Environmental risk factors and their footprints in vivo – a proposal for the classification of oxidative stress biomarkers

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. 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

Adding dimensions to the analysis of the quality of health information of websites returned by Google. Cluster analysis identifies patterns of websites according to their classification and the type of intervention described.

Background and aims: Most of the instruments used to assess the quality of health information on the Web (e.g. the JAMA criteria) only analyze one dimension of information quality, trustworthiness. We try to compare these characteristics with the type of treatments the website describe, whether evidence-based medicine or note, and correlate this with the established criteria. Methods: We searched Google for “migraine cure” and analyzed the first 200 websites for: 1) JAMA criteria (authorship, attribution, disclosure, currency); 2) class of websites (commercial, health portals, professional, patient groups, no-profit); and 3) type of intervention described (approved drugs, alternative medicine, food, procedures, lifestyle, drugs still at the research stage). We used hierarchical cluster analysis to assess associations between classes of websites and types of intervention described. Subgroup analysis on the first 10 websites returned was performed. Results: Google returned health portals (44%), followed by commercial websites (31%) and journalism websites (11%). The type of intervention mentioned most often was alternative medicine (55%), followed by procedures (49%), lifestyle (42%), food (41%) and approved drugs (35%). Cluster analysis indicated that health portals are more likely to describe more than one type of treatment while commercial websites most often describe only one. The average JAMA score of commercial websites was significantly lower than for health portals or journalism websites, and this was mainly due to lack of information on the authors of the text and indication of the date the information was written. Looking at the first 10 websites from Google, commercial websites are under-represented and approved drugs over-represented. Conclusions: This approach allows the appraisal of the quality of health-related information on the Internet focusing on the type of therapies/prevention methods that are shown to the patient

Hypoxia enhances the tissue protective effect of erythropoietin and its analogues in an endothelial cell injury model

PO has tissue protective activities in ischemic disease but also has prothrombotic, erythropoietic effects. Carbamylated EPO (CEPO) retains the protective actions without the erythropoietic effects. To assess the potential of these molecules in atherosclerosis (an ischemic heart disease), we investigated EPO and CEPO in an in vitro model of injury using bovine aortic endothelial cells (BAEC) in hypoxia and normoxia.. BAECs were grown to confluence in 10% FBS in 12 well culture plates. They were then cultured under normoxia (21% oxygen) or hypoxia (5% oxygen) 24 h prior to their use in an injury model using the ‘scratch assay.’ The effects of EPO and CEPO on endothelial closure were assessed using a range of concentrations (0-10 ng/mL). In separate experiments, the effects of EPO and CEPO on BAEC proliferation and chemotaxis were also assessed under similar hypoxic conditions. Gene expression of the receptors that may be involved in their protective pathway [EPOR and the β common chain receptor (βCR)] were assessed using quantitative PCR. The effects of both EPO and CEPO were enhanced under hypoxic conditions (13 ± 2.6 %, and 10 ± 1.69 %, p0.05). Whilst, the expression of EPOR gene increased by 2.1 ± 0.8 folds (p<0.05) In hypoxia, βCR expression was not affected by the change in oxygen tension. The effects of EPO and CEPO in the scratch assay appeared to be mediated by enhancing cell proliferation and migration of BAECs (p<0.05). In conclusion, the enhanced effects of EPO and CEPO on endothelial cells under hypoxia requires further investigation in processes in which hypoxia may play a role, e.gfor example. in atherogenesis and re-stensosis following angioplasty

Redox proteomics applied to the thiol secretome

Significance: Secreted proteins are important both as signaling molecules and potential biomarkers. Recent Advances: Protein can undergo different types of oxidation, both in physiological conditions or under oxidative stress. Several redox proteomics techniques have been successfully applied to the identification of glutathionylated proteins, an oxidative post-translational modification consisting in the formation of a mixed disulfide between a protein cysteine and glutathione. Redox proteomics has also been used to study other forms of protein oxidation. Critical Issues: Because of the highest proportion of free cysteines in the cytosol, redox proteomics of protein thiols has focused, so far, on intracellular proteins. However, plasma proteins, such as transthyretin and albumin, have been described as glutathionylated or cysteinylated. The present review discusses the redox state of protein cysteines in relation to their cellular distribution. We describe the various approaches used to detect secreted glutathionylated proteins, the only thiol modification studied so far in secreted proteins, and the specific problems presented in the study of the secretome. Future Directions: This review focusses on glutathionylated proteins secreted under inflammatory conditions and that may act as soluble mediators (cytokines). Future studies on the redox secretome (including other forms of oxidation) might identify new soluble mediators and biomarkers of oxidative stress

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

The quality of online health information on breast augmentation

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Editorial: dimensions of health information quality

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Definition of a family of tissue-protective cytokines using functional cluster analysis: a proof-of-concept study

The discovery of the tissue-protective activities of erythropoietin (EPO) has underlined the importance of some cytokines in tissue-protection, repair, and remodeling. As such activities have been reported for other cytokines, we asked whether we could define a class of tissue-protective cytokines. We therefore explored a novel approach based on functional clustering. In this pilot study, we started by analyzing a small number of cytokines (30). We functionally classified the 30 cytokines according to their interactions by using the bioinformatics tool STRING (Search Tool for the Retrieval of Interacting Genes), followed by hierarchical cluster analysis. The results of this functional clustering were different from those obtained by clustering cytokines simply according to their sequence. We previously reported that the protective activity of EPO in a model of cerebral ischemia was paralleled by an upregulation of synaptic plasticity genes, particularly early growth response 2 (EGR2). To assess the predictivity of functional clustering, we tested some of the cytokines clustering close to EPO (interleukin-11, IL-11; kit ligand, KITLG; leukemia inhibitory factor, LIF; thrombopoietin, THPO) in an in vitro model of human neuronal cells for their ability to induce EGR2. Two of these, LIF and IL-11, induced EGR2 expression. Although these data would need to be extended to a larger number of cytokines and the biological validation should be done using more robust in vivo models, rather then just one cell line, this study shows the feasibility of this approach. This type of functional cluster analysis could be extended to other fields of cytokine research and help design biological experiments

The role of novel biomarkers of inflammation in arterial stiffness, and in predicting further vascular events after TIA and lacunar stroke

Objective: To explore the role of biomarkers (hsCRP, sRANKL, PRDX1 and EPO) in arterial stiffness and in predicting further vascular events. Methods: Patients from the ongoing ASIST study each attended a laboratory visit within fourteen days of their diagnosed TIA or lacunar stroke. Arterial stiffness was calculated using cfPWV (carotid-femoral pulse wave velocity) measured with Complior ®Artech, France, and with the CAVI ®Fukuda, Japan (cardio-ankle vascular index) method. Blood samples were taken for ELISA assays. Analysis was completed with SPSS software. Results: Forty patients were evaluated in this preliminary project (29 male/11 female, mean age 70.7 ± 11.99), with four experiencing a further event during the six month follow up (10%). All biomarkers and both measurements for arterial stiffness had a higher mean value in patients with a further event (hsCRP 3.89 vs 1.42 ug/ml, P=0.08; EPO 9.06 vs 9.01 mU/ml, P=0.85; sRANKL 0.05 vs 0.03 pmol/L, P=0.31; PRDX1 6.27 vs 6.21 ng/ml, P=0.95; CAVI 11.13 vs 9.69, P=0.15; cfPWV 10.82 vs 10.2 m/s, P=0.55), however none were statistically significant. Levels of PRDX1 were elevated acutely post-event before falling significantly (R=-0.475, P=0.002), while hsCRP and EPO continued to be elevated at >10 days post-event. In addition, CAVI correlated closely with hsCRP (R=0.28, P=0.09) and EPO (R=0.29, P=0.08), but cfPWV was not closely related to any of the biomarkers. Conclusions: This preliminary data suggests that biomarkers, particularly EPO and hsCRP, are more closely related to CAVI than cfPWV. hsCRP was the most relevant as an independent predictive factor for further vascular events

Glutathione fine-tunes the innate immune response toward antiviral pathways in a macrophage cell line independently of its antioxidant properties

Glutathione (GSH), a major cellular antioxidant, is considered an inhibitor of the inflammatory response involving reactive oxygen species (ROS). However, evidence is largely based on experiments with exogenously added antioxidants/reducing agents or pro-oxidants. We show that depleting macrophages of 99% of GSH does not exacerbate the inflammatory gene expression profile in the RAW264 macrophage cell line or increase expression of inflammatory cytokines in response to the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS); only two small patterns of LPS-induced genes were sensitive to GSH depletion. One group, mapping to innate immunity and antiviral responses (Oas2, Oas3, Mx2, Irf7, Irf9, STAT1, il1b), required GSH for optimal induction. Consequently, GSH depletion prevented the LPS-induced activation of antiviral response and its inhibition of influenza virus infection. LPS induction of a second group of genes (Prdx1, Srxn1, Hmox1, GSH synthase, cysteine transporters), mapping to nrf2 and the oxidative stress response, was increased by GSH depletion. We conclude that the main function of endogenous GSH is not to limit inflammation but to fine-tune the innate immune response to infection