Moderate alcohol consumption aggravates high-fat diet induced steatohepatitis in rats.

Background: Nonalcoholic steatohepatitis (NASH) develops in the absence of chronic and excessive alcohol consumption. However, it remains unknown whether moderate alcohol consumption aggravates liver inflammation in pre-existing NASH condition.

Methods: Sprague-Dawley rats were first fed ad libitum with Lieber-DeCarli high-fat diet (71% energy from fat) for 6 weeks to induce NASH, as demonstrated previously.

Liver stiffness is directly influenced by central venous pressure.

Background & Aims: Liver stiffness (LS) as measured by transient elastography [Fibroscan] offers a novel non-invasive approach to assess liver cirrhosis. Since Fibroscan seems to be unreliable in patients with congestive heart failure, it remains to be determined whether hemodynamic changes affect LS irrespective of fibrosis.

Methods & Results: Using landrace pigs, we studied the direct relationship between the central venous pressure and LS measured by Fibroscan.

[Hereditary hyperferritinemia cataract syndrome--the first family in Germany].

We report on a 23-year-old woman who presented with elevated serum ferritin values at our department. She had undergone cataract surgery at the age of 14 and her family pedigree showed hereditary autosomal-dominant cataract. The combination of isolated hyperferritinemia with autosomal-dominant hereditary cataract led to the diagnosis of the hereditary hyperferritinemia cataract syndrome (HHCS) which we now describe in a German family for the first time.

Sorting of Drosophila small silencing RNAs partitions microRNA* strands into the RNA interference pathway.

In flies, small silencing RNAs are sorted between Argonaute1 (Ago1), the central protein component of the microRNA (miRNA) pathway, and Argonaute2 (Ago2), which mediates RNA interference. Extensive double-stranded character-as is found in small interfering RNAs (siRNAs)-directs duplexes into Ago2, whereas central mismatches, like those found in miRNA/miRNA* duplexes, direct duplexes into Ago1. Central to this sorting decision is the affinity of the small RNA duplex for the Dcr-2/R2D2 heterodimer, which loads small RNAs into Ago2.

Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism.

Chronic ethanol consumption is a strong risk factor for the development of certain types of cancer including those of the upper aerodigestive tract, the liver, the large intestine and the female breast. Multiple mechanisms are involved in alcohol-mediated carcinogenesis. Among those the action of acetaldehyde (AA), the first metabolite of ethanol oxidation is of particular interest.

High urinary excretion of lipid peroxidation-derived DNA damage in patients with cancer-prone liver diseases.

Chronic inflammatory processes induce oxidative and nitrative stress that trigger lipid peroxidation (LPO), whereby DNA-reactive aldehydes such as trans-4-hydroxy-2-nonenal (HNE) are generated. Miscoding etheno-modified DNA adducts including 1,N(6)-etheno-2'-deoxyadenosine (epsilondA) are formed by reaction of HNE with DNA-bases which are excreted in urine, following elimination from tissue DNA. An ultrasensitive and specific immunoprecipitation/HPLC-fluorescence detection method was developed for quantifying epsilondA excreted in urine.

The Drosophila HP1 homolog Rhino is required for transposon silencing and piRNA production by dual-strand clusters.

Piwi-interacting RNAs (piRNAs) silence transposons and maintain genome integrity during germline development. In Drosophila, transposon-rich heterochromatic clusters encode piRNAs either on both genomic strands (dual-strand clusters) or predominantly one genomic strand (uni-strand clusters). Primary piRNAs derived from these clusters are proposed to drive a ping-pong amplification cycle catalyzed by proteins that localize to the perinuclear nuage.

Endocultivation: 3D printed customized porous scaffolds for heterotopic bone induction.

The aim of this study was to evaluate the ability of computer assisted designed (CAD) synthetic hydroxyapatite and tricalciumphosphate blocks to serve as precise scaffolds for intramuscular bone induction in a rat model. A central channel to allow for vessel pedicle or nerve integration was added. Natural bovine hydroxyapatite blocks served as controls to evaluate and compare biocompatibility of the new matrices.

Structural determinants of miRNAs for RISC loading and slicer-independent unwinding.

MicroRNAs (miRNAs) regulate expression of their target mRNAs through the RNA-induced silencing complex (RISC), which contains an Argonaute (Ago) family protein as a core component. In Drosophila melanogaster, miRNAs are generally sorted into Ago1-containing RISC (Ago1-RISC). We established a native gel system that can biochemically dissect the Ago1-RISC assembly pathway.

DNA damage by low-energy electron impact: dependence on guanine content.

Single-stranded DNA oligonucleotides (33-mers) containing different numbers of guanines (n=1-4) were tethered to a gold surface and exposed to 1 eV electrons. The electrons induced DNA damage, which was analyzed with fluorescence and infrared spectroscopy methods. The damage was identified as strand breaks and found to correlate linearly with the number of guanines in the sequence.

Alcoholic liver disease and hepatitis C: a frequently underestimated combination.

Alcoholic liver disease (ALD) and hepatitis C virus (HCV) infection represent, either alone or in combination, more than two thirds of all patients with liver disease in the Western world. This review discusses the epidemiology and combined impact of ALD and HCV on the progression of liver disease. ALD and HCV affect the progression of liver disease to liver cirrhosis and hepatocellular carcinoma (HCC) in a synergistic manner.

A common toxin fold mediates microbial attack and plant defense.

Many plant pathogens secrete toxins that enhance microbial virulence by killing host cells. Usually, these toxins are produced by particular microbial taxa, such as bacteria or fungi. In contrast, many bacterial, fungal and oomycete species produce necrosis and ethylene-inducing peptide 1 (Nep1)-like proteins (NLPs) that trigger leaf necrosis and immunity-associated responses in various plants.

Ethanol-induced cytochrome P4502E1 causes carcinogenic etheno-DNA lesions in alcoholic liver disease.

Unlabelled: Oxidative stress is thought to play a major role in the pathogenesis of hepatocellular cancer (HCC), a frequent complication of alcoholic liver disease (ALD). However, the underlying mechanisms are poorly understood. In hepatocytes of ALD patients, we recently detected by immunohistochemistry significantly increased levels of carcinogenic etheno-DNA adducts that are formed by the reaction of the major lipid peroxidation product, 4-hydroxynonenal (4-HNE) with nucleobases.

The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis.

Unlabelled: It is unknown whether transforming growth factor beta1 (TGF-beta1) signaling uniformly participates in fibrogenic chronic liver diseases, irrespective of the underlying origin, or if other cytokines such as interleukin (IL)-13 share in fibrogenesis (e.g., due to regulatory effects on type I pro-collagen expression).

Collapse of germline piRNAs in the absence of Argonaute3 reveals somatic piRNAs in flies.

Piwi-interacting RNAs (piRNAs) silence transposons in animal germ cells. piRNAs are thought to derive from long transcripts spanning transposon-rich genomic loci and to direct an autoamplification loop in which an antisense piRNA, bound to Aubergine or Piwi protein, triggers production of a sense piRNA bound to the PIWI protein Argonaute3 (Ago3). In turn, the new piRNA is envisioned to produce a second antisense piRNA.

Redefining microRNA targets.

Animal microRNAs (miRNAs) guide proteins to repress the translation of target mRNAs via imperfect base pairing between the miRNA and the target. Computational analyses suggest that each miRNA regulates tens or hundreds of targets [1, 2], yet genetic studies usually show that the repression of a few targets plays a physiological role [3-5]. The extent of miRNA-mediated repression (which rarely exceeds 2-fold [1, 2]) is also surprisingly lower than most well-tolerated, intrinsic variations in gene expression [6, 7].

Identification of novel transcriptional regulators involved in macrophage differentiation and activation in U937 cells.

Background: Monocytes and macrophages play essential role in innate immunity. Understanding the underlying mechanism of macrophage differentiation and the identification of regulatory mechanisms will help to find new strategies to prevent their harmful effects in chronic inflammatory diseases and sepsis.

Results: Maturation of blood monocytes into tissue macrophages and subsequent inflammatory response was mimicked in U937 cells of human histocytic lymphoma origin.

In vitro-targeted gene identification in patients with hepatitis C using a genome-wide microarray technology.

Unlabelled: Iron in association with reactive oxygen species (ROS) is highly toxic, aggravating oxidative stress reactions. Increased iron not only plays an important role in the progression of hereditary hemochromatosis (HH) but also in common liver diseases such as chronic hepatitis C. The underlying mechanisms of hepatitis C virus (HCV)-mediated iron accumulation, however, are poorly understood.

Inducible expression of a Nep1-like protein serves as a model trigger system of camalexin biosynthesis.

Camalexin, the major Arabidopsis phytoalexin, is synthesized in response to a great variety of pathogens. Specific pathogen-associated molecular patterns, such as Nep1-like proteins from oomycetes act as signals triggering the transcriptional activation of the camalexin biosynthetic genes. PaNie, a Nep1-like protein from Pythiumaphanidermatum was expressed in Arabidopsis under the control of an ethanol-inducible promoter.

Alcohol and colorectal cancer: the role of alcohol dehydrogenase 1C polymorphism.

Background: Chronic alcohol consumption is a risk factor for colorectal cancer. Animal experiments as well as genetic linkage studies in Japanese individuals with inactive acetaldehyde dehydrogenase leading to elevated acetaldehyde concentrations following ethanol ingestion support the hypothesis that acetaldehyde may be responsible for this carcinogenic effect of alcohol. In Caucasians, a polymorphism of alcohol dehydrogenase 1C (ADH1C) exists resulting in different acetaldehyde concentrations following ethanol oxidation.

Contribution of alcohol and tobacco use in gastrointestinal cancer development.

Tobacco smoke and alcohol are major risk factors for a variety of cancer sites, including those of the gastrointestinal tract. Tobacco smoke contains a great number of mutagenic and carcinogenic compounds, including polycyclic carbohydrates, nitrosamines, and nicotine, while ethanol per se has only weak carcinogenic potential, but its first metabolite, acetaldehyde, is a mutagen and carcinogen, since it forms stable adducts with DNA. The possibility of proto-oncogene mutation in gastrointestinal mucosa cells may be associated with tobacco smoking-induced cancers through the formation of unfavorable DNA adducts.

Hypoxia-inducible factor 1 alpha under rapid enzymatic hypoxia: cells sense decrements of oxygen but not hypoxia per se.

HIF1 (hypoxia-inducible factor 1 alpha) is considered a central oxygen-threshold sensor in mammalian cells. In the presence of oxygen, HIF1 is marked by prolyl hydroxylases (PHDs) at the oxygen-dependent degradation (ODD) domain for ubiquitination followed by rapid proteasomal degradation. However, the actual mechanisms of oxygen sensing by HIF1 are still controversial.

Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis.

Unlabelled: Transient elastography (FibroScan [FS]) is a novel non-invasive tool to assess liver fibrosis/cirrhosis. However, it remains to be determined if other liver diseases such as extrahepatic cholestasis interfere with fibrosis assessment because liver stiffness is indirectly measured by the propagation velocity of an ultrasound wave within the liver. In this study, we measured liver stiffness immediately before endoscopic retrograde cholangiopancreatography and 3 to 12 days after successful biliary drainage in patients with extrahepatic cholestasis mostly due to neoplastic invasion of the biliary tree.