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Analysis of Metabolic Alterations Related to Pathogenic Process of Diabetic Encephalopathy Rats.

ABSTRACT: Diabetic encephalopathy (DE) is a diabetic complication characterized by alterations in cognitive function and nervous system structure. The pathogenic transition from hyperglycemia to DE is a long-term process accompanied by multiple metabolic disorders. Exploring time-dependent metabolic changes in hippocampus will facilitate our understanding of the pathogenesis of DE. In the present study, we first performed behavioral and histopathological experiments to confirm the appearance of DE in rats with streptozotocin-induced diabetes. We then utilized nuclear magnetic resonance-based metabonomics to analyze metabolic disorders in the hippocampus at different stages of DE. After 1 week, we observed no cognitive or structural impairments in diabetic rats, although some metabolic changes were observed in local hippocampal extracts. At 5 weeks, while cognitive function was still normal, we then examined initial levels of neuronal apoptosis. The characteristic metabolic changes of this stage included elevated levels of energy metabolites (i.e., ATP, ADP, AMP, and creatine phosphate/creatine). At 9 weeks, significant cognitive decline and histopathological brain damage were observed, in conjunction with reduced levels of some amino acids. Thus, this stage was classified as the DE period. Our findings indicated that the pathogenesis of DE is associated with time-dependent alterations in metabolic features in hippocampal regions, such as glycolysis, osmoregulation, energy metabolism, choline metabolism, branched-chain amino acid metabolism, and the glutamate-glutamine cycle. Furthermore, we observed alterations in levels of lactate and its receptor in hippocampal cells, which may be involved in the pathogenesis of DE.

SUBMITTER: Dong M

PROVIDER: S-EPMC6339875 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Analysis of Metabolic Alterations Related to Pathogenic Process of Diabetic Encephalopathy Rats.

Dong Minjian M Ren Mengqian M Li Chen C Zhang Xi X Yang Changwei C Zhao Liangcai L Gao Hongchang H

Frontiers in cellular neuroscience 20190114

Diabetic encephalopathy (DE) is a diabetic complication characterized by alterations in cognitive function and nervous system structure. The pathogenic transition from hyperglycemia to DE is a long-term process accompanied by multiple metabolic disorders. Exploring time-dependent metabolic changes in hippocampus will facilitate our understanding of the pathogenesis of DE. In the present study, we first performed behavioral and histopathological experiments to confirm the appearance of DE in rats ...[more]

PMID: 30692917

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Project description:BackgroundDiabetic encephalopathy (DE) is a complication of diabetes that leads to cognitive and behavioral decline. Utilizing safe and effective complementary and alternative medications for its management is a wise choice. Previous studies have shown that GuanXinNing Tablet (GXNT), an oral preparation primarily derived from two Chinese herbs, Salvia miltiorrhiza Bge. and Ligusticum chuanxiong Hort., exerts a beneficial neuroprotective effect. In this study, we explored the protective effects of GXNT on DE in male Zucker diabetic fatty (ZDF) rats induced by a high-fat diet, aiming to ascertain its significance and potential mechanisms.MethodsZDF rats were induced to develop type 2 diabetes (T2DM) with DE by a high-fat diet and treated with GXNT for 8 weeks until they were 20 weeks old. Throughout the experiment, the animals' vital parameters, such as body weight, were continuously monitored. Cognitive function was evaluated using the Y maze test. Biochemical kits were employed to analyze blood glucose, lipids, and vascular endothelial-related factors. Cerebrovascular lesions were assessed using magnetic resonance angiography (MRA) imaging. Brain lesions were evaluated using hematoxylin and eosin (H&E) staining and ultrastructure observation. IgG and albumin (ALB) leakage were detected using immunofluorescence.ResultsGXNT demonstrated an enhancement in the overall well-being of the animals. It notably improved cognitive and behavioral abilities, as demonstrated by extended retention time in the novel heterogeneous arm during the Y-maze test. GXNT effectively regulated glucose and lipid metabolism, reducing fasting and postprandial blood glucose, glycated hemoglobin (HbA1c), and total cholesterol (TC) levels. Additionally, it exhibited a protective effect on the vascular endothelium by reducing the serum TXB2/PGI2 ratio while elevating NO and PGI2 levels. Moreover, GXNT ameliorated stenosis and occlusion in cerebral vessel branches, increased the number of microvessels and neurons around the hippocampus, and improved microvascular occlusion in the cerebral cortex, along with addressing perivascular cell abnormalities. Immunofluorescence staining showed a decrease in the fluorescence intensity of IgG and ALB in the cerebral cortex.ConclusionsGXNT demonstrated a highly satisfactory protective effect on DE in ZDF rats. Its mechanism of action could be based on the regulation of glucolipid metabolism and its protective effect on the vascular endothelium.

Project description:Most herbal polyphenols and flavonoids reveals multiple ameliorative benefits for obesity caused by chronic metabolic disorders. Accumulated studies have revealed that preferable therapeutic effects can be obtained through clinical combination of these two kinds of natural compounds for obesity improvement. The typical representative research was the combination of quercetin and resveratrol (CQR), in which the ratio of quercetin and resveratrol is 2:1, demonstrating a synergistic effect in anti-obesity process. Although there exists reports clarifying the mechanism of the combination of two to improve obesity from the perspective of improving adipose tissue inflammation or modulating the composition of intestinal flora, there are few further studies on the mechanism of drug action from the perspective of metabolites transformation. In this research, we mainly focused on the alterations of endogenous metabolites in rats, and analyzed the urine metabolites of obese and intervention model. Therefore, a gas chromatography-mass spectrometry (GC-MS) based metabolomics approach was applied to assess the potential effects and mechanisms of CQR at different dosages (45, 90, and 180 mg/kg) in high fat diet (HFD)-induced obesity rats. Body weight gain and visceral fat weight were reduced by CQR, as well as blood lipid and inflammatory factor levels were increased by CQR in a dose-related manner. Urinary metabolomics revealed 22 differential metabolites related to the HFD-induced obesity, which were reversed in a dose-dependent manner by CQR, of which 8 were reversed in the 45 mg/kg CQR group, 15 were reversed in the 90 mg/kg CQR group, and 18 were reversed in the 180 mg/kg CQR group. Combined with bioinformatics and pattern recognition, the results demonstrated that the key differential metabolites were basically involved in amino acid metabolism, galactose metabolism, pantothenate and CoA biosynthesis, pyruvate metabolism and lysine degradation. In summary, our results showed significant therapeutic action by CQR administration and remarkable metabolomic changes after HFD feeding and CQR intervention. Urinary metabolomic analysis was highlighted on account of providing holistic and comprehensive insights into the pathophysiological mechanisms of the HFD-induced obesity, which also supplied clues for the future mechanism studies of CQR's anti-obesity effects.

Project description:While genome-wide association studies are an established method of identifying genetic variants associated with disease, environment-wide association studies (EWAS) highlight the contribution of nongenetic components to complex phenotypes. However, the lack of high-throughput quality control (QC) pipelines for EWAS data lends itself to analysis plans where the data are cleaned after a first-pass analysis, which can lead to bias, or are cleaned manually, which is arduous and susceptible to user error. We offer a novel software, CLeaning to Analysis: Reproducibility-based Interface for Traits and Exposures (CLARITE), as a tool to efficiently clean environmental data, perform regression analysis, and visualize results on a single platform through user-guided automation. It exists as both an R package and a Python package. Though CLARITE focuses on EWAS, it is intended to also improve the QC process for phenotypes and clinical lab measures for a variety of downstream analyses, including phenome-wide association studies and gene-environment interaction studies. With the goal of demonstrating the utility of CLARITE, we performed a novel EWAS in the National Health and Nutrition Examination Survey (NHANES) (N overall Discovery=9063, N overall Replication=9874) for body mass index (BMI) and over 300 environment variables post-QC, adjusting for sex, age, race, socioeconomic status, and survey year. The analysis used survey weights along with cluster and strata information in order to account for the complex survey design. Sixteen BMI results replicated at a Bonferroni corrected p < 0.05. The top replicating results were serum levels of g-tocopherol (vitamin E) (Discovery Bonferroni p: 8.67x10-12, Replication Bonferroni p: 2.70x10-9) and iron (Discovery Bonferroni p: 1.09x10-8, Replication Bonferroni p: 1.73x10-10). Results of this EWAS are important to consider for metabolic trait analysis, as BMI is tightly associated with these phenotypes. As such, exposures predictive of BMI may be useful for covariate and/or interaction assessment of metabolic-related traits. CLARITE allows improved data quality for EWAS, gene-environment interactions, and phenome-wide association studies by establishing a high-throughput quality control infrastructure. Thus, CLARITE is recommended for studying the environmental factors underlying complex disease.

Project description:BackgroundThere is a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM) due to the worldwide obesity epidemic. However, a significant proportion of T2DM patients are non-obese and they also have an increased risk of cardiovascular diseases. As the Goto-Kakizaki (GK) rat is a well-known model of non-obese T2DM, the goal of this study was to investigate the effect of non-obese T2DM on cardiac alterations of the transcriptome in GK rats.MethodsFasting blood glucose, serum insulin and cholesterol levels were measured at 7, 11, and 15 weeks of age in male GK and control rats. Oral glucose tolerance test and pancreatic insulin level measurements were performed at 11 weeks of age. At week 15, total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 41,012 genes, and then expression of selected genes was confirmed by qRT-PCR. Gene ontology and protein-protein network analyses were performed to demonstrate potentially characteristic gene alterations and key genes in non-obese T2DM.ResultsFasting blood glucose, serum insulin and cholesterol levels were significantly increased, glucose tolerance and insulin sensitivity were significantly impaired in GK rats as compared to controls. In hearts of GK rats, 204 genes showed significant up-regulation and 303 genes showed down-regulation as compared to controls according to microarray analysis. Genes with significantly altered expression in the heart due to non-obese T2DM includes functional clusters of metabolism (e.g. Cyp2e1, Akr1b10), signal transduction (e.g. Dpp4, Stat3), receptors and ion channels (e.g. Sln, Chrng), membrane and structural proteins (e.g. Tnni1, Mylk2, Col8a1, Adam33), cell growth and differentiation (e.g. Gpc3, Jund), immune response (e.g. C3, C4a), and others (e.g. Lrp8, Msln, Klkc1, Epn3). Gene ontology analysis revealed several significantly enriched functional inter-relationships between genes influenced by non-obese T2DM. Protein-protein interaction analysis demonstrated that Stat is a potential key gene influenced by non-obese T2DM.ConclusionsNon-obese T2DM alters cardiac gene expression profile. The altered genes may be involved in the development of cardiac pathologies and could be potential therapeutic targets in non-obese T2DM.

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Analysis of Metabolic Alterations Related to Pathogenic Process of Diabetic Encephalopathy Rats.

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Analysis of Metabolic Alterations Related to Pathogenic Process of Diabetic Encephalopathy Rats.

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