Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients

Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host–microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients

Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease

Objective: Liver biopsy is currently the most reliable way of evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Its inherent risks limit its widespread use. Differential liver DNA methylation of peroxisome proliferator-activated receptor gamma (PPARγ) gene promoter has recently been shown to stratify patients in terms of fibrosis severity but requires access to liver tissue. The aim of this study was to assess whether DNA methylation of circulating DNA could be detected in human plasma and potentially used to stratify liver fibrosis severity in patients with NAFLD.Design: Patients with biopsy-proven NAFLD and age-matched controls were recruited from the liver and gastroenterology clinics at the Newcastle upon Tyne Hospitals NHS Foundation Trust. Plasma cell-free circulating DNA methylation of PPARγ was quantitatively assessed by pyrosequencing. Liver DNA methylation was quantitatively assessed by pyrosequencing NAFLD explant tissue, subjected to laser capture microdissection (LCM). Patients with alcoholic liver disease (ALD) were also subjected to plasma DNA and LCM pyrosequencing.Results: 26 patients with biopsy-proven NAFLD were included. Quantitative plasma DNA methylation of PPARγ stratified patients into mild (Kleiner 1–2) and severe (Kleiner 3–4) fibrosis (CpG1: 63% vs 86%, p0.05). Hypermethylation at the PPARγ promoter of plasma DNA correlated with changes in hepatocellular rather than myofibroblast DNA methylation. Similar results were demonstrated in patients with ALD cirrhosis.Conclusions: Differential DNA methylation at the PPARγ promoter can be detected within the pool of cell-free DNA of human plasma. With further validation, plasma DNA methylation of PPARγ could potentially be used to non-invasively stratify liver fibrosis severity in patients with NAFLD. Plasma DNA methylation signatures reflect the molecular pathology associated with fibrotic liver disease

Evaluation of the epigenetic alterations and gene expression levels of HepG2 cells exposed to zearalenone and alpha-zearalenol

Zearalenone, produced by various Fusarium species, is a non-steroidal estrogenic mycotoxin that contaminates cereals, resulting in adverse effects on human health. We investigated the effects of zearalenone and its metabolite alpha zearalenol on epigenetic modifications and its relationship with metabolic pathways in human hepatocellular carcinoma cells following 24 h of exposure. Zearalenone and alpha zearalenol at the concentrations of 1, 10 and 50 mu M significantly increased global levels of DNA methylation and global histone modifications (H3K27me3, H3K9me3, H3K9ac). Expression levels of the chromatin modifying enzymes EHMT2, ESCO1, HAT1, KAT2B, PRMT6 and SETD8 were upregulated by 50 mu M of zearalenone exposure using PCR arrays, consistent with the results of global histone modifications. Zearalenone and alpha zearalenol also changed expression levels of the AhR, LXR alpha, PPAR alpha, PPAR gamma, L-fabp, LDLR, Glut2, Akt1 and HK2 genes, which are related to nuclear receptors and metabolic pathways. PPAR gamma, a key regulator of lipid metabolism, was selected from among these genes for further analysis. The PPAR gamma promoter reduced methylation significantly following zearalenone exposure. Taken together, the epigenetic mechanisms of DNA methylation and histone modifications may be key mechanisms in zearalenone toxicity. Furthermore, effects of zearalenone in metabolic pathways could be mediated by epigenetic modifications

The Potential Use of Metabolic Cofactors in Treatment of NAFLD

Non-alcoholic fatty liver disease (NAFLD) is caused by the imbalance between lipid deposition and lipid removal from the liver, and its global prevalence continues to increase dramatically. NAFLD encompasses a spectrum of pathological conditions including simple steatosis and non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and liver cancer. Even though there is a multi-disciplinary effort for development of a treatment strategy for NAFLD, there is not an approved effective medication available. Single or combined metabolic cofactors can be supplemented to boost the metabolic processes altered in NAFLD. Here, we review the dosage and usage of metabolic cofactors including l-carnitine, Nicotinamide riboside (NR), l-serine, and N-acetyl-l-cysteine (NAC) in human clinical studies to improve the altered biological functions associated with different human diseases. We also discuss the potential use of these substances in treatment of NAFLD and other metabolic diseases including neurodegenerative and cardiovascular diseases of which pathogenesis is linked to mitochondrial dysfunction

The effects of once- or thrice-weekly mupirocin application on mupirocin resistance in patients on continuous ambulatory peritoneal dialysis--first 6 months' experience.

In the present study, we prospectively investigated the effects of once- or thrice-weekly prophylactic application of mupirocin to catheter exit sites on Staphylococcus aureus carriage, methicillin and mupirocin resistance, and catheter-related infections in continuous ambulatory peritoneal dialysis (CAPD) patients. We enrolled 36 CAPD patients (men/women: 21/ 15; mean age: 55.1 +/- 1.4 years) in the study. At the start of the study, patients had been on once-weekly mupirocin treatment for 3.1 +/- 2.0 years. They were then randomly assigned to use mupirocin either once weekly (group I; n = 18; men/women: 10/8; age: 55.3 +/- 1.8 years) or thrice weekly (group II; n = 18; men/women: 11/7; age: 55.0 +/- 2.3 years). During the study period, swabs were taken monthly from nares, axillae, the inguinal area, and the catheter exit site. We evaluated a total of 806 samples in the first 6 months of the study. The two study groups were similar in terms of age and sex. In group I, 5 isolations of S. aureus in 3 patients came from initial S. aureus carriers. During the first 6 months of the study, only 2 new S. aureus carriers were detected in group I, for a total of 7 isolations. Mupirocin resistance (MuR) was present in only 1 isolate and methicillin resistance (MeR) was not observed. In group II, no S. aureus carriers were present at the initial evaluation, and we encountered only 1 new S. aureus carrier during the first 6 months of the study. During the same period, MuR and MeR were absent in group II. During the 6 months, we observed 1 exit-site infection and 1 peritonitis episode attributable to coagulase-negative staphylococcus (CNS) in group I. In group II, we observed 1 exit-site infection attributable to CNS. During the first 6 months of the study, once- or thrice-weekly application of mupirocin to the catheter exit site has not led to any significant change in S. aureus carriage, MeR and MuR, or catheter-related infection in our CAPD patients

Emergence of resistance in staphylococci after long-term mupirocin application in patients on continuous ambulatory peritoneal dialysis.

In the present study, we evaluated the effects of once-weekly mupirocin application to catheter exit sites on Staphylococcus aureus and coagulase-negative staphylococcus (CNS) colonization and investigated the resistance of those bacteria to methicillin (MeR) and mupirocin (MuR). We enrolled 36 continuous ambulatory peritoneal dialysis (CAPD) patients (mean age: 55.1 +/- 1.4 years) into the study. The patients (men/women: 21/15) had been applying mupirocin to the catheter exit site once weekly before the start of the study (mupirocin treatment duration: 3.1 +/- 2.0 years). During the study period, swabs were taken monthly from the nares, axillae, inguinal area, and catheter exit site. The swabs were inoculated on blood plates. Methicillin and mupirocin susceptibility were tested by disc diffusion according to the interpretative criteria of the National Committee for Clinical Laboratory Standards. We evaluated a total of 144 cultures. Among CNS isolates, the MuR was 66%, and the MeR was 38.8%. At the start of the study period, 3 patients were S. aureus nasal carriers. In nasal swabs, no MeR S. aureus was identified, and only 1 MuR S. aureus was found. Once-weekly application of mupirocin at the exit site in CAPD patients led to comparable rates of colonization by MuR S. aureus as did thrice-weekly or more frequent application. Clinical results showing high mupirocin and methicillin resistance in CNS are controversial

TASL Practice Guidance on the Clinical Assessment and Management of Patients with Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease and is significantly associated with obesity, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. NAFLD has become the most prevalent chronic liver disease in Western countries, and the proportion of NAFLD-related cirrhosis among patients on liver transplantation waiting lists has increased. In light of the accumulated data about NAFLD, and to provide a common approach with multi-disciplines dealing with the subject, it has become necessary to create new guidance for diagnosing and treating NAFLD. This guidance was prepared following an interdisciplinary study under the leadership of the Turkish Association for the Study of the Liver (TASL), Fatty Liver Special Interest Group. This new TASL Guidance is a practical application guide on NAFLD and was prepared to standardize the clinical approach to diagnosing and treating NAFLD patients. This guidance reflects many advances in the field of NAFLD. The proposals in this guidance are meant to aid decision-making in clinical practice. The guidance is primarily intended for gastroenterology, endocrinology, metabolism diseases, cardiology, internal medicine, pediatric specialists, and family medicine specialists

Ivacaftor and symptoms of extra-oesophageal reflux in patients with cystic fibrosis and G551D mutation

© 2016 The Authors Background Extra-oesophageal reflux (EOR) may lead to microaspiration in patients with cystic fibrosis (CF), a probable cause of deteriorating lung function. Successful clinical trials of ivacaftor highlight opportunities to understand EOR in a real world study. Methods Data from 12 patients with CF and the G551D mutation prescribed ivacaftor (150 mg bd) was collected at baseline, 6, 26 and 52 weeks. The changes in symptoms of EOR were assessed by questionnaire (reflux symptom index (RSI) and Hull airway reflux questionnaire (HARQ)). Results Six patients presented EOR at baseline (RSI > 13; median 13; range 2–29) and 5 presented airway reflux (HARQ > 13; median 12; range 3 to 33). Treatment with ivacaftor was associated with a significant reduction of EOR symptoms (P