Hepatocyte expressed chemerin-156 does not protect from experimental non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a rapidly growing liver disease. The chemoattractant chemerin is abundant in hepatocytes, and hepatocyte expressed prochemerin protected from NASH. Prochemerin is inactive and different active isoforms have been described. Here, the effect of hepatocyte expressed muChem-156, a highly active murine chemerin isoform, was studied in the methionine-choline deficient dietary model of NASH. Mice overexpressing muChem-156 had higher hepatic chemerin protein. Serum chemerin levels and the capability of serum to activate the chemerin receptors was unchanged showing that the liver did not release active chemerin. Notably, activation of the chemerin receptors by hepatic vein blood did not increase in parallel to total chemerin protein in patients with liver cirrhosis. In experimental NASH, muChem-156 had no effect on liver lipids. Accordingly, overexpression of active chemerin in hepatocytes or treatment of hepatocytes with recombinant chemerin did not affect cellular triglyceride and cholesterol levels. Importantly, overexpression of muChem-156 in the murine liver did not change the hepatic expression of inflammatory and profibrotic genes. The downstream targets of chemerin such as p38 kinase were neither activated in the liver of muChem-156 producing mice nor in HepG2, Huh7 and Hepa1-6 cells overexpressing this isoform. Recombinant chemerin had no effect on global gene expression of primary human hepatocytes and hepatic stellate cells within 24 h of incubation. Phosphorylation of p38 kinase was, however, increased upon short-time incubation of HepG2 cells with chemerin. These findings show that muChem-156 overexpression in hepatocytes does not protect from liver steatosis and inflammation

Chemerin Overexpression in the Liver Protects against Inflammation in Experimental Non-Alcoholic Steatohepatitis

Non-alcoholic steatohepatitis (NASH) is marked by macrophage infiltration and inflammation. Chemerin is a chemoattractant protein and is abundant in hepatocytes. The aim of this study was to gain insight into the role of hepatocyte-produced prochemerin in NASH. Therefore, mice were infected with adeno-associated virus 8 to direct hepatic overexpression of prochemerin in a methionine–choline deficient dietary model of NASH. At the end of the study, hepatic and serum chemerin were higher in the chemerin-expressing mice. These animals had less hepatic oxidative stress, F4/80 and CC-chemokine ligand 2 (CCL2) protein, and mRNA levels of inflammatory genes than the respective control animals. In order to identify the underlying mechanisms, prochemerin was expressed in hepatocytes and the hepatic stellate cells, LX-2. Here, chemerin had no effect on cell viability, production of inflammatory, or pro-fibrotic factors. Notably, cultivation of human peripheral blood mononuclear cells (PBMCs) in the supernatant of Huh7 cells overexpressing chemerin reduced CCL2, interleukin-6, and osteopontin levels in cell media. CCL2 was also low in RAW264.7 cells exposed to Hepa1–6 cell produced chemerin. In summary, the current study showed that prochemerin overexpression had little effect on hepatocytes and hepatic stellate cells. Of note, hepatocyte-produced chemerin deactivated PBMCs and protected against inflammation in experimental NASH

Learning How to Ask - Does a one-day training increase trauma inquiry in routine substance use disorder practice? Results of a cluster-randomized controlled trial

Aims To examine the effectiveness of a one-day skills training program for increasing trauma inquiry in routine substance use disorder treatment. Design Cluster-randomized two-armed controlled trial, with 12 substance use disorder (SUD) organizations operating 25 counseling centers, randomly assigned to training in trauma inquiry (13 counseling centers of 8 SUD organizations) or no training (12 counseling centers of 4 SUD organizations). Setting SUD counseling centers in Northern Germany. Cases N = 5204 SUD counseling services. Intervention The professionals assigned to the intervention group received a one-day training in trauma inquiry plus a 1.5-hour refresher session 3 months later. Professionals in the control group received no training. Measures Over a 12-month period, professionals documented for each counseling service whether they asked the client about four traumatic events: physical abuse, emotional abuse, sexual abuse and neglect. Analysis Primary outcomes were rates of asking about physical abuse, sexual abuse, emotional abuse and neglect in the 6 months after training. These were compared across conditions, while adjusting for baseline probabilities in the 6 months before the intervention, using mixed-effects logistic regression. Findings In the 6 months after training, the rate of asking about physical abuse was 18% higher in the SUD counseling services of trained professionals, relative to services of untrained professionals (OR = 1.18, 95% CI = [1.01–1.37, p = .035]). No effect was found for asking about sexual abuse, emotional abuse and neglect. Conclusion A one-day training program in trauma inquiry, combined with a brief refresher session, was effective in increasing inquiries about physical abuse in routine counseling practice. The training was ineffective in increasing inquiries about sexual abuse, emotional abuse and neglect. The effectiveness of a one-day training of trauma inquiry might be increased by a longer training, or by combining it with additional elements, such as ongoing supervision

Association Between TAS2R38 Gene Polymorphisms and Colorectal Cancer Risk: A Case-Control Study in Two Independent Populations of Caucasian Origin

Molecular sensing in the lingual mucosa and in the gastro-intestinal tract play a role in the detection of ingested harmful drugs and toxins. Therefore, genetic polymorphisms affecting the capability of initiating these responses may be critical for the subsequent efficiency of avoiding and/or eliminating possible threats to the organism. By using a tagging approach in the region of Taste Receptor 2R38 (TAS2R38) gene, we investigated all the common genetic variation of this gene region in relation to colorectal cancer risk with a case-control study in a German population (709 controls and 602 cases) and in a Czech population (623 controls and 601 cases). We found that there were no significant associations between individual SNPs of the TAS2R38 gene and colorectal cancer in the Czech or in the German population, nor in the joint analysis. However, when we analyzed the diplotypes and the phenotypes we found that the non-taster group had an increased risk of colorectal cancer in comparison to the taster group. This association was borderline significant in the Czech population, (OR = 1.28, 95% CI 0.99–1.67; Pvalue = 0.058) and statistically significant in the German population (OR = 1.36, 95% CI 1.06–1.75; Pvalue = 0.016) and in the joint analysis (OR = 1.34, 95% CI 1.12–1.61; Pvalue = 0.001). In conclusion, we found a suggestive association between the human bitter tasting phenotype and the risk of CRC in two different populations of Caucasian origin

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Pentraxin-3 is not related to disease severity in cirrhosis and hepatocellular carcinoma patients.

The acute-phase protein pentraxin-3 (PTX3) is a component of the innate immune system. Inflammation and tissue injury increased PTX3 in the injured liver, and accordingly, circulating PTX3 was induced in patients with chronic liver diseases. In the present study, PTX3 protein was determined in systemic, hepatic, and portal vein plasma of patients with liver cirrhosis to assess a possible association between hepatic PTX3 release and extent of liver injury. However, PTX3 levels were not related to disease severity. Of note, portal PTX3 levels were higher than concentrations in the hepatic vein. PTX3 in the hepatic and portal veins was negatively correlated with factor V, antithrombin 3, and prothrombin time. PTX3 did neither correlate with C-reactive protein nor galectin-3 or resistin, whereby the latter two proteins are associated with hepatic injury. PTX3 levels were not changed in cirrhosis patients with ascites or varices and did not correlate with the hepatic venous pressure gradient. Likewise, serum PTX3 was not correlated with histological steatosis, inflammation, or fibrosis stage in patients with hepatocellular carcinoma (HCC). Moreover, PTX3 was not associated with tumor node metastasis classification in HCC. Above all, PTX3 increased in hepatic, portal, and systemic blood immediately after transjugular intrahepatic portosystemic shunt (TIPS). Higher PTX3 in portal than hepatic vein plasma and further increase after TIPS suggests that the liver eliminates PTX3 from the circulation. In summary, PTX3 is not of diagnostic value in cirrhosis and HCC patients

Chemerin Isoforms and Activity in Obesity

Overweight and adiposity are risk factors for several diseases, like type 2 diabetes and cancer. White adipose tissue is a major source for adipokines, comprising a diverse group of proteins exerting various functions. Chemerin is one of these proteins whose systemic levels are increased in obesity. Chemerin is involved in different physiological and pathophysiological processes and it regulates adipogenesis, insulin sensitivity, and immune response, suggesting a vital role in metabolic health. The majority of serum chemerin is biologically inert. Different proteases are involved in the C-terminal processing of chemerin and generate diverse isoforms that vary in their activity. Distribution of chemerin variants was analyzed in adipose tissues and plasma of lean and obese humans and mice. The Tango bioassay, which is suitable to monitor the activation of the beta-arrestin 2 pathway, was used to determine the ex-vivo activation of chemerin receptors by systemic chemerin. Further, the expression of the chemerin receptors was analyzed in adipose tissue, liver, and skeletal muscle. Present investigations assume that increased systemic chemerin in human obesity is not accompanied by higher biologic activity. More research is needed to fully understand the pathways that control chemerin processing and chemerin signaling