structure but with focal serrated feature. Traditional serrated adenoma with serrated dysplasia had a significantly higher frequency of BRAF mutation than traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature (P ¼ 0.006), whereas traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature had higher frequencies of KRAS mutation than traditional serrated adenoma with serrated dysplasia (Po0.0001). Only traditional serrated adenoma with serrated dysplasia showed sessile serrated adenoma-like lesions at the periphery (n ¼ 3) and developed invasive carcinomas when the lesions were o15 mm in size. Abnormal nuclear accumulation of b-catenin was detected in traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature but not in traditional serrated adenoma with serrated dysplasia. The frequency of the positive CpG island methylator phenotype was similar among the three dysplastic subtypes, and immunostaining of four mismatch repair proteins in the nucleus was retained in all traditional serrated adenomas and associated invasive malignancies. Traditional serrated adenoma-associated adenocarcinomas (n ¼ 28) displayed distinctive morphological features: oval cell nuclei, serrated glands, infiltrating borders, rare occurrences of necrosis and mucinous differentiation. Overexpression of p53 was detected only in high-grade dysplasia and invasive adenocarcinoma. Our findings indicate that traditional serrated adenoma is a heterogeneous neoplasm with two pathways of neoplastic progression, which are distinct from the sessile serrated pathway of colorectal carcinogenesis.

The pathogenesis of Parkinson's disease (PD) remains to be elucidated. Metabolomic analysis has the potential to identify biochemical pathways and metabolic profiles that are involved in PD pathogenesis. Here, we performed a targeted metabolomics to quantify the plasma levels of 184 metabolites in a discovery cohort including 82 PD patients and 82 normal controls (NCs) and found two up-regulated (dopamine, putrescine/ornithine ratio) and four down-regulated (octadecadienylcarnitine C18:2, asymmetric dimethylarginine, tryptophan, and kynurenine (KYN)) metabolites in the plasma of PD patients. We then measured the plasma levels of a panel of metabolic products of KYN pathway in an independent validation cohort including 118 PD patients, 22 Huntington's disease (HD) patients, and 37 NCs. Lower kynurenic acid (KA)/KYN ratio, higher quinolinic acid (QA) level, and QA/KA ratio were observed in PD patients compared to HD patients and NCs. PD patients at advanced stage (Hoehn-Yahr stage > 2) showed lower KA and KA/KYN ratio, as well as higher QA and QA/KA ratio compared to PD patients at early stage (Hoehn-Yahr stage ≤ 2) and NCs. Levels of KA and QA, as well as the ratios of KA/KYN and QA/KA between PD patients with and without psychiatric symptoms, dementia, or levodopa-induced dyskinesia in the advanced PD were similar. This metabolomic analyses demonstrate a number of plasma biomarker candidates for PD, suggesting a shift toward neurotoxic QA synthesis and away from neuroprotective KA production in KYN pathway.

Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up-regulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3 0 untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKb2).The TUG1/miR-455-3p/AMPKb2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. Conclusion: Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKb2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (HEPATOLOGY 2018;67:188-203) H epatocellular carcinoma (HCC) is one of the most common malignant liver tumors worldwide. Long-term prognosis for HCC remains extremely poor, with metastasis being the major underlying cause of mortality.(1) Advances in our understanding of the mechanisms underlying metastasis in HCC and strategies to enhance the efficacy of current treatment options are essential to improve prognosis.The metabolic properties of cancer cells are distinct from those of normal cells.(2) Cancer cells exhibit unique metabolic phenotypes, such as enhanced uptake of glucose and conversion of pyruvate to lactate. This phenomenon, termed the Warburg effect, confers Abbreviations: 2-DG, 2-deoxyglucose; AMPKb2, adenosine monophosphate-activated protein kinase subunit beta 2; ChIP, chromatin immunoprecipitation; EED, embryonic ectoderm development; EZH2, enhancer of zeste homolog

Oxidative stress is known to be a determinant of a host's susceptibility to pathogens. Natural compounds with antioxidant activity may provide a preventive measure against infection. Tea polyphenols were evaluated for their ability to inhibit enterovirus 71 (EV71) replication in Vero cell culture. Among the polyphenolic compounds tested, epigallocatechin gallate (EGCG) and gallocatechin gallate (GCG) potently inhibited replication of EV71. EGCG and GCG reduced the titer of infectious progeny virus by 95%. Quantitative RT-PCR analysis also revealed that EGCG suppressed replication of genomic RNA. It was accompanied by an increased cytoprotective effect. EGCG and GCG caused 5-fold increase in the viability of EV71-infected cells. The viral inhibitory effect correlated well with the antioxidant capacity of polyphenol. Mechanistically, EV71 infection led to increased oxidative stress, as shown by increased dichlorofluorescein and MitoSOX Red fluorescence. Upon EGCG treatment, reactive oxygen species (ROS) generation was significantly reduced. Consistent with this, EV71 replication was enhanced in glucose-6-phosphate dehydrogenase deficient cells, and such enhancement was largely reversed by EGCG. These findings suggest that EGCG may suppress viral replication via modulation of cellular redox milieu.

Glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway, is indispensable to maintenance of the cytosolic pool of NADPH and thus the cellular redox balance. The role of G6PD as an antioxidant enzyme has been recognized in erythrocytes for a long time, as its deficiency is associated with neonatal jaundice, drug- or infection-mediated hemolytic crisis, favism and, less commonly, chronic non-spherocytic hemolytic anemia. To a large extent, advances in the field were made on the pathophysiology of G6PD-deficient erythrocytes, and the molecular characterization of different G6PD variants. Not until recently did numerous studies cast light on the importance of G6PD in other aspects of the physiology of both cells and organisms. Deficiency in G6PD activity, and hence a disturbance in redox homeostasis, can lead to dysregulation of cell growth and signaling, anomalous embryonic development, altered susceptibility to viral infection as well as increased susceptibility to degenerative diseases. The present review covers recent developments in this field. Additionally, molecular characterization of G6PD variants, especially those frequently found in Taiwan and Southern China, is also addressed.