The Emerging Role of Disturbed CoQ Metabolism in Nonalcoholic Fatty Liver Disease Development and Progression

Although non-alcoholic fatty liver disease (NAFLD), characterised by the accumulation of triacylglycerol in the liver, is the most common liver disorder, the causes of its development and progression to the more serious non-alcoholic steatohepatitis (NASH) remain incompletely understood. Oxidative stress has been implicated as a key factor in both these processes, and mitochondrial dysfunction and inflammation are also believed to play a part. Coenzyme Q (CoQ) is a powerful antioxidant found in all cell membranes which has an essential role in mitochondrial respiration and also has anti-inflammatory properties. NAFLD has been shown to be associated with disturbances in plasma and liver CoQ concentrations, but the relationship between these changes and disease development and progression is not yet clear. Dietary supplementation with CoQ has been found to be hepatoprotective and to reduce oxidative stress and inflammation as well as improving mitochondrial dysfunction, suggesting that it may be beneficial in NAFLD. However, studies using animal models or patients with NAFLD have given inconclusive results. Overall, evidence is now emerging to indicate that disturbances in CoQ metabolism are involved in NAFLD development and progression to NASH, and this highlights the need for further studies with human subjects to fully clarify its role

Phospholipase A2 Mediates Apolipoprotein-Independent Uptake of Chylomicron Remnant-Like Particles by Human Macrophages

Apolipoprotein E-receptor-mediated pathways are the main routes by which macrophages take up chylomicron remnants, but uptake may also be mediated by receptor-independent routes. To investigate these mechanisms, triacylglycerol (TG) accumulation induced by apolipoprotein-free chylomicron remnant-like particles (CRLPw/o) in human monocyte-derived macrophages was evaluated. Macrophage TG content increased about 5-fold after incubation with CRLPw/o, and this effect was not reduced by the inhibition of phagocytosis, macropinocytosis, apolipoprotein E function, or proteoglycan bridging. The role of lipases, including lipoprotein lipase, cholesteryl ester hydrolase, and secretory (sPLA2) and cytosolic phospholipase A2, was studied using [3H]TG-labelled CRLPw/o. Total cell radioactivity after incubation with [3H]TG CRLPw/o was reduced by 15–30% by inhibitors of lipoprotein lipase and cholesteryl ester hydrolase and by about 45% by inhibitors of sPLA2 and cytosolic PLA2 . These results suggest that macrophage lipolytic enzymes mediate the internalization of postprandial TG-rich lipoproteins and that sPLA2 and cytosolic PLA2, play a more important role than extracellular lipoprotein lipase-mediated TG hydrolysis

Neutrophil unsaturated fatty acid release by GM-CSF is impaired in cystic fibrosis

Dysregulated inflammation in cystic fibrosis (CF) is attributed to an altered production of inflammatory mediators derived from polyunsaturated lipids. In comparison to the arachidonic acid (AA) cascade, little is known about the modulation of docosahexaenoic acid (DHA) membrane release. We compared data on neutrophil DHA- and AA- release from both control (CT) and patients with CF using [3H]AA or [14C]DHA as a markers for, respectively, AA and DHA- release. Granulocyte-macrophage-colony stimulating factor stimulated DHA release from CT, but not CF, neutrophils. Comparison showed that both [14C]DHA and [3H]AA liberated after stimulation was higher in CT than in CF neutrophils. Since bioactive mediators derived from DHA are resolving factors and those derived from AA are both pro- and anti- inflammatory, these results suggest that CF is associated with a reduction of the release of PUFA-precursors of lipooxygenated resolving mediators. This leads to the hypothesis that defects in the resolving factors production could contribute to the inflammatory dysregulated processes in CF. Furthermore, the methodology used may help to improve knowledge on the regulation and resolution of inflammation

CFM: a convolutional neural network for first-motion polarity classification of seismic records in volcanic and tectonic areas

First-motion polarity determination is essential for deriving volcanic and tectonic earthquakes’ focal mechanisms, which provide crucial information about fault structures and stress fields. Manual procedures for polarity determination are time-consuming and prone to human error, leading to inaccurate results. Automated algorithms can overcome these limitations, but accurately identifying first-motion polarity is challenging. In this study, we present the Convolutional First Motion (CFM) neural network, a label-noise robust strategy based on a Convolutional Neural Network, to automatically identify first-motion polarities of seismic records. CFM is trained on a large dataset of more than 140,000 waveforms and achieves a high accuracy of 97.4% and 96.3% on two independent test sets. We also demonstrate CFM’s ability to correct mislabeled waveforms in 92% of cases, even when they belong to the training set. Our findings highlight the effectiveness of deep learning approaches for first-motion polarity determination and suggest the potential for combining CFM with other deep learning techniques in volcano seismology

The European Research Infrastructures of the ESFRI Roadmap in Biological and Medical Sciences: status and perspectives

Introduction. Since 2002, the European Strategy Forum on Research Infrastructures  identified  the  needs  for  Research  Infrastructures  (RIs)  in  Europe  in  priority  fields  of  scientific research and drafted a strategic document, the ESFRI Roadmap, defining the  specific RIs essential to foster European research and economy. The Biological and Medical Sciences RIs (BMS RIs) were developed thanks to the active participation of many  institutions  in  different  European  member  states  associated  to  address  the  emerging  needs in biomedicine and, among these, the Italian National Institute of Health (ISS),  in virtue of its role in public health and research, has been specifically involved in the  national development and implementation of three RIs: the Biobanking and Biomolecu-lar Resources Research Infrastructure (BBMRI), the European Advanced Translational  Research Infrastructure in Medicine (EATRIS) and the European Clinical Research Infrastructures Network (ECRIN). Aim.  This  article  outlines  the  design  and  development  of  these  RIs  up  to  the  recent  achievement of the ERIC status, their importance in the Horizon 2020 programme and  their societal and economic potential impact, with special attention to their development  and significance in Italy. Conclusions.  The  ISS  plays  a  unique  role  in  fostering  a  coordinated  participation  of  excellence Italian institutes/facilities to different European biomedical RIs, thus contributing to health innovation, healthcare optimization, and healthcare cost containment.

The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma

Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (α-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co-treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting α-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms

Coenzyme Q Metabolism Is Disturbed in High Fat Diet-Induced Non Alcoholic Fatty Liver Disease in Rats

Oxidative stress is believed to be a major contributory factor in the development of non alcoholic fatty liver disease (NAFLD), the most common liver disorder worldwide. In this study, the effects of high fat diet-induced NAFLD on Coenzyme Q (CoQ) metabolism and plasma oxidative stress markers in rats were investigated. Rats were fed a standard low fat diet (control) or a high fat diet (57% metabolizable energy as fat) for 18 weeks. The concentrations of total (reduced + oxidized) CoQ9 were increased by >2 fold in the plasma of animals fed the high fat diet, while those of total CoQ10 were unchanged. Reduced CoQ levels were raised, but oxidized CoQ levels were not, thus the proportion in the reduced form was increased by about 75%. A higher percentage of plasma CoQ9 as compared to CoQ10 was in the reduced form in both control and high fat fed rats. Plasma protein thiol (SH) levels were decreased in the high fat-fed rats as compared to the control group, but concentrations of lipid hydroperoxides and low density lipoprotein (LDL) conjugated dienes were unchanged. These results indicate that high fat diet-induced NAFLD in rats is associated with altered CoQ metabolism and increased protein, but not lipid, oxidative stress

Business Planning in Biobanking: How to Implement a Tool for Sustainability

Worldwide, the sustainability of public health systems is challenged by the increasing number and cost of personalized therapies. Quality biological samples stored in biobanks are essential for the provision of appropriate health services and also act as a reservoir for the development of precision medicine and biotechnological innovation. Economic sustainability is a crucial factor in the maintenance of biobanking activities. Traditionally, management of biobanking is performed by health researchers and/or clinicians whose knowledge of economic issues is inadequate. On the other hand, familiarity with financial instruments used by economists is not often accompanied by a consolidated understanding of biobanking features. This article aims to be a guide for the implementation of business plans in biobanking and proposes models for the facilitation of their preparation, thus contributing to recognition of the importance of efficient management of resources of public health services

Italian corporate museums as industrial tourism destinations: \u410 segmentation study based on strategic orientation

The main aim of this study is to propose a segmentation of Italian corporate museums, based on their strategic orientation and their actual willingness to cooperate with other local stakeholders in order to enhance industrial tourism in the area. The study is based on empirical data collected from 88 Italian museums belonging to private firms. A cluster analysis was used to identify three different groups of corporate museums, shedding light on the diverse role played as platforms from which firms may directly communicate with tourists and other stakeholders. The results of the study demonstrate the high heterogeneity of corporate museums, whose strategic priorities and orientation may vary significantly. Such variety has relevant implications for their potential role in the enhancement of the tourist attractiveness of the area