Quantitative proteomics study of carnosine effect in an animal model of Western diet-induced nonalcoholic fatty liver disease.

The nonalcoholic fatty liver disease (NAFLD), which is closely related to westernized dietary (WD) patterns, displays a rising epidemiological and economic burden. Since there is no pharmacological therapy approved for this disease, mechanistic studies are warranted. In this work, we investigated the action of carnosine (CAR), a natural dipeptide with several protection roles against oxidative stress in the liver of NAFLD rats. NAFLD was induced by WD-rich sugars and fat, verifying the histological evidence of steatosis. As intraperitoneal administration of CAR reversed liver steatosis, the protein profiles of NAFLD liver and CAR NAFLD liver were evaluated by label-free proteomics approach. A total of 2531 proteins were identified and the 230 and 276 were significantly up- and downregulated, respectively, by CAR treatment of NAFLD rats and involved in fundamental pathways such as oxidative stress and lipid metabolism. Perilipin 2 and apolipoprotein E, components of the plasma membrane of vesicle, resulted in highly downregulated in the CAR-treated NAFLD liver. The advanced bioanalytical approach demonstrated the efficacy of CAR in overcoming the main symptoms of NAFLD, ameliorating the steatosis in the liver.

Hepatic Hedgehog Signaling Participates in the Crosstalk between Liver and Adipose Tissue in Mice by Regulating FGF21.

The Hedgehog signaling pathway regulates many processes during embryogenesis and the homeostasis of adult organs. Recent data suggest that central metabolic processes and signaling cascades in the liver are controlled by the Hedgehog pathway and that changes in hepatic Hedgehog activity also affect peripheral tissues, such as the reproductive organs in females. Here, we show that hepatocyte-specific deletion of the Hedgehog pathway is associated with the dramatic expansion of adipose tissue in mice, the overall phenotype of which does not correspond to the classical outcome of insulin resistance-associated diabetes type 2 obesity. Rather, we show that alterations in the Hedgehog signaling pathway in the liver lead to a metabolic phenotype that is resembling metabolically healthy obesity. Mechanistically, we identified an indirect influence on the hepatic secretion of the fibroblast growth factor 21, which is regulated by a series of signaling cascades that are directly transcriptionally linked to the activity of the Hedgehog transcription factor GLI1. The results of this study impressively show that the metabolic balance of the entire organism is maintained via the activity of morphogenic signaling pathways, such as the Hedgehog cascade. Obviously, several pathways are orchestrated to facilitate liver metabolic status to peripheral organs, such as adipose tissue.

Integratomics of Human Dermal Fibroblasts Treated with Low Molecular Weight Hyaluronic Acid.

Hyaluronic acid (HA) is a glycosaminoglycan very common in commercial products from pharmaceuticals to cosmetics due to its widespread distribution in humans and its diversified physico-chemical proprieties. Despite its extended use and preliminary evidence showing even also opposite activities to the native form, the precise cellular effects of HA at low-molecular-weight (LWM-HA) are currently unclear. The 'omics sciences currently in development offer a new and combined perspective on the cellular and organismal environment. This work aims to integrate lipidomics analyses to our previous quantitative proteomics one for a multi-omics vision of intra- and extra-cellular impact of different concentrations (0.125, 0.25, and 0.50%) of LMW-HA (20-50 kDa) on normal human dermal fibroblasts by LC-high resolution mass spectrometry (LC-HRMS). Untargeted lipidomics allowed us to identify 903 unique lipids mostly represented by triacylglycerols, ceramides, and phosphatidylcholines. According to proteomics analyses, LMW-HA 0.50% was the most effective concentration also in the lipidome rearrangement especially stimulating the synthesis of ceramides involved in skin hydration and reparation, cell signaling, and energy balance. Finally, integrative analyses showed 25 nodes covering several intra- and extra-cellular functions. The more complete comprehension of intra- and extra-cellular effects of LMW-HA here pointed out will be useful to further exploit its features and improve current formulations even though further studies on lipids biosynthesis and degradation are necessary.

Study of Carnosine's effect on nude mice skin to prevent UV-A damage.

The skin is an important barrier against external attacks from bacteria, radicals, or radiations. UV-A radiations cause significant impairment of this barrier, inducing inflammation, oxidative stress, and wrinkle formation, thereby promoting photoaging. Previous studies reported that carnosine, a potent antioxidant, and carbonyl scavenger agent, may prevent photoaging features in the skin of hairless mice exposed to UV-A radiations. In the present study, we used a quantitative proteomic approach to analyze the changes evoked by carnosine in the skin proteome of hairless mice exposed to UV-A. This approach allowed to quantify more than 2480 proteins, among them consistent differences were observed for 89 proteins in UV-A exposed vs control unexposed skins, and 252 proteins in UV-A-exposed skin preventively treated by carnosine (UVAC) vs UV-A. Several functional pathways were altered in the skins of UV-A exposed hairless mice, including the integrin-linked kinase, calcium signaling, fibrogenesis, cell migration and filament formation. An impairment of mitochondrial function and metabolism was observed, with an up-regulation of cytochrome C oxidase 6B1 and NADH: ubiquinone oxidoreductase S8. Skins pre-treated by carnosine were prevented from UV-A induced proteome alterations. In conclusion, our study emphasizes the potency of a proteomic approach to identify the consequences of UV radiations in the skins, and points out the capacity of carnosine to prevent the alterations of skin proteome evoked by UV-A.

Advanced quantitative proteomics to evaluate molecular effects of low-molecular-weight hyaluronic acid in human dermal fibroblasts.

Hyaluronic acid (HA) is physiologically synthesized by several human cells types but it is also a widespread ingredient of commercial products, from pharmaceuticals to cosmetics. Despite its extended use, the precise intra- and extra-cellular effects of HA at low-molecular-weight (LWM-HA) are currently unclear. At this regard, the aim of this study is to in-depth identify and quantify proteome's changes in normal human dermal fibroblasts after 24 h treatment with 0.125, 0.25 and 0.50 % LMW-HA (20-50 kDa) respectively, vs controls. To do this, a label-free quantitative proteomic approach based on high-resolution mass spectrometry was used. Overall, 2328 proteins were identified of which 39 significantly altered by 0.125 %, 149 by 0.25 % and 496 by 0.50 % LMW-HA. Protein networking studies indicated that the biological effects involve the enhancement of intracellular activity at all concentrations, as well as the extracellular matrix reorganization, proteoglycans and collagen biosynthesis. Moreover, the cell's wellness was confirmed, although mild inflammatory and immune responses were induced at the highest concentration. The more complete comprehension of intra- and extra-cellular effects of LMW-HA here provided by an advanced analytical approach and protein networking will be useful to further exploit its features and improve current formulations.

The Burden of Opioid Adverse Events and the Influence on Cancer Patients' Symptomatology.

CONTEXT: Opioids are frequently used for the treatment of moderate-to-severe pain and their use may produce a number of unwanted adverse events (AEs). OBJECTIVES: The objective of this study was to understand the burden of opioid-induced AEs in cancer patients with pain after the introduction of strong opioids (WHO Step III). METHODS: This is a cohort study derived from a randomized controlled trial involving 498 cancer patients with pain who received strong opioids. During 28-day follow-up, we analyzed frequency, intensity, and changes over time of the main opioid-induced AEs; the influence of previous pain therapy on AEs; and the relationships between the presence of AEs and analgesic response. RESULTS: After starting strong opioids, dry mouth, nausea, and vomiting immediately increased and persisted over time, constipation continued to increase, while drowsiness and confusion tended to decrease. Patients previously treated with weak opioids had more frequent and severe AEs. While at all observation points the percentage of patients without AEs was 37%-39%, considering all the five scheduled visits, from Day 3 to Day 28, 17% of patients never experienced any AEs, while 48% of patients had four or more concomitant AEs. Patients with no AEs experienced significantly lower pain intensity. CONCLUSION: Opioid introduction induces various AEs that persist over time and worse patients' symptomatology. Moreover, there seems to be a different expression of the opioid toxicity among patients, and a possible interaction between AEs and the analgesic response. The balance between the opioids analgesic effect and induced toxicity is fundamental in deciding the best management for pain in cancer patients.

Use of Health Apps and Wearable Devices: Survey Among Italian Associations for Patient Advocacy.

BACKGROUND: Technological tools such as Web-based social networks, telemedicine, apps, or wearable devices are becoming more widespread in health care like elsewhere. Although patients are the main users, for example, to monitor symptoms and clinical parameters or to communicate with the doctor, their perspective is seldom analyzed, and to the best of our knowledge, no one has focused on the patients' health care advocacy associations' point of view. OBJECTIVE: The objective of this study was to assess patients' health care advocacy associations' opinions about the use, usefulness, obstacles, negative aspects, and impact of health apps and wearable devices through a Web-based survey. METHODS: We conducted a Web-based survey through SurveyMonkey over nearly 3 months. Participants were contacted via an email explaining the aims of the survey and providing a link to complete the Web-based questionnaire. All the 20 items were mandatory, and the anonymized data were collected automatically into a database. Only fully completed questionnaires were considered for analysis. RESULTS: We contacted 1998 patients' health care advocacy associations; a total of 258 questionnaires were received back (response rate 12.91%), and 227 of the received questionnaires were fully completed (completion rate 88.0%). Informative apps, hospital apps for viewing medical reports or booking visits, and those for monitoring physical activity are the most used. They are considered especially useful to improve patients' engagement and compliance with treatment. Wearable devices to check physical activity and glycemia are the most widespread considering, again, their benefits in increasing patients' involvement and treatment compliance. For health apps and wearable devices, the main obstacles to their use are personal and technical reasons; the risk of overmedicalization is considered the most negative aspect of their constant use, while privacy and confidentiality of data are not rated a limitation. No statistical difference was found on stratifying the answers by responders' technological level (P=.30), age (P=.10), and the composition of the association's advisory board (P=.15). CONCLUSIONS: According to responders, health apps and wearable devices are sufficiently known and used and are considered potential supports for greater involvement in health management. However, there are still obstacles to their adoption, and the developers need to work to make them more accessible and more useful. The involvement of patients and their associations in planning services and products based on these technologies (as well as others) would be desirable to overcome these barriers and boost awareness about privacy and the confidentiality of data.

Trends in the consumption of opioids for the treatment of severe pain in Europe, 1990-2016.

BACKGROUND: Over the last decades, consumption of opioids for the treatment of pain increased steadily in the United States, Australia, and a few European countries. To date, no study has analysed time trends in opioid consumption across Europe. METHODS: We analysed data provided by International Narcotics Control Boards on the consumption of fentanyl, oxycodone, morphine, hydromorphone and pethidine in 40 European countries over the last decade. Trends in total opioid consumption from 1990 to 2016 in 22 selected European countries, the European Union (EU) as a whole, and, for comparison purpose, the United States, were analysed using the joinpoint regression analysis. RESULTS: In 2014-2016, opioid use was >10,000 defined daily doses for statistical purposes (s-DDD) per 1,000,000 inhabitants die in Western/Northern countries, whereas it was <1000 s-DDD in Southern/Eastern ones. In most European countries, opioid consumption increased to a great extent between 2004-2006 and 2014-2016; it rose from 6,477 to 8,967 s-DDD (+38.4%) in the EU, and from 14,598 to 16,491 s-DDD (+13%) in the United States. The increase in opioid use was steady since the early to mid-1990s in most European countries and it slowed down after the mid- to late 2000s. In Denmark, Finland, France, Ireland, Switzerland, Poland and the EU, opioid use levelled off or declined over most recent years. CONCLUSIONS: Consumption of opioid analgesics sharply increased in most of European countries since the early to mid-1990s. This notwithstanding, in the mid-2010s there was still a more than 10-fold difference between the highest consumption in Western/Northern countries and the lowest one in Southern/Eastern countries. SIGNIFICANCE: This study provides an updated and comprehensive analysis of time trends and geographic variations in opioid consumption use across European countries over the last three decades.

Transparency in ovarian cancer clinical trial results: ClinicalTrials.gov versus PubMed, Embase and Google scholar.

BACKGROUND: In recent years the question of the lack of transparency in clinical research has been debated by clinicians, researchers, citizens and their representatives, authors and publishers. This is particularly important for infrequent cancers such as ovarian cancer, where treatment still gives disappointing results in the majority of cases. Our aim was to assess the availability to the public of results in ClinicalTrials.gov, and the frequency of non-publication of results in ClinicalTrials.gov and in PubMed, Embase and Google Scholar. We collected all trials on ovarian cancer identified as "completed status" in the ClinicalTrials.gov registry on 17 January 2017. We checked the availability of the results in ClinicalTrials.gov and systematically identified published manuscripts on results. RESULTS: Out of 2725 trials on ovarian cancer identified, 752 were classified as "completed status". In those closed between 2008 and 2015, excluding phase I, the frequency of results in ClinicalTrials.gov was 35%. Of the 752 completed studies the frequency of published results in PubMed, Embase or Google Scholar ranged from 57.9% to 69.7% in the last years. CONCLUSIONS: These findings show a lack of transparency and credibility of research. Citizens or patients' representatives, with the medical community, should continuously support initiatives to improve the publication and dissemination of clinical study results.