SHMT2 Mediates Small‐Molecule‐Induced Alleviation of Alzheimer Pathology Via the 5′UTR‐dependent ADAM10 Translation Initiation

Advanced Science, Год журнала: 2024, Номер 11(11)

Опубликована: Янв. 6, 2024

Abstract It is long been suggested that one‐carbon metabolism (OCM) associated with Alzheimer's disease (AD), whereas the potential mechanisms remain poorly understood. Taking advantage of chemical biology, mitochondrial serine hydroxymethyltransferase (SHMT2) directly regulated translation ADAM metallopeptidase domain 10 (ADAM10), a therapeutic target for AD reported. That small‐molecule kenpaullone (KEN) promoted ADAM10 via 5′ untranslated region (5′UTR) and improved cognitive functions in APP/PS1 mice found. SHMT2, which identified as gene KEN 5′UTR‐interacting RNA binding protein (RBP), mediated KEN‐induced vitro vivo. SHMT2 controls signaling pathways through to large number RNAs enhances 5′UTR activity by direct interaction GAGGG motif, this motif affected ribosomal scanning eukaryotic initiation factor 2 (eIF2) 5′UTR. Together, exhibits linking OCM processing, metabolic enzyme “moonlighted” RBP promoting 5′UTR‐dependent initiation.

Язык: Английский

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Folate receptor overexpression induces toxicity in a diet-dependent manner in C. elegans

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 11, 2024

Folate receptor (FR) alpha (FOLR1) and beta (FOLR2) are membrane-anchored folate transporters that expressed at low levels in normal tissues, while their expression is strongly increased several cancers. Intriguingly, although the function of these receptors in, for example, development cancer has been studied intensively, role aging still unknown. To address this, we utilized Caenorhabditis elegans, which FOLR-1 sole ortholog receptors. We found loss does not affect reproduction, physical condition, proteostasis or lifespan, indicating it required transport to maintain health. Interestingly, detectably only uterine-vulval cells, histone-binding protein LIN-53 inhibits its other tissues. Furthermore, whereas knockdown lin-53 known shorten partially rescues this phenotype, suggesting elevated folr-1 detrimental Indeed, our data demonstrate overexpression toxic, phenotype dependent on diet. Altogether, work could serve as a basis further studies elucidate organismal effects abnormal FR diseases such cancer.

Язык: Английский

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O-GlcNAc signaling increases neuron regeneration through one-carbon metabolism in Caenorhabditis elegans

eLife, Год журнала: 2024, Номер 13

Опубликована: Фев. 9, 2024

Cellular metabolism plays an essential role in the regrowth and regeneration of a neuron following physical injury. Yet, our knowledge specific metabolic pathways that are beneficial to remains sparse. Previously, we have shown modulation O-linked β-N-acetylglucosamine (O-GlcNAc) signaling, ubiquitous post-translational modification acts as cellular nutrient sensor, can significantly enhance vivo regeneration. Here, define pathway by which O-GlcNAc transferase ( ogt-1 ) loss function mediates increased regenerative outgrowth. Performing laser axotomy measuring subsequent individual neurons C. elegans , find glycolysis, serine synthesis (SSP), one-carbon (OCM), downstream transsulfuration (TSP) all this process. The effects mutation abrogated genetic and/or pharmacological disruption OCM SSP linking glycolysis. Testing branches pathway, enhanced is dependent only on vitamin B12 independent shunt pathway. These results further supported RNA sequencing reveals dramatic transcriptional changes mutation, genes involved OCM, TSP, ATP metabolism. Strikingly, be recapitulated simple supplementation metabolite methionine wild-type animals. Taken together, these data unearth capacity damaged animals highlight therapeutic possibilities its related treatment neuronal

Язык: Английский

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Mass spectrometry for biomarkers, disease mechanisms, and drug development in cerebrospinal fluid metabolomics

TrAC Trends in Analytical Chemistry, Год журнала: 2024, Номер 173, С. 117626 - 117626

Опубликована: Фев. 29, 2024

Язык: Английский

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One-carbon metabolism-related compounds are associated with epigenetic aging biomarkers: Results from National Health and Nutrition Examination Survey (NHANES) 1999-2002

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

One-carbon metabolism (OCM), a biochemical pathway dependent on micronutrients including folate and vitamin B12, plays an essential role in aging-related physiological processes. DNA methylation-based aging biomarkers may be influenced by OCM. This study investigated associations of OCM-related with epigenetic the National Health Nutrition Examination Survey (NHANES). Blood methylation was measured adults aged ≥50 years 1999-2000 2001-2002 cycles NHANES. The following were included: Horvath1, Horvath2, Hannum, PhenoAge, GrimAge2, DunedinPoAm, telomere length (DNAmTL). We tested for serum folate, red blood cell (RBC) homocysteine, methylmalonic acid concentrations age deviation (EAD) among 2,346 participants nutritional status using survey weighted general linear regression models adjusting sociodemographics, BMI, behavioral factors. A doubling concentration associated -0.82 (95% confidence interval (CI) = -1.40, -0.23) lower GrimAge EAD, -0.13 SDs (-0.22, -0.03) 0.02 kb (0.00, 0.04) greater DNAmTL EAD. Associations attenuated after smoking alcohol intake, antagonists. Conversely, homocysteine 1.05 (0.06, 2.04) PhenoAge 1.93 (1.16, 2.71) GrimAge2 0.26 (0.10, 0.41) DunedinPoAm. EAD DunedinPoAm robust to adjustment. In nationally representative sample U.S. adults, carbon donor, indicator OCM deficiencies, EAD; however, some status. Future research should focus high-risk populations. Randomized controlled trials long-term follow-up are also needed established causality investigate clinical relevance changes

Язык: Английский

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Downregulation of NAD Kinase Expression in β‐Cells Contributes to the Aging‐Associated Decline in Glucose‐Stimulated Insulin Secretion

Aging Cell, Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

Nicotinamide adenine dinucleotide kinase (NADK) is essential to the generation of nicotinamide phosphate (NADP(H)), an important metabolic coupling factor involved in glucose-stimulated insulin secretion. In present study, we showed that expression Nadk and Nadk2 transcripts NADP(H) content were lower islets 80-week-old (aged) mice than those 8-week-old (young) mice. This was associated with diminished oral glucose tolerance old secretion (GSIS) response islets. Knockdown (KD) or gene NIT-1 cells impaired Metabolomic analysis revealed KD specifically affected purine metabolism cells. The levels 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) higher non-targeting control (NTC) Phosphorylation AMP-activated protein (AMPK) elevated glucose-treated compared NTC Increased AICAR level AMPKα phosphorylation observed aged Genetic pharmacological inhibition AMPK promoted release by mouse It likely NADK modulatory activation pancreatic β-cells their GSIS response. Enhanced formation accompanied significantly increased conversion from inosine monophosphate (IMP) a tetrahydrofolate (THF)-dependent manner. Folate supplementation augmented Taken together, these findings suggest aging-associated decline may underlie reduced secretory capacity β-cells.

Язык: Английский

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Tyrosine phosphorylation coupling of one carbon metabolism and virulence in an endogenous pathogen

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

Endogenous pathogens can constrain virulence to ensure survival in the host. Pathogenic state be controlled by metabolic responses prevailing microenvironment; however, coupling and effector mechanisms are not well understood. Flux through One Carbon Metabolism (OCM) pathway modulate of oral pathobiont Porphyromonas gingivalis , here we show that this is tyrosine phosphorylation-dependent differential partitioning gingipain proteases. The OCM essential precursor pABA inhibits low molecular weight phosphatase Ltp1, consequently relieves inhibition its cognate kinase, Ptk1. We found absence pABA, reduced Ptk1 kinase activity blocks extracellular release gingipains. Surface retention gingipains confers resistance neutrophil mobilization killing, animal models disease elevated. Reciprocally, required for maximal flux OCM, phosphorylate enzymes GlyA GcvT. Further, ALP, an alkaline involved synthesis DHPPP, which combines with make DHP, phosphorylated activated propose, therefore, although primary function maintain balance, it mechanistically couples metabolism tunable pathogenic potential directing location proteolytic factors.

Язык: Английский

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Vitamin biosynthesis in the gut: interplay between mammalian host and its resident microbiota

Microbiology and Molecular Biology Reviews, Год журнала: 2025, Номер unknown

Опубликована: Апрель 2, 2025

SUMMARYIn recent years, exhaustive efforts have been made to dissect the composition of gut-associated microbial communities and associated interactions with their human host, which are thought play a crucial role in host development, physiology, metabolic functions. Although such studies were initially focused on description compositional shifts microbiota that occur between different health conditions, more recently, they provided key insights into functional contributions gut overall physiology. In this context, an important activity is believed be represented by synthesis various vitamins may elicit considerable benefits health. A growing body scientific literature now available relating (predicted) bacterial vitamin biosynthetic abilities, ever-growing information concerning prevalence these abilities among members microbiota. This review aimed at disentangling if how cooperative trophic contribute production, such, microbiota-mediated production varies according life stages. Moreover, it offers brief exploration diets influence shaping while also providing preliminary potential correlations microbiota-associated occurrence diseases and/or disorders.

Язык: Английский

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Plasma metabolomics of oral squamous cell carcinomas based on NMR and MS approaches provides biomarker identification and survival prediction

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Май 26, 2023

Abstract Metabolomics has proven to be an important omics approach understand the molecular pathways underlying tumour phenotype and identify new clinically useful markers. The literature on cancer illustrated potential of this as a diagnostic prognostic tool. present study aimed analyse plasma metabolic profile patients with oral squamous cell carcinoma (OSCC) controls compare metastatic primary tumours at different stages subsites using nuclear magnetic resonance mass spectrometry. To our knowledge, is only report that compared replicates collected in diverse institutions times these methodologies. Our results showed OSCC suggestive abnormal ketogenesis, lipogenesis energy metabolism, which already early phases but more evident advanced disease. Reduced levels several metabolites were also associated unfavorable prognosis. observed metabolomic alterations may contribute inflammation, immune response inhibition growth, explained by four nonexclusive views—differential synthesis, uptake, release, degradation metabolites. interpretation assimilates views cross talk between neoplastic normal cells microenvironment or distant anatomical sites, connected biofluids, signalling molecules vesicles. Additional population samples evaluate details processes lead discovery biomarkers novel strategies for prevention treatment.

Язык: Английский

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Transsulfuration pathway: a targeting neuromodulator in Parkinson’s disease

Reviews in the Neurosciences, Год журнала: 2023, Номер 34(8), С. 915 - 932

Опубликована: Июль 6, 2023

The transsulfuration pathway (TSP) is a metabolic involving sulfur transfer from homocysteine to cysteine. Transsulfuration leads many metabolites, principally glutathione, H2S, taurine, and Key enzymes of the TSP, such as cystathionine β-synthase γ-lyase, are essential regulators at multiple levels in this pathway. TSP metabolites implicated physiological processes central nervous system other tissues. important controlling balance optimal cellular functions glutathione synthesis. Alterations related pathways (transmethylation remethylation) altered several neurodegenerative diseases, including Parkinson's disease, suggesting their participation pathophysiology progression these diseases. In disease comprised mainly those that regulate redox homeostasis, inflammation, reticulum endoplasmic stress, mitochondrial function, oxidative content involved damage processes. Current research on has primarily focused synthesis function certain particularly glutathione. However, our understanding regulation pathway, well relationships with Parkinson´s remain limited. Thus, paper highlights importance studying molecular dynamics different affect disease.

Язык: Английский

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