1. IntroductionStroke presents a more significant health burden on women than in men as women present with more stroke events and are less likely to recover . While age-specific stroke rates are higher in men, women present with more stroke incidents than men because of their longer life expectancy and much of a higher incidence at older ages . Similar to age-adjusted mortality, women present with more overall lower age-adjusted stroke incidence than men [3,4]. In addition, functional outcomes and quality of life after stroke are consistently poorer in women, and women are reported to present with worse pre-stroke disability than men [3,5]. Moreover, men and women with stroke differ concerning the prevalence of stroke risk factors [6,7]. Women with stroke are older at onset and are more likely to have atrial fibrillation and hypertension . In contrast, men with stroke are more likely to present with a history of heart disease, myocardial infarction, peripheral arterial disease, diabetes, and alcohol and tobacco use [9,10]. The most common biological explanation for differences in stroke between men and women is posited to be hormonal . In addition, studies in animal models demonstrate that women have smaller stroke volumes than men .The human blood contains a wide variety of chemically diverse low molecular weight compounds, the metabolome, which can be measured in parallel through modern metabolomic technologies . Analysis of the metabolome in AIS patients provides new opportunities to understand the pathophysiology of ischemic stroke . Therefore, metabolomics is a promising technique for the evaluation of global metabolic changes in stroke . By comparing metabolic profiles and their dynamic changes, changes in pretreated and treated patients can be elucidated. Metabolites in blood have been reported to be associated with vascular diseases . For example, lipoprotein associated phospholipase A2 (Lp-PLA2) was reported to be linked with atherosclerosis and transient ischemic attack [16,17], and lysophosphatidylcholines (LysoPCs) were significantly associated with recurrent stroke . In addition, metabolic profiles in AIS are reported to be significantly different from healthy people [19,20]. For example, changes in sphingomyelin and phosphatidylcholine metabolism were independently linked with risk of infarction in healthy adults. While different, there are multiple blood-based biomarkers investigated in AIS patients. For example, multiple blood biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP], d-dimer, S100β, neuron-specific enolase, vitamin D, cortisol, interleukin-6, insulin, uric acid, and albumin) were effective in the identification of patients with increased possibility of cardioembolism and AF . Moreover, various blood-based biomarkers including BNP/NT-proBNP, d-dimer, CRP, TNF-α, IL-6, and IL-1 are reported to be significantly associated with ischemic stroke [21,22,23]. Findings from the existing studies indicate that metabolomics is a powerful tool that can be used to explore biomarkers and related pathways in stroke. The vulnerability to several diseases and the response to treatments differ between men and women . Therefore, the differential treatment for men and women AIS patients would represent personalized medicine approach  to provide care for AIS patients. However, this requires an extensive understanding not only clinical risk factors but also the intrinsic molecular differences between men and women AIS patients. As a basis for a gender-specific care for AIS patients, the characterization of the molecular differences between the men and women AIS patients is necessary. Moreover, affected pathways may reveal gender-specific susceptibility. Knowledge of the underlying metabolic differences might lead to concrete starting points for a future research to improve care for men and women AIS patients. Existing studies [13,14,26,27,28,29,30,31,32,33,34] that investigated metabolites in stroke focused on differences between stroke and control, hemorrhagic strokes compared with non-hemorrhagic or ischemic strokes. For example, elevated plasma DNA concentrations were detected in patients with hemorrhagic strokes compared with non-hemorrhagic strokes, with a 31% sensitivity and 83% specificity for discriminating the two types of stroke . Moreover, plasma levels of miR-124-3p, miR-125b-5p, and miR-192-5p, were found to be elevated and correlated positively with infarct volume of stroke patients [35,36,37]. In addition, protein biomarkers for brain injury and thrombosis were categorized and used to discriminate hemorrhagic stroke from ischemic stroke patients . A recent study by Daokun et al.  analyzed serum metabolites and risk of ischemic stroke in men and women patients. The results reveal circulating biomarkers for stroke and novel pathways for AIS and its subtypes. However, differences between men and women patients were not reported. While findings from existing studies [13,14,26,27,28,29,30,31,32,33,34] highlight the potential of metabolomics for discovering novel circulating biomarkers for stroke and its subtypes, existing studies did not report gender-differentiated results. Therefore, the specific metabolites and related pathways that are directly associated with men and women AIS patients are not fully understood. Therefore, we conducted an untargeted metabolomics study to investigate whether metabolic profiles and related pathways are different in men and women patients with AIS.
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