scholarly journals Protective Action of Betulinic Acid on Cerebral Ischemia/Reperfusion Injury through Inflammation and Energy Metabolic Homeostasis

2020 ◽  
Vol 10 (7) ◽  
pp. 2578
Author(s):  
Wenjiao Jiang ◽  
Kun Hao
Keyword(s):  
Cerebral Ischemia ◽  
Betulinic Acid ◽  
Cell Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Protective Action ◽  
Enzyme Linked Immunosorbent Assay ◽  
Protective Effects ◽  
Cerebral Ischemia Reperfusion

This work evaluated the protective effects of betulinic acid (BA) in vitro cerebral ischemia/reperfusion and provides clues about its pharmacological mechanism. A rat model of middle cerebral artery occlusion (MCAO) was established to investigate the effects of BA on cerebral ischemia. SHSY5Y cell injury was induced by oxygen–glucose deprivation and recovery (OGD/R) to further verify the action of BA in vitro. Our data show a significant improvement in infarct size, neurological score, and cerebral edema after BA treatment. Enzyme linked immunosorbent assay (ELISA) data show that BA inhibited interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in vivo and in vitro. Protein expression results show that BA down-regulated hypoxia-inducible factor-1α (HIF-1α), up-regulated adenosine monophosphate activated protein kinase (AMPK), peroxisome proliferative activated receptor (PPAR)-α, and PPAR-γ coactivator-1α (PGC-1α), and blocked phosphorylation of IκBα and nuclear factor kappa Bp65 (NF-κB-p65) in the brains of MCAO rats and OGD/R-stimulated SHSY5Y cells. The results reveal the potent effects of BA on cerebral ischemia, suggesting that HIF-1α might be a crucial therapeutic target to regulate energy metabolism and inflammation.

scholarly journals Sphk1-induced Autophagy in Microglia Promotes Neuronal Injury Following Cerebral Ischemia-Reperfusion

2020 ◽  
Author(s):  
Manhua Lv ◽  
Yongjia Jiang ◽  
Dayong Zhang ◽  
Dan Yao ◽  
Yuefeng Cheng ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neuronal Injury ◽  
Glucose Deprivation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cerebral Ischemia Reperfusion ◽  
The Impact

Abstract Background: Microglial hyperactivation driven by SphK1/S1P signaling and consequent inflammatory mediator production is a key driver of cerebral ischemia-reperfusion injury (CIRI). While SphK1 reportedly controls autophagy and microglial activation, it remains uncertain as to whether it is similarly able to regulate damage mediated by CIRI-activated microglia. Methods: In the present study, we utilized both an in vitro oxygen-glucose deprivation reperfusion (OGDR) model and an in vivo rat model of focal CIRI to test whether Sphk1 and autophagy is expressed in microglia. Western blot analysis was used to estimate the autophagy protein level (LC3 and SQSTM ) at different time points after OGDR. To detect cytokine secretion in microglial supernatants in response to OGDR, we measured the concentration of IL-1β, IL-6 and TNF-α in the culture supernatants using an enzyme-linked immunosorbent assay (ELISA). To evaluate whether microglia subjected to OGDR exhibited neuronal injury, we used a commercially available terminal transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) kit and flow cytometry to detect apoptotic neurons.Results: We determined that in the context of CIRI, microglia upregulated SphK1 and induced autophagy, while inhibiting these changes by lentivirus targeting SphK1 significantly decreased expression of autophagy . Moreover, we determined that autophagic body formation was enhanced in cerebral tissues following I/R. We also explored the impact of SphK1-induced autophagy on microglial inflammatory cytokine production and associated neuronal apoptosis using an in vitro OGDR model system. At a mechanistic level, we found that SphK1 promotes autophagy via the tumor necrosis factor receptor-associated factor 2 (TRAF2) pathway. Conclusion: These results reveal a novel mechanism whereby SphK1-induced autophagy in microglia can contribute to the pathogenesis of CIRI, potentially highlighting novel avenues for future therapeutic intervention in IS patients.

scholarly journals OM-MSCs Alleviate the Golgi Apparatus Stress Response following Cerebral Ischemia/Reperfusion Injury via the PEDF-PI3K/Akt/mTOR Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Jialin He ◽  
Jianyang Liu ◽  
Yan Huang ◽  
Xiangqi Tang ◽  
Han Xiao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Stress Response ◽  
Cerebral Ischemia ◽  
Stress Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

The mechanism of Golgi apparatus (GA) stress responses mediated by GOLPH3 has been widely studied in ischemic stroke, and the neuroprotection effect of olfactory mucosa mesenchymal stem cells (OM-MSCs) against cerebral ischemia/reperfusion injury (IRI) has been preliminarily presented. However, the exact role of OM-MSCs in the GA stress response following cerebral IRI remains to be elucidated. In the present study, we used an oxygen-glucose deprivation/reoxygenation (OGD/R) model and reversible middle cerebral artery occlusion (MCAO) model to simulate cerebral IRI in vitro and in vivo. Our results showed that the level of GOLPH3 protein, reactive oxygen species (ROS), and Ca2+ was upregulated, SPCA1 level was downregulated, and GA fragmentation was increased in ischemic stroke models, and OM-MSC treatment clearly ameliorated these GA stress responses in vitro and in vivo. Subsequently, the knockdown of PEDF in OM-MSCs using PEDF-specific siRNA further demonstrated that secretion of PEDF in OM-MSCs protected OGD/R-treated N2a cells and MCAO rats from GA stress response. Additionally, rescue experiment using specific pathway inhibitors suggested that OM-MSCs could promote the phosphorylation of the PI3K/Akt/mTOR pathway, thereby mitigating OGD/R-induced GA stress response and excessive autophagy. In conclusion, OM-MSCs minimized the GA stress response following cerebral IRI, at least partially, through the PEDF-PI3K/Akt/mTOR pathway.

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