1,720,979 research outputs found
Lipid metabolism, remodelling and intercellular transfer in the CNS
No full textLipid metabolism encompasses the catabolism and anabolism of lipids, and is fundamental for the maintenance of cellular homeostasis, particularly within the lipid-rich CNS. Increasing evidence further underscores the importance of lipid remodelling and transfer within and between glial cells and neurons as key orchestrators of CNS lipid homeostasis. In this Review, we summarize and discuss the complex landscape of processes involved in lipid metabolism, remodelling and intercellular transfer in the CNS. Highlighted are key pathways, including those mediating lipid (and lipid droplet) biogenesis and breakdown, lipid oxidation and phospholipid metabolism, as well as cell-cell lipid transfer mediated via lipoproteins, extracellular vesicles and tunnelling nanotubes. We further explore how the dysregulation of these pathways contributes to the onset and progression of neurodegenerative diseases, and examine the homeostatic and pathogenic impacts of environment, diet and lifestyle on CNS lipid metabolism.The authors thank all members of the Bogie, Hendriks and Miron laboratories for the discussions. The research of S.V. is funded by the FWO Vlaanderen (1246724N) and Charcot Research Foundation (CHARCO24VS). V.E.M is funded by the John David Eaton Chair in Multiple Sclerosis Research (Barlo MS Centre, St. Michael’s Hospital Foundation), the Sloan-Hall MS Basic Research Fund, MS Canada and a Senior Non-Clinical Research Fellowship from the Medical Research Council. J.J.A.H is funded by the Research Foundation of Flanders (FWO Vlaanderen; G0A7922, G0A7922, S01623N) and the Charcot Research Foundation (CHARCO23HJ, CHARCO24HJ). J.F.J.B is funded by the Research Foundation of Flanders (FWO Vlaanderen; G075823, G0A3B24), Charcot Research Foundation (CHARCO23BJ, CHARCO24BJ), Geneeskundige Stichting Koningin Elisabeth (G.S.K.E; GSKE-BOGJ), MS Liga Vlaanderen (MSLIGABOGJ) and the special research fund Hasselt University (22DOC38BOF, 23INC06BOF)
Protein Lipidation by Palmitate Controls Macrophage Function
No full textMacrophages are present in all tissues within our body, where they promote tissue homeostasis by responding to microenvironmental triggers, not only through clearance of pathogens and apoptotic cells but also via trophic, regulatory, and repair functions. To accomplish these divergent functions, tremendous dynamic fine-tuning of their physiology is needed. Emerging evidence indicates that S-palmitoylation, a reversible post-translational modification that involves the linkage of the saturated fatty acid palmitate to protein cysteine residues, directs many aspects of macrophage physiology in health and disease. By controlling protein activity, stability, trafficking, and protein–protein interactions, studies identified a key role of S-palmitoylation in endocytosis, inflammatory signaling, chemotaxis, and lysosomal function. Here, we provide an in-depth overview of the impact of S-palmitoylation on these cellular processes in macrophages in health and disease. Findings discussed in this review highlight the therapeutic potential of modulators of S-palmitoylation in immunopathologies, ranging from infectious and chronic inflammatory disorders to metabolic conditions
Phloretin enhances remyelination by stimulating OPC differentiation
No full textthe number of activated and quiescent NSCs, indicating that ET-1 signaling is required for maintenance of NSCs in the healthy adult mouse. Following focal demyelination of the corpus callosum, SVZ NSCs upregulated expression of ET-1. Ablation of ET-1 reduced the percentages of proliferating NSCs and proliferating OPCs in the SVZ, suggesting that ET-1 plays a critical role in the SVZ proliferative response to injury. RNAseq of cultured primary NSCs and OPCs treated with ET-1 identified genes involved in stem cell maintenance, including Notch signaling, and OPC migration. Lastly, we confirmed that ET-1 and EDNRB expression are conserved in the adult human SVZ, indicating that this pathway may be a potential target for promoting SVZ-mediated cellular repair. Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Why endogenous repair mechanisms frequency fail in these disorders is poorly understood, however, there is now strong evidence that this is related to an overly inflammatory microenvironment combined with the intrinsic inability of oligodendrocyte precursor cells (OPCs) to differentiate into mature myelinating cells. Previously, we found that phloretin, a flavonoid abundantly present in apples and strawberries reduces neuroinflammation by driving macrophages towards an anti-inflammatory phenotype. Here, we show that phloretin also markedly stimulates remyelination in ex vivo and in vivo animals models. However, improved remyelination was attributed to a direct impact of phloretin on OPC maturation and occurred autonomously from alterations in microglia function and inflammation. Mechanistically, phloretin activated the fatty acid sensing nuclear receptor peroxisome proliferator-activated receptor gamma PPARy, thereby promoting the maturation of OPC. Altogether, our findings indicate that phloretin has pro-regenerative properties in CNS disorders, with potentially broad implications for the development of therapeutic strategies and dietary interventions
Targeting lipophagy in macrophages improves repair in multiple sclerosis
No full textFoamy macrophages containing abundant intracellular myelin remnants are an important pathological hallmark of multiple sclerosis. Reducing the intracellular lipid burden in foamy macrophages is considered a promising therapeutic strategy to induce a phagocyte phenotype that promotes central nervous system repair. Recent research from our group showed that sustained intracellular accumulation of myelin-derived lipids skews these phagocytes toward a disease-promoting and more inflammatory phenotype. Our data now demonstrate that disturbed lipophagy, a selective form of autophagy that helps with the degradation of lipid droplets, contributes to the induction of this phenotype. Stimulating autophagy using the natural disaccharide trehalose reduced the lipid load and inflammatory phenotype of myelin-laden macrophages. Importantly, trehalose was able to boost remyelination in the ex vivo brain slice model and the in vivo cuprizone-induced demyelination model. In summary, our results provide a molecular rationale for impaired metabolism of myelin-derived lipids in macrophages, and identify lipophagy induction as a promising treatment strategy to promote remyelination.The work has been supported by the Flemish Fund for ScientificResearch (FWO Vlaanderen; 1141920N, 12U7718N and 1502120N), theBelgian Charcot Foundation (Fondation Charcot 2020-0004), and thespecial research fund UHasselt (BOF
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Stearoyl-CoA desaturase-1: a potential therapeutic target for neurological disorders
No full textDisturbances in the fatty acid lipidome are increasingly recognized as key drivers in the progression of various brain disorders. In this review article, we delve into the impact of Δ9 fatty acid desaturases, with a particular focus on stearoyl-CoA desaturase-1 (SCD1), within the setting of neuroinflammation, neurodegeneration, and brain repair. Over the past years, it was established that inhibition or deficiency of SCD1 not only suppresses neuroinflammation but also protects against neurodegeneration in conditions such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. This protective effect is achieved through different mechanisms including enhanced remyelination, reversal of synaptic and cognitive impairments, and mitigation of α-synuclein toxicity. Intriguingly, metabolic rerouting of fatty acids via SCD1 improves the pathology associated with X-linked adrenoleukodystrophy, suggesting context-dependent benign and harmful effects of SCD1 inhibition in the brain. Here, we summarize and discuss the cellular and molecular mechanisms underlying both the beneficial and detrimental effects of SCD1 in these neurological disorders. We explore commonalities and distinctions, shedding light on potential therapeutic challenges. Additionally, we touch upon future research directions that promise to deepen our understanding of SCD1 biology in brain disorders and potentially enhance the clinical utility of SCD1 inhibitors.This work was funded by the Flemish Fund for Scientific Research (FWO Vlaanderen), the Belgian Charcot Foundation, GSK Funding, the special research fund UHasselt (BOF), and the Transnational University Limburg (TUL)
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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