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Newspapers are a major source of health information, including on COVID-19. Many news articles are based on press releases describing research published in scientific journals. We studied a sample of articles in US and Italian newspapers for their mention of non-pharmacological interventions (face masks and lockdown) and pharmacological ones, both effective and ineffective (convalescent plasma, hydroxychloroquine, ivermectin, vaccines and vitamin D), and whether these were mentioned in a favorable or unfavorable way. We checked for the presence or absence of explicit mentions or links of the primary source of scientific information. Finally, we analyzed whether there was a trend to form “information bubbles” where some opinions around different treatments cluster together.Of 480,819 news in the USA and 767,172 in Italy, vaccines, face masks and lockdown were the most mentioned interventions. Of the pharmacological interventions other than vaccines, ivermectin and hydroxychloroquine were more frequently mentioned in the USA than in Italy (5- and 6-fold, respectively) although, when analyzing a sample of 210 news returned from a search on COVID-19 mentioning a research publication, articles from the USA were less favorable than those in Italy. We also found that the frequency of articles with a negative stance on vaccines was very small, indicating that the main newspapers do not contribute significantly to vaccine hesitancy. There was also evidence of information bubbles, where articles with a favorable or unfavorable view of a non-approved drug had the same stance on other non-approved treatments.Of the 210 news articles analyzed, half specifically mentioned a scientific publication. However, a link (or a complete citation) to the original source was provided in only 16% of Italian newspapers as opposed to 58% of those in the USA. The results highlight the fact that often news stories do not cite the scientific article they are reporting on, thus allowing the reader to verify the original source. This weakness in the citation behavior is particularly evident in Italian newspapers. This study suggests that linking to the original research article, rather than basing the news story on a press release, would improve the trustworthiness of the news and the critical thinking in the reader.

Background. Measures against the COVID-19 pandemics have been subject of political polarization also in the United Kingdom. While this has been studied in the broader context of misinformation, the debate around non-pharmacological interventions (NPI) , the and the political implications of different views of their risks and benefits, has not been taken into account with sufficient depth Research question. Our research question was: Are politically-oriented UK newspapers more likely to promote a more, or less, precautionary views toward the use of NPIs?Methods. We used the Mediacloud database to search the names of scientists with different precautionary views (i.e.: signatories of the Great Barrington Declaration and of the John Snow Memorandum) and analyze the frequency with which they are mentioned in newspapers with different political orientation.Results. Scientists with more precautionary positions are more likely to be mentioned in left-leaning newspapers, whereas those with less precautionary views on right-leaning ones. The two groups segregated also in terms of co-authorship of academic papers.Conclusions. Scientists with different opinions in relation to NPIs are mentioned by UK newspapers in a way that is dependent on the political orientation of the newspaper.

Several redox modifications have been described during viral infection, including influenza virus infection, but little is known about glutathionylation and this respiratory virus. Glutathionylation is a reversible, post-translational modification, in which protein cysteine forms transient disulfides with glutathione (GSH), catalyzed by cellular oxidoreductases and in particular by glutaredoxin (Grx). We show here that (i) influenza virus infection induces protein glutathionylation, including that of viral proteins such as hemagglutinin (HA); (ii) Grx1-mediated deglutathionylation is important for the viral life cycle, as its inhibition, either with an inhibitor of its enzymatic activity or by siRNA, decreases viral replication. Overall these data contribute to the characterization of the complex picture of redox regulation of the influenza virus replication cycle and could help to identify new targets to control respiratory viral infection.

Long-term ingestion of arsenicals, a heterogeneous group of toxic compounds, has been associated with a wide spectrum of human pathologies, which include various malignancies. Although their mechanism of toxicity remains largely unknown, it is generally believed that arsenicals mainly produce their effects via direct binding to protein thiols and ROS formation in different subcellular compartments. The generality of these mechanisms most probably accounts for the different effects mediated by different forms of the metalloid in a variety of cells and tissues. In order to learn more about the molecular mechanisms of cyto- and genotoxicity, there is a need to focus on specific arsenic compounds under tightly controlled conditions. This review focuses on the mechanisms regulating the mitochondrial formation of ROS after exposure to low concentrations of a specific arsenic compound, NaAsO2, and their crosstalk with the nuclear factor (erythroid-2 related) factor 2 antioxidant signaling and the endoplasmic reticulum stress response.

Rhian M. Touyz, Associate Editor, Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data–enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine., This study was supported by the European Research Council Advanced Investigator Grant/RadMed [Grant 294683], Proof-of-Concept Grant/SAVEBRAIN [Grant 737586], and H2020 Project REPO-TRIAL [Grant 777111] (to H.H.H.W.S.) and short-term scientific missions by the COST Actions EU-ROS and Open-MultiMed, and Kootstra Talented Fellowship (Maastricht University) (to A.I.C.).

Oxidative stress is defined as an imbalance between the levels of reactive oxygen species (ROS) and antioxidant defences. The view of oxidative stress as a cause of cell damage has evolved over the past few decades to a much more nuanced view of the role of oxidative changes in cell physiology. This is no more evident than in the field of immunity, where oxidative changes are now known to regulate many aspects of the immune response, and inflammatory pathways in particular. Our understanding of redox regulation of immunity now encompasses not only increases in reactive oxygen and nitrogen species, but also changes in the activities of oxidoreductase enzymes. These enzymes are important regulators of immune pathways both via changes in their redox activity, but also via other more recently identified cytokine-like functions. The emerging picture of redox regulation of immune pathways is one of increasing complexity and while therapeutic targeting of the redox environment to treat inflammatory disease is a possibility, any such strategy is likely to be more nuanced than simply inhibiting ROS production.

Graphical abstract, Background Oxidative stress is conjectured to be related to many diseases. Furthermore, it is hypothesized that radiofrequency fields may induce oxidative stress in various cell types and thereby compromise human and animal health. This systematic review (SR) aims to summarize and evaluate the literature related to this hypothesis. Objectives The main objective of this SR is to evaluate the associations between the exposure to radiofrequency electromagnetic fields and oxidative stress in experimental models (in vivo and in vitro). Methods The SR framework has been developed following the guidelines established in the WHO Handbook for Guideline Development and the Handbook for Conducting a Literature-Based Health Assessment). We will include controlled in vivo and in vitro laboratory studies that assess the effects of an exposure to RF-EMF on valid markers for oxidative stress compared to no or sham exposure. The protocol is registered in PROSPERO. We will search the following databases: PubMed, Embase, Web of Science Core Collection, Scopus, and the EMF-Portal. The reference lists of included studies and retrieved review articles will also be manually searched. Study appraisal and synthesis method Data will be extracted according to a pre-defined set of forms developed in the DistillerSR online software and synthesized in a meta-analysis when studies are judged sufficiently similar to be combined. If a meta-analysis is not possible, we will describe the effects of the exposure in a narrative way. Risk of bias The risk of bias will be assessed with the NTP/OHAT risk of bias rating tool for human and animal studies. We will use GRADE to assess the certainty of the conclusions (high, moderate, low, or inadequate) regarding the association between radiofrequency electromagnetic fields and oxidative stress. Funding This work was funded by the World Health Organization (WHO). Registration The protocol was registered on the PROSPERO webpage on July 8, 2021.

ObjectiveCountries have major differences in the acceptance of face mask use for the prevention of COVID-19. This work aims at studying the information online in different countries in terms of information quality and content.DesignContent analysis.MethodWe analysed 450 webpages returned by searching the string ‘are face masks dangerous’ in Italy, the UK and the USA using three search engines (Bing, Duckduckgo and Google) in August 2020. The type of website and the stance about masks were assessed by two raters for each language and inter-rater agreement reported as Cohen’s kappa. The text of the webpages was collected from the web using WebBootCaT and analysed using a corpus analysis software to identify issues mentioned.ResultsMost pages were news outlets, and few (2%–6%) from public health agencies. Webpages with a negative stance on masks were more frequent in Italian (28%) than English (19%). Google returned the highest number of mask-positive pages and Duckduckgo the lowest. Google also returned the lowest number of pages mentioning conspiracy theories and Duckduckgo the highest. Webpages in Italian scored lower than those in English in transparency (reporting authors, their credentials and backing the information with references). When issues about the use of face masks were analysed, mask effectiveness was the most discussed followed by hypercapnia (accumulation of carbon dioxide), contraindication in respiratory disease and hypoxia, with issues related to their contraindications in mental health conditions and disability mentioned by very few pages.ConclusionsThis study suggests that: (1) public health agencies should increase their web presence in providing correct information on face masks; (2) search engines should improve the information quality criteria in their ranking; (3) the public should be more informed on issues related to the use of masks and disabilities, mental health and stigma arising for those people who cannot wear masks.

Peroxiredoxin 1 (PRDX1) is an antioxidant enzyme that, when secreted, can act as a proinflammatory signal. Here we studied the regulation of intracellular PRDX1 by lipopolysaccharide (LPS) and interferon-gamma (IFN-γ) in the RAW 264.7 mouse macrophage cell line. While LPS or IFN-γ alone did not affect PRDX1 protein levels, their combination led to an almost complete loss of the PRDX1 dimer. This was likely mediated by the increased production of nitric oxide (NO) as it was reversed by the NO synthase inhibitor L-N-methylarginine (L-NMMA), while a NO-releasing agent decreased PRDX1 levels. Inhibition of the proteasome with MG132 also prevented the loss of the PRDX1 dimer, suggesting that the decrease is due to a NO-activated proteasomal degradation pathway. By contrast with the decrease in protein levels, LPS increased PRDX1 mRNA and this effect was amplified by IFN-γ. Two other Nrf2 target genes, thioredoxin reductase (TXNRD1) and haem oxygenase (HMOX1), were also induced by LPS but IFN-γ did not increase their expression further. This study shows that inflammation differentially regulates PRDX1 at the levels of protein stability and gene expression, and that NO plays a key role in this mechanism.By contrast with the decrease in protein levels, LPS increased PRDX1 mRNA and this effect was amplified by IFNγ. Two other Nrf2 target genes, thioredoxin reductase (TXNRD1) and heme oxygenase (HMOX1), were also induced by LPS but IFNγ did not increase their expression further. This study shows that inflammation differentially regulates PRDX1 at the levels of protein stability and gene expression, and that NO plays a key role in this mechanism.\ud \ud For illustration see published version.

Objective.To investigate the effects of soluble uric acid (UA) on expression and activation of the NOD-like receptor (NLR) pyrin domain containing protein 3 (NLRP3) inflammasome in human monocytes to elucidate the role of hyperuricemia in the pathogenesis of gout.Methods.Primary human monocytes and the THP-1 human monocyte cell line were used to determine the effects of short- and longterm exposure to UA on activation of the NLRP3 inflammasome and subsequent interleukin 1β (IL-1β) secretion by ELISA and cell-based assays. Expression of key NLRP3 components in monocytes from patients with a history of gout were analyzed by quantitative PCR.Results.Precipitation of UA was required for activation of the NLRP3 inflammasome and subsequent release of IL-1β in human monocytes. Neither monosodium urate (MSU) crystals nor soluble UA had any effect on activation of the transcription factor, nuclear factor-κB. Prolonged exposure of monocytes to soluble UA did not alter these responses. However, both MSU crystals and soluble UA did result in a 2-fold increase in reactive oxygen species. Patients with gout (n = 15) had significantly elevated serum UA concentrations compared to healthy individuals (n = 16), yet secretion of IL-1β and expression of NLRP3 inflammasome components in monocytes isolated from these patients were not different from those of healthy controls.Conclusion.Despite reports indicating that soluble UA can prime and activate the NLRP3 inflammasome in human peripheral blood mononuclear cells, precipitation of soluble UA into MSU crystals is essential forin vitroNLRP3 signaling in primary human monocytes.

Background There is a growing literature on the potential medical uses of Cannabis sativa and cannabinoid compounds. Although these have only been approved by regulatory agencies for a few indications, there is a hype about their possible benefits in a variety of conditions and a large market in the wellness industry. As in many cases patients search for information on cannabis products online, we have analyzed the information on medical cannabis available on the Internet. Therefore, this study aims at assessing the quality of the information available online on medical cannabis. Methods We searched “medical cannabis” on June 2019 using google.com and downloaded the first 243 websites. After excluding dead links or websites with no information about cannabis, 176 websites were included. They were then classified for their typology (e.g., commercial, government, news outlets). As an indicator of trustworthiness, we used the Journal of American Medical Association (JAMA) score, which assesses the indication of date, author, ownership of the website, and the presence of references. We also considered if a website is certified by Health-On-the-Net (HON), an independent organization, by displaying a HONCode symbol. Subsequently, we performed a content analysis to assess both the medical cannabis indications mentioned by webpages and the completeness of the information provided (whether they mentioned potential side effects and legal/regulatory issues or not). Results Analyzing 176 webpages returned by a search engine, we found that 52% of them were news websites. Pain, epilepsy, and multiple sclerosis were the most frequently mentioned therapeutic areas (cited in 92, 84 and 80 webpages, respectively), which did not always match those for which there is regulatory approval. Information was also incomplete, with only 22% of the webpages mentioning potential side effects. Health portal websites provided the most complete information, with all of them (n = 7) reporting side effects. On average, 80% of webpages had a neutral stance on the potential benefits of medical cannabis, with commercial websites having more frequently a positive stance (67%). Conclusions We conclude that the information that can be found online is not always aligned in terms of the therapeutic areas for which science-based evidence is often still weak.

Many studies reported that redox enzymes, particularly thioredoxin and peroxiredoxin, can be released by cells and act as soluble mediators in immunity. Recently, it became clear that peroxiredoxins can be secreted via the exosome-release route, yet it remains unclear how this exactly happens and why. This review will first introduce briefly the possible redox states of protein cysteines and the role of redox enzymes in their regulation. We will then discuss the studies on the extracellular forms of some of these enzymes, their association with exosomes/extracellular vesicles and with exosome micro-RNAs (miRNAs)/mRNAs involved in oxidative processes, relevant in infection and inflammation.

Objective: Many online and printed media publish health news of questionable trustworthiness and it may be difficult for laypersons to determine the information quality of such articles. The purpose of this work was to propose a methodology for the automatic assessment of the quality of health-related news stories using natural language processing and machine learning.Materials and Methods: We used a database from the website HealthNewsReview.org that aims to improve the public dialogue about health care. HealthNewsReview.org developed a set of criteria to critically analyze health care interventions' claims. In this work, we attempt to automate the evaluation process by identifying the indicators of those criteria using natural language processing-based machine learning on a corpus of more than 1,300 news stories. We explored features ranging from simple n-grams to more advanced linguistic features and optimized the feature selection for each task. Additionally, we experimented with the use of pre-trained natural language model BERT.Results: For some criteria, such as mention of costs, benefits, harms, and “disease-mongering,” the evaluation results were promising with an F1 measure reaching 81.94%, while for others the results were less satisfactory due to the dataset size, the need of external knowledge, or the subjectivity in the evaluation process.Conclusion: These used criteria are more challenging than those addressed by previous work, and our aim was to investigate how much more difficult the machine learning task was, and how and why it varied between criteria. For some criteria, the obtained results were promising; however, automated evaluation of the other criteria may not yet replace the manual evaluation process where human experts interpret text senses and make use of external knowledge in their assessment.

SCOPUS: ed.j, info:eu-repo/semantics/published

Multiple organ dysfunction or even failure after sepsis or trauma is due to a dysregulated host response. Currently, besides (surgical) source control (e.g., control of bleeding or drainage of abscesses) and administration of antimicrobial drugs, therapeutic approaches are limited to supportive care. Advances in our understanding of the key pathophysiological pathways involved in the excessive inflammation triggered by trauma, sepsis and/or ischemia-reperfusion have had limited impact. The 28 article in this Research Topic focus on the molecular mechanisms behind (hyper) inflammation after sepsis or trauma, with special emphasis on preclinical and translational studies that target potential organ-protective and/or -resuscitative therapeutic strategies. Most studies report rodent models of trauma and elective surgery (three articles), non-microbial hyper-inflammation induced with endotoxin exposure (LPS; seven articles) and chemical pancreatitis (one article), and cecal ligation and puncture-induced sepsis (six articles). Additional papers summarize investigations of human material (six articles) or fully-resuscitated large animal models (two articles). These article are complimented by four reviews and a commentary.

The hypothesis that reactive oxygen species (ROS) can be not just associated with but causally implicated in disease was first made in 1956, but so far, the oxidative stress theory of disease has not led to major therapeutic breakthrough, and the use of antioxidant is now confined to the field of complementary medicine. This chapter reviews the lack of high-level clinical evidence for the effectiveness of antioxidants in preventing disease and the epistemological problems of the oxidative stress theory of disease. We conclude on possible ways forward to test this hypothesis with approaches that take into account personalized medicine. The previous oxidative stress model has helped neither to diagnose nor to treat possibly ROS-related or ROS-dependent diseases. The redox balance concept that low ROS levels are beneficial or tolerable and high levels are disease triggers and best reduced is apparently wrong. Physiological ROS signalling may become dysfunctional or a disease trigger by at least five mechanisms: a physiological source may appear at an unphysiological site, a physiological source may be underactivated (less common) or overactivated (more common), a new source may appear, a physiological source may be overactivated or underactivated, and a toxifying enzyme may convert an ROS signal molecule into a more reactive molecule. The latter three mechanisms may reach a physiological or nonphysiological target. All of these dysregulations may be the direct and essential cause of a disease (rarely the case) or just a secondary epiphenomenon, which will disappear once the non-ROS-related cause of the disease is cured (much more common). Importantly, these mechanisms are the same for almost every signalling system. Causal target validation (sources, toxifiers and targets) is essential in order to identify effective drugs and therapies for ROSopathies.

Endothelial injury is an early and enduring feature of cardiovascular disease. Inflammation and hypoxia may be responsible for this, and are often associated with the up-regulation of several transcriptional factors that include Hypoxia Inducible Factor-1 (HIF-1). Although it has been reported that HIF-1α is detectable in plasma, it is known to be unstable. Our aim was to optimize an assay for HIF-1α to be applied to in vitro and in vivo applications, and to use this assay to assess the release kinetics of HIF-1α following endothelial injury.An ELISA for the measurement of HIF-1α in cell-culture medium and plasma was optimized, and the assay was used to determine the best conditions for sample collection and storage. The results of the ELISA were validated using Western blotting and immunohistochemistry (IHC). In vitro, a standardized injury was produced in a monolayer of rat aortic endothelial cells (RAECs) and intracellular HIF-1α was measured at intervals over 24 h. In vivo, a rat angioplasty model was used. The right carotid artery was injured using a 2F Fogarty balloon catheter. HIF-1α was measured in the plasma and in the arterial tissue (0, 1, 2, 3 and 5 days post injury).The HIF-1α ELISA had a limit of detection of 2.7 pg/mL and was linear up to 1000 pg/ mL. Between and within-assay, the coefficient of variation values were less than 15%. HIF-1α was unstable in cell lysates and plasma, and it was necessary to add a protease inhibitor immediately after collection, and to store samples at -80 °C prior to analysis. The dynamics of HIF-1α release were different for the in vitro and in vivo models. In vitro, HIF-1α reached maximum concentrations approximately 2 h post injury, whereas peak values in plasma and tissues occurred approximately 2 days post injury, in the balloon injury model.HIF-1α can be measured in plasma, but this requires careful sample collection and storage. The carotid artery balloon injury model is associated with the transient release of HIF-1α into the circulation that probably reflects the hypoxia induced in the artery wall.

An amendment to this paper has been published and can be accessed via the original article.

Patients who have experienced a first cerebral ischemic event are at increased risk of recurrent stroke. There is strong evidence that low-level inflammation as measured by high sensitivity C-reactive protein (hs-CRP) is a predictor of further ischemic events. Other mechanisms implicated in the pathogenesis of stroke may play a role in determining the risk of secondary events, including oxidative stress and the adaptive response to it and activation of neuroprotective pathways by hypoxia, for instance through induction of erythropoietin (EPO). This study investigated the association of the levels of CRP, peroxiredoxin 1 (PRDX1, an indicator of the physiological response to oxidative stress) and EPO (a neuroprotective factor produced in response to hypoxia) with the risk of a second ischemic event. Eighty patients with a diagnosis of lacunar stroke or transient ischemic attack (TIA) were included in the study and a blood sample was collected within 14 days from the initial event. Hs-CRP, PRDX1, and EPO were measured by ELISA. Further ischemic events were recorded with a mean follow-up of 42 months (min 24, max 64). Multivariate analysis showed that only CRP was an independent predictor of further events with an observed risk (OR) of 1.14 (P = 0.034, 95% CI 1.01-1.29). No association was observed with the levels of PRDX1 or EPO. A receiver operating curve (ROC) determined a cut-off CRP level of 3.25 μg/ml, with a 46% sensitivity and 81% specificity. Low-level inflammation as detected by hs-CRP is an independent predictor of recurrent cerebrovascular ischemic events.

Probiotics are over-the-counter products marketed for enhancing human health. Online information has been key in promoting probiotics worldwide. However, only few rigorous clinical studies have met the stringent criteria required to establish the efficacy and safety of probiotics. The present study was undertaken to assess the information quality of webpages referring to probiotics and to compare the recommendations available online with the information collected from trusted scientific sources. We evaluated 150 webpages returned by Google searching “probiotics” in terms of typology of website, health information quality based on the JAMA score and the HONcode certification, as well as completeness of the information based on the presence of four criteria: (1) links to scientific references supporting health claims, (2) cautionary notes about level of evidence for alleged benefits, (3) safety considerations, and (4) regulatory status. We then enumerated the health claims mentioned online and the corresponding clinical trials and reviews registered in the Cochrane library. Finally, the conclusions of Cochrane reviews were used to assess the level of scientific evidence of the information available through Google search. HON-certified websites were significantly more frequent in the top 10 websites than in the remaining websites. In terms of completeness of information, only 10% of webpages met all four criteria, 40% had a cautionary note on benefits, 35% referred to scientific literature, and only 25% mentioned potential side effects. The results of the content analysis led us to conclude that: (1) the most frequent typologies of webpages returned by Google are commercial and news, (2) commercial websites on average provide the least reliable information, and (3) significant numbers of claimed benefits of probiotics are not supported by scientific evidence. This study highlights important biases in the probiotics information available online, underlining the need to improve the quality and objectivity of information provided to the public., SCOPUS: ar.j, info:eu-repo/semantics/published

Environmental agents, including socioeconomic condition, and host factors can act as causal agents and risk factors in disease. We use biomarkers and sociomarkers to study causal factors, such as overproduction of reactive oxygen species (ROS) which could play a role in disease through oxidative stress. It is therefore important to define the exact meaning of the biomarker we measure. In this review we attempt a classification of biomarkers related to oxidative stress based on their biological meaning. We define as type zero biomarkers the direct measurement of ROS in vivo in patients. Type 1 biomarkers are the most frequently used indicators of oxidative stress, represented by oxidized lipids, proteins or nucleic acids and their bases. Type 2 biomarkers are indicators of the activation of biochemical pathways that can lead to the formation of ROS. Type 3 biomarkers are host factors such as small-molecular weight antioxidants and antioxidant enzymes, while type 4 biomarkers measure genetic factors and mutations that could modify the susceptibility of an individual to oxidative stress. We also discuss whether biomarkers are actionable or not, that is if the specific blockade of these molecules can ameliorate disease or if they are just surrogate markers.\ud The proposed classification of biomarkers of oxidative stress based on their meaning and ambiguities, within the theoretical framework of the oxidative stress theory of disease may help identify those diseases, and individuals, where oxidative stress has a causal role, to allow targeted therapy and personalized medicine.

The hypothesis that reactive oxygen species (ROS) can be not just associated with but causally implicated in disease was first made in 1956, but so far, the oxidative stress theory of disease has not led to major therapeutic breakthrough, and the use of antioxidant is now confined to the field of complementary medicine. This chapter reviews the lack of high-level clinical evidence for the effectiveness of antioxidants in preventing disease and the epistemological problems of the oxidative stress theory of disease. We conclude on possible ways forward to test this hypothesis with approaches that take into account personalized medicine. The previous oxidative stress model has helped neither to diagnose nor to treat possibly ROS-related or ROS-dependent diseases. The redox balance concept that low ROS levels are beneficial or tolerable and high levels are disease triggers and best reduced is apparently wrong. Physiological ROS signalling may become dysfunctional or a disease trigger by at least five mechanisms: a physiological source may appear at an unphysiological site, a physiological source may be underactivated (less common) or overactivated (more common), a new source may appear, a physiological source may be overactivated or underactivated, and a toxifying enzyme may convert an ROS signal molecule into a more reactive molecule. The latter three mechanisms may reach a physiological or nonphysiological target. All of these dysregulations may be the direct and essential cause of a disease (rarely the case) or just a secondary epiphenomenon, which will disappear once the non-ROS-related cause of the disease is cured (much more common). Importantly, these mechanisms are the same for almost every signalling system. Causal target validation (sources, toxifiers and targets) is essential in order to identify effective drugs and therapies for ROSopathies.

The fact that Internet companies may record our personal data and track our online behavior for commercial or political purpose has emphasized aspects related to online privacy. This has also led to the development of search engines that promise no tracking and privacy. Search engines also have a major role in spreading low-quality health information such as that of anti-vaccine websites. This study investigates the relationship between search engines' approach to privacy and the scientific quality of the information they return. We analyzed the first 30 webpages returned searching “vaccines autism” in English, Spanish, Italian, and French. The results show that not only “alternative” search engines (Duckduckgo, Ecosia, Qwant, Swisscows, and Mojeek) but also other commercial engines (Bing, Yahoo) often return more anti-vaccine pages (10–53%) than Google.com (0%). Some localized versions of Google, however, returned more anti-vaccine webpages (up to 10%) than Google.com. Health information returned by search engines has an impact on public health and, specifically, in the acceptance of vaccines. The issue of information quality when seeking information for making health-related decisions also impact the ethical aspect represented by the right to an informed consent. Our study suggests that designing a search engine that is privacy savvy and avoids issues with filter bubbles that can result from user-tracking is necessary but insufficient; instead, mechanisms should be developed to test search engines from the perspective of information quality (particularly for health-related webpages) before they can be deemed trustworthy providers of public health information., SCOPUS: ar.j, info:eu-repo/semantics/published

The discovery of the formation of reactive oxygen species (ROS) in biological systems and their biological consequences in terms of oxidation of proteins, lipids and DNA constitute the basis of the concept of oxidative stress (OS), and there is good evidence that this occurs in many pathological conditions. However, the idea that OS is a cause of disease and, more importantly, its logical application of translational medicine, the use of low-molecular mass antioxidants, the so-called ROS scavengers, lags behind. As a result, the only market for low-molecular mass ROS scavengers is, so far, only if the field of alternative medicine and nutritional supplement, not that of approved medicines. This chapters deals with several issues with the “oxidative stress theory of disease” (OSTD) in terms of its epistemological challenges in drawing a causal link from the association of indicators of OS in disease. This is due not only to difficulty to extrapolate conclusions from basic observation to patients but also to the fact that the OSTD is often applied to multicausal diseases where OS may not be present and contribute to the disease in all individual patients. Finally, we elaborate on the fact that ROS, unlike other disease mediators (e.g., cytokines, prostaglandins, and bacteria) cannot be measured in patients due to their short half-life, and we need to rely on markers that are indirectly linked to ROS (“biomarkers of oxidative stress”) that can be ambiguous in their meaning and, for multicausal diseases, not be elevated in all patients. We also discuss the possibility that OS, when demonstrated in all patients with a pathology, may not be a causal component of the disease but a terminal metabolic derangement. A reflection on the epistemological basis of the OSTD could explain the lack of success of ROS-targeting therapies and possibly indicate other roles of OS in disease.

Objective: There is an association between frailty and arterial stiffness. However, arterial stiffness does not uniformly correlate with the spectrum of frailty states. Both oxidative stress and inflammaging contribute to vascular ageing. There are no human studies exploring links between arterial stiffness, oxidative stress, inflammaging and frailty. Our objective is to investigate arterial stiffness and inflammaging as predictors of frailty states. Methods: An observational longitudinal cohort study will be used to examine the association between arterial stiffness, oxidative stress and inflammation in 50 older adults (⩾70 years) with clinical frailty scores (CFS) ⩽6 over 6 months. All study measurements will be taken at baseline. Frailty assessment will include hand-grip strength, timed-up and go test, mini-mental state examination, geriatric depression scale and sarcopenia using body composition measurements with Tanita®. Arterial stiffness measurements will include carotid-femoral pulse wave velocity (cfPWV) and carotid-radial pulse wave velocity (crPWV) using Complior (Alam Medical, France). CAVI device will measure Cardio-ankle vascular index and ankle brachial index (ABI). Oxidative stress blood markers nitrotyrosine (NT) and 8-hydroxy-2’-deoxyguanosin (8-oxo-dG) and inflammation markers high-sensitive C-reactive protein (hs-CRP) and interlukin-6(IL-6) will be measured at baseline and 6 month along with lipid profile and glycated haemoglobin. Results (data analysis plan): Descriptive statistics for continuous data using means and standard deviations for normality distributed variables or medians and inter-quartile ranges for skewed variables will be used. Participants will be categorised into CFS 1-3, and CFS 4-6. Categorical data will use frequencies and comparison between groups. Change in frailty between the groups over 6 months will be compared using paired t-test. Simple linear regression will be done between frailty measures, arterial stiffness, inflammation and oxidative stress biomarkers. Significance will be at P < .05. Conclusion: This study data will inform a larger, multi-centre study exploring further the interplay between frailty, biomarkers and arterial stiffness parameters.

It is thought that excessive production of reactive oxygen species (ROS) can be a causal component in many diseases, some of which have an inflammatory component. This led to an oversimplification whereby ROS are seen as inflammatory and antioxidants anti-inflammatory. This paper aims at reviewing some of the literature on thiols in host defense. The review will first summarize the mechanisms by which we survive infections by pathogens. Then we will consider how the redox field evolved from the concept of oxidative stress to that of redox regulation and how it intersects the field of innate immunity. A third section will analyze how an oversimplified oxidative stress theory of disease led to a hypothesis on the role of ROS and glutathione (GSH) in immunity, respectively as pro- and anti-inflammatory mediators. Finally, we will discuss some recent research and how to think out of the box of that oversimplification and link the role of thiols in redox regulation to the mechanisms by which we survive an infection outlined in the first section., Graphical abstract Image 1

Aim: This study aimed to assess the quality of the information available on the Web on gum disease.\ud \ud Methods: The term ‘gum disease’ was searched in Google and in MedlinePlus. The first 200 websites were analysed by the Journal of the American Medical Association (JAMA) criteria and the Health On the Net Foundation (HONCode) certification, instruments for assessing quality of health information. Data was analysed through the Mann-Whitney test or KruskalWallis test, followed by the Dunn’s test, using the GraphPad Prism Software version 6.\ud \ud Results: MedlinePlus presented a significantly higher JAMA score than Google. Google’s first ten results had a higher JAMA score than the remaining websites. Journalism and health portals are the most reliable affiliations, while commercial and dental practices had low JAMA scores. JAMA score was significantly higher in websites with the HONCode certification compared to the ones without it.\ud \ud Conclusion: There are current concerns regarding patients’ use of the Internet for accessing health information. However, the conclusion we can make is that Google seems to favour websites with high quality information, at least in terms of JAMA score or HONCode accreditation. The JAMA score of dental practices’ websites could be improved by providing basic information such as authorship and date.

The aim of this study was to develop and evaluate an optimized 3D bioprinting technology in order to fabricate novel scaffolds for the application of endothelial cell repair. Various biocompatible and biodegradable macroporous scaffolds (D = 10 mm) with interconnected pores (D = ~500 &micro, m) were fabricated using a commercially available 3D bioprinter (r3bEL mini, SE3D, USA). The resolution of the printing layers was set at ~100 &micro, m for all scaffolds. Various compositions of polylactic acid (PLA), polyethylene glycol (PEG) and pluronic F127 (F127) formulations were prepared and optimized to develop semi-solid viscous bioinks. Either dimethyloxalylglycine (DMOG) or erythroprotein (EPO) was used as a model drug and loaded in the viscous biocompatible ink formulations with a final concentration of 30% (w/w). The surface analysis of the bioinks via a spectroscopic analysis revealed a homogenous distribution of the forming materials throughout the surface, whereas SEM imaging of the scaffolds showed a smooth surface with homogenous macro-porous texture and precise pore size. The rheological and mechanical analyses showed optimum rheological and mechanical properties of each scaffold. As the drug, DMOG, is a HIF-1 inducer, its release from the scaffolds into PBS solution was measured indirectly using a bioassay for HIF-1&alpha, This showed that the release of DMOG was sustained over 48 h. The release of DMOG was enough to cause a significant increase in HIF-1&alpha, levels in the bioassay, and when incubated with rat aortic endothelial cells (RAECs) for 2 h resulted in transcriptional activation of a HIF-1&alpha, target gene (VEGF). The optimum time for the increased expression of VEGF gene was approximately 30 min and was a 3-4-fold increase above baseline. This study provides a proof of concept, that a novel bioprinting platform can be exploited to develop biodegradable composite scaffolds for potential clinical applications in endothelial cell repair in cardiovascular disease (CVD), or in other conditions in which endothelial damage occurs.

The Internet has become a prime source of health information available to the public. Our aims were to assess the content and quality of online information for the treatment of depression.We searched, “How to cure depression” on Google and analysed the first 200 websites according to the website typology and a standard health information assessment tool, the Journal of the American Medical Association (JAMA) criteria (presence of authorship, date, disclosure, and references). We also analyzed content in terms of treatments mentioned and developed a Quality Indicator Score (QIS) based on the guidelines for treating depression from the UK National Institute for Health and Care Excellence (NICE).News websites were the most frequent typology followed by health portals, non-profit, professional and government; commercial websites were the least represented. In the top ten websites, news and health portals remained first and second respectively. Antidepressants were the most mentioned treatment, followed by psychotherapy, lifestyle & exercise, social support, diet. The least mentioned interventions were sunlight & light therapy, routine, and ketamine & psychedelics. Commercial websites preferentially mentioned supplements, while ketamine and psychedelic drugs were the most covered by news outlets. Analysing webpages according to our QIS showed the median of NICE recommended treatments was 2.5 out of 5 possible treatments: antidepressants, lifestyle & exercise, psychotherapy, social support and ECT. Government websites had the highest QIS, news and commercial websites the lowest. Webpages with high QIS ranked higher in Google.

The 1998 Lancet paper by Wakefield et al. despite subsequent retraction and evidence indicating no causal link between vaccinations and autism, triggered significant parental concern. The aim of this study was to analyze the online information available on this topic. Using localized versions of Google, we searched "autism vaccine" in English, French, Italian, Portuguese, Mandarin, and Arabic and analyzed 200 websites for each search engine result page (SERP). A common feature was the newsworthiness of the topic, with news outlets representing 25-50% of the SERP, followed by unaffiliated websites (blogs, social media) that represented 27-41% and included most of the vaccine-negative websites. Between 12 and 24% of websites had a negative stance on vaccines, while most websites were pro-vaccine (43-70%). However, their ranking by Google varied. While in Google.com, the first vaccine-negative website was the 43rd in the SERP, there was one vaccine-negative webpage in the top 10 websites in both the British and Australian localized versions and in French and two in Italian, Portuguese, and Mandarin, suggesting that the information quality algorithm used by Google may work better in English. Many webpages mentioned celebrities in the context of the link between vaccines and autism, with Donald Trump most frequently. Few websites (1-5%) promoted complementary and alternative medicine (CAM) but 50-100% of these were also vaccine-negative suggesting that CAM users are more exposed to vaccine-negative information. This analysis highlights the need for monitoring the web for information impacting on vaccine uptake., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Vitamin D deficiency increases the risk of developing multiple sclerosis (MS) but it is unclear whether vitamin D supplementation improves the clinical course of MS, and there is uncertainty about the dose and form of vitamin D (D2 or D3) to be used. The mechanisms underlying the effects of vitamin D in MS are not clear. Vitamin D3 increases the rate of differentiation of primary oligodendrocyte precursor cells (OPCs), suggesting that it might help remyelination in addition to modulating the immune response. Here we analyzed the transcriptome of differentiating rat CG4 OPCs treated with vitamin D2 or with vitamin D3 at 24 h and 72 h following onset of differentiation. Methods Gene expression in differentiating CG4 cells in response to vitamin D2 or D3 was quantified using Agilent DNA microarrays (n = 4 replicates), and the transcriptome data were processed and analysed using the R software environment. Differential expression between the experimental conditions was determined using LIMMA, applying the Benjamini and Hochberg multiple testing correction to p-values, and significant genes were grouped into co-expression clusters by hierarchical clustering. The functional significance of gene groups was explored by pathway enrichment analysis using the clusterProfiler package. Results Differentiation alone changed the expression of about 10% of the genes at 72 h compared to 24 h. Vitamin D2 and D3 exerted different effects on gene expression, with D3 influencing 1272 genes and D2 574 at 24 h. The expression of the vast majority of these genes was either not changed in differentiating cells not exposed to vitamin D or followed the same trajectory as the latter. D3-repressed genes were enriched for Gene Ontology (GO) categories including transcription factors and the Notch pathway, while D3-induced genes were enriched for the Ras pathway. Conclusions This study shows that vitamin D3, compared with D2, changes the expression of a larger number of genes in OLs. Identification of genes affected by D3 in OLs should help to identify mechanisms mediating its action in MS.

Background: The concept that one can "boost" immunity is a popular one. Although the only evidence-based approach to this is vaccination, the lay public is exposed to a wide range of information on how to boost immunity. The aim of this study was to analyze such information available on the Internet. Methods and findings: We visited 185 webpages returned from a Google search on "boost immunity" and classified them by typology (blogs, commercial, government, no-profit, news, professional, scientific journals) and by using standard indicators of health information quality (JAMA score, HONCode). We then analyzed their content in terms of disease and "boosters" mentioned. Commercial and news websites represented one third of the results each. Of the 37 approaches to boost immunity recorded, the top ones were diet (77% of webpages), fruit (69%), vitamins (67%), antioxidants (52%), probiotics (51%), minerals (50%), and vitamin C (49%). Interestingly, vaccines ranked 27th, with only 12% of webpages mentioning them. Conclusions: Commercial websites are an important component of the information available to the public on the topic, and thus contribute providing biased information.

Introduction\ud The ABSORB bioresorbable vascular scaffold (BVS) is associated with greater neointimal proliferation and thrombotic rate than the metal stent. The role of inflammatory biomarkers on neointimal proliferation has not been studied in the setting of BVS implantation.\ud \ud Patients and methods\ud Thirty patients had arterial blood sampling before elective percutaneous coronary intervention with the ABSORB BVS and at 9-months follow-up. Plasma levels of interleukin-6, soluble CD40 ligand, monocyte chemotactic protein-1 and C-reactive protein were measured using enzyme-linked immunosorbent assay. Baseline and follow-up levels were compared for each biomarker. Optical frequency domain imaging was performed at follow-up and the neointimal burden was calculated as the ratio of neointimal area to scaffold area. The levels of inflammatory mediators were correlated with the neointimal burden.\ud \ud Results\ud There was no significant increase in the levels of biomarkers from baseline to follow-up. Median C-reactive protein levels changed from 1.1 [interquartile range (IQR): 0.5–2.5] to 2.2 (IQR: 0.5–3.5) μg/ml, interleukin-6 from 1.0 (IQR: 0.6–1.4) to 1.0 (95% confidence interval: 0.6–1.4) pg/ml, monocyte chemotactic protein-1 from 120.4 (IQR: 86.0–153.4) to 102.0 (IQR: 70.3–148.1) pg/ml and soluble CD40 ligand from 108.3 (IQR: 74.1–173.7) to 112.0 (IQR: 71.0–225.9) pg/ml. The average neointimal burden in the cohort was 18±6%. Baseline, follow-up and change in plasma levels of inflammatory markers between these two time points did not correlate with the neointimal burden.\ud \ud Conclusion\ud Elective percutaneous coronary intervention with the ABSORB BVS does not provoke a chronic inflammatory response. The degree of neointimal proliferation after elective implantation of the ABSORB BVS is independent of the pre-existing inflammatory environment.

Inflammation is associated with production of reactive oxygen species (ROS) and results in the induction of thioredoxin (TXN) and peroxiredoxins (PRDXs) and activation of nuclear factor-like 2 (Nrf2). In this study we have used the mouse RAW 264.7 macrophage and the human THP-1 monocyte cell line to investigate the pattern of expression of three Nrf2 target genes, PRDX1, TXN reductase (TXNRD1) and heme oxygenase (HMOX1), by activation of different Toll-like receptors (TLRs). We found that, while the TLR4 agonist lipopolysaccharide (LPS) induces all three genes, the pattern of induction with agonists for TLR1/2, TLR3, TLR2/6 and TLR7/8 differs depending on the gene and the cell line. In all cases, the extent of induction was HMOX1>TXNRD1>PRDX1. Since LPS was a good inducer of all genes in both cell lines, we studied the mechanisms mediating LPS induction of the three genes using mouse RAW 264.7 cells. To assess the role of ROS we used the antioxidant N-acetylcysteine (NAC). Only LPS induction of HMOX1 was inhibited by NAC while that of TXNRD1 and PRDX1 was unaffected. These three genes were also induced by phorbol myristate acetate (PMA), a ROS-inducer acting by activation of protein kinase C (PKC). The protein kinase inhibitor staurosporine inhibited the induction of all three genes by PMA but only that of HMOX1 by LPS. This indicates that activation of these genes by inflammatory agents is regulated by different mechanisms involving either ROS or protein kinases, or both.

The proinflammatory cytokine interleukin-1β (IL-1β) plays important roles in immunity but is also implicated in autoimmune disease. The most well-established mechanism of IL-1β secretion is via activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome which requires an initial priming signal followed by an activating signal. However, the precise mechanism by which the inflammasome is activated remains unclear. The role of reactive oxygen species (ROS) in this process is contradictory, with some studies suggesting that ROS are crucial while others describe opposite effects. In this study, we evaluated the effects of oxidative stress on IL-1β secretion. \ud \ud Gout is a disease driven solely by IL-1β secretion in response to monosodium urate (MSU) crystals which form during periods of hyperuricemia and thus presents an opportunity to study factors contributing to IL-1β secretion. Sera and monocytes were isolated from patients with gout to determine whether differences in antioxidant status could explain the susceptibility of these individuals to gout attacks. In addition, sera and monocytes were collected from patients with chronic kidney disease (CKD) for comparison as this condition is associated with high levels of oxidative stress and disturbances in serum uric acid levels. \ud \ud There were differences in some aspects of antioxidant defenses in gout patients and these were mainly due to higher serum uric acid. Monocytes from gout patients were more responsive to priming, but not activation, of the NLRP3 inflammasome. However, expression of the components of the NLRP3 inflammasome were unaffected by priming or activation of the inflammasome, nor were these expression levels differentially regulated in gout patients. Inhibition of ROS by N-Acetyl Cysteine inhibited TLR2-induced priming of the NLRP3 inflammasome, but had no effect on MSU-induced activation. Together these findings demonstrate that oxidative stress only affects priming of the NLRP3 inflammasome but does not influence activation.

Fibromyalgia is a multi-factorial illness primarily characterised by widespread chronic pain and fatigue, with several symptoms and associated conditions. Due to a lack of clinical awareness and an absence of objective diagnostic measures, fibromyalgia patients often engage with online health information. The aim is to investigate the completeness and trustworthiness of the information available online on fibromyalgia. Google.co.uk was searched for ‘fibromyalgia’, the first 200 webpages were imported and 148 were analysed for standard health information quality criteria (JAMA score, HONcode) as well as completeness of information in terms of symptoms, causes and treatments mentioned. The most frequent typology of webpages was from health professionals (38%), with commercial websites being less frequent (7%). Overall, the quality, completeness and accessibility of online health information was poor. Completeness of coverage for symptoms, causes and associated conditions was especially lacking, with pages from not-for-profit organisations discussing the highest number of symptoms (median 8, min 0, max 11, interquartile range, IQR 4.5; n = 14) compared to the rest of the websites in the search engine results (median 4, min 0, max 11, IQR 4; n = 134). Mean readability was grade 9 (median 9, min 1, max 18, IQR 3), with only 8% websites meeting the recommended readability of grade 6. The Internet provides incomplete information on fibromyalgia, which does not fulfil the most queried aspect(s) by patients, symptoms, and may be difficult to understand by lay persons. Not-for-profit organisations provide the most complete information compared to other types of websites.

The theory that oxidative stress (OS) is at the root of several diseases is extremely popular. However, so far, no antioxidant has been recommended or offered by healthcare systems neither has any been approved as therapy by regulatory agencies that base their decisions on evidence-based medicine. This is simply because, so far, despite many preclinical and clinical studies indicating a beneficial effect of antioxidants in many disease conditions, randomised clinical trials have failed to provide the evidence of efficacy required for drug approval. In this review, we discuss the levels of evidence required to claim causality in preclinical research on OS, the weakness of the oversimplification associated with OS theory of disease and the importance of the narrative in its popularity. Finally, from a more translational perspective, we discuss the reasons why antioxidants acting by scavenging ROS might not only prevent their detrimental effects but also interfere with essential signalling roles. We propose that ROS have a complex metabolism and are generated by different enzymes at diverse sites and at different times. Aggregating this plurality of systems into a single theory of disease may not be the best way to develop new drugs, and future research may need to focus on specific oxygen-toxifying pathways rather than on non-specific ROS scavengers. Finally, similarly to what is nowadays required for clinical trials, we recommend making unpublished data available in repositories (open data), as this will allow big data approaches or meta-analyses, without the drawbacks of publication bias. Linked Articles This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc

To investigate the effects of soluble uric acid (UA) on expression and activation of the NOD-like receptor (NLR) pyrin domain containing protein 3 (NLRP3) inflammasome in human monocytes to elucidate the role of hyperuricemia in the pathogenesis of gout.Primary human monocytes and the THP-1 human monocyte cell line were used to determine the effects of short- and longterm exposure to UA on activation of the NLRP3 inflammasome and subsequent interleukin 1β (IL-1β) secretion by ELISA and cell-based assays. Expression of key NLRP3 components in monocytes from patients with a history of gout were analyzed by quantitative PCR.Precipitation of UA was required for activation of the NLRP3 inflammasome and subsequent release of IL-1β in human monocytes. Neither monosodium urate (MSU) crystals nor soluble UA had any effect on activation of the transcription factor, nuclear factor-κB. Prolonged exposure of monocytes to soluble UA did not alter these responses. However, both MSU crystals and soluble UA did result in a 2-fold increase in reactive oxygen species. Patients with gout (n = 15) had significantly elevated serum UA concentrations compared to healthy individuals (n = 16), yet secretion of IL-1β and expression of NLRP3 inflammasome components in monocytes isolated from these patients were not different from those of healthy controls.Despite reports indicating that soluble UA can prime and activate the NLRP3 inflammasome in human peripheral blood mononuclear cells, precipitation of soluble UA into MSU crystals is essential for

Glutathione (GSH) deficiency may play a pivotal role in a variety of apparently unrelated clinical conditions and diseases. Orally administered N-acetylcysteine (NAC), which replenishes the cysteine required for GSH synthesis, has been tested in a large number of randomized placebo-controlled trials involving these diseases and conditions. This chapter focused on developing a base of evidence suggesting that NAC administration improves disease by increasing cysteine and/or GSH in a variety of diseases, thereby implying a significant role for GSH deficiency in the clinical basis of many diseases. To develop this base of evidence, we systematically selected studies which considered the hypothesis that the therapeutic efficacy for NAC is an indication that cysteine and/or GSH deficiency is a pathophysiological part of the diseases studied. In this manner we focus this chapter on explaining the biological mechanisms of NAC therapy in a wide variety of disorders and demonstrate its ubiquitous role in improving disease that involves disrupted GSH and/or cysteine metabolism.

Besides understanding the effectiveness of N-acetylcysteine (NAC) for the treatment of disease and its effect on physiological systems, other considerations of NAC are important, including the pharmacology, formulations, and adverse effects of NAC. This chapter will review these important aspects of NAC. Few published trials have examined the pharmacokinetics of NAC. Maximum plasma concentration increases with oral NAC doses (up to 1200 mg has been studied), particularly with sustained-release formulations. Oral and intravenous NAC seems to have similar half-lives (around 6 h). The pharmacokinetics of NAC is altered by chronic liver and renal disease as well as exercise. Clearance is altered in the neonatal period and with dialysis. NAC does not appear to alter the concentration of several common antibiotics, including amoxicillin, cefadroxil, cefpodoxime, doxycycline, and erythromycin. There are many nonprescription forms of NAC that are not regulated, particularly in the United States, which can easily oxidize in its dimeric form (“di-NAC”) which can result in opposite physiological effects. There are several formulations that follow Good Manufacturing Practice standards that are believed to be more stable.

Introduction. The popularity of seeking health information online makes information quality (IQ) a public health issue. The present study aims at building a theoretical framework of health information quality (HIQ) that can be applied to websites and defines which IQ criteria are important for a website to be trustworthy and meet users’ expectations.\ud \ud Methods. We have identified a list of HIQ criteria from existing tools and assessment criteria and elaborated them into a questionnaire that was promoted via social media and mainly the University. Responses (329) were used to rank the different criteria for their importance in trusting a website and to identify patterns of criteria using hierarchical cluster analysis.\ud \ud Results. HIQ criteria were organized in five dimensions based on previous theoretical frameworks as well as on how they cluster together in the questionnaire response. We could identify a top-ranking dimension (scientific completeness) that describes what the user is expecting to know from the websites (in particular: description of symptoms, treatments, side effects). Cluster analysis also identified a number of criteria borrowed from existing tools for assessing HIQ that could be subsumed to a broad “ethical” dimension (such as conflict of interests, privacy, advertising policies) that were, in general, ranked of low importance by the participants. Subgroup analysis revealed significant differences in the importance assigned to the various criteria based on gender, nationality and whether or not of a biomedical educational background.\ud \ud Conclusions. We identified criteria of HIQ and organized them in dimensions. We observed that ethical criteria, while regarded highly in the academic and medical environment, are not considered highly by the public.

Background Endothelial injury is an early and enduring feature of cardiovascular disease. Inflammation and hypoxia may be responsible for this, and are often associated with the up-regulation of several transcriptional factors that include Hypoxia Inducible Factor-1 (HIF-1). Although it has been reported that HIF-1α is detectable in plasma, it is known to be unstable. Our aim was to optimize an assay for HIF-1α to be applied to in vitro and in vivo applications, and to use this assay to assess the release kinetics of HIF-1α following endothelial injury. Methods An ELISA for the measurement of HIF-1α in cell-culture medium and plasma was optimized, and the assay was used to determine the best conditions for sample collection and storage. The results of the ELISA were validated using Western blotting and immunohistochemistry (IHC). In vitro, a standardized injury was produced in a monolayer of rat aortic endothelial cells (RAECs) and intracellular HIF-1α was measured at intervals over 24 h. In vivo, a rat angioplasty model was used. The right carotid artery was injured using a 2F Fogarty balloon catheter. HIF-1α was measured in the plasma and in the arterial tissue (0, 1, 2, 3 and 5 days post injury). Results The HIF-1α ELISA had a limit of detection of 2.7 pg/mL and was linear up to 1000 pg/ mL. Between and within-assay, the coefficient of variation values were less than 15%. HIF-1α was unstable in cell lysates and plasma, and it was necessary to add a protease inhibitor immediately after collection, and to store samples at -80 °C prior to analysis. The dynamics of HIF-1α release were different for the in vitro and in vivo models. In vitro, HIF-1α reached maximum concentrations approximately 2 h post injury, whereas peak values in plasma and tissues occurred approximately 2 days post injury, in the balloon injury model. Conclusion HIF-1α can be measured in plasma, but this requires careful sample collection and storage. The carotid artery balloon injury model is associated with the transient release of HIF-1α into the circulation that probably reflects the hypoxia induced in the artery wall. Electronic supplementary material The online version of this article (10.1186/s10020-018-0026-5) contains supplementary material, which is available to authorized users.

Background The pro-myelinating effects of leukemia inhibitory factor (LIF) and other cytokines of the gp130 family, including oncostatin M (OSM) and ciliary neurotrophic factor (CNTF), have long been known, but controversial results have also been reported. We recently overexpressed erythropoietin receptor (EPOR) in rat central glia-4 (CG4) oligodendrocyte progenitor cells (OPCs) to study the mechanisms mediating the pro-myelinating effects of erythropoietin (EPO). In this study, we investigated the effect of co-treatment with EPO and LIF. Methods Gene expression in undifferentiated and differentiating CG4 cells in response to EPO and LIF was analysed by DNA microarrays and by RT-qPCR. Experiments were performed in biological replicates of N ≥ 4. Functional annotation and biological term enrichment was performed using DAVID (Database for Annotation, Visualization and Integrated Discovery). The gene-gene interaction network was visualised using STRING (Search Tool for the Retrieval of Interacting Genes). Results In CG4 cells treated with 10 ng/ml of EPO and 10 ng/ml of LIF, EPO-induced myelin oligodendrocyte glycoprotein (MOG) expression, measured at day 3 of differentiation, was inhibited ≥4-fold (N = 5, P

Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases., This work was supported by Grants SAF2015-71304-REDT, SAF2016-76520-R, SAF2013-4874R, SAF2015-65267-R, and BIO2014-57518 of the Spanish Ministry of Economy and Competiveness; PII4/00372 from the Health Institute Carlos III; PROMETEOII/2014/071 of Generalitat Valenciana; P_37_732/2016 REDBRAIN of the European Regional Development Fund; Competitiveness Operational Program 2014-2020; and the ERC Advanced Grant RadMed 294683 and COST action 15120 OpenMultiMed (H.H.H.W.S.). M.P. is the recipient of a FPU fellowship of Autonomous University of Madrid. E.G. is supported by a European-cofunded Beatriu de Pinos fellowship. R.L. is supproted by the Miguel Servet II fellow (CPII16/00014).

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed., Graphical abstract fx1, Highlights • RONS are chemical mediators and a communication tool. • RONS and disturbed redox balance play a role in a broad range of diseases and aging. • Bacteria and toxins are important stimulators of cellular RONS formation. • Drugs should preserve beneficial redox signaling and inhibit detrimental RONS sources. • Redox drugs may target the origin, identity, location and time of RONS formation.