Small molecule metabolites: discovery of biomarkers and therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Март 20, 2023

Metabolic abnormalities lead to the dysfunction of metabolic pathways and metabolite accumulation or deficiency which is well-recognized hallmarks diseases. Metabolite signatures that have close proximity subject's phenotypic informative dimension, are useful for predicting diagnosis prognosis diseases as well monitoring treatments. The lack early biomarkers could poor serious outcomes. Therefore, noninvasive methods with high specificity selectivity desperately needed. Small molecule metabolites-based metabolomics has become a specialized tool biomarker pathway analysis, revealing possible mechanisms human various deciphering therapeutic potentials. It help identify functional related variation delineate biochemical changes indicators pathological damage prior disease development. Recently, scientists established large number profiles reveal underlying networks target exploration in biomedicine. This review summarized analysis on potential value small-molecule candidate metabolites clinical events, may better diagnosis, prognosis, drug screening treatment. We also discuss challenges need be addressed fuel next wave breakthroughs.

Язык: Английский

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Antibiotic-induced intestinal microbiota depletion can attenuate the acute kidney injury to chronic kidney disease transition via NADPH oxidase 2 and trimethylamine-N-oxide inhibition

Kidney International, Год журнала: 2024, Номер 105(6), С. 1239 - 1253

Опубликована: Фев. 29, 2024

Intestinal microbiota and their metabolites affect systemic inflammation kidney disease outcomes. Here, we investigated the key associated with acute injury (AKI)-to chronic (CKD) transition effect of antibiotic-induced depletion (AIMD) on this transition. In 61 patients AKI, 59 plasma were assessed to determine risk AKI-to-CKD An murine model was established four weeks after unilateral ischemia-reperfusion (IRI) effects AIMD gut microbiome, metabolites, pathological responses related CKD Human proximal tubular epithelial cells challenged transition-related inhibitory NADPH oxidase 2 (NOX2) signals tested. Based clinical metabolomics, trimethylamine N-oxide (TMAO) a significant increased for [adjusted odds ratio 4.389 (95% confidence interval 1.106–17.416)]. vivo, inhibited IRI-induced increase in TMAO, along decreased apoptosis, inflammation, fibrosis. The expression NOX2 oxidative stress AIMD. vitro, TMAO induced fibrosis activation stress. inhibition successfully attenuated suppression G2/M arrest. (in vivo) showed improvement changes decrease without levels. Thus, is metabolite identified as regulator TMAO-related both vivo vitro.

Язык: Английский

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Using Machine Learning to Identify Metabolomic Signatures of Pediatric Chronic Kidney Disease Etiology

Journal of the American Society of Nephrology, Год журнала: 2022, Номер 33(2), С. 375 - 386

Опубликована: Янв. 11, 2022

Untargeted plasma metabolomic profiling combined with machine learning (ML) may lead to discovery of metabolic profiles that inform our understanding pediatric CKD causes. We sought identify signatures in based on diagnosis: FSGS, obstructive uropathy (OU), aplasia/dysplasia/hypoplasia (A/D/H), and reflux nephropathy (RN).

Язык: Английский

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Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

JCI Insight, Год журнала: 2022, Номер 7(20)

Опубликована: Сен. 1, 2022

BACKGROUNDMetabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into pathogenesis.METHODSWe examined association between blood metabolites CKD progression, defined as subsequent development of end-stage renal (ESRD) or estimated glomerular filtrate rate (eGFR) halving, 1,773 participants Chronic Renal Insufficiency Cohort (CRIC) study, 962 African-American Study Kidney Disease Hypertension (AASK), 5,305 Atherosclerosis Risk Communities (ARIC) study.RESULTSIn CRIC, more than half measured were associated progression minimally adjusted Cox proportional hazards models, but number strength associations markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten significantly fully models CRIC; 3 these also significant AASK ARIC, highlighting markers filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), azotemia (homocitrulline). Our findings highlight N-acetylserine a marker tubular function, observed CRIC ARIC.CONCLUSIONOur demonstrate application metabolomics causal pathways progression.FUNDINGThis study was supported NIH (U01 DK106981, U01 DK106982, DK085689, R01 DK108803, DK124399).

Язык: Английский

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Metabolomic profiling reveals key metabolites associated with hypertension progression

Frontiers in Cardiovascular Medicine, Год журнала: 2024, Номер 11

Опубликована: Фев. 8, 2024

Introduction Pre-hypertension is a prevalent condition among the adult population worldwide. It characterized by asymptomatic elevations in blood pressure beyond normal levels but not yet reaching threshold for hypertension. If left uncontrolled, pre-hypertension can progress to hypertension, thereby increasing risk of serious complications such as heart disease, stroke, kidney damage, and others. Objective The precise mechanisms driving progression hypertension remain unknown. Thus, identifying metabolic changes associated with this provide valuable insights into potential markers or pathways implicated development Methods In study, we utilized untargeted metabolomics profiling, which examines over 1,000 metabolites identify novel contributing from Data were collected 323 participants through Qatar Biobank. Results By comparing profiles between pre-hypertensive, hypertensive normotensive individuals, six including stearidonate, hexadecadienoate, N6-carbamoylthreonyladenosine, 9 13-S-hydroxyoctadecadienoic acid (HODE), 2,3-dihydroxy-5-methylthio- 4-pentenoate (DMTPA), linolenate found be increased both discovery validation cohorts. Moreover, these showed significant diagnostic performance area under curve >0.7. Conclusion These findings suggest possible biomarkers that predict This will aid early detection, diagnosis, management disease well its complications.

Язык: Английский

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Childhood Obesity: Insight into Kidney Involvement

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(24), С. 17400 - 17400

Опубликована: Дек. 12, 2023

This review examines the impact of childhood obesity on kidney from an epidemiological, pathogenetic, clinical, and pathological perspective, with aim providing pediatricians nephrologists most current data this topic. The prevalence chronic disease (CKD) is steadily increasing worldwide, reaching epidemic proportions. While in children CKD less pronounced than adults, recent studies suggest a similar trend child population. likely due to significant association between two leading causes end-stage renal (ESRD): diabetes mellitus (DM) hypertension. Obesity complex, systemic that reflects interactions environmental genetic factors. A key mechanism damage related metabolic syndrome insulin resistance. Therefore, we can speculate about adipose tissue-kidney axis which neurohormonal immunological mechanisms exacerbate complications resulting obesity. Adipose tissue, now recognized as endocrine organ, secretes cytokines called adipokines may induce adaptive or maladaptive responses cells, fibrosis. transplant-related outcomes for both donors recipients also significant, making stringent preventive measures critical pre- post-transplant phases. challenge lies identifying involvement early possible, it often completely asymptomatic not detectable through common markers function. Ongoing research into innovative technologies, such proteomics metabolomics, aims identify new biomarkers constantly evolving. Many aspects pediatric progression population still require clarification. However, latest scientific evidence field nephrology offers glimpses various perspectives, factors, comorbidities, novel biomarkers. Investigating these could potentially improve prognosis young patients diagnostic therapeutic strategies. Hence, provide comprehensive exploration pathogenetic prevalent patterns observed

Язык: Английский

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Longitudinal Plasma Metabolome Patterns and Relation to Kidney Function and Proteinuria in Pediatric CKD

Clinical Journal of the American Society of Nephrology, Год журнала: 2024, Номер 19(7), С. 837 - 850

Опубликована: Май 6, 2024

Key Points Longitudinal untargeted metabolomics. Children with CKD have a circulating metabolome that changes over time. Background Understanding plasma patterns in relation to changing kidney function pediatric is important for continued research identifying novel biomarkers, characterizing biochemical pathophysiology, and developing targeted interventions. There are limited number of studies longitudinal metabolomics virtually none CKD. Methods The study multi-institutional, prospective cohort enrolled children aged 6 months 16 years eGFR 30–90 ml/min per 1.73 m 2 . Untargeted profiling was performed on samples from the baseline, 2-, 4-year visits. were technologic updates metabolomic platform used between baseline follow-up assays. Statistical approaches adopted avoid direct comparison measurements. To identify metabolite associations or urine protein-creatinine ratio (UPCR) among all three time points, we applied linear mixed-effects (LME) models. metabolites associated time, LME models 2- data. We regression analysis examine change level (∆level) (∆eGFR) UPCR (∆UPCR). reported significance basis both false discovery rate (FDR) <0.05 P < 0.05. Results 1156 person-visits ( N : baseline=626, 2-year=254, 4-year=276) included. 622 standardized measurements at points. In modeling, 406 343 FDR <0.05, respectively. Among 530 person-visits, 158 showed differences <0.05. For participants complete data visits n =123), report 35 ∆level–∆eGFR significant no ∆level–∆UPCR 0.05 modeling Conclusions characterized large population. Many these signals been progression, etiology, proteinuria previous Biomarkers Consortium studies. also detected.

Язык: Английский

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Revealing novel biomarkers for diagnosing chronic kidney disease in pediatric patients

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

Опубликована: Май 21, 2024

Abstract Pediatric chronic kidney disease (CKD) is a clinical condition characterized by progressive renal function deterioration. CKD diagnosis based on glomerular filtration rate, but its reliability limited, especially at the early stages. New potential biomarkers (citrulline (CIT), symmetric dimethylarginine (SDMA), S-adenosylmethionine (SAM), n-butyrylcarnitine (nC4), cis-4-decenoylcarnitine, sphingosine-1-phosphate and bilirubin) in addition to creatinine (CNN) have been proposed for diagnosis. To verify value of these we performed comprehensive targeted metabolomics study representative cohort healthy pediatric patients. Sixty-seven children with forty-five enrolled study. Targeted liquid chromatography-triple quadrupole mass spectrometry has used serum plasma samples analysis. Univariate data analysis showed statistically significant differences ( p < 0.05) concentration CNN, CIT, SDMA, nC4 among The predictive ability was also confirmed through specificity sensitivity expressed Receiver Operating Characteristic curves (AUC = 0.909). In group patients, AUC 0.831 obtained, improving diagnostic CNN alone. Moreover, models built combined nC4, allowed distinguish patients from control regardless blood matrix type (serum or plasma). Our demonstrate

Язык: Английский

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Associations of Urine and Plasma Metabolites with Kidney Failure and Death in a CKD Cohort

American Journal of Kidney Diseases, Год журнала: 2024, Номер 84(4), С. 469 - 481

Опубликована: Май 28, 2024

Язык: Английский

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Gut-derived metabolites as treatment targets in chronic kidney disease—an avenue toward personalized medicine

Pediatric Nephrology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 16, 2025

Язык: Английский

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