Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights.

Nonalcoholic fatty liver disease (NAFLD) is a disease of increasing interest, as its prevalence is on the rise. NAFLD has been linked to metabolic syndrome, which is becoming more common due to the Western diet. Because NAFLD can lead to cirrhosis and related complications including hepatocellular carcinoma, the increasing prevalence is concerning, and medical therapy aimed at treating NAFLD is of great interest. Researchers studying the effects of medical therapy on NAFLD use dietary mouse models. The two main types of mouse model diets are the methionine- and choline-deficient (MCD) diet and the Western-like diet (WD). Although both induce NAFLD, the mechanisms are very different. We reviewed several studies conducted within the last 5 years that used MCD diet or WD mouse models in order to mimic this disease in a way most similar to humans. The MCD diet inconsistently induces NAFLD and fibrosis and does not completely induce metabolic syndrome. Thus, the clinical significance of the MCD diet is questionable. In contrast, WD mouse models consisting of high fat, cholesterol, and a combination of high-fructose corn syrup, sucrose, fructose, or glucose not only lead to metabolic syndrome but also induce NAFLD with fibrosis, making these choices most suitable for research.

The emerging role of mast cells in liver disease.

The depth of our knowledge regarding mast cells has widened exponentially in the last 20 years. Once thought to be only important for allergy-mediated events, mast cells are now recognized to be important regulators of a number of pathological processes. The revelation that mast cells can influence organs, tissues, and cells has increased interest in mast cell research during liver disease. The purpose of this review is to refresh the reader's knowledge of the development, type, and location of mast cells and to review recent work that demonstrates the role of hepatic mast cells during diseased states. This review focuses primarily on liver diseases and mast cells during autoimmune disease, hepatitis, fatty liver disease, liver cancer, and aging in the liver. Overall, these studies demonstrate the potential role of mast cells in disease progression.

Cellular crosstalk during cholestatic liver injury.

The functions of the liver are very diverse. From detoxifying blood to storing glucose in the form of glycogen and producing bile to facilitate fat digestion, the liver is a very active and important organ. The liver is comprised of many varied cell types whose functions are equally diverse. Cholangiocytes line the biliary tree and aid in transporting and adjusting the composition of bile as it travels to the gallbladder. Hepatic stellate cells and portal fibroblasts are located in different areas within the liver architecture, but both contribute to the development of fibrosis upon activation after liver injury. Vascular cells, including those that constitute the peribiliary vascular plexus, are involved in functions other than blood delivery to and from the liver, such as supporting the growth of the biliary tree during development. Mast cells are normally found in healthy livers but in very low numbers. However, after injury, mast cell numbers greatly increase as they infiltrate and release factors that exacerbate the fibrotic response. While not an all-inclusive list, these cells have individual roles within the liver, but they are also able to communicate with each other by cellular crosstalk. In this review, we examine some of these pathways that can lead to an increase in the homeostatic dysfunction seen in liver injury.

Identification of an Orally Bioavailable, Potent, and Selective Inhibitor of GlyT1.

Amalgamation of the structure-activity relationship of two series of GlyT1 inhibitors developed at Merck led to the discovery of a clinical candidate, compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy of GlyT1 transporters in rhesus monkey as determined by displacement of a PET tracer ligand.

Alcohol and cognitive function: assessment in everyday life and laboratory settings using mobile phones.

BACKGROUND: Mobile phone (cellphone) technology makes it practicable to assess cognitive function in a natural setting. We assessed this method and compared impairment of performance due to alcohol in everyday life with measurements made in the laboratory. METHODS: Thirty-eight volunteers (20 male, aged 18-54 years) took part in the everyday study, completing assessments twice a day for 14 days following requests sent by text messages to the mobile phone. Twenty-six of them (12 male, aged 19-54) took part in a subsequent two-period crossover lab study comparing alcohol with no alcohol (placebo). RESULTS: Everyday entries with 5 or more units of alcohol consumed in the past 6 hours (inferred mean blood alcohol concentration 95 ml/100 ml) showed higher scores for errors in tests of attention and working memory compared with entries with no alcohol consumed that day. Response times were impaired for only 1 test, sustained attention to response. The laboratory comparison of alcohol (mean blood alcohol concentration 124 mg/100 ml) with placebo showed impairment to both reaction time and error scores for all tests. A similar degree of subjective drunkenness was reported in both settings. CONCLUSIONS: We found that mobile phones allowed practical research on cognitive performance in an everyday life setting. Alcohol impaired function in both laboratory and everyday life settings at relevant doses of alcohol.

Optimisation of a series of potent, selective and orally bioavailable GlyT1 inhibitors.

A series of heterocyclic sulfonamides have been developed which are potent and selective inhibitors of hGlyT1. SAR studies to optimise the in vitro and in vivo properties are described. Optimisation of the central scaffold resulted in cyclohexane sulfones 28 and 29, which have good PK properties and show promise for further development.