MicroRNAs are fine tuners of diverse biological responses and are expressed in various cell types of the liver. Here we hypothesized that circulating microRNAs (miRNAs) may serve as biomarkers of liver damage and inflammation. We studied miRNA-122 that is abundant in hepatocytes and miR-155, -146a and -125b that regulate inflammation in immune cells in mouse models of alcoholic liver disease (ALD), drug (acetaminophen; APAP)-induced liver injury (DILI), and Toll-like receptor (TLR) 9+4 ligands-induced inflammatory cell-mediated liver damage. We found that serum/plasma miR-122 correlated with ALT increases in the liver damage caused by alcohol, APAP and TLR9 (CpG)+4 (LPS) ligands. MiR-155, a regulator of inflammation, was increased in serum/plasma in alcoholic and inflammatory liver injury. Alcohol failed to increase serum miR-122 in TLR4-deficient and p47phox-deficient mice that were protected from ALD. We found the most robust increase in plasma miR-122 in DILI and it correlated with the highest ALT levels. Consistent with the massive inflammatory cell infiltration in the liver, plasma miR-155 and miR-146a were significantly elevated after CpG+LPS administration. We show for the first time that, depending on the type of liver injury, circulating miRNAs show association either with the exosome-rich or protein-rich compartments. In ALD and in inflammatory liver injury, serum/plasma miR-122 and miR-155 were predominantly associated with exosome-rich fraction while in DILI/APAP injury these miRNAs were present in the protein-rich fraction. In conclusion, our results suggest that circulating miRNAs may serve as biomarkers to differentiate between hepatocyte injury and inflammation and the exosome versus protein association of miRNAs may provide further specificity to mechanisms of liver pathology.

We have identified, by quantitative real-time PCR, hundreds of miRNAs that are dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients. Most of these circulating microRNAs decrease toward normal levels during treatment with N-acetyl cysteine (NAC). We identified a set of 11 miRNAs whose profiles and dynamics in the circulation during NAC treatment can discriminate APAP hepatotoxicity from ischemic hepatitis. The elevation of certain miRNAs can precede the dramatic rise in the standard biomarker, alanine aminotransferase (ALT), and these miRNAs also respond more rapidly than ALT to successful treatment. Our results suggest that miRNAs can serve as sensitive diagnostic and prognostic clinical tools for severe liver injury and could be useful for monitoring drug-induced liver injury during drug discovery.hsa-miR-122-5p | hsa-miR-3646-3p | hsa-miR-412 A cetaminophen (APAP) overdose (OD) is the major cause of acute liver failure and death due to analgesics in the developed world (1-3), with over 500 deaths per year in the United States (3, 4). APAP misuse results in over 78,000 emergency department (ED) visits annually, at a cost of more than $86 million/ year (5).Patients who present with a report of APAP ingestion are assessed for treatment with N-acetyl cysteine (NAC) by measuring serum APAP concentrations and liver function tests, including alanine aminotransferase (ALT) activity (4). There are limits to the utility of the current biomarker, ALT, in assessing the status of potentially APAP-poisoned patients. For example, ALT may take greater than 72 h to reach peak activity in blood (6), and elevated ALT activity is not specific for APAP hepatotoxicity. New biomarkers could serve as more sensitive and specific signatures to predict hepatotoxicity following APAP overdose and to distinguish APAP hepatotoxicity from other causes of liver disease. Ideal biomarkers should identify liver damage at an early stage, accelerating appropriate treatment.MicroRNAs (miRNAs) are short (∼22 nt in length) regulatory RNAs that control gene expression posttranscriptionally (7,8). The human genome contains more than 1,000 genes encoding distinct miRNAs whose levels in a biological sample can be quantified with great sensitivity and precision using quantitative real-time PCR (qRT-PCR) (9). Many miRNAs are expressed tissue-specifically or enriched in certain cell types, with the expression pattern providing signatures for the physiological or pathological status of specific cells and tissues (10, 11). Importantly, miRNAs can be exported from cells and are detectable in stable complexes extracellularly, in blood, serum, or plasma (12).There is ample evidence that circulating extracellular miRNAs in blood can serve as biomarkers for internal organ physiology and pathology (11,13,14). Increased levels of miR-122 and miR-192 were found in the plasma of APAP-overdosed (300 mg/kg) mice (15). A number of additional miRNAs (miR-135a, miR-466g, miR-574-5p, and miR-1196) were elevated in the plasma of mice with hi...

Malignant progression of gliomas is characterized by acquisition of inappropriate growth and invasive properties. In vitro, these malignant properties are reflected in, and measured by, the ability to grow in an anchorage-independent manner and to invade artificial extracellular matrices. The results of numerous studies have suggested that the extracellular and pericellular matrix polysaccharide, hyaluronan, plays an important role in these attributes of malignant cancer cells. However, with respect to glioma cells, most studies have addressed the effect of exogenously added hyaluronan rather than the function of endogenous tumor cell-associated hyaluronan. In this study we manipulate hyaluronan-glioma cell interactions by two methods. The first is administration of small hyaluronan oligosaccharides that compete for endogenous hyaluronan polymer interactions, resulting in attenuation of hyaluronan-induced signaling. The second is overexpression of soluble hyaluronanbinding proteins that act as a competitive sink for interaction with endogenous hyaluronan, again leading to attenuated signaling. We find that both treatments inhibit anchorage-independent growth, as measured by colony formation in soft agar, and invasiveness, as measured by penetration of reconstituted basement membrane matrices. Based on our findings, we conclude that endogenous hyaluronan interactions are essential for these two fundamental malignant properties of glioma cells. Malignant forms of glioblastoma rarely metastasize to distant sites but they are highly proliferative and invasive tumors that destroy normal brain structure and result in high morbidity. As with many types of cancers, up-regulation of growth factor pathways and loss of tumor suppressors have been implicated in glioma development but the mechanisms underlying progression of gliomas to malignancy are by no means established. 1 It has become increasingly apparent that cooperation between signaling pathways induced by growth factors and cytokines and those induced by cell-cell and cell-extracellular matrix interactions are central to regulation of cell behavior. Recent work has highlighted the importance of altered cell-matrix interactions in the acquisition of malignant characteristics. [2][3][4] Hyaluronan is a very large, negatively charged polysaccharide composed of repeating units of glucuronic acid and N-acetylglucosamine. It is ubiquitously associated with extracellular and pericellular matrices but is especially enriched around proliferating and migrating cells. 5 Interactions of hyaluronan with a variety of cell-surface receptors activate intracellular signaling pathways that regulate various aspects of cell behavior 6 and, in tumor cells, promote malignant characteristics. [7][8][9] Several studies have provided evidence that hyaluronan-cell interactions may play a role in glioma invasiveness. For example, addition of exogenous hyaluronan enhances glioma cell migration and invasion in vitro, and this effect is blocked by antibodies or anti-sense oligonucleotides to C...

Background Atrial fibrillation is common among patients with cardiovascular disease and is a frequent complication of the acute coronary syndrome. Data are needed on recent trends in the magnitude, clinical features, treatment, and prognostic impact of pre-existing and new-onset atrial fibrillation in patients hospitalized with an acute coronary syndrome. Methods The study population consisted of 59,032 patients hospitalized with an acute coronary syndrome at 113 sites in the Global Registry of Acute Coronary Events Study between 2000 and 2007. Results 4,494 participants (7.6%) with acute coronary syndrome reported a history of atrial fibrillation and 3,112 (5.3%) developed new-onset atrial fibrillation during their hospitalization. Rates of new-onset atrial fibrillation (5.5% to 4.5%) and pre-existing atrial fibrillation (7.4% to 6.7%) declined during the study. Pre-existing atrial fibrillation was associated with older age and greater cardiovascular disease burden, whereas new-onset atrial fibrillation was closely related to the severity of the index acute coronary syndrome. Patients with atrial fibrillation were less likely than patients without atrial fibrillation to receive evidence-based therapies and were more likely to develop in-hospital complications, including heart failure. Overall hospital death rates in patients with new-onset and pre-existing atrial fibrillation were 14.5% and 8.9%, respectively, compared to 1.2% in those without atrial fibrillation. Short-term death rates in atrial fibrillation patients declined over the study period. Conclusions Despite a reduction in the rates of, and mortality from, atrial fibrillation, this arrhythmia exerts a significant adverse effect on survival among patients hospitalized with an acute coronary syndrome. Opportunities exist to improve the identification and treatment of acute coronary syndrome patients with, or at risk for, atrial fibrillation to reduce the incidence and resultant complications of this dysrhythmia.