Serine mistranslation induces the integrated stress response through the P stalk

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108447 - 108447

Published: March 1, 2025

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that support robust and accurate protein synthesis. A rapidly expanding number of studies show mutations in aaRSs lead to multiple human diseases, including neurological disorders cancer. How aaRS impact health is not fully understood. In particular, our knowledge how aminoacylation errors affect stress responses fitness eukaryotic cells remains limited. The integrated response (ISR) an adaptive mechanism stresses. However, chronic activation the ISR contributes development diseases such as neuropathies. this study, we Ser misincorporation into Ala Thr codons, resulting from either editing defects or tRNAs, actives ISR. We further demonstrate by mistranslation does depend on accumulation uncharged but rather requires P stalk associated with ribosome, implying ribosome stalling collision involved. Our work highlights certain types can ISR, potentially affecting disease progression.

Language: Английский

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Application of Metabolomics and the Discovery of Potential Serum Biomarkers for Diuretic Resistance in Heart Failure

Reviews in Cardiovascular Medicine, Journal Year: 2025, Volume and Issue: 26(4)

Published: April 22, 2025

Diuretic resistance (DR) is characterized by insufficient fluid and sodium excretion enhancement despite maximum loop diuretic doses, indicating a phenotype of refractory heart failure (HF). Recently, metabolomics has emerged as crucial tool for diagnosing understanding the pathogenesis various diseases. This study aimed to differentiate diuretic-resistant patients from non-resistant HF identify biomarkers linked emergence DR. Serum samples patients, both with without DR, were subjected non-targeted metabolomic analysis using liquid chromatography-tandem mass spectrometry. Metabolite variations between groups identified principal component orthogonal partial least-square discriminant analysis. Metabolic pathways assessed through Kyoto Encyclopedia Genes Genomes database enrichment analysis, potential determined receiver operating characteristic curves (ROCs). In total, 192 metabolites exhibited significant differences across two sample groups. Among these, up-regulation was observed in 164 metabolites, while 28 down-regulated. A total involving neuroactive ligand-receptor interaction amino acid biosynthesis affected. The top five ROC DR hydroxykynurenine, perillic acid, adrenic 5-acetamidovalerate, adipic acid. Significant metabolite profiles non-diuretic-resistant among HF. differentially expressed endogenous metabolic primary implicated noted energy, nucleotide metabolism. registered China Clinical Trials Registry (https://www.chictr.org.cn/hvshowproject.html?id=197183&v=1.7, ChiCTR2100053587).

Language: Английский

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Comprehensive profile of circRNAs in formaldehyde induced heart development

Food and Chemical Toxicology, Journal Year: 2022, Volume and Issue: 162, P. 112899 - 112899

Published: Feb. 26, 2022

Language: Английский

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The discovery of combined toxicity effects and mechanisms of hexaconazole and arsenic to mice based on untargeted metabolomics

Ecotoxicology and Environmental Safety, Journal Year: 2021, Volume and Issue: 226, P. 112859 - 112859

Published: Oct. 6, 2021

The high detected frequencies of hexaconazole (Hex) and arsenic (As) increased the probabilities their co-existence in agricultural products. However, combined toxicity effect mechanism action for these two pollutants were still unclear. In this study, an untargeted metabolomics method with ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed to monitor changes endogenous metabolites metabolism pathways mice liver. Our study revealed that significant differences profiles observed after Hex, As, Hex+As exposure 90 d. Hex altered 54 11 significantly which mainly lipid-related. For As exposure, 63 9 affected most amino acid-related. induced 93 34% lipids lipid-like molecules 22% organic acids derivatives. shared by indicated interaction might be independent action. results could provide important insight understanding helpful evaluating health risk human.

Language: Английский

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Metabolomics profile and 10-year atherosclerotic cardiovascular disease (ASCVD) risk score

Frontiers in Cardiovascular Medicine, Journal Year: 2023, Volume and Issue: 10

Published: May 3, 2023

The intermediate metabolites associated with the development of atherosclerotic cardiovascular disease (ASCVD) remain largely unknown. Thus, we conducted a large panel metabolomics profiling to identify new candidate that were 10-year ASCVD risk.Thirty acylcarnitines and twenty amino acids measured in fasting plasma 1,102 randomly selected individuals using targeted FIA-MS/MS approach. risk score was calculated based on 2013 ACC/AHA guidelines. Accordingly, subjects stratified into four groups: low-risk (n = 620), borderline-risk 110), intermediate-risk 225), high-risk 147). 10 factors comprising collinear extracted from principal component analysis.C4DC, C8:1, C16OH, citrulline, histidine, alanine, threonine, glycine, glutamine, tryptophan, phenylalanine, glutamic acid, arginine, aspartic acid significantly (p-values ≤ 0.044). group had higher odds factor 1 (12 long-chain acylcarnitines, OR 1.103), 2 (5 medium-chain 1.063), 3 (methionine, leucine, valine, tyrosine, 1.074), 5 (6 short-chain 1.205), 6 1.229), 7 (alanine, proline, 1.343), 8 (C18:2OH, 1.188), (ornithine, 1.570) compared ones; 9 (glycine, serine, 0.741), however, lower group. "D-glutamine D-glutamate metabolism", "phenylalanine, tryptophan biosynthesis", "valine, isoleucine biosynthesis" metabolic pathways having highest association borderline/intermediate/high events, respectively.Abundant found be events this study. Utilization could promising strategy for early detection prevention events.

Language: Английский

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FARSB serves as a novel hypomethylated and immune cell infiltration related prognostic biomarker in hepatocellular carcinoma

Aging, Journal Year: 2023, Volume and Issue: unknown

Published: April 3, 2023

Purpose: Hepatocellular carcinoma (HCC) is a prevalent tumor with high morbidity, and an unfavourable prognosis. FARSB aminoacyl tRNA synthase, plays key role in protein synthesis cells. Furthermore, previous reports have indicated that overexpressed gastric tissues associated poor prognosis tumorigenesis. However, the function of HCC has not been studied. Results: The results showed mRNA levels were upregulated closely related to many clinicopathological characteristics. Besides, according multivariate Cox analysis, expression was linked shorter survival time may be independent prognostic factor. In addition, promoter methylation level negatively FARSB. enrichment analysis cell cycle. And TIMER revealed purity immune infiltration. TCGA ICGC data suggested greatly m6A modifier genes. Potential FARSB-related ceRNA regulatory networks also constructed. What's more, based on FARSB-protein interaction network, molecular docking models RPLP1 Finally, drug susceptibility testing susceptible 38 different drugs or small molecules. Conclusions: can serve as biomarker for provide clues about infiltration, modification.

Language: Английский

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Recessive aminoacyl-tRNA synthetase disorders: lessons learned from in vivo disease models

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: May 9, 2023

Protein synthesis is a fundamental process that underpins almost every aspect of cellular functioning. Intriguingly, despite their common function, recessive mutations in aminoacyl-tRNA synthetases (ARSs), the family enzymes pair tRNA molecules with amino acids prior to translation on ribosome, cause diverse range multi-system disorders affect specific groups tissues. Neurological development impaired most ARS-associated disorders. In addition central nervous system defects, diseases caused by cytosolic ARSs commonly liver and lungs. Patients biallelic mitochondrial often present encephalopathies, variable involvement peripheral systems. Many these severe disability, as understanding pathogenesis currently limited, there are no effective treatments available. To address this, accurate vivo models for ARS urgently needed. Here, we discuss approaches have been taken model , highlighting some challenges arisen this process, well key results obtained from models. Further refinement animal essential facilitate better pathophysiology underlying diseases, ultimately enable testing therapies.

Language: Английский

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Predictive biomarkers for the early detection and management of heart failure

Heart Failure Reviews, Journal Year: 2023, Volume and Issue: 29(2), P. 331 - 353

Published: Sept. 13, 2023

Language: Английский

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miR-153-3p Targets βII Spectrin to Regulate Formaldehyde-Induced Cardiomyocyte Apoptosis

Frontiers in Cardiovascular Medicine, Journal Year: 2021, Volume and Issue: 8

Published: Dec. 15, 2021

Background: Formaldehyde (FA) is ubiquitous in the environment and can be transferred to fetus through placental circulation, causing miscarriage congenital heart disease (CHD). Studies have shown that βII spectrin necessary for cardiomyocyte survival differentiation, its loss leads development defects apoptosis. Additionally, previous studies demonstrated miRNA essential remodeling. However, whether regulates FA-induced CHD apoptosis remains unclear. Methods: Using commercially available rat embryonic cardiomyocytes a model of fetal Real-time quantitative PCR (RT-qPCR) Western blot were performed examine level miR-153-3p, spectrin, caspase 7, cleaved caspase7, Bax, Bcl-2 expression Apoptotic cell populations evaluated by flow cytometry Tunel. Luciferase activity assay RNA pull-down used detect interaction between miR-153-3p spectrin. Masson's trichrome staining detects degree tissue fibrosis. Fluorescence situ hybridization (FISH) Immunohistochemistry tissues. Results: apoptosis, our indicate plays regulatory role directly targeting promote mainly regulating further elucidating importance development. Finally, results with animal revealed miR-153-3p/βII pathway effectively regulated damage during Recovery experiments antagomir resulted reversal cardiac Conclusion: This study investigated molecular mechanism underpinning associated upstream pathway. The findings suggest may provide potential target clinical diagnosis treatment CHD.

Language: Английский

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Machine learning–based biomarker profile derived from 4210 serially measured proteins predicts clinical outcome of patients with heart failure

European Heart Journal - Digital Health, Journal Year: 2023, Volume and Issue: 4(6), P. 444 - 454

Published: Oct. 4, 2023

Risk assessment tools are needed for timely identification of patients with heart failure (HF) reduced ejection fraction (HFrEF) who at high risk adverse events. In this study, we aim to derive a small set out 4210 repeatedly measured proteins, which, along clinical characteristics and established biomarkers, carry optimal prognostic capacity events, in HFrEF.In 382 patients, performed repeated blood sampling (median follow-up: 2.1 years) applied an aptamer-based multiplex proteomic approach. We used machine learning select the predictors primary endpoint (PEP: composite cardiovascular death, transplantation, left ventricular assist device implantation, HF hospitalization). The association between measures selected proteins PEP was investigated by multivariable joint models. Internal validation (cross-validated c-index) external (Henry Ford PharmacoGenomic Registry cohort) were performed. Nine addition MAGGIC score, N-terminal pro-hormone B-type natriuretic peptide, troponin T: suppression tumourigenicity 2, tryptophanyl-tRNA synthetase cytoplasmic, histone H2A Type 3, angiotensinogen, deltex-1, thrombospondin-4, ADAMTS-like protein anthrax toxin receptor 1, cathepsin D. peptide angiotensinogen showed strongest associations [hazard ratio (95% confidence interval): 1.96 (1.17-3.40) 0.66 (0.49-0.88), respectively]. model yielded c-index 0.85 upon internal c-indices up 0.80 validation. higher than that containing factors (P = 0.021).Nine serially captured most essential information occurrence events HFrEF, provided incremental value prognostication beyond factors. These could be dynamic, individual prospective setting. findings also illustrate potential relatively 'novel' biomarkers prognostication.https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 24.

Language: Английский

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