Liraglutide restores chronic ER stress, autophagy impairments and apoptotic signalling in SH-SY5Y cells

Growing evidence suggests that agonists of glucagon-like peptide (GLP-1) receptor exert neuroprotective and neurorestorative effects across a range of experimental models of neuronal degeneration, and, recently, a pilot clinical trial of Liraglutide in Alzheimer's disease patients showed improvements in cerebral glucose consumption that signifies disease progression. However, the exact underlying mechanism of action remains unclear. Chronic endoplasmic reticulum (ER) stress has recently emerged as a mechanism for neuronal injury, rendering it a potent therapeutic target for acute and chronic neurodegenerative disorders. Here, we investigate the neuroprotective effects of Liraglutide along with the signalling network against prolong ER stress and autophagy impairments induced by the non-competitive inhibitor of sarco/ER Ca2+-ATPase, thapsigargin. We show that Liraglutide modulates the ER stress response and elicits ER proteostasis and autophagy machinery homeostasis in human SH-SY5Y neuroblastoma cell line. These effects correlate with resolution of hyper-activity of the antioxidant Nrf2 factor and restoration of the impaired cell viability and proliferation. Mechanistically, Liraglutide engages Akt and signal transducer and activator of transcription 3 (STAT3) signalling to favour adaptive responses and shift cell fate from apoptosis to survival under chronic stress conditions in SH-SY5Y cells

Priming stress patterns in word recognition

This study addresses the lexical representation of stress in a series of five intra-modal and cross-modal priming experiments in the Greek language using lexical decision tasks with auditory and visual targets. Three-syllable primes and targets were matched in first syllable segments, length, and other variables, and differed segmentally in the second and third syllable. Primes matched or mismatched targets in stress, which was placed on the penultimate or antepenultimate syllable. There was no evidence for stress priming in either accuracy or latency of responses to either words or pseudowords in any of these experiments, either intra-modally or cross-modally. In contrast, a control fragment priming experiment using only the first two syllables of the primes produced a significant effect of stress congruence for words but not for pseudowords. The results are interpreted in the context of previous findings in the literature as arising from lexical activation rather than from matching stress patterns. Overall, findings are consistent with lexical representations including stress information that is inseparable from segmental specification, rather than with abstract representations of metrical templates

Role of the cystathionine beta-synthase / H2S pathway in the development of cellular metabolic dysfunction and pseudohypoxia in down syndrome

Background: Overexpression of the transsulfuration enzyme cystathionine-beta-synthase (CBS), and overproduction of its product, hydrogen sulfide (H2S) are recognized as potential pathogenetic factors in Down syndrome (DS). The purpose of the study was to determine how the mitochondrial function and core metabolic pathways are affected by DS and how pharmacological inhibition of CBS affects these parameters. Methods: 8 human control and 8 human DS fibroblast cell lines have been subjected to bioenergetic and fluxomic and proteomic analysis with and without treatment with a pharmacological inhibitor of CBS. Results: DS cells exhibited a significantly higher CBS expression than control cells, and produced more H2S. They also exhibited suppressed mitochondrial electron transport and oxygen consumption and suppressed Complex IV activity, impaired cell proliferation and increased ROS generation. Inhibition of H2S biosynthesis with aminooxyacetic acid reduced cellular H2S, improved cellular bioenergetics, attenuated ROS and improved proliferation. C-13 glucose fluxomic analysis revealed that DS cells exhibit a suppression of the Krebs cycle activity with a compensatory increase in glycolysis. CBS inhibition restored the flux from glycolysis to the Krebs cycle and reactivated oxidative phosphorylation. Proteomic analysis revealed no CBS-dependent alterations in the expression level of the enzymes involved in glycolysis, oxidative phosphorylation and the pentose phosphate pathway. DS was associated with the dysregulation of several components of the autophagy network; CBS inhibition normalized several of these parameters. Conclusions: Increased H2S generation in DS promotes pseudohypoxia and contributes to cellular metabolic dysfunction by causing a shift from oxidative phosphorylation to glycolysis.Peer reviewe

Spatiotemporal quantitative microRNA-155 imaging reports immune-mediated changes in a triple-negative breast cancer model

IntroductionMicroRNAs are small non-coding RNAs and represent key players in physiology and disease. Aberrant microRNA expression is central to the development and progression of cancer, with various microRNAs proposed as potential cancer biomarkers and drug targets. There is a need to better understand dynamic microRNA expression changes as cancers progress and their tumor microenvironments evolve. Therefore, spatiotemporal and non-invasive in vivo microRNA quantification in tumor models would be highly beneficial.MethodsWe developed an in vivo microRNA detector platform in which the obtained signals are positively correlated to microRNA presence, and which permitted stable expression in cancer cells as needed for long-term experimentation in tumor biology. It exploits a radionuclide-fluorescence dual-reporter for quantitative in vivo imaging of a microRNA of choice by radionuclide tomography and fluorescence-based downstream ex vivo tissue analyses. We generated and characterized breast cancer cells stably expressing various microRNA detectors and validated them in vitro.ResultsWe found the microRNA detector platform to report on microRNA presence in cells specifically and accurately, which was independently confirmed by real-time PCR and through microRNA modulation. Moreover, we established various breast tumor models in animals with different levels of residual immune systems and observed microRNA detector read-outs by imaging. Applying the detector platform to the progression of a triple-negative breast cancer model, we found that miR-155 upregulation in corresponding tumors was dependent on macrophage presence in tumors, revealing immune-mediated phenotypic changes in these tumors as they progressed.ConclusionWhile applied to immunooncology in this work, this multimodal in vivo microRNA detector platform will be useful whenever non-invasive quantification of spatiotemporal microRNA changes in living animals is of interest

Self-report measures assessing aspects of personal recovery in relatives and other informal carers of those with psychosis:a systematic review

Background: Providing long-term care for a family member with psychosis can cause significant distress for informal carers due to the trauma of seeing their loved one in crisis, dealing with the difficult symptoms of psychosis and the burden of providing care. An important aspect of carers’ adjustment can be construed as their personal recovery in relation to having a relative affected by psychosis. Self-report measures are increasingly used to assess personal recovery in service users, but less is known about the utility of such tools for carers. Aims: This review aimed to identify all self-report measures assessing aspects of carers’ personal recovery, and to quality appraise them. Methods: Academic Search Ultimate, CINAHL, MEDLINE, PsychINFO and PubMed were searched for articles that reported the development of self-report measures created for carers of those with psychosis. Studies were appraised using the COnsensus-based Standards for the Selection of health status Measurement INstruments (COSMIN) checklist. A Levels of Evidence synthesis provided overall quality scores for each measure. Results: The search identified 3,154 articles for initial screening. From a total of 322 full text articles, 95 self-report measures were identified with a final 10 measures included for the quality assessment showing varying levels of psychometric rigor. Conclusions: The results show that no single self-report measure is currently available for use to comprehensively assess personal recovery for carers, highlighting the need for further research in this area and the development of a new measure

Overproduction of H2S, generated by CBS, inhibits mitochondrial Complex IV and suppresses oxidative phosphorylation in Down syndrome

Down syndrome (DS) is associated with significant perturbances in mitochondrial function. Here we tested the hypothesis that the suppression of mitochondrial electron transport in DS cells is due to high expression of cystathionine-β-synthase (CBS) and subsequent overproduction of the gaseous transmitter hydrogen sulfide (H2S). Fibroblasts from DS individuals showed higher CBS expression than control cells; CBS localization was both cytosolic and mitochondrial. DS cells produced significantly more H2S and polysulfide and exhibited a profound suppression of mitochondrial electron transport, oxygen consumption, and ATP generation. DS cells also exhibited slower proliferation rates. In DS cells, pharmacological inhibition of CBS activity with aminooxyacetate or siRNA-mediated silencing of CBS normalized cellular H2S levels, restored Complex IV activity, improved mitochondrial electron transport and ATP synthesis, and restored cell proliferation. Thus, CBS-derived H2S is responsible for the suppression of mitochondrial function in DS cells. When H2S overproduction is corrected, the tonic suppression of Complex IV is lifted, and mitochondrial electron transport is restored. CBS inhibition offers a potential approach for the pharmacological correction of DS-associated mitochondrial dysfunction

Mental health, deprivation, and the neighbourhood social environment: a network analysis

Different aspects of the neighbourhood social environment have been linked with mental ill-health, however the mechanisms underlying these associations remain poorly understood because of the number and complexity of the components involved. We used a novel statistical approach, network analysis, to explore the complex associations between neighbourhood social cohesion, social disorder and mental health symptoms in a sample of 3,670 adults from an economically deprived region of the UK (mean age [SD] = 49.34 years [18.87]; 57% female). Elasso regularised networks were estimated, and network comparisons were conducted by level of deprivation. Mental health symptoms and neighbourhood components formed relatively distinct clusters of items. These domains were linked primarily by paranoia, although only in the most deprived group. Drunken/rowdy behaviour was particularly influential within the neighbourhood cluster, therefore policies aimed at reducing such disruptive behaviour could have positive knock-on effects for social cohesion and mental health

Health and social care: Is integration of care to meet growing demands effective?

Integration of care has been suggested as a solution to overcome the increasing financial and service pressures on the healthcare system. The aim of this second part of a two-part commentary is to critically evaluate a systematic review that investigated the national and international evidence base in relation to outcomes of integrated care on actual and perceived service delivery, and to identify implication for practice, policy and future research based on the quality of evidence

A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder:the REACT RCT

BACKGROUND: Relatives caring for people with severe mental health problems find information and emotional support hard to access. Online support for self-management offers a potential solution. OBJECTIVE: The objective was to determine the clinical effectiveness and cost-effectiveness of an online supported self-management tool for relatives: the Relatives' Education And Coping Toolkit (REACT). DESIGN AND SETTING: This was a primarily online (UK), single-blind, randomised controlled trial, comparing REACT plus a resource directory and treatment as usual with the resource directory and treatment as usual only, by measuring user distress and other well-being measures at baseline and at 12 and 24 weeks. PARTICIPANTS: A total of 800 relatives of people with severe mental health problems across the UK took part; relatives who were aged ≥ 16 years, were experiencing high levels of distress, had access to the internet and were actively seeking help were recruited. INTERVENTION: REACT comprised 12 psychoeducation modules, peer support through a group forum, confidential messaging and a comprehensive resource directory of national support. Trained relatives moderated the forum and responded to messages. MAIN OUTCOME MEASURE: The main outcome was the level of participants' distress, as measured by the General Health Questionnaire-28 items. RESULTS: Various online and offline strategies, including social media, directed potential participants to the website. Participants were randomised to one of two arms: REACT plus the resource directory (n = 399) or the resource directory only (n = 401). Retention at 24 weeks was 75% (REACT arm, n = 292; resource directory-only arm, n = 307). The mean scores for the General Health Questionnaire-28 items reduced substantially across both arms over 24 weeks, from 40.2 (standard deviation 14.3) to 30.5 (standard deviation 15.6), with no significant difference between arms (mean difference -1.39, 95% confidence interval -3.60 to 0.83; p = 0.22). At 12 weeks, the General Health Questionnaire-28 items scores were lower in the REACT arm than in the resource directory-only arm (-2.08, 95% confidence interval -4.14 to -0.03; p = 0.027), but this finding is likely to be of limited clinical significance. Accounting for missing data, which were associated with higher distress in the REACT arm (0.33, 95% confidence interval -0.27 to 0.93; p = 0.279), in a longitudinal model, there was no significant difference between arms over 24 weeks (-0.56, 95% confidence interval -2.34 to 1.22; p = 0.51). REACT cost £142.95 per participant to design and deliver (£62.27 for delivery only), compared with £0.84 for the resource directory only. A health economic analysis of NHS, health and Personal Social Services outcomes found that REACT has higher costs (£286.77), slightly better General Health Questionnaire-28 items scores (incremental General Health Questionnaire-28 items score adjusted for baseline, age and gender: -1.152, 95% confidence interval -3.370 to 1.065) and slightly lower quality-adjusted life-year gains than the resource directory only; none of these differences was statistically significant. The median time spent online was 50.8 minutes (interquartile range 12.4-172.1 minutes) for REACT, with no significant association with outcome. Participants reported finding REACT a safe, confidential environment (96%) and reported feeling supported by the forum (89%) and the REACT supporters (86%). No serious adverse events were reported. LIMITATIONS: The sample comprised predominantly white British females, 25% of participants were lost to follow-up and dropout in the REACT arm was not random. CONCLUSIONS: An online self-management support toolkit with a moderated group forum is acceptable to relatives and, compared with face-to-face programmes, offers inexpensive, safe delivery of National Institute for Health and Care Excellence-recommended support to engage relatives as peers in care delivery. However, currently, REACT plus the resource directory is no more effective at reducing relatives' distress than the resource directory only. FUTURE WORK: Further research in improving the effectiveness of online carer support interventions is required. TRIAL REGISTRATION: Current Controlled Trials ISRCTN72019945. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 32. See the NIHR Journals Library website for further project information. Relatives of people with severe mental health problems need better access to information and emotional support. The Relatives’ Education And Coping Toolkit (REACT) is a website designed to do this. It includes lots of information presented in text and video, an online forum for relatives to share knowledge and experience, a messaging system where they can ask questions in confidence and a comprehensive directory of contact details for national organisations offering relevant support. Trained relatives support the forum and messaging. In the UK, we recruited 800 relatives of people with severe mental health problems: all were aged ≥ 16 years, had high levels of distress, had access to the internet and wanted help. We divided them into two equal groups: one group received REACT (including the resource directory), whereas the other group received the resource directory only. To ensure that there were no differences between groups at the start, relatives were allocated to the two groups randomly, so they had an equal chance of being in either group. We followed up with both groups at 12 and 24 weeks, and received data from approximately three-quarters of the participants. This trial found that REACT was acceptable, safe and inexpensive to deliver (£62.27 per relative), compared with face-to-face interventions, and that relatives using it felt well supported. However, once we accounted for missing data (relatives who dropped out of the trial or did not complete the follow-up questionnaires), there were no significant differences between the groups. There was no evidence that REACT increased relatives’ quality of life or saved money for the NHS

Down syndrome is an oxidative phosphorylation disorder

Down syndrome is the most common genomic disorder of intellectual disability and is caused by trisomy of chromosome 21. Several genes in this chromosome repress mitochondrial biogenesis. The goal of this study was to evaluate whether early overexpression of these genes may cause a prenatal impairment of oxidative phosphorylation negatively affecting neurogenesis. Reduction in the mitochondrial energy production and a lower mitochondrial function have been reported in diverse tissues or cell types, and also at any age, including early fetuses, suggesting that a defect in oxidative phosphorylation is an early and general event in Down syndrome individuals. Moreover, many of the medical conditions associated with Down syndrome are also frequently found in patients with oxidative phosphorylation disease. Several drugs that enhance mitochondrial biogenesis are nowadays available and some of them have been already tested in mouse models of Down syndrome restoring neurogenesis and cognitive defects. Because neurogenesis relies on a correct mitochondrial function and critical periods of brain development occur mainly in the prenatal and early neonatal stages, therapeutic approaches intended to improve oxidative phosphorylation should be provided in these periods.Funding sources: This work was supported by grants from Instituto de Salud Carlos III [FIS-PI17/00021, FIS-PI17/00166]; Fundación Mutua Madrileña [MMA17/01]; Precipita-FECYT crowdfunding program [PR194]; Gobierno de Aragón [LMP135_18, Grupos Consolidados B33_17R] and FEDER 2014–2020 “Construyendo Europa desde Aragón”. CIBERER is an initiative of the ISCIII