Demystifying Oxidative Stress.

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.

Vitamins D3 and D2 have marked but different global effects on gene expression in a rat oligodendrocyte precursor cell line.

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.

Boosting the Immune System, From Science to Myth: Analysis the Infosphere With Google.

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.

Fake News or Weak Science? Visibility and Characterization of Antivaccine Webpages Returned by Google in Different Languages and Countries.

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.

Quality of online information on breast cancer treatment options.

Offering breast cancer patients treatment choice has become a priority as the involvement of patients in the decision-making process is associated with improved physical and psychological outcomes. As the Internet is increasingly being used by patients as a source of medical information, it is important to evaluate the quality of information relating to breast cancer on the Internet. We analysed 200 websites returned by google.co.uk searching "breast cancer treatment options" in terms of their typology and treatment options described. These were related to standard measures of health information quality such as the JAMA score and the presence of quality certifications, as well as readability. We found that health portals were of higher quality whilst commercial and professional websites were of poorer quality in terms of JAMA criteria. Overall, readability was higher than previously reported for other conditions, and Google ranked websites with better readability higher. Most websites discussed surgical and medical treatments. Few websites, with a large proportion being of commercial typology, discussed complementary and alternative medicine. Google ranked professional websites low whilst websites from non-profit organizations were promoted in the ranking.

Online Information on Antioxidants: Information Quality Indicators, Commercial Interests, and Ranking by Google.

The idea that antioxidant supplements can prevent or cure many diseases is extremely popular. To study the public understanding of antioxidants on the Web, we searched the term "antioxidants" in http://Google.com and analyzed 200 websites in terms of typology (news, commercial, professional, health portal, no-profit or government organization, scientific journals), disease or biological process mentioned (aging, immunity, neurological disease, diabetes, arthritis, etc.), and stance toward antioxidants, whether neutral, positive, or negative. Commercial and news websites were prevalent (over half of the total) but not in the top 10 returned by Google, where the most frequent were health portals, government, and professional websites. Among the diseases mentioned, cancer was the first, followed by vascular and eye diseases. A negative stance toward supplements was prevalent in the whole search, and this was even more evident for cancer. Information on aging or immunity had the largest proportion of pro-supplement and commercial websites. This study shows that some diseases are highly associated with antioxidants on the Internet and that information on antioxidants in aging and immunity is more likely to describe the positive effects of antioxidant supplements.

Bad News: Analysis of the Quality of Information on Influenza Prevention Returned by Google in English and Italian.

Information available to the public influences the approach of the population toward vaccination against influenza compared with other preventative approaches. In this study, we have analyzed the first 200 websites returned by searching Google on two topics (prevention of influenza and influenza vaccine), in English and Italian. For all the four searches above, websites were classified according to their typology (government, commercial, professional, portals, etc.) and for their trustworthiness as defined by the Journal of the American Medical Association (JAMA) score, which assesses whether they provide some basic elements of information quality (IQ): authorship, currency, disclosure, and references. The type of information described was also assessed to add another dimension of IQ. Websites on influenza prevention were classified according to the type of preventative approach mentioned (vaccine, lifestyle, hygiene, complementary medicine, etc.), whether the approaches were in agreement with evidence-based medicine (EBM) or not. Websites on influenza vaccination were classified as pro- or anti-vaccine, or neutral. The great majority of websites described EBM approaches to influenza prevention and had a pro-vaccine orientation. Government websites mainly pointed at EBM preventative approaches and had a pro-vaccine orientation, while there was a higher proportion of commercial websites among those which promote non-EBM approaches. Although the JAMA score was lower in commercial websites, it did not correlate with the preventative approaches suggested or the orientation toward vaccines. For each of the four search engine result pages (SERP), only one website displayed the health-of-the-net (HON) seal. In the SERP on vaccines, journalistic websites were the most abundant category and ranked higher than average in both languages. Analysis using natural language processing showed that journalistic websites were mostly reporting news about two specific topics (different in the two languages). While the ranking by Google favors EBM approaches and, in English, does not promote commercial websites, in both languages it gives a great advantage to news. Thus, the type of news published during the influenza season probably has a key importance in orienting the public opinion due to its high visibility. This raises important questions on the relationships between health IQ, trustworthiness, and newsworthiness.

Pharmacology and Clinical Drug Candidates in Redox Medicine.

SIGNIFICANCE: Oxidative stress is suggested to be a disease mechanism common to a wide range of disorders affecting human health. However, so far, the pharmacotherapeutic exploitation of this, for example, based on chemical scavenging of pro-oxidant molecules, has been unsuccessful. RECENT ADVANCES: An alternative emerging approach is to target the enzymatic sources of disease-relevant oxidative stress. Several such enzymes and isoforms have been identified and linked to different pathologies. For some targets, the respective pharmacology is quite advanced, that is, up to late-stage clinical development or even on the market; for others, drugs are already in clinical use, although not for indications based on oxidative stress, and repurposing seems to be a viable option. CRITICAL ISSUES: For all other targets, reliable preclinical validation and drug ability are key factors for any translation into the clinic. In this study, specific pharmacological agents with optimal pharmacokinetic profiles are still lacking. Moreover, these enzymes also serve largely unknown physiological functions and their inhibition may lead to unwanted side effects. FUTURE DIRECTIONS: The current promising data based on new targets, drugs, and drug repurposing are mainly a result of academic efforts. With the availability of optimized compounds and coordinated efforts from academia and industry scientists, unambiguous validation and translation into proof-of-principle studies seem achievable in the very near future, possibly leading towards a new era of redox medicine.

Preventive administration of Mycobacterium tuberculosis 10-kDa heat shock protein (hsp10) suppresses adjuvant arthritis in Lewis rats.

Adjuvant arthritis (AA) can be induced in Lewis rats by immunization with Mycobacterium tuberculosis (Mt) in oil. We have investigated the modulation of AA by mycobacterial 10-kDa heat shock protein (hsp10), administered according to several protocols known to induce immune tolerance and immune deviation. Subcutaneous immunization with hsp10 in aqueous solution did not induce a cellular immune response, evaluated as delayed-type hypersensitivity (DTH) reaction, although anti-hsp10 antibodies, mainly of the IgG2a isotype, were detected in serum of treated animals. When rats were pretreated with hsp10 in aqueous solution before AA induction, no effects were seen on arthritis-induced joint swelling, although osteolysis and lymphocyte infiltration were slightly decreased. When other routes of administration were attempted, the strongest suppression was seen in the group of animals which received four intranasal (i.n.) administrations of protein and a subsequent challenge of hsp10 in incomplete Freund's adjuvant (IFA). We also found that the extent of disease suppression among the different groups of animals correlated with serum anti-hsp10 antibody levels. These antibodies mostly belonged to the IgG2a subtype, suggesting that immune deviation may play a role in the mechanism of disease suppression by hsp10.