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An Integrated Metabolomic Screening Platform Discovers the Potential Biomarkers of Ischemic Stroke and Reveals the Protective Effect and Mechanism of Folic Acid.

ABSTRACT: Folic acid has a protective effect against ischemic stroke. However, the protective pharmacological mechanism remains unclear. The aim of this study is to explore the protective effect of folic acid on ischemic stroke animals by an integrated metabolomic biomarker screening platform. Based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS) coupled with multivariate data analysis, the changes in metabolites and pathways were characterized. We found that the metabolic alteration involved a total of 37 metabolites, of which 26 biomarkers such as γ-aminobutyric acid, lysine, glutamate, ribose, and valine can be regulated by folic acid via metabolic pathways of amino acid metabolism, carbohydrate metabolism, fatty acid metabolism, citrate cycle, and pyruvate metabolism, which may be the potential therapeutic targets of folic acid against ischemic stroke. Folic acid as an emerging potential natural anti-fibrosis agent has significant activity in protecting against middle cerebral artery occlusion-induced rat ischemic stroke model by delaying pathological development, reversing the metabolic biomarkers, and mainly regulating the perturbation in amino acid metabolism, carbohydrate metabolism, fatty acid metabolism, citrate cycle, and pyruvate metabolism. It also showed that the integrated metabolic biomarker screening platform could provide a better understanding of the therapeutic effect and mechanism of drugs.

SUBMITTER: Yang YH

PROVIDER: S-EPMC9158342 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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An Integrated Metabolomic Screening Platform Discovers the Potential Biomarkers of Ischemic Stroke and Reveals the Protective Effect and Mechanism of Folic Acid.

Yang Yan-Hui YH Lei Lei L Bao Yin-Ping YP Zhang Lu L

Frontiers in molecular biosciences 20220518

Folic acid has a protective effect against ischemic stroke. However, the protective pharmacological mechanism remains unclear. The aim of this study is to explore the protective effect of folic acid on ischemic stroke animals by an integrated metabolomic biomarker screening platform. Based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS) coupled with multivariate data analysis, the changes in metabolites and pathways were characterized. We found that the metabolic al ...[more]

PMID: 35664672

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Project description:Background To explore the pathophysiological features of ischemic stroke in patients with atrial fibrillation (AF), we evaluated the association between 268 plasma proteins and subsequent ischemic stroke in 2 large AF cohorts receiving oral anticoagulation. Methods and Results A case-cohort sample of patients with AF from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, including 282 cases with ischemic stroke or systemic embolism and a random sample of 4124 without these events, during 1.9 years of follow-up was used for identification. Validation was provided by a similar case-cohort sample of patients with AF from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, including 149 cases with ischemic stroke/systemic embolism and a random sample of 1062 without these events. In plasma obtained before randomization, 268 unique biomarkers were measured with OLINK proximity extension assay panels (CVD II, CVD III, and Inflammation) and conventional immunoassays. The association between biomarkers and outcomes was evaluated by random survival forest and adjusted Cox regression. According to random survival forest or Cox regression analyses, the biomarkers most strongly and consistently associated with ischemic stroke/systemic embolism were matrix metalloproteinase-9, NT-proBNP (N-terminal pro-B-type natriuretic peptide), osteopontin, sortilin, soluble suppression of tumorigenesis 2, and trefoil factor-3. The corresponding hazard ratios (95% CIs) for an interquartile difference were as follows: 1.18 (1.00-1.38), 1.55 (1.28-1.88), 1.28 (1.07-1.53), 1.19 (1.02-1.39), 1.23 (1.05-1.45), and 1.19 (0.97-1.45), respectively. Conclusions In patients with AF, of 268 unique biomarkers, the 6 biomarkers most strongly associated with subsequent ischemic stroke/systemic embolism represent fibrosis/remodeling (matrix metalloproteinase-9 and soluble suppression of tumorigenesis 2), cardiac dysfunction (NT-proBNP), vascular calcification (osteopontin), metabolism (sortilin), and mucosal integrity/ischemia (trefoil factor-3). Registration URL: https://www.clinicaltrials.gov. Unique Identifiers: NCT00412984 and NCT00262600.

Project description:Bai-Mi-Decoction (BMD), which is composed of Eugenia caryophyllata, Myristica fragrans, Moschus berezovskii, and Crocus sativu, is a characteristic TCM multi-herb formula for brain disease. However, the mechanism of protective effects of BMD on ischemic stroke (IS) still has not been clarified. Our study is designed to elucidate the protective effects and underlying mechanisms of BMD on IS by employing pharmacodynamic and serum and brain metabolomic methods. In this experiment, 90 adult male Sprague–Dawley rats were randomly divided into the sham operation group (SHAM, vehicle), middle cerebral artery occlusion–reperfusion injury model group (MCAO/R, vehicle), positive control group (NMDP, 36 mg/kg/day nimodipine), and low (BMDL, 0.805 g/kg/day), moderate (BMDM, 1.61 g/kg/day), and high (BMDH, 3.22 g/kg/day) dosage of BMD prophylactic administration groups. The drugs were dissolved in 0.5% CMC-Na and orally administered to rats with equal volumes (100 g/ml body weight) once a day for 14 consecutive days. Neurological deficit score, cerebral infarct volume, change in body weight, and serum NO, SOD, MDA, GSH, and GSSG levels were determined. Pathological abnormalities using hematoxylin and eosin staining and the expression of VEGF, caspase-3, and NF-κB were analyzed. Furthermore, serum and brain metabolic profiles were explored to reveal the underlying mechanism using UHPLC-QTOF-MS/MS technology. BMD exhibited significant neuroprotective effects on MCAO/R rats. As compared to the MCAO/R model group, it could reduce the neurological deficit score and cerebral infarct volume, increase body weight, enhance GSH, SOD, and GSSG activities, and decrease NO and MDA contents of MCAO/R rats. Meanwhile, BMD could ameliorate pathological abnormalities of MCAO/R rats through reducing neuronal loss, vacuolated spaces, shrunken neurons, and destructed neuron structure, as well as regulating the expression of VEGF, caspase-3, and NF-κB. UHPLC-QTOF-MS/MS-based serum and brain metabolomics analysis found a total of 53 differential metabolites between MCAO/R and SHAM groups, of which 30 were significantly regulated by BMD intervention, and further metabolic pathway analysis implied that the protective effects were mainly associated with amino acid and glycerophospholipid metabolisms. Our pharmacodynamic and metabolomic results revealed the neuroprotective effects of BMD on MCAO/R rats, and the underlying mechanisms were probably related to amino acid and glycerophospholipid metabolisms.

Dataset Information

An Integrated Metabolomic Screening Platform Discovers the Potential Biomarkers of Ischemic Stroke and Reveals the Protective Effect and Mechanism of Folic Acid.

Publications

An Integrated Metabolomic Screening Platform Discovers the Potential Biomarkers of Ischemic Stroke and Reveals the Protective Effect and Mechanism of Folic Acid.

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