Metabolomic Profiles Associated With Incident Ischemic Stroke

Balasubramanian, Raji; Hu, Jie; Guasch‐Ferré, Marta; Li, Jun; Sorond, Farzaneh A.; Zhao, Yibai; Shutta, Katherine H.; Salas‐Salvadó, Jordi; Hu, Frank B.; Clish, Clary B.; Rexrode, Kathryn M

doi:10.1212/wnl.0000000000013129

Cited by 13 publications

(13 citation statements)

References 47 publications

(65 reference statements)

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“…A recent large‐scale prospective metabolomics study revealed that MetO was significantly associated with incident stroke, and its related metabolite score improved the prediction of the risk of incident ischemic stroke. 26 Another study confirmed the protective role of MetO reductase system to neurovascular inflammation in ischemic stroke, which attenuated ROS‐augmented NF‐κB activation in endothelial cells and protected against the oxidation of Met residues in the regulatory domain of calcium/calmodulin‐dependent protein kinase II (CaMKII). 27 Furthermore, the deficiency of MetO reductase A (MsrA) has been shown to promote vascular smooth muscle cell (VSMC) proliferation and neointimal hyperplasia through the extracellular signal‐regulated kinase 1/2 signaling pathway, 28 which were also pathological changes associated with MMD.…”

Section: Discussionmentioning

confidence: 85%

“…Previous studies have discussed the relationship between MetO and cerebrovascular disease. A recent large‐scale prospective metabolomics study revealed that MetO was significantly associated with incident stroke, and its related metabolite score improved the prediction of the risk of incident ischemic stroke 26 . Another study confirmed the protective role of MetO reductase system to neurovascular inflammation in ischemic stroke, which attenuated ROS‐augmented NF‐κB activation in endothelial cells and protected against the oxidation of Met residues in the regulatory domain of calcium/calmodulin‐dependent protein kinase II (CaMKII) 27 .…”

Section: Discussionmentioning

confidence: 99%

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Integrated analysis of the association between methionine cycle and risk of moyamoya disease

Liu

et al. 2023

CNS Neurosci Ther

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ObjectiveThe role of methionine (Met) cycle in the pathogenesis and progression of cardiovascular and cerebrovascular diseases has been established, but its association with moyamoya disease (MMD) has rarely been studied. This study aimed to analyze the levels of Met cycle‐related metabolites and constructed a risk model to explore its association with the risk of MMD.MethodsIn this prospective study, a total of 302 adult MMD patients and 88 age‐matched healthy individuals were consecutively recruited. The serum levels of Met cycle‐related metabolites were quantified by liquid chromatography‐mass spectrometry (LC–MS). Participants were randomly divided into training set and testing set at a ratio of 1:1. The training set was used to construct the risk score model by LASSO regression. The association between Met cycle‐related risk score and the risk of MMD was analyzed using logistic regression and assessed by ROC curves. The testing set was used for validation.ResultsThe levels of methionine sulfoxide and homocysteine were significantly increased, while the levels of betaine and choline were significantly decreased in MMD and its subtypes compared to healthy controls (p < 0.05 for all). The training set was used to construct the risk model and the risk score of each participant has been calculated. After adjusting for potential confounders, the risk score was independently associated with the risk of MMD and its subtypes (p < 0.05 for all). We then divided the participants into low‐risk and high‐risk groups, the high‐risk score was significantly associated with the risk of MMD and its subtypes (p < 0.05 for all). The risk scores were further assessed as tertiles, the highest tertile was significantly associated with a higher risk of MMD and its subtypes compared to the lowest (p < 0.05 for all). The results were validated in the testing set.ConclusionThis study has constructed and validated a risk model based on Met cycle‐related metabolites, which was independently associated with the risk of MMD and its subtypes. The findings provided a new perspective on the risk evaluation and prevention of MMD.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Integrated analysis of the association between methionine cycle and risk of moyamoya disease

Liu

et al. 2023

CNS Neurosci Ther

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“…The link between MetO and cerebrovascular disease has been shown. A recent large prospective study on metabolomic characteristics of ischemic stroke found a significant association between MetO and incident stroke, with higher levels being associated with increased risk ( Balasubramanian et al, 2022 ). Another study demonstrated that betaine could decrease proinflammatory cytokine production and reduce oxidative stress after brain ischemia and reperfusion injury by upragulating MetO reductase ( Li et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Association between methionine sulfoxide and risk of moyamoya disease

et al. 2023

Front. Neurosci.

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ObjectiveMethionine sulfoxide (MetO) has been identified as a risk factor for vascular diseases and was considered as an important indicator of oxidative stress. However, the effects of MetO and its association with moyamoya disease (MMD) remained unclear. Therefore, we performed this study to evaluate the association between serum MetO levels and the risk of MMD and its subtypes.MethodsWe eventually included consecutive 353 MMD patients and 88 healthy controls (HCs) with complete data from September 2020 to December 2021 in our analyzes. Serum levels of MetO were quantified using liquid chromatography-mass spectrometry (LC–MS) analysis. We evaluated the role of MetO in MMD using logistic regression models and confirmed by receiver-operating characteristic (ROC) curves and area under curve (AUC) values.ResultsWe found that the levels of MetO were significantly higher in MMD and its subtypes than in HCs (p < 0.001 for all). After adjusting for traditional risk factors, serum MetO levels were significantly associated with the risk of MMD and its subtypes (p < 0.001 for all). We further divided the MetO levels into low and high groups, and the high MetO level was significantly associated with the risk of MMD and its subtypes (p < 0.05 for all). When MetO levels were assessed as quartiles, we found that the third (Q3) and fourth (Q4) MetO quartiles had a significantly increased risk of MMD compared with the lowest quartile (Q3, OR: 2.323, 95%CI: 1.088–4.959, p = 0.029; Q4, OR: 5.559, 95%CI: 2.088–14.805, p = 0.001).ConclusionIn this study, we found that a high level of serum MetO was associated with an increased risk of MMD and its subtypes. Our study raised a novel perspective on the pathogenesis of MMD and suggested potential therapeutic targets.

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“…It is a major derivative of methionine oxidation with ROS by a two-electron dependent mechanism [ 149 ]. Balasubramanian et al [ 95 ] reported an association between the methionine sulfoxide and the increased risk of incident stroke. Another study conducted by Li et al [ 150 ] observed a neuroprotective impact in ischemia/reperfusion injuries when when an increase in methionine sulfoxide reductases enzymes occurred following betaine administration; the methionine sulfoxide reductases enzymes.…”

Section: Oxidative Protein Modificationsmentioning

confidence: 99%

The Role of Potential Oxidative Biomarkers in the Prognosis of Acute Ischemic Stroke and the Exploration of Antioxidants as Possible Preventive and Treatment Options

Zahra

Lefter

Jaber

et al. 2023

IJMS

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Ischemic strokes occur when the blood supply to a part of the brain is interrupted or reduced due to arterial blockage, and it often leads to damage to brain cells or death. According to a myriad of experimental studies, oxidative stress is an important pathophysiological mechanism of ischemic stroke. In this narrative review, we aimed to identify how the alterations of oxidative stress biomarkers could suggest a severity-reflecting diagnosis of ischemic stroke and how these interactions may provide new molecular targets for neuroprotective therapies. We performed an eligibility criteria-based search on three main scientific databases. We found that patients with acute ischemic stroke are characterized by increased oxidative stress markers levels, such as the total antioxidant capacity, F2-isoprostanes, hydroxynonenal, total and perchloric acid oxygen radical absorbance capacity (ORACTOT and ORACPCA), malondialdehyde (MDA), myeloperoxidase, and urinary 8-oxo-7,8-dihydro-2′-deoxyguanosine. Thus, acute ischemic stroke is causing significant oxidative stress and associated molecular and cellular damage. The assessment of these molecular markers could be useful in diagnosing ischemic stroke, finding its causes, predicting its severity and outcomes, reducing its impact on the cellular structures of the brain, and guiding preventive treatment towards antioxidant-based therapy as novel therapeutic alternatives.

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Metabolomic Profiles Associated With Incident Ischemic Stroke

Cited by 13 publications

References 47 publications

Integrated analysis of the association between methionine cycle and risk of moyamoya disease

Integrated analysis of the association between methionine cycle and risk of moyamoya disease

Association between methionine sulfoxide and risk of moyamoya disease

The Role of Potential Oxidative Biomarkers in the Prognosis of Acute Ischemic Stroke and the Exploration of Antioxidants as Possible Preventive and Treatment Options

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