Resveratrol (RSV) is a small compound first identified as an activator of sirtuin 1 (SIRT1), a key factor in mediating the effects of caloric restriction. Since then, RSV received great attention for its widespread beneficial effects on health and in connection to many diseases. RSV improves the metabolism and the mitochondrial function, and more recently it was shown to restore fatty acid β-oxidation (FAO) capacities in patient fibroblasts harboring mutations with residual enzyme activity. Many of RSV's beneficial effects are mediated by the transcriptional coactivator PGC-1α, a direct target of SIRT1 and a master regulator of the mitochondrial fatty acid oxidation. Despite numerous studies RSV's mechanism of action is still not completely elucidated. Our aim was to investigate the effects of RSV on gene regulation on a wide scale, possibly to detect novel genes whose up-regulation by RSV may be of interest with respect to disease treatment. We performed Next Generation Sequencing of RNA on normal fibroblasts treated with RSV. To investigate whether the effects of RSV are mediated through SIRT1 we expanded the analysis to include SIRT1-knockdown fibroblasts. We identified the aspartoacylase (ASPA) gene, mutated in Canavan disease, to be strongly up-regulated by RSV in several cell lines, including Canavan disease fibroblasts. We further link RSV to the up-regulation of other genes involved in myelination including the glial specific transcription factors POU3F1, POU3F2, and myelin basic protein (MBP). We also observe a strong up-regulation by RSV of the riboflavin transporter gene SLC52a1. Mutations in SLC52a1 cause transient multiple acyl-CoA dehydrogenase deficiency (MADD). Our analysis of alternative splicing identified novel metabolically important genes affected by RSV, among which is particularly interesting the α subunit of the stimulatory G protein (Gsα), which regulates the cellular levels of cAMP through adenylyl cyclase. We conclude that in fibroblasts RSV stimulates the PGC-1α and p53 pathways, and up-regulates genes affecting the glucose metabolism, mitochondrial β-oxidation, and mitochondrial biogenesis. We further confirm that RSV might be a relevant treatment in the correction of FAO deficiencies and we suggest that treatment in other metabolic disorders including Canavan disease and MADD might be also beneficial.
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http://dx.doi.org/10.1016/j.ymgme.2018.10.004 | DOI Listing |
Hum Gene Ther
December 2024
BridgeBio Gene Therapy, Palo Alto, California, USA.
Cell Commun Signal
November 2024
Department of Biology, University of Rome Tor Vergata, Rome, 00133, Italy.
Background: Microglia play a crucial role in brain development and repair by facilitating processes such as synaptic pruning and debris clearance. They can be activated in response to various stimuli, leading to either pro-inflammatory or anti-inflammatory responses associated with specific metabolic alterations. The imbalances between microglia activation states contribute to chronic neuroinflammation, a hallmark of neurodegenerative diseases.
View Article and Find Full Text PDFNeurology
December 2024
From the HRB Clinical Research Facility Galway (C.R., M.C., C.J., M.J.O.), School of Medicine, University of Galway; Wellcome Trust-HRB (C.R.), Irish Clinical Academic Training, Dublin, Ireland; Institute of Health Informatics (C.R.), University College London, United Kingdom; Perron Institute Chair in Stroke Research (G.J.H.), Medical School, The University of Western Australia; Perron Institute for Neurological and Translational Science (G.J.H.), Perth, Australia; Rush Alzheimer Disease Research Center (S.O.), Rush University Medical Center, Chicago, IL; Academic Section of Geriatric Medicine (P.L.), Glasgow Royal Infirmary, University of Glasgow, United Kingdom; Beijing Hypertension League Institute (X.W.), China; Health and Medical Sciences (H.K.I.), University of Copenhagen, Denmark; Faculty of Medicine (F.L.), Universidad de La Frontera, Temuco, Chile; King Saud University (F.A.-H.), Riyadh, Saudi Arabia; Institute of Psychiatry and Neurology (A.C.), Warsaw, Poland; Department of Internal Medicine (A.O.), Faculty of Medicine, Istanbul Medeniyet University, Turkey; Sahlgrenska University Hospital and Sahlgrenska Academy (A.R.), University of Gothenburg, Sweden; St Johns Medical College and Research Institute (D.X.), Bangalore, India; and Population Health Research Institute (S.Y., M.J.O.), Hamilton Health Sciences and McMaster University, Ontario, Canada.
Background And Objectives: Acute stroke is associated with a spectrum of functional deficits. The objective of this analysis was to explore whether the importance of individual risk factors differ by stroke severity, which may be of relevance to public health strategies to reduce disability.
Methods: INTERSTROKE is an international case-control study of risk factors of first acute stroke (recruitment 2007-August 2015) in 32 countries.
Sci Adv
September 2024
Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland.
This study performed an in-depth investigation into the myeloid cellular landscape in the synovium of patients with rheumatoid arthritis (RA), "individuals at risk" of RA, and healthy controls (HC). Flow cytometric analysis demonstrated the presence of a CD40-expressing CD206CD163 macrophage population dominating the inflamed RA synovium, associated with disease activity and treatment response. In-depth RNA sequencing and metabolic analysis demonstrated that this macrophage population is transcriptionally distinct, displaying unique inflammatory and tissue-resident gene signatures, has a stable bioenergetic profile, and regulates stromal cell responses.
View Article and Find Full Text PDFChembiochem
December 2024
Department of Chemistry, Indrashil University, Kadi, Mehsana, Gujarat, India.
The transformation of metabolites into amyloidogenic aggregates represent an intriguing dimension in the pathophysiology of metabolic disorders, including alkaptonuria, canavan disease, and isovaleric acidemia. Central to this phenomenon are the metabolites homogentisic acid (HA), N-acetyl aspartic acid (NAA), and isovaleric acid (IVA), which we found, weave an intricate network of self-assembled structures. Leveraging an array of microscopy techniques, we traced the morphological behavior of these assemblies that exhibit concentration and time-dependent morphological transitions from isolated globules to clustered aggregates.
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