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Phenylacetylglutamine, a Novel Biomarker in Acute Ischemic Stroke.

ABSTRACT: Background: To discover novel metabolic biomarkers of ischemic stroke (IS), we carried out a two-stage metabolomic profiling of IS patients and healthy controls using untargeted and targeted metabolomic approaches. Methods: We applied untargeted liquid chromatography-mass spectrometry (LC-MS) to detect the plasma metabolomic profiles of 150 acute IS patients and 50 healthy controls. The candidate differential microbiota-derived metabolite phenylacetylglutamine (PAGln) was validated in 751 patients with IS and 200 healthy controls. We evaluated the associations between PAGln levels and the severity and functional outcomes of patients with IS. Clinical mild stroke was defined as the National Institutes of Health Stroke Scale (NIHSS) score 0-5, and moderate-severe stroke as NIHSS score >5. A favorable outcome at 3 months after IS was defined as the modified Rankin Scale (mRS) score 0-2, and unfavorable outcome as mRS score 3-6. Results: In untargeted metabolomic analysis, we detected 120 differential metabolites between patients with IS and healthy controls. Significantly altered metabolic pathways were purine metabolism, TCA cycle, steroid hormone biosynthesis, and pantothenate and CoA biosynthesis. Elevated plasma PAGln levels in IS patients, compared with healthy controls, were observed in untargeted LC-MS analysis and confirmed by targeted quantification (median 2.0 vs. 1.0 μmol/L; p < 0.001). Patients with moderate-severe stroke symptoms and unfavorable short-term outcomes also had higher levels of PAGln both in discovery and validation stage. After adjusting for potential confounders, high PAGln levels were independently associated with IS (OR = 3.183, 95% CI 1.671-6.066 for the middle tertile and OR = 9.362, 95% CI 3.797-23.083 for the highest tertile, compared with the lowest tertile) and the risk of unfavorable short-term outcomes (OR = 2.286, 95% CI 1.188-4.401 for the highest tertile). Conclusions: IS patients had higher plasma levels of PAGln than healthy controls. PAGln might be a potential biomarker for IS and unfavorable functional outcomes in patients with IS.

SUBMITTER: Yu F

PROVIDER: S-EPMC8733610 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveAcute ischemic stroke (AIS) is characterized by high rates of morbidity, disability, mortality, and recurrence, often leaving patients with varying degrees of sequelae. Symptomatic intracranial atherosclerotic stenosis (sICAS) is a significant contributor to AIS pathogenesis and recurrence. The formation and progression of sICAS are influenced by pathways such as lipid metabolism and inflammatory response. Given its high risk of clinical recurrence, timely assessment of intracranial vascular stenosis in AIS is crucial for diagnosing sICAS, treating stroke, and preventing stroke recurrence.MethodsFourteen AIS patients were divided into stenosis and control groups based on the presence or absence of intracranial vessel stenosis. Initially, 4D Label-free proteome quantification technology was employed for mass spectrometry analysis to identify differential proteins between the groups. Subsequently, functional enrichment analysis, including GO classification, KEGG pathway, and Domain, revealed trends related to differential proteins. The STRING (v.11.5) protein interaction network database was used to identify differential protein interactions and target proteins. Finally, parallel reaction monitoring (PRM) validated the selected target proteins.ResultsMass spectrometry identified 1,096 proteins, with 991 being quantitatively comparable. Using a p-value <0.05 and differential expression change thresholds of >1.3 for significant up-regulation and < 1/1.3 for significant down-regulation, 46 differential proteins were identified: 24 significantly up-regulated and 22 significantly down-regulated. PRM experiments validated five proteins related to lipid metabolism and inflammatory response: namely alpha-2-macroglobulin (A2M), lipopolysaccharide-binding protein (LBP), cathepsin G (CTSG), cystatin (CST)3, and fatty acid-binding protein (FABP)1.ConclusionThe detection of changes in these five proteins in AIS patients can aid in the diagnosis of sICAS, inform stroke treatment, and assist in preventing stroke recurrence. Moreover, it can contribute to the development of drugs for preventing AIS recurrence by integrating traditional Chinese and Western medicine.

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Phenylacetylglutamine, a Novel Biomarker in Acute Ischemic Stroke.

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