Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide

Irvine, Hannah; Acharjee, Animesh; Wolcott, Zoe; Ament, Zsuzsanna; Hinson, Holly E.; Molyneaux, Bradley J.; Simard, J. Marc; Sheth, Kevin N; Kimberly, W. Taylor

doi:10.1016/j.xcrm.2022.100654

Cited by 7 publications

(3 citation statements)

References 36 publications

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“…Hypoxanthine is a downstream product in the purine degradation pathway. The elevated hypoxanthine has been demonstrated to be a marker of oxidative stress ( Irvine et al., 2022 ). These evidences suggest that declined metabolic antioxidants and elevated purines reflect a more severe oxidative stress condition in null LDLR mutations carriers comparing to subjects carrying defective mutations.…”

Section: Discussionmentioning

confidence: 99%

Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia

Du¹,

Li²,

Li³

et al. 2022

iScience

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Section: Discussionmentioning

confidence: 99%

Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia

Du¹,

Li²,

Li³

et al. 2022

iScience

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“…11,12 The panel consisted of a total of 162 metabolites including amino acids, tricarboxylic acid cycle substrates, nucleotides, and nucleosides known to represent metabolites from a wide range of biological pathways using a validated method performed in our previous studies. 11,12,21,22 Full details of metabolite detection are provided elsewhere. 11,21,23,24 Briefly, polar metabolites were extracted by protein precipitation.…”

Section: Methodsmentioning

confidence: 99%

Plasma Metabolites and Life’s Simple 7 in REGARDS

Kijpaisalratana,

Ament,

Patki

et al. 2024

Stroke

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BACKGROUND: The American Heart Association’s Life’s Simple 7 (LS7) is a health metric that captures important factors associated with cardiovascular and cerebrovascular health. Previous studies highlight the potential of plasma metabolites to serve as a marker for lifestyle and health behavior that could be a target for stroke prevention. The objectives of this study were to identify metabolites that were associated with LS7 and incident ischemic stroke and mediate the relationship between the two. METHODS: Targeted metabolomic profiling of 162 metabolites by liquid chromatography–tandem mass spectrometry was used to identify candidate metabolites in a stroke case–cohort nested within the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Weighted linear regression and weighted Cox proportional hazard models were used to identify metabolites that were associated with LS7 and incident ischemic stroke, respectively. Effect measures were based on a 1-SD change in metabolite level. Metabolite mediators were examined using inverse odds ratio weighting mediation analysis. RESULTS: The study comprised 1075 ischemic stroke cases and 968 participants in the random cohort sample. Three out of 162 metabolites were associated with the overall LS7 score including guanosine (β, −0.46 [95% CI, −0.65 to −0.27]; P =2.87×10 −6 ), cotinine (β, −0.49 [95% CI, −0.70 to −0.28]; P =7.74×10 −6 ), and acetylneuraminic acid (β, −0.59 [95% CI, −0.77 to −0.42]; P =4.29×10 −11 ). Guanosine (hazard ratio, 1.47 [95% CI, 1.31–1.65]; P =6.97×10 −11 ), cotinine (hazard ratio, 1.30 [95% CI, 1.16–1.44]; P =2.09×10 −6 ), and acetylneuraminic acid (hazard ratio, 1.29 [95% CI, 1.15–1.45]; P =9.24×10 −6 ) were associated with incident ischemic stroke. The mediation analysis identified guanosine (27% mediation, indirect effect; P =0.002), cotinine (30% mediation, indirect effect; P =0.004), and acetylneurminic acid (22% mediation, indirect effect; P =0.041) partially mediated the relationship between LS7 and ischemic stroke. CONCLUSIONS: We identified guanosine, cotinine, and acetylneuraminic acid that were associated with LS7, incident ischemic stroke, and mediated the relationship between LS7 and ischemic stroke.

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“…The metabolites in each pattern shown in this figure are provided in Table S4. A group of 16 metabolites, including dihydrouracil, pyridine, ethanolamine phosphate, hypoxanthine, adenine, and ethanolamine, which are known to play important functions in brain metabolism, [49][50][51][52][53] were impacted at all three stages. In contrast, a larger group (n = 84) of metabolites were impacted in the postnatal and adult ages but unaffected in the prenatal brain (Table S4).…”

Section: Ablation Of Placental Rest Impacted Metabolism Of the Offspr...mentioning

confidence: 99%

Ablation of placental REST deregulates fetal brain metabolism and impacts gene expression of the offspring brain at the postnatal and adult stages

Islam,

Samal,

Davis

et al. 2023

The FASEB Journal

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In this study, the transcriptional repressor REST (Repressor Element 1 Silencing Transcription factor) was ablated in the mouse placenta to investigate molecular and cellular impacts on the offspring brain at different life stages. Ablation of placental REST deregulated several brain metabolites, including glucose and lactate that fuel brain energy, vitamin C (ascorbic acid) that functions in the epigenetic programming of the brain during postnatal development, and glutamate and creatine that help the brain to respond to stress conditions during adult life. Bulk RNA‐seq analysis showed that a lack of placental REST persistently altered multiple transport genes, including those related to oxygen transportation in the offspring brain. While metabolic genes were impacted in the postnatal brain, different stress response genes were activated in the adult brain. DNA methylation was also impacted in the adult brain due to the loss of placental REST, but in a sex‐biased manner. Single‐nuclei RNA‐seq analysis showed that specific cell types of the brain, particularly those of the choroid plexus and ependyma, which play critical roles in producing cerebrospinal fluid and maintaining metabolic homeostasis, were significantly impacted due to the loss of placental REST. These cells showed significant differential expression of genes associated with the metabotropic (G coupled protein) and ionotropic (ligand‐gated ion channel) glutamate receptors, suggesting an impact of ablation of placental REST on the glutamatergic signaling of the offspring brain. The study expands our understanding of placental influences on the offspring brain.

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Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide

Cited by 7 publications

References 36 publications

Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia

Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia

Plasma Metabolites and Life’s Simple 7 in REGARDS

Ablation of placental REST deregulates fetal brain metabolism and impacts gene expression of the offspring brain at the postnatal and adult stages

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