FTO inhibition mitigates high-fat diet-induced metabolic disturbances and cognitive decline in SAMP8 mice

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: Feb. 21, 2025

Abstract This study investigated the effects of fat mass and obesity-associated (FTO) inhibition on cognitive function metabolic parameters senescence-accelerated mouse prone 8 (SAMP8) mice fed a high-fat diet (HFD). SAMP8 an HFD exhibited increased body weight, impaired glucose tolerance, elevated serum leptin levels. In epididymal white adipose tissue (eWAT), pharmacological treatment with FB23, well-established FTO inhibitor, production modulated genes involved in lipid metabolism (Cpt1a, Atgl , Hsl Fas) oxidative stress (OS) ( Bip Edem ), inflammation (Mcp1, Tnfα) . Expression hepatic related to Mgl, Dgat2, Srebp Plin2) OS (catalase, Edem) were by although steatosis remained unchanged. Remarkably, FB23 m6A RNA methylation brain, accompanied changes N6-methyladenosine (m6A)-regulatory enzymes modulation neuroinflammatory markers (Il6, Mcp1, iNOS) reduced activity matrix metalloproteases (Mmp2, Mmp9) altered IGF1 signaling (Igf1, Pten) Notably, enhanced was observed through expression immediate early (Arc, Fos) transcription factor Stat3 Improved synaptic plasticity evident, as shown levels neurotrophic factors (Bdnf Ngf) restored neurite length spine density. Consistent these findings, behavioral tests demonstrated that effectively rescued impairments mice. The novel object recognition test (NORT) location (OLT) revealed treated short- long-term memory spatial compared control group. Additionally, open field showed reduction anxiety-like behavior after FB23. conclusion, ameliorated HFD-induced disturbances decline These results suggest targeting may be promising therapeutic approach counteract obesity-induced impairment age-related neurodegeneration.

Language: Английский

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Effects of m6A methylation of MAT2A mRNA regulated by METTL16 on learning and memory, hippocampal synaptic plasticity and Aβ1–42 in 5 × FAD mice

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: April 16, 2025

Alzheimer's disease (AD) is a common neurodegenerative disorder affecting older adults, characterized by progressive cognitive decline and pathological features such as amyloid plaque deposition, neuronal loss, synaptic reduction. RNA N6-methyladenosine (m6A) methylation prevalent in the brain intricately linked to plasticity, learning, memory AD. However, precise mechanisms underlying these associations remain elusive. This study employed overexpression of methyltransferase-like protein 16 (METTL16), or methionine adenosyltransferase 2A (MAT2A), combination METTL16 with MAT2A knockdown explore influence on regulation function, hippocampal amyloid-beta (Aβ1-42) metabolism 5 × FAD mice. Our findings indicated reduction m6A levels expression hippocampus Overexpression led an increase overall levels, furthermore, either enhanced learning mice, elevated postsynaptic density 95 (PSD95) synaptophysin (Syp), increased dendritic spine density, decreased accumulation Aβ1-42 hippocampus. In was found upregulate both mRNA MAT2A, well enhance levels. Concurrent, resulted impaired alongside accumulation. The present demonstrated that enhances mice regulating methylation, which leads PSD95 Syp, greater reduced These reveal novel approach for investigating pathophysiological role AD offer new insights developing potential therapeutic targets

Language: Английский

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Alkbh5 promotes Ythdf1 expression through demethylation thereby facilitating Fth1 translation to inhibit ferroptosis of myocardial infarction

BMC Cardiovascular Disorders, Journal Year: 2025, Volume and Issue: 25(1)

Published: April 18, 2025

Myocardial infarction (MI) is a leading cause of global mortality. Ferroptosis, an iron-dependent form programmed cell death, has recently emerged as critical player in cardiovascular diseases. N6-methyladenosine (m6A), the most prevalent RNA methylation modification eukaryotic cells, been implicated various pathological processes; however, its regulatory role MI through ferroptosis remains poorly understood. This study aimed to elucidate mechanism by which m6A mediates via ferroptosis. A hypoxia/reoxygenation (H/R) model was established using H9C2 cells simulate myocardial injury. levels were quantified dot blot assay. Ferroptosis evaluated measuring lactate dehydrogenase (LDH) release, Fe2+ levels, glutathione (GSH), lipid reactive oxygen species (ROS), malondialdehyde (MDA), and apoptosis. The underlying molecular mechanisms investigated western blotting, quantitative real-time PCR (qPCR), methylated immunoprecipitation (MeRIP), RIP. Findings further validated ischemia/reperfusion injury (MIRI) rat model. results revealed that significantly elevated H/R model, accompanied reduced expression Alkbh5 mRNA. Moreover, overexpression inhibited increased Mechanistically, decreased Ythdf1 while promoting Fth1 translation enhancing mRNA expression. Knockdown restored counteracting effects overexpression. Furthermore, alleviated MIRI upregulated expression, protein levels. demonstrates ameliorates inhibiting demethylation Fth1. These findings provide novel insights into highlight potential therapeutic targets for treatment.

Language: Английский

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Pharmacology of Epitranscriptomic Modifications: Decoding the Therapeutic Potential of RNA Modifications in Drug Resistance

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: 994, P. 177397 - 177397

Published: Feb. 18, 2025

Language: Английский

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Combating cancer stem cells: RNA m6A methylation and small-molecule drug discovery

Frontiers in Drug Discovery, Journal Year: 2024, Volume and Issue: 4

Published: Sept. 30, 2024

Cancer stem cells (CSCs) are a small population of less differentiated with robust self-renewal ability. CSCs have been recognized as the root cause tumor initiation, progression, relapse, and drug resistance. Recent studies from us others highlighted that N 6 -methyladenosine (m A), most prevalent modification in mRNA, plays crucial role carcinogenesis CSC homeostasis. Dysregulation m A machinery has implicated survival self-renewal, thereby regulating cancer progression therapeutic In this review, we provide an overview roles molecular mechanisms RNA self-renewal. Additionally, summarize currently known small-molecule inhibitors targeting dysregulated discuss proof-of-concept focusing on efficacy these compounds eliminating cancers.

Language: Английский

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Maximal Fat Oxidation During Exercise in Healthy Individuals: Lack of Genetic Association with the FTO rs9939609 Polymorphism

Genes, Journal Year: 2024, Volume and Issue: 16(1), P. 4 - 4

Published: Dec. 24, 2024

Background/Objectives: Previous studies suggest that there is a genetically determined component of fat oxidation at rest and during exercise. To date, the FTO gene has been proposed as candidate to affect exercise because association "at-risk" A allele with different obesity-related factors such increased body fat, higher appetite elevated insulin triglyceride levels. The may also be linked obesity through reduced capacity for exercise, topic remains largely underexplored in current literature. aim this study was analyze between rs9939609 polymorphism rate metabolic syndrome criteria healthy participants. Methods: total 80 participants (41 men 39 women) underwent comprehensive assessments, including measurements anthropometric variables, blood pressure measures fasting glucose, triglycerides, low- high-density lipoprotein cholesterol (LDL-c HDL-c), insulin, interleukin-6 (IL-6) C-reactive protein (CRP) concentrations. Additionally, Homeostatic Model Assessment (HOMA-IR) used evaluate resistance. Peak oxygen uptake (VO2peak) maximal (MFO) were measured an incremental cycling test. genotyping (TT, AT, AA) performed using genomic DNA samples obtained from buccal swab PCR. Results: There 32 (40.0%) TT genotype; 31 (38.8%) AT 17 (21.2%) AA genotype. Age, characteristics, VO2peak, variables similar across all three genotypes. However, serum concentration HOMA-IR associated genotype values respect (p < 0.050). Still, MFO TT, (0.35 ± 0.13, 0.37 0.11, 0.33 0.11 g/min, p = 0.702). In dominant model, no statistical difference carriers. recessive model revealed had mass, mass index, than T carriers 0.050), differences MFO. Conclusions: our sample individuals, several phenotypes resistance, particularly under vs. allele/recessive model. not This suggests unlikely cause obesogenic influence Clinically, these findings effects are driven by impaired Instead, attention should focus on mechanisms like regulation energy intake. Moreover, interventions still effectively mitigate risk, individuals retain normal

Language: Английский

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