Targeting microRNAs as a Therapeutic Strategy to Reduce Oxidative Stress in Diabetes

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia as a consequence of pancreatic β cell loss and/or dysfunction, also caused by oxidative stress. The molecular mechanisms involved inβ cell dysfunction and in response to oxidative stress are also regulated by microRNAs (miRNAs). miRNAs are a class of negative gene regulators, which modulate pathologic mechanisms occurring in diabetes and its complications. Although several pharmacological therapies specifically targeting miRNAs have already been developed and brought to the clinic, most previous miRNA-based drug delivery methods were unable to target a specific miRNA in a single cell type or tissue, leading to important off-target effects. In order to overcome these issues, aptamers and nanoparticles have been described as non-cytotoxic vehicles for miRNA-based drug delivery. These approaches could represent an innovative way to specifically target and modulate miRNAs involved in oxidative stress in diabetes and its complications. Therefore, the aims of this review are: (i) to report the role of miRNAs involved in oxidative stress in diabetes as promising therapeutic targets; (ii) to shed light onto the new delivery strategies developed to modulate the expression of miRNAs in diseases

A programme evaluation of \u27First Steps\u27: A peer-conceived, developed and led self-management intervention for people after a Parkinson\u27s diagnosis

\ua9 The Author(s) 2023. Objective: A diagnosis of Parkinson\u27s often leads to uncertainty about the future and loss of perceived control. Peer support may offer a means to address these concerns and promote self-management. Design: A programme evaluation of the feasibility and potential effects of ‘First Steps’, utilising a pragmatic step wedge approach. Comparing First Steps (intervention) to (control) conditions. Setting: In the community at four sites in southern England. Participants: Newly diagnosed (≤ 12months) people with Parkinson\u27s. Intervention: First Steps was a 2-day peer-conceived, developed and led intervention to support self-management. Main measures: At 0, 12 and 24 weeks anxiety and depression (Hospital, Anxiety and Depression Scale, HADS), daily functioning (World Health Organisation Disability Assessment Schedule, WHODAS), physical activity, quality of life (EQ5D), carer strain and service utilisation were assessed. Results: Between February 2018 and July 2019, 36 participants were enrolled into intervention and 21 to control conditions, all were included in statistical analysis. Lost to follow up was n = 1 (intervention) and n = 1 adverse event was reported (control, unrelated). Of the 36 allocated to the intervention n = 22 participants completed both days of First Steps during the study period. Completion of outcome measures was >95% at 24 weeks. Small effects favouring the intervention were found for HADS (odds ratio (OR) = 2.06, 95% confidence interval (CI) 0.24:17.84), Carer Strain Index (OR = 2.22, 95% CI 0.5:9.76) and vigorous (d = 0.42, 95% CI −0.12:0.97) and total physical activity (d = 0.41, 95% CI −0.13:0.95). EQ5D, WHOSDAS and service utilisation, was similar between groups. Conclusions: First Steps was feasible and safe and we found potential to benefit physical activity, mental health and carer strain. Further research with longer-term follow up is warranted

Identifying resources used by young people to overcome mental distress in three Latin American cities: a qualitative study

OBJECTIVE: To explore which resources and activities help young people living in deprived urban environments in Latin America to recover from depression and/or anxiety. DESIGN: A multimethod, qualitative study with 18 online focus groups and 12 online structured group conversations embedded into arts workshops. SETTING: This study was conducted in Bogotá (Colombia), Buenos Aires (Argentina) and Lima (Peru). PARTICIPANTS: Adolescents (15–16 years old) and young adults (20–24 years old) with capacity to provide assent/consent and professionals (older than 18 years of age) that had experience of professionally working with young people were willing to share personal experience within a group, and had capacity to provide consent. RESULTS: A total of 185 participants took part in this study: 111 participants (36 adolescents, 35 young adults and 40 professionals) attended the 18 focus groups and 74 young people (29 adolescents and 45 young adults) took part in the 12 arts workshops. Eight categories captured the resources and activities that were reported by young people as helpful to overcome mental distress: (1) personal resources, (2) personal development, (3) spirituality and religion, (4) social resources, (5) social media, (6) community resources, (7) activities (subcategorised into artistic, leisure, sports and outdoor activities) and (8) mental health professionals. Personal and social resources as well as artistic activities and sports were the most common resources identified that help adolescents and young adults to overcome depression and anxiety. CONCLUSION: Despite the different contexts of the three cities, young people appear to use similar resources to overcome mental distress. Policies to improve the mental health of young people in deprived urban settings should address the need of community spaces, where young people can play sports, meet and engage in groups, and support community organisations that can enable and facilitate a range of social activities

Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome

Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model (Scn1a Stop/+) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells

MicroRNA Expression in the Aqueous Humor of Patients with Diabetic Macular Edema.

We identified and compared secreted microRNA (miRNA) expression in aqueous humor (AH) and plasma samples among patients with: type 2 diabetes mellitus (T2D) complicated by non-proliferative diabetic retinopathy (DR) associated with diabetic macular edema (DME) (DME group: 12 patients); T2D patients without DR (D group: 8 patients); and non-diabetic patients (CTR group: 10 patients). Individual patient AH samples from five subjects in each group were profiled on TaqMan Low Density MicroRNA Array Cards. Differentially expressed miRNAs identified from profiling were then validated in single assay for all subjects. The miRNAs validated in AH were then evaluated in single assay in plasma. Gene Ontology (GO) analysis was conducted. From AH profiling, 119 mature miRNAs were detected: 86 in the DME group, 113 in the D group and 107 in the CTR group. miRNA underexpression in the DME group was confirmed in single assay for let-7c-5p, miR-200b-3p, miR-199a-3p and miR-365-3p. Of these four, miR-199a-3p and miR-365-3p were downregulated also in the plasma of the DME group. GO highlighted 54 validated target genes of miR-199a-3p, miR-200b-3p and miR-365-3p potentially implied in DME pathogenesis. Although more studies are needed, miR-200b-3p, let-7c-5p, miR-365-3p and miR-199a-3p represent interesting molecules in the study of DME pathogenesis

Which resources help young people to prevent and overcome mental distress in deprived urban areas in Latin America? A protocol for a prospective cohort study

Introduction: Improving the mental health of young people is a global public health priority. In Latin America, young people living in deprived urban areas face various risk factors for mental distress. However, most either do not develop mental distress in the form of depression and anxiety, or recover within a year without treatment from mental health services. This research programme seeks to identify the personal and social resources that help young people to prevent and recover from mental distress. / Methods and analysis: A cross-sectional study will compare personal and social resources used by 1020 young people (aged 15–16 and 20–24 years) with symptoms of depression and/or anxiety and 1020 without. A longitudinal cohort study will follow-up young people with mental distress after 6 months and 1 year and compare resource use in those who do and do not recover. An experience sampling method study will intensively assess activities, experiences and mental distress in subgroups over short time periods. Finally, we will develop case studies highlighting existing initiatives that effectively support young people to prevent and recover from mental distress. The analysis will assess differences between young people with and without distress at baseline using t-tests and χ2 tests. Within the groups with mental distress, multivariate logistic regression analyses using a random effects model will assess the relationship between predictor variables and recovery. / Ethics and dissemination: Ethics approvals are received from Ethics Committee in Biomedical Research, Faculty of Medicine, University of Buenos Aires; Faculty of Medicine-Research and Ethics Committee of the Pontificia Universidad Javeriana, Bogotá; Institutional Ethics Committee of Research of the Universidad Peruana Cayetano Heredia and Queen Mary Ethics of Research Committee. Dissemination will include arts-based methods and target different audiences such as national stakeholders, researchers from different disciplines and the general public. / Trial registration number: ISRCTN72241383

Elovl5 is required for proper action potential conduction along peripheral myelinated fibers

Elovl5 elongates fatty acids with 18 carbon atoms and in cooperation with other enzymes guarantees the normal levels of very long‐chain fatty acids, which are necessary for a proper membrane structure. Action potential conduction along myelinated axons depends on structural integrity of myelin, which is maintained by a correct amount of fatty acids and a proper interaction between fatty acids and myelin proteins. We hypothesized that in Elovl5 (−/−) mice, the lack of elongation of Elovl5 substrates might cause alterations of myelin structure. The analysis of myelin ultrastructure showed an enlarged periodicity with reduced G‐ratio across all axonal diameters. We hypothesized that the structural alteration of myelin might affect the conduction of action potentials. The sciatic nerve conduction velocity was significantly reduced without change in the amplitude of the nerve compound potential, suggesting a myelin defect without a concomitant axonal degeneration. Since Elovl5 is important in attaining normal amounts of polyunsaturated fatty acids, which are the principal component of myelin, we performed a lipidomic analysis of peripheral nerves of Elovl5‐deficient mice. The results revealed an unbalance, with reduction of fatty acids longer than 18 carbon atoms relative to shorter ones. In addition, the ratio of saturated to unsaturated fatty acids was strongly increased. These findings point out the essential role of Elovl5 in the peripheral nervous system in supporting the normal structure of myelin, which is the key element for a proper conduction of electrical signals along myelinated nerves

Advances in multispectral and hyperspectral imaging for archaeology and art conservation

Multispectral imaging has been applied to the field of art conservation and art history since the early 1990s. It is attractive as a noninvasive imaging technique because it is fast and hence capable of imaging large areas of an object giving both spatial and spectral information. This paper gives an overview of the different instrumental designs, image processing techniques and various applications of multispectral and hyperspectral imaging to art conservation, art history and archaeology. Recent advances in the development of remote and versatile multispectral and hyperspectral imaging as well as techniques in pigment identification will be presented. Future prospects including combination of spectral imaging with other noninvasive imaging and analytical techniques will be discussed