New insights on neurodegeneration triggered by iron accumulation: Intersections with neutral lipid metabolism, ferroptosis, and motor impairment.

Brain iron accumulation constitutes a pathognomonic indicator in several neurodegenerative disorders. Metal accumulation associated with dopaminergic neuronal death has been documented in Parkinson's disease. Through the use of in vivo and in vitro models, we demonstrated that lipid dysregulation manifests as a neuronal and glial response during iron overload. In this study, we show that cholesterol content and triacylglycerol (TAG) hydrolysis were strongly elevated in mice midbrain. Lipid cacostasis was concomitant with the loss of dopaminergic neurons, astrogliosis and elevated expression of α-synuclein. Exacerbated lipid peroxidation and markers of ferroptosis were evident in the midbrain from mice challenged with iron overload. An imbalance in the activity of lipolytic and acylation enzymes was identified, favoring neutral lipid hydrolysis, and consequently reducing TAG and cholesteryl ester levels. Notably, these observed alterations were accompanied by motor impairment in iron-treated mice. In addition, neuronal and glial cultures along with their secretomes were used to gain further insight into the mechanism underlying TAG hydrolysis and cholesterol accumulation as cellular responses to iron accumulation. We demonstrated that TAG hydrolysis in neurons is triggered by astrocyte secretomes. Moreover, we found that the ferroptosis inhibitor, ferrostatin-1, effectively prevents cholesterol accumulation both in neurons and astrocytes. Taken together, these results indicate that lipid disturbances occur in iron-overloaded mice as a consequence of iron-induced oxidative stress and depend on neuron-glia crosstalk. Our findings suggest that developing therapies aimed at restoring lipid homeostasis may lead to specific treatment for neurodegeneration associated with ferroptosis and brain iron accumulation.

Can Communication Technologies Reduce Loneliness and Social Isolation in Older People? A Scoping Review of Reviews.

BACKGROUND: Loneliness and social isolation in older age are considered major public health concerns and research on technology-based solutions is growing rapidly. This scoping review of reviews aims to summarize the communication technologies (CTs) (review question RQ1), theoretical frameworks (RQ2), study designs (RQ3), and positive effects of technology use (RQ4) present in the research field. METHODS: A comprehensive multi-disciplinary, multi-database literature search was conducted. Identified reviews were analyzed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework. A total of N = 28 research reviews that cover 248 primary studies spanning 50 years were included. RESULTS: The majority of the included reviews addressed general internet and computer use (82% each) (RQ1). Of the 28 reviews, only one (4%) worked with a theoretical framework (RQ2) and 26 (93%) covered primary studies with quantitative-experimental designs (RQ3). The positive effects of technology use were shown in 55% of the outcome measures for loneliness and 44% of the outcome measures for social isolation (RQ4). CONCLUSION: While research reviews show that CTs can reduce loneliness and social isolation in older people, causal evidence is limited and insights on innovative technologies such as augmented reality systems are scarce.

[Sexual health information on social media: a systematic scoping review]. / Sexuelle Gesundheitsinformationen in sozialen Medien: Ein systematisches Scoping Review.

BACKGROUND: Information on sexual and reproductive health is increasingly disseminated via social media and reaches a large audience. RESEARCH AIM: Against this background, the aim of this paper is to systematically summarize the international state of research on sexual health information on social media for the first time with a scoping review. Seven research questions were explored, relating to the amount (F1), methods (F2: content analysis, F3: quality analysis), and results (F4: providers, F5: target groups, F6: topics, F7: quality of information) of previous studies. MATERIALS AND METHODS: The study follows the PRISMA framework for scoping reviews as well as the Open Science approach. It is preregistered, and all materials (codebook with reliability coefficients) and data (list of identified studies and coding of studies) are available on the Open Science Foundation server. RESULTS: A total of 69 studies with 72 data sets were identified, with more than half of the publications referring to YouTube (F1). Qualitative and quantitative methods of content analysis are used equally (F2) and quality analyses are rare (F3). Health laypersons dominate as the information providers (F4). The target groups are mostly unspecified (F5). The health information on social media examined in the previous studies covers a broad range of topics (F6). Where quality assessments were made, they tended to be negative (F7). DISCUSSION: More research is needed to better understand sexual and reproductive health information on social media and to promote its quality and constructive use.

Novel antiadipogenic effect of menadione in 3T3-L1 cells.

Inhibition of adipocyte differentiation can be used as a strategy for preventing adipose tissue expansion and, consequently, for obesity management. Since reactive oxygen species (ROS) have emerged as key modulators of adipogenesis, the effect of menadione (a synthetic form of vitamin K known to induce the increase of intracellular ROS) on 3T3-L1 preadipocyte differentiation was studied. Menadione (15 µM) increased ROS and lipid peroxidation, generating mild oxidative stress without affecting cell viability. Menadione drastically inhibited adipogenesis, accompanied by decreased intracellular lipid accumulation and diminished expression of the lipo/adipogenic markers peroxisome proliferator-activated receptor (PPAR)γ, fatty acid synthase (FAS), CCAAT/enhancer-binding protein (C/EBP) α, fatty acid binding protein (FABP) 4, and perilipin. Menadione treatment also increased lipolysis, as indicated by augmented glycerol release and reinforced by the increased expression of hormone-sensitive lipase (HSL). Additionally, menadione increased the inhibitory phosphorylation of acetyl-CoA-carboxylase (ACC), which results in the inhibition of fatty acid synthesis. As a consequence, triglyceride content was decreased. Menadione also inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Further, treatment with increased concentration of insulin, a potent physiological activator of the PI3K/Akt pathway, rescued the normal level of expression of PPARγ, the master regulator of adipogenesis, and overcame the restraining effect of menadione on the differentiation capacity of 3T3-L1 preadipocytes. Our study reveals novel antiadipogenic action for menadione, which is, at least in part, mediated by the PI3K/Akt pathway signaling and raises its potential as a therapeutic agent in the treatment or prevention of adiposity.

Neutral lipids as early biomarkers of cellular fate: the case of α-synuclein overexpression.

α-synuclein (α-syn) accumulation and aggregation is a common pathological factor found in synucleinopathies, a group of neurodegenerative disorders that includes Parkinson´s disease (PD). It has been proposed that lipid dyshomeostasis is responsible for the occurrence of PD-related processes, however, the precise role of lipids in the onset and progression of neurodegenerative disorders remains unclear. Our aim was to investigate the effect of α-syn overexpression on neutral lipid metabolism and how this impacts on neuronal fate. We found lipid droplet (LD) accumulation in cells overexpressing α-syn to be associated with a rise in triacylglycerol (TAG) and cholesteryl ester (CE) levels. α-syn overexpression promoted diacylglycerol acyltransferase 2 upregulation and acyl-CoA synthetase activation, triggering TAG buildup, that was accompanied by an increase in diacylglycerol acylation. Moreover, the CE increment was associated with higher activity of acyl-CoA:cholesterol acyltransferase. Interestingly, α-syn overexpression increased cholesterol lysosomal accumulation. We observed that sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 were differentially regulated by α-syn overexpression. The latter gave rise to a reduction in SREBP-1 nuclear translocation and consequently in fatty acid synthase expression, whereas it produced an increase in SREBP-2 nuclear localization. Surprisingly, and despite increased cholesterol levels, SREBP-2 downstream genes related to cholesterolgenesis were not upregulated as expected. Notably, phospholipid (PL) levels were diminished in cells overexpressing α-syn. This decrease was related to the activation of phospholipase A2 (PLA2) with a concomitant imbalance of the PL deacylation-acylation cycle. Fatty acids released from PLs by iPLA2 and cPLA2 action were esterified into TAGs, thus promoting a biological response to α-syn overexpression with uncompromised cell viability. When the described steady-state was disturbed under conditions favoring higher levels of α-syn, the response was an enhanced LD accumulation, this imbalance ultimately leading to neuronal death.

In vitro 6-hydroxydopamine-induced neurotoxicity: New insights on NFκB modulation.

Neuronal exposure to 6-hydroxydopamine (6-OHDA), a hydroxylated analog of dopamine, constitutes a very useful strategy for studying the molecular events associated with neuronal death in Parkinson's disease. 6-OHDA increases oxidant levels and impairs mitochondrial respiratory chain, thus promoting neuronal injury and death. Despite the extensive use of 6-OHDA in animal models, the exact molecular events triggered by this neurotoxicant at the neuronal level have not been yet fully understood. Human IMR-32 neuroblastoma cells exposed to increasing concentrations of 6-OHDA displayed high levels of reactive oxygen species and increased plasma membrane permeability with concomitant cell viability diminution. As part of the neuronal response to 6-OHDA exposure, the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) p65 subunit was observed. NFκB nuclear localization was also accompanied by an increase of IκB phosphorylation as well as a rise in cyclooxygenase-2 (COX-2) and the prostaglandin receptor, EP4, mRNA levels. Even though the canonical pathways participating in the modulation of NFκB have been extensively described, here we tested the hypothesis that 6-OHDA-induced injury can activate lipid signaling and, in turn, modulate the transcriptional response. 6-OHDA challenge triggered the activation of lipid signaling pathways and increased phosphatidic acid (PA), diacylglycerol and free fatty acid levels in human neuroblastoma cells. The inhibition of PA production was able to prevent the decrease in cell viability triggered by 6-OHDA, the nuclear translocation of NFκB p65 subunit and the rise in COX-2 mRNA expression. Our results indicate that the onset of the inflammatory process triggered by 6-OHDA involves the activation of PA signaling that, in turn, governs NFκB subcellular localization and COX-2 expression.

Lipids at the Crossroad of α-Synuclein Function and Dysfunction: Biological and Pathological Implications.

Since its discovery, the study of the biological role of α-synuclein and its pathological implications has been the subject of increasing interest. The propensity to adopt different conformational states governing its aggregation and fibrillation makes this small 14-kDa cytosolic protein one of the main etiologic factors associated with degenerative disorders known as synucleinopathies. The structure, function, and toxicity of α-synuclein and the possibility of different therapeutic approaches to target the protein have been extensively investigated and reviewed. One intriguing characteristic of α-synuclein is the different ways in which it interacts with lipids. Though in-depth studies have been carried out in this field, the information they have produced is puzzling and the precise role of lipids in α-synuclein biology and pathology and vice versa is still largely unknown. Here we provide an overview and discussion of the main findings relating to α-synuclein/lipid interaction and its involvement in the modulation of lipid metabolism and signaling.

Phospholipase D1 downregulation by α-synuclein: Implications for neurodegeneration in Parkinson's disease.

We have previously shown that phospholipase D (PLD) pathways have a role in neuronal degeneration; in particular, we found that PLD activation is associated with synaptic injury induced by oxidative stress. In the present study, we investigated the effect of α-synuclein (α-syn) overexpression on PLD signaling. Wild Type (WT) α-syn was found to trigger the inhibition of PLD1 expression as well as a decrease in ERK1/2 phosphorylation and expression levels. Moreover, ERK1/2 subcellular localization was shown to be modulated by WT α-syn in a PLD1-dependent manner. Indeed, PLD1 inhibition was found to alter the neurofilament network and F-actin distribution regardless of the presence of WT α-syn. In line with this, neuroblastoma cells expressing WT α-syn exhibited a degenerative-like phenotype characterized by a marked reduction in neurofilament light subunit (NFL) expression and the rearrangement of the F-actin organization, compared with either the untransfected or the empty vector-transfected cells. The gain of function of PLD1 through the overexpression of its active form had the effect of restoring NFL expression in WT α-syn neurons. Taken together, our findings reveal an unforeseen role for α-syn in PLD regulation: PLD1 downregulation may constitute an early mechanism in the initial stages of WT α-syn-triggered neurodegeneration.

Phosphoinositides: Two-Path Signaling in Neuronal Response to Oligomeric Amyloid ß Peptide.

We have previously demonstrated that oligomeric amyloid ß peptide (oAß) together with iron overload generates synaptic injury and activation of several signaling cascades. In this work, we characterized hippocampal neuronal response to oAß. HT22 neurons exposed to 500 nM oAß showed neither increased lipid peroxidation nor altered mitochondrial function. In addition, biophysical studies showed that oAß did not perturb the lipid order of the membrane. Interestingly, although no neuronal damage could be demonstrated, oAß was found to trigger bifurcated phosphoinositide-dependent signaling in the neuron, on one hand, the phosphorylation of insulin receptor, the phosphatidylinositol 3-kinase (PI3K)-dependent activation of Akt, its translocation to the nucleus and the concomitant phosphorylation, inactivation, and nuclear exclusion of the transcription factor Forkhead Box O3a (FoxO3a), and on the other, phosphoinositide-phospholipase C (PI-PLC)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Pharmacological manipulation of the signaling cascades was used in order to better characterize the role of oAß-activated signals, and mitochondrial function was determined as a measure of neuronal viability. The inhibition of PI3K, PI-PLC, and general phosphoinositide metabolism impaired neuronal mitochondrial function. Furthermore, increased oAß-induced cell death was observed in the presence of phosphoinositide metabolism inhibition. Our results allow us to conclude that oAß triggers the activation of phosphoinositide-dependent signaling, which results in the subsequent activation of neuroprotective mechanisms that could be involved in the determination of neuronal fate.