Membrane lipid modifications and therapeutic effects mediated by hydroxydocosahexaenoic acid on Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative pathology with relevant unmet therapeutic needs. Both natural aging and AD have been associated with a significant decline in the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), and accordingly, administration of DHA has been proposed as a possible treatment for this pathology. However, recent clinical trials in mild-to-moderately affected patients have been inconclusive regarding the real efficacy of DHA in halting this disease. Here, we show that the novel hydroxyl-derivative of DHA (2-hydroxydocosahexaenoic acid - OHDHA) has a strong therapeutic potential to treat AD. We demonstrate that OHDHA administration increases DHA levels in the brain of a transgenic mouse model of AD (5xFAD), as well as those of phosphatidylethanolamine (PE) species that carry long polyunsaturated fatty acids (PUFAs). In 5xFAD mice, administration of OHDHA induced lipid modifications that were paralleled with a reduction in amyloid-β (Αβ) accumulation and full recovery of cognitive scores. OHDHA administration also reduced Aβ levels in cellular models of AD, in association with alterations in the subcellular distribution of secretases and reduced Aβ-induced tau protein phosphorylation as well. Furthermore, OHDHA enhanced the survival of neuron-like differentiated cells exposed to different insults, such as oligomeric Aβ and NMDA-mediated neurotoxicity. These results were supported by model membrane studies in which incorporation of OHDHA into lipid-raft-like vesicles was shown to reduce the binding affinity of oligomeric and fibrillar Aβ to membranes. Finally, the OHDHA concentrations used here did not produce relevant toxicity in zebrafish embryos in vivo. In conclusion, we demonstrate the pleitropic effects of OHDHA that might prove beneficial to treat AD, which suggests that an upstream event, probably the modulation of the membrane lipid composition and structure, influences cellular homeostasis reversing the neurodegenerative process. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy

Evaluation of the psychometric performance of the Spanish and Catalan versions of the patient reported experiences and Outcomes of Safety in Primary Care (PREOS-PC)-Compact questionnaire

Patients provide a unique, irreplaceable, and essential perspective in evaluating patient safety. The suite of Patient Reported Experiences and Outcomes of Safety in Primary Care (PREOS-PC) tools are a notable exception to the scarcity of patient-reported patient safety measures. Full evaluation of their performance has only been attempted for the English version, thereby limiting its international applicability. To assess the psychometric performance of the Spanish and Catalan versions of the PREOS-PC-Compact. Cross-sectional validation study. We used Classical Test Theory methods to examine scale score distribution, internal consistency, and construct validity; and Item Response Theory (IRT) methods to further explore construct validity. 3287 patients completed the Spanish version, and 1007 the Catalan version. Similar results were obtained for both versions. Confirmatory Factor Analysis supported a single construct for each scale. The correlations between PREOS-PC-Compact scales and known group analysis suggested adequate construct validity (inconclusive for known groups at the provider level). All four multi-item scales demonstrated adequate internal consistency reliability (α > 0.7), which was only confirmed for test-retest reliability for ‘Practice activation.’ A sample between 60–90 patients per practice was estimated sufficient to produce scores with reliability > 0.7 for all scales except for harm scales. IRT models showed disordered thresholds for ‘Practice activation’ and ‘Harm burden’ but showed excellent fit after reducing the response categories. The Spanish and Catalan versions of the PREOS-PC-Compact are broadly valid and reliable tools to measure patient safety in Spanish primary care centres; confirmation of lower-than-expected test-rest reliability merits further examination .</p

Membrane lipid modifications and therapeutic effects mediated by hydroxydocosahexaenoic acid on Alzheimer's disease

AbstractAlzheimer's disease (AD) is a neurodegenerative pathology with relevant unmet therapeutic needs. Both natural aging and AD have been associated with a significant decline in the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), and accordingly, administration of DHA has been proposed as a possible treatment for this pathology. However, recent clinical trials in mild-to-moderately affected patients have been inconclusive regarding the real efficacy of DHA in halting this disease. Here, we show that the novel hydroxyl-derivative of DHA (2-hydroxydocosahexaenoic acid — OHDHA) has a strong therapeutic potential to treat AD. We demonstrate that OHDHA administration increases DHA levels in the brain of a transgenic mouse model of AD (5xFAD), as well as those of phosphatidylethanolamine (PE) species that carry long polyunsaturated fatty acids (PUFAs). In 5xFAD mice, administration of OHDHA induced lipid modifications that were paralleled with a reduction in amyloid-β (Αβ) accumulation and full recovery of cognitive scores. OHDHA administration also reduced Aβ levels in cellular models of AD, in association with alterations in the subcellular distribution of secretases and reduced Aβ-induced tau protein phosphorylation as well. Furthermore, OHDHA enhanced the survival of neuron-like differentiated cells exposed to different insults, such as oligomeric Aβ and NMDA-mediated neurotoxicity. These results were supported by model membrane studies in which incorporation of OHDHA into lipid-raft-like vesicles was shown to reduce the binding affinity of oligomeric and fibrillar Aβ to membranes. Finally, the OHDHA concentrations used here did not produce relevant toxicity in zebrafish embryos in vivo. In conclusion, we demonstrate the pleitropic effects of OHDHA that might prove beneficial to treat AD, which suggests that an upstream event, probably the modulation of the membrane lipid composition and structure, influences cellular homeostasis reversing the neurodegenerative process. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy

Effect of a mobile-based intervention on mental health in frontline healthcare workers against COVID-19: Protocol for a randomized controlled trial.

To evaluate the impact of a psychoeducational, mobile health intervention based on cognitive behavioural therapy and mindfulness-based approaches on the mental health of healthcare workers at the frontline against COVID-19 in Spain. We will carry out a two-week, individually randomized, parallel group, controlled trial. Participants will be individually randomized to receive the PsyCovidApp intervention or control App intervention. The PsyCovidApp intervention will include five modules: emotional skills, lifestyle behaviour, work stress and burnout, social support, and practical tools. Healthcare workers having attended patients with COVID-19 will be randomized to receive the PsyCovidApp intervention (intervention group) or a control App intervention (control group). A total of 440 healthcare workers will be necessary to assure statistical power. Measures will be collected telephonically by a team of psychologists at baseline and immediately after the 2 weeks intervention period. Measures will include stress, depression and anxiety (DASS-21 questionnaire-primary endpoint), insomnia (ISI), burnout (MBI-HSS), post-traumatic stress disorder (DTS), and self-efficacy (GSE). The study was funded in May 2020, and was ethically approved in June 2020. Trial participants, outcome assessors and data analysts will be blinded to group allocation. Despite the increasing use of mobile health interventions to deliver mental health care, this area of research is still on its infancy. This study will help increase the scientific evidence about the effectiveness of this type of intervention on this specific population and context. Despite the lack of solid evidence about their effectiveness, mobile-based health interventions are already being widely implemented because of their low cost and high scalability. The findings from this study will help health services and organizations to make informed decisions in relation to the development and implementation of this type of interventions, allowing them pondering not only their attractive implementability features, but also empirical data about its benefits. NCT04393818 (ClinicalTrials.gov identifier). May 2020

Effect of a mobile‐based intervention on mental health in frontline healthcare workers against COVID‐19: Protocol for a randomized controlled trial

To evaluate the impact of a psychoeducational, mobile health intervention based on cognitive behavioural therapy and mindfulness-based approaches on the mental health of healthcare workers at the frontline against COVID-19 in Spain. We will carry out a two-week, individually randomized, parallel group, controlled trial. Participants will be individually randomized to receive the PsyCovidApp intervention or control App intervention. The PsyCovidApp intervention will include five modules: emotional skills, lifestyle behaviour, work stress and burnout, social support, and practical tools. Healthcare workers having attended patients with COVID-19 will be randomized to receive the PsyCovidApp intervention (intervention group) or a control App intervention (control group). A total of 440 healthcare workers will be necessary to assure statistical power. Measures will be collected telephonically by a team of psychologists at baseline and immediately after the 2 weeks intervention period. Measures will include stress, depression and anxiety (DASS-21 questionnaire-primary endpoint), insomnia (ISI), burnout (MBI-HSS), post-traumatic stress disorder (DTS), and self-efficacy (GSE). The study was funded in May 2020, and was ethically approved in June 2020. Trial participants, outcome assessors and data analysts will be blinded to group allocation. Despite the increasing use of mobile health interventions to deliver mental health care, this area of research is still on its infancy. This study will help increase the scientific evidence about the effectiveness of this type of intervention on this specific population and context. Despite the lack of solid evidence about their effectiveness, mobile-based health interventions are already being widely implemented because of their low cost and high scalability. The findings from this study will help health services and organizations to make informed decisions in relation to the development and implementation of this type of interventions, allowing them pondering not only their attractive implementability features, but also empirical data about its benefits. NCT04393818 (ClinicalTrials.gov identifier). May 2020

2-hydroxy arachidonic acid: a new non-steroidal anti-inflammatory drug.

BackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) are a family of COX1 and COX2 inhibitors used to reduce the synthesis of pro-inflammatory mediators. In addition, inflammation often leads to a harmful generation of nitric oxide. Efforts are being done in discovering safer NSAIDs molecules capable of inhibiting the synthesis of pro-inflammatory lipid mediators and nitric oxide to reduce the side effects associated with long term therapies.Methodology/principal findingsThe analogue of arachidonic acid (AA), 2-hydroxy-arachidonic acid (2OAA), was designed to inhibit the activities of COX1 and COX2 and it was predicted to have similar binding energies as AA for the catalytic sites of COX1 and COX2. The interaction of AA and 2OAA with COX1 and COX2 was investigated calculating the free energy of binding and the Fukui function. Toxicity was determined in mouse microglial BV-2 cells. COX1 and COX2 (PGH2 production) activities were measured in vitro. COX1 and COX2 expression in human macrophage-like U937 cells were carried out by Western blot, immunocytochemistry and RT-PCR analysis. NO production (Griess method) and iNOS (Western blot) were determined in mouse microglial BV-2 cells. The comparative efficacy of 2OAA, ibuprofen and cortisone in lowering TNF-α serum levels was determined in C57BL6/J mice challenged with LPS. We show that the presence of the -OH group reduces the likelihood of 2OAA being subjected to H* abstraction in COX, without altering significantly the free energy of binding. The 2OAA inhibited COX1 and COX2 activities and the expression of COX2 in human U937 derived macrophages challenged with LPS. In addition, 2OAA inhibited iNOS expression and the production of NO in BV-2 microglial cells. Finally, oral administration of 2OAA decreased the plasma TNF-α levels in vivo.Conclusion/significanceThese findings demonstrate the potential of 2OAA as a NSAID

Changes in Membrane Organization upon Spontaneous Insertion of 2-Hydroxylated Unsaturated Fatty Acids in the Lipid Bilayer

Recent research regarding 2-hydroxylated fatty acids (2OHFAs) showed clear evidence of their benefits in the treatment of cancer, inflammation, and neurodegenerative disorders such as Alzheimer’s disease. Monolayer compressibility isotherms and isothermal titration calorimetry of 2OHFA (C18−C22) in phosphatidylcholine/phosphatidylethanolamine/sphingomyelin/cholesterol (1:1:1:1 mole ratio), a mixture that mimics the composition of mammalian plasma membrane, were performed to assess the membrane binding capacity of 2OHFAs and their natural, nonhydroxylated counterparts. The results show that 2OHFAs are surfaceactive substances that bind membranes through exothermic, spontaneous processes. The main effects of 2OHFAs are a decrease in lipid order, with a looser packing of the acyl chains, and a decreased dipole potential, regardless of the 2OHFAs’ relative affinity for the lipid bilayer. The strongest effects are usually observed for 2-hydroxyarachidonic (C20:4) acid, and the weakest one, for 2-hydroxydocosahexaenoic acid (C22:6). In addition, 2OHFAs cause increased hydration, except in gel-phase membranes, which can be explained by the 2OHFA preference for membrane defects. Concerning the membrane dipole potential, the magnitude of the reduction induced by 2OHFAs was particularly marked in the liquid-ordered (lo) phase (cholesterol/sphingomyelin-rich) membranes, those where order reduction was the smallest, suggesting a disruption of cholesterol−sphingolipid interactions that are responsible for the large dipole potential in those membranes. Moreover, 2OHFA effects were larger than for both lo and ld phases separately in model membranes with liquid disordered (ld)/lo coexistence when both phases were present in significant amounts, possibly because of the facilitating effect of ld/lo domain interfaces. The specific and marked changes induced by 2OHFAs in several membrane properties suggest that the initial interaction with the membrane and subsequent reorganization might constitute an important step in their mechanisms of action.Ministerio de Economía y Competitividad (Torres-Quevedo Research Contracts, PTQ-10-04214 and PTQ-09-02-02113). Fundación Marathon Grants to Research Groups of Excellence from Govern de les Illes Balears Basque Government (IT849-13) Spanish Ministerio de Ciencia e Innovación (BFU2012-36241, BIO2010-21132) Portuguese national funds and Fundo Social Europeu through FCT, the Portuguese Foundation for Science and Technology, by “Ciência 2007”and “Investigador FCT 2012” Initiatives (POPH), and by grant PEst-OE/QUI/UI0612/2011-2013. Fundação Amadeu Dias/Universidade de Lisboa