Analysis of Metabolite and Lipid Association Networks Reveals Molecular Mechanisms Associated with 3-Month Mortality and Poor Functional Outcomes in Patients with Acute Ischemic Stroke after Thrombolytic Treatment with Recombinant Tissue Plasminogen Activator

Licari, Cristina; Tenori, Leonardo; Giusti, Betti; Sticchi, Elena; Kura, Ada; Cario, Rosina De; Inzitari, Domenico; Piccardi, Benedetta; Nesi, Mascia; Sarti, Cristina; Arba, Francesco; Palumbo, Vanessa; Nencini, Patrizia; Marcucci, Rossella; Gori, Anna Maria; Luchinat, Claudio; Saccenti, Edoardo

doi:10.1021/acs.jproteome.1c00406

Cited by 10 publications

(6 citation statements)

References 68 publications

(123 reference statements)

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“…Our ndings validated previously described changes in serum levels of ketone bodies, BCAAs, and energy compounds in acute stroke 4,18,19 . Involvement of these metabolite subclasses should come from interplay of different metabolic pathways, all triggered by cerebral vessel occlusion (Fig.…”

Section: Discussionsupporting

confidence: 90%

Comparison of Acute and Chronic Stage Ischemic Stroke Metabolome with Controls

Sidorov

Rout

et al. 2023

Preprint

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Background Acute Ischemic Stroke (AIS), a major cause of disability, was previously associated with multiple metabolomic changes, but many findings were contradictory. Case-control and longitudinal study designs could have played a role in that. To clarify metabolomic changes, we performed a simultaneous comparison of ischemic stroke metabolome in acute, chronic stages of stroke and controls. Methods Through the nuclear magnetic resonance (NMR) platform, we evaluated 271 serum metabolites from a cohort of 297 AIS patients in acute and chronic stages and 159 controls. We used Sparse Partial Least Squares-Discriminant analysis (sPLS-DA) to evaluate group disparity; multivariate regression to compare metabolome in acute, chronic stages of stroke and controls; and mixed regression to compare metabolome acute and chronic stages of stroke. We applied false discovery rate (FDR) to our calculations. Results The sPLS-DA revealed separation of the metabolome in acute, chronic stages of stroke and controls. Regression analysis identified 38 altered metabolites. Ketone bodies, branched-chain amino acids (BCAAs), energy, and inflammatory compounds were elevated in the acute stage, but declined in the chronic stage, often to the same levels as in controls. Levels of other amino acids, phosphatidylcholines, phosphoglycerides, and sphingomyelins mainly did not change between acute and chronic stages, but was different comparing to controls. Conclusion Our pilot study identified metabolites associated with acute stage of ischemic stroke and those that are altered in stroke patients comparing to controls regardless of stroke acuity. Future investigation in a larger independent cohort is needed to validate these findings.

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Section: Discussionsupporting

confidence: 90%

Comparison of Acute and Chronic Stage Ischemic Stroke Metabolome with Controls

Sidorov

Rout

et al. 2023

Preprint

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“…Studies have shown that after brain injury, the expressions of citric acid, fumaric acid, and malic acid were decreased, indicating that the TCA pathway was inhibited [ 28 ]. The increased ketone body metabolism could provide alternative energy sources and to maintain free radical homeostasis during ischemia reperfusion injury [ 29 ]. 1-(4-methoxyphenyl)-4-methylpenta-1,4-pentadien-3-one, the precursor of ketone body, was significantly downregulated in MCAO model group in this experiment, which implied the ketone body metabolism was decreased.…”

Section: Discussionmentioning

confidence: 99%

The Combination of Individual Herb of Mi-Jian-Chang-Pu Formula Exerts a Synergistic Effect in the Treatment of Ischemic Stroke in Rats

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Mi-Jian-Chang-Pu formula (MJCPF), composed of Crocus sativus L. and Acorus tatarinowii Schott, is a well-known TCM for treatment of hemiplegia, facial paralysis as well as language dysfunction caused by stroke both in ancient and modern times. By using pharmacodynamics, pharmacokinetics, and metabolomics, our present study discusses whether the combination of individual herbs or major active components of MJCPF possess synergistic neuroprotective effects against ischemic stroke (IS). 108 adult male Sprague-Dawley rats were randomly and equally divided into 9 groups, including sham group (N, vehicle), middle cerebral artery occlusion (MCAO) model group (M, vehicle), positive group (P, 36 mg/kg/day nimodipine), crocin I (A1, 40 mg/kg/day), β-asarone (B1, 15 mg/kg/day), crocin I + β-asarone (A1B1, 55 mg/kg/day), C. sativus (A, 580 mg/kg/day), A. tatarinowii (B, 480 mg/kg/day), and C. sativus + A. tatarinowii, also named MJCPF (AB, 1060 mg/kg/day) groups. All drugs were orally administered to rats once a day for 14 consecutive days. Neurological deficit score, cerebral infarct volume, body weight change, TTC, HE and IHC staining, behavioral evaluation, metabolic profiles, and pharmacokinetic parameters were determined. MCAO led to severe brain damage including large infarct volume, more severe brain tissue injury, and worse neurological function as compared to the sham rats. All treatment groups showed a significant neuroprotective effect on MCAO rats. Furthermore, the pharmacodynamics’ results demonstrated that MJCPF had a synergistic effect evidenced by small infarct volume, more regular arrangement of neuronal cells, and more improved neural function, and the levels of inflammatory factors were closer to normality. A total of 53 differential metabolites between MCAO and sham groups were screened by integration of serum and brain metabolisms, all of which were restored at varying degrees in treatment. PCA and PLS-DA analysis showed that the levels of differential metabolites treated with MJCPF were closer to the sham group than the individual herb and single compound alone or A1B1 combination. The pharmacokinetic parameters further verified the above results that MJCPF could synergistically promote drug absorption greater than others. Our integrated pharmacodynamics, metabolomics, and pharmacokinetic approach reveals the synergistic effect of MJCPF on treatment of IS, which powerfully contribute to the understanding of scientific connotation of TMC formula.

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“…Despite the advantages of using metabolomics to identify differentially regulated processes related to stroke outcomes, few studies focus on this metric. In a large Italian study with over 200 available serum samples obtained within 24 h of treatment with tPA, Licari et al ( 45 ) identified only three metabolites as significantly changed between subjects with a poor 3-month functional outcome (mRS ≥3) compared to those with a good 3-month functional outcome (mRS ≤ 2) ( 45 ). These included upregulation of 3-hydroxybutyrate, Subfraction ApoB LDL-3, and LDL3_PN in patients with a good functional outcome compared to those with a poor functional outcome.…”

Section: Discussionmentioning

confidence: 99%

Sex as a biological variable in determining the metabolic changes influencing acute ischemic stroke outcomes—Where is the data: A systematic review

Dylla

Higgins

Piper³

et al. 2022

Front. Neurol.

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Women continue to face a greater lifetime morbidity and mortality from stroke and have been shown to respond differently to stroke treatments compared to men. Since 2016, updated National Institutes of Health (NIH) policies require research studies to consider sex as a biological variable. However, the way in which this policy affects study design, analysis, and reporting is variable, with few studies performing and reporting a subgroup analysis based on biological sex. In acute ischemic stroke, the underlying biological explanation for sex-based differences in patient outcomes and response to treatments remains understudied. We performed a systematic review of preclinical and clinical research studies that explored sex differences in the metabolic response to acute ischemic stroke as it relates to neurological outcomes. Through a literature search in Ovid Medline, Embase, and Web of Science, 1,004 potential references were identified for screening. After abstract and full-text review, we identified only two studies which assessed metabolic response to acute ischemic stroke (within 72 h of last known well) and neurological outcome [Barthel Index, modified Rankin Scale (mRS) or an equivalent in preclinical models] and reported results based on biological sex. One article was a preclinical rat model and the other a clinical cohort study. In both studies, metabolites involved in amino acid metabolism, energy metabolism, fat metabolism, or oxidative stress were identified. We review these results and link to additional articles that use metabolomics to identify metabolites differentially expressed by sex or regulated based on stroke outcomes, but not both. The results of this systematic review should not only help identify targets in need of further investigation to improve the understanding of sex differences in the pathophysiology of acute ischemic stroke, but also highlight the critical need to expand the incorporation of sex as a biological variable in acute stroke research beyond simply including both sexes and reporting the proportion of males/females in each population studied.

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Analysis of Metabolite and Lipid Association Networks Reveals Molecular Mechanisms Associated with 3-Month Mortality and Poor Functional Outcomes in Patients with Acute Ischemic Stroke after Thrombolytic Treatment with Recombinant Tissue Plasminogen Activator

Cited by 10 publications

References 68 publications

Comparison of Acute and Chronic Stage Ischemic Stroke Metabolome with Controls

Comparison of Acute and Chronic Stage Ischemic Stroke Metabolome with Controls

The Combination of Individual Herb of Mi-Jian-Chang-Pu Formula Exerts a Synergistic Effect in the Treatment of Ischemic Stroke in Rats

Sex as a biological variable in determining the metabolic changes influencing acute ischemic stroke outcomes—Where is the data: A systematic review

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