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Lycium Barbarum Polysaccharides Decrease Hyperglycemia-Aggravated Ischemic Brain Injury through Maintaining Mitochondrial Fission and Fusion Balance.

ABSTRACT: Although it has been reported that polysaccharides found in Lycium barbarum possess neuroprotective effects, little is known of their ability to ameliorate hyperglycemia-aggravated ischemia/reperfusion brain injury. In this study, normoglycemic (NG) and hyperglycemic (HG) rats were compared after 30 minutes of middle cerebral artery occlusion (MCAO), followed by 24 or 27 hours of reperfusion, with HG rats pretreated with lyceum barbarum polysaccharides (LBP) or insulin. In each group, the neurological deficit, infarct volume, pathohistology, and expression of proteins, Opa1 and Drp1, were assessed to determine the efficacy of LBP in alleviating hyperglycemia-aggravated ischemia/reperfusion brain injury. Our results show that, compared to the NG group, the HG group had increases in neurological deficits, infarct volume, and evidence of neuronal pyknosis at 24- and/or 72-h of reperfusion (P<0.05) and that pre-treatment with LBP decreased these effects (P<0.05). In addition, immunohistochemistry revealed an increase of Drp1 and a decrease of Opa1 positive neurons in the HG group after 24 and 72 hours of reperfusion when compared to the NG group. LBP treatment prevented the HG-induced alterations in Drp-1 and Opa1 expression. Western blots further confirmed these findings showing that HG caused an increase in phospho-Drp1 and a decrease in Opa1 which were subsequently reversed by LBP addition. These results suggest that hyperglycemia-aggravated ischemic brain damage is associated with an alteration of mitochondrial dynamics and that pre-treatment with LBP ameliorates the hyperglycemia-enhanced ischemic brain damage through maintaining mitochondrial dynamic balance.

SUBMITTER: Liu WJ

PROVIDER: S-EPMC5555107 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:Mitochondrial dysfunction is a predominant risk factor in ischemic heart disease, in which the imbalance of mitochondrial fusion and fission deteriorates mitochondrial function and might lead to cardiomyocyte death. C-phycocyanin (C-pc), an active component from blue-green algae, such as Spirulina platensis, has been reported to have anti-apoptosis and anti-oxidation functions. In this study, the effects of C-pc on mitochondrial dynamics of cardiomyocytes was examined using an oxygen-glucose deprivation/reoxygenation (OGD/R) model in H9c2 cells, an in vitro model to study the ischemia in the heart. Cell viability assay showed that C-pc dose-dependently reduced OGD/R-induced cell death. Intracellular reactive oxygen species production induced by OGD/R was decreased in C-pc-treated groups in a dose-dependent manner as well. H9c2 cells subjected to OGD/R showed excessive mitochondrial fission and diminished mitochondrial fusion. C-pc treatment significantly ameliorated unbalanced mitochondrial dynamics induced by OGD/R and regulated mitochondrial remodeling through inhibiting mitochondrial fission while promoting fusion. The enhanced expressions of dynamin 1-like protein and mitochondrial fission 1 protein induced by OGD/R were suppressed by C-pc, while the subdued expressions of mitochondrial fusion proteins mitofusins 1 and 2 and optic atrophy 1 induced by OGD/R increased in C-pc-treated groups. Triple immunofluorescence staining revealed that C-pc treatment reduced the recruitment of dynamin 1-like protein from cytoplasm to mitochondrial membranes. Furthermore, C-pc protected H9c2 cells against OGD/R-induced cytochrome c/apoptotic protease activating factor-1 intrinsic apoptosis and suppressed the phosphorylations of extracellular signal-regulated kinase and c-Jun N-terminal kinase. These results suggest that C-pc protects cardiomyocytes from ischemic damage by affecting mitochondrial fission and fusion dynamics and reducing apoptosis and, thus, may be of potential as a prophylactic or therapeutic agent for ischemic heart disease.

Project description:ObjectiveAtherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients. Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s).Methods and resultsWild-type mice were injected with gain-of-function PCSK9D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis, two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery) were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi) mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic plaques of HGHCi HFD animals were larger, showed a less stable phenotype (measured by the increased necrotic core area, reduced fibrous cap thickness, and less α-SMA-positive area) and had more inflammation (increased plasma IL-1β level, aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA) after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and extracellular matrix degradation (Adamts4 and Mmp14). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks. Hyperlipidemic and hyperglycemic mice fed a PD (HGHCi PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells) within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks.ConclusionWe established a nongenetically inducible mouse model allowing comparative analyses of atherosclerosis in HCi and HGHCi conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice.

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Lycium Barbarum Polysaccharides Decrease Hyperglycemia-Aggravated Ischemic Brain Injury through Maintaining Mitochondrial Fission and Fusion Balance.

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