Metabolomic investigation of regional brain tissue dysfunctions induced by global cerebral ischemia

Wang, Weiwei; Huang, Jin; Liu, Xia; Zhang, Haiyan; Zhang, Nai-Xia

doi:10.1186/s12868-016-0256-9

Cited by 23 publications

(19 citation statements)

References 40 publications

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“…In that report, we observed an early upregulation of S1P in CA3 that was not observed in CA1, and we hypothesized that this intracellular S1P upregulation is one of the mechanisms by which the CA3 sub-region evades cell death after tGCI. Previous studies using global cerebral ischemia model have observed several metabolic changes to occur in the hippocampus, such as changes in phosphatidylcholine 31 and other phospholipids 35 as well as small metabolites and amino acids 41 , however, none of these studies attempted an approach as wide-scoped as the one reported here. www.nature.com/scientificreports www.nature.com/scientificreports/ In our work, we highlighted several pathways that were enriched following transient global cerebral ischemia in both CA1 and CA3 sub-regions.…”

Section: Discussionmentioning

confidence: 91%

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

Rashad

Saigusa

Yamazaki

et al. 2020

Sci Rep

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Understanding the root causes of neuronal vulnerability to ischemia is paramount to the development of new therapies for stroke. Transient global cerebral ischemia (tGCI) leads to selective neuronal cell death in the CA1 sub-region of the hippocampus, while the neighboring CA3 sub-region is left largely intact. By studying factors pertaining to such selective vulnerability, we can develop therapies to enhance outcome after stroke. Using untargeted liquid chromatography-mass spectrometry, we analyzed temporal metabolomic changes in CA1 and CA3 hippocampal areas following tGCI in rats till the setting of neuronal apoptosis. 64 compounds in CA1 and 74 in CA3 were found to be enriched and statistically significant following tGCI. Pathway analysis showed that pyrimidine and purine metabolism pathways amongst several others to be enriched after tGCI in CA1 and CA3. Metabolomics analysis was able to capture very early changes following ischemia. We detected 6 metabolites to be upregulated and 6 to be downregulated 1 hour after tGCI in CA1 versus CA3. Several metabolites related to apoptosis and inflammation were differentially expressed in both regions after tGCI. We offer a new insight into the process of neuronal apoptosis, guided by metabolomic profiling that was not performed to such an extent previously.Metabolomics is the study of metabolite composition of cells, tissues or biological fluids. Recent technological advances in this field has allowed the discovery of new biomarkers of diseases such as coronary artery disease, septic shock and brain tumors as well as the discovery of new drugs 1-5 . Metabolomic analysis has also deepened our understanding of several disease models, leading to the discovery of new pathways or targets for drug therapies that could later be applied to the treatment of various diseases [6][7][8][9][10][11] . Indeed, metabolomics are closer to the phenotype of a given disease compared with transcriptomic or proteomic analysis, both of which are prone to downstream modifications and changes in activities 1,12 .Several techniques, tools and software platforms exist to study metabolomics, all of which complement each other 13 . The application of these tools has greatly enhanced our understanding of the pathophysiology of diseases in almost every field of research 14 . In the field of neuroscience, metabolomic analysis is used to study stroke 15 , brain tumors 16 , traumatic brain injury (TBI) 17,18 , neurodegenerative diseases 19 , hypoxic-ischemic encephalopathy 20 and depression 21 to name a few 22 . The application of metabolomic tools to study brain diseases have greatly enhanced our understanding of different pathologies, for example; we demonstrated the upregulation of the ceramide "Cer(d18:0/18:0)" and phosphocreatine following transient ischemia-reperfusion in mice using a mass spectrometric imaging approach 15 . Several studies have highlighted an array of small molecules, amino acids and lipids that were linked to stroke severity, progression or post-stroke cognitive deficits [23][...

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Section: Discussionmentioning

confidence: 91%

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

Rashad

Saigusa

Yamazaki

et al. 2020

Sci Rep

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“…Cerebral infarction (CI) and ischemia (IS) are common diseases in elderly people seriously affecting the quality of life. Patients with IS exhibit insufficient blood supply, which is considered an early stage of CI ( 1 , 2 ). It is predicted that by 2030, the Chinese population aged ≥60 will be >300 million, and ~2/3 patients with primary cerebral vascular disease will be aged ≥60 years.…”

Section: Introductionmentioning

confidence: 99%

Analysis of intestinal microbial communities of cerebral infarction and ischemia patients based on high throughput sequencing technology and glucose and lipid metabolism

Zhu

Kan

et al. 2017

Molecular Medicine Reports

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Currently, cerebral infarction (CI) is the leading cause of disability and the second leading cause of mortality in China, seriously affecting patient quality of life. Ischemia (IS) is considered to be the early stage of CI. The present study aims to investigate the variation of intestinal microbial communities in patients with CI and IS using high throughput sequencing technology, and then analyze the results to identify a novel potential pathogenic mechanism of CI and IS. In total, 8 patients with CI, 2 patients with IS and 10 healthy volunteers as a control were selected. Throughput sequencing technology was used to analyze the character and microbial population of the gut. The abundance of Escherichia, Bacteroides, Megamonas, Parabacteroides, Akkermansia, Prevotella, Faecalibacterium, Dialister, Bifidobacterium and Ruminococcus was the significant difference in the intestinal microbial communities of the CI and IS patients compared with the healthy group. It was also observed that CI and IS were closely associated with internal glucose metabolism. The intestinal gut disturbance of CI patients may be one of the causes inducing CI by glucose metabolism and maybe considered as a potential method to predict the disease.

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“…The whole pancreatic tissues were quickly removed after the experimental mice were killed by dislocation of the cervical vertebrae, immediately snap-frozen in liquid nitrogen and then stored at −80°C until further analysis. Extractions of polar metabolites from the pancreas tissues were performed following the reported procedure [16][17][18]. In short, tissue samples, which were preweighed and thawed on ice, were homogenized and extracted with an ice-cold methanol-chloroform-water solvent system (4, 4, and 2.85 μL, respectively per mg/tissue).…”

Section: Serum and Pancreas Extraction Proceduresmentioning

confidence: 99%

Interplay between Alzheimer’s disease and global glucose metabolism revealed by the metabolic profile alterations of pancreatic tissue and serum in APP/PS1 transgenic mice

et al. 2019

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Increasing evidence suggests that there is a correlation between type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD). Increased Aβ polypeptide production in AD patients would promote metabolic abnormalities, insulin signaling dysfunction and perturbations in glucose utilization, thus leading to the onset of T2D. However, the metabolic mechanisms underlying the interplay between AD and its diabetes-promoting effects are not fully elucidated. Particularly, systematic metabolomics analysis has not been performed for the pancreas tissues of AD subjects, which play key roles in the glucose metabolism of living systems. In the current study, we characterized the dynamic metabolic profile alterations of the serum and the pancreas of APP/PS1 double-transgenic mice (an AD mouse model) using the untargeted metabolomics approaches. Serum and pancreatic tissues of APP/PS1 transgenic mice and wild-type mice were extracted and subjected to NMR analysis to evaluate the functional state of pancreas in the progress of AD. Multivariate analysis of principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were conducted to define the global and the local (pancreas) metabolic features associated with the possible initiation of T2D in the progress of AD. Our results showed the onset of AD-induced global glucose metabolism disorders in AD mice. Hyperglycemia and its accompanying metabolic disorders including energy metabolism down-regulation and oxidative stress were observed in the serum of AD mice. Meanwhile, global disturbance of branched-chain amino acid (BCAA) metabolism was detected, and the change of BCAA (leucine) was positively correlated to the alteration of glucose. Moreover, increased level of glucose and enhanced energy metabolism were observed in the pancreas of AD mice. The results suggest that the diabetes-promoting effects accompanying the progress of AD are achieved by down-regulating the global utilization of glucose and interfering with the metabolic function of pancreas. Since T2D is a risk factor for the pathogenesis of AD, our findings suggest that targeting the glucose metabolism dysfunctions might serve as a supplementary therapeutic strategy for Alzheimer's disease.

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Metabolomic investigation of regional brain tissue dysfunctions induced by global cerebral ischemia

Cited by 23 publications

References 40 publications

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

Analysis of intestinal microbial communities of cerebral infarction and ischemia patients based on high throughput sequencing technology and glucose and lipid metabolism

Interplay between Alzheimer’s disease and global glucose metabolism revealed by the metabolic profile alterations of pancreatic tissue and serum in APP/PS1 transgenic mice

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