Protection against cerebral infarction by Withaferin A involves inhibition of neuronal apoptosis, activation of PI3K/Akt signaling pathway, and reduced intimal hyperplasia via inhibition of VSMC migration and matrix metalloproteinases

2017 ◽  
Vol 62 (1) ◽  
pp. 186-192 ◽  
Author(s):  
Qi-Zhi Zhang ◽  
Yu-Dong Guo ◽  
Hao-Mei Li ◽  
Rui-Zheng Wang ◽  
Shou-Gang Guo ◽  
...  
2019 ◽  
Vol 56 (12) ◽  
pp. 8203-8219 ◽  
Author(s):  
Takeshi Okada ◽  
Budbazar Enkhjargal ◽  
Zachary D. Travis ◽  
Umut Ocak ◽  
Jiping Tang ◽  
...  

2020 ◽  
Vol 75 (4) ◽  
pp. 387-397
Author(s):  
Linlin Wei ◽  
Kexue Zeng ◽  
Juanjuan Gai ◽  
Feixiong Zhou ◽  
Zhenglin Wei ◽  
...  

OBJECTIVE: To study the effect of acupuncture on neurovascular units after cerebral infarction (CI) in rats through the phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/AKT) signaling pathway. METHODS: A total of 36 Sprague-Dawley rats were randomly divided into sham group (n = 12), model group (n = 12) and acupuncture group (n = 12). The external carotid artery was only exposed in model group, while the post-CI ischemia-reperfusion model was established using the suture method in the other 2 groups. After modeling, the rats in sham group and model group were fixed and sampled, while those in acupuncture group were treated with acupuncture intervention for 2 weeks and sampled. The neurological deficits of rats were evaluated using the Zea-Longa score, and the spatial learning and memory of rats were detected via water maze test. Moreover, the expressions of vascular endothelial growth factor (VEGF), growth associated protein-43 (GAP-43) and synuclein (SYN) in brain tissues were detected via immunohistochemistry, and the relative protein expressions of PI3K p85, PI3K p110 and p-AKT were detected via Western blotting. The messenger ribonucleic acid (mRNA) expressions of VEGF, GAP-43 and SYN were detected via quantitative polymerase chain reaction (qPCR). RESULTS: The Zea-Longa score was significantly increased in model group and acupuncture group compared with that in sham group (p < 0.05), while it significantly declined in acupuncture group compared with that in model group (p < 0.05). The escape latency was significantly prolonged and the times of crossing platform were significantly reduced in model group and acupuncture group compared with those in sham group (p < 0.05), while the escape latency was significantly shortened and the times of crossing platform were significantly increased in acupuncture group compared with those in model group (p < 0.05). The positive expressions of VEGF, GAP-43 and SYN were obviously increased in model group and acupuncture group compared with those in sham group (p < 0.05), while they were obviously increased in acupuncture group compared with those in model group (p < 0.05). Besides, model group and acupuncture group had significantly higher relative protein expressions of PI3K p85, PI3K p110 and p-AKT than sham group (p < 0.05), while acupuncture group also had significantly higher relative protein expressions of PI3K p85, PI3K p110 and p-AKT than model group (p < 0.05). The relative mRNA expressions of VEGF, GAP-43 and SYN were remarkably increased in model group and acupuncture group compared with those in sham group (p < 0.05), while they were remarkably increased in acupuncture group compared with those in model group (p < 0.05). CONCLUSION: Acupuncture promotes the repair of neurovascular units after CI in rats through activating the PI3K/AKT signaling pathway, thereby exerting a protective effect on neurovascular units.


2013 ◽  
Vol 30 (2) ◽  
pp. 933-938 ◽  
Author(s):  
DAE HYUNG LEE ◽  
IN-HYE LIM ◽  
EON-GI SUNG ◽  
JOO-YOUNG KIM ◽  
IN-HWAN SONG ◽  
...  

2020 ◽  
Vol 326 ◽  
pp. 113179
Author(s):  
Ling-Yun Wu ◽  
Budbazar Enkhjargal ◽  
Zhi-Yi Xie ◽  
Zachary D. Travis ◽  
Cheng-Mei Sun ◽  
...  

2021 ◽  
Vol 22 (14) ◽  
pp. 7275
Author(s):  
Emilia Barrio ◽  
Rebeca Vecino ◽  
Irene Sánchez-Morán ◽  
Cristina Rodríguez ◽  
Alberto Suárez-Pindado ◽  
...  

One of the most important mechanisms of preconditioning-mediated neuroprotection is the attenuation of cell apoptosis, inducing brain tolerance after a subsequent injurious ischemia. In this context, the antiapoptotic PI3K/AKT signaling pathway plays a key role by regulating cell differentiation and survival. Active AKT is known to increase the expression of murine double minute-2 (MDM2), an E3-ubiquitin ligase that destabilizes p53 to promote the survival of cancer cells. In neurons, we recently showed that the MDM2–p53 interaction is potentiated by pharmacological preconditioning, based on subtoxic stimulation of NMDA glutamate receptor, which prevents ischemia-induced neuronal apoptosis. However, whether this mechanism contributes to the neuronal tolerance during ischemic preconditioning (IPC) is unknown. Here, we show that IPC induced PI3K-mediated phosphorylation of AKT at Ser473, which in turn phosphorylated MDM2 at Ser166. This phosphorylation triggered the nuclear stabilization of MDM2, leading to p53 destabilization, thus preventing neuronal apoptosis upon an ischemic insult. Inhibition of the PI3K/AKT pathway with wortmannin or by AKT silencing induced the accumulation of cytosolic MDM2, abrogating IPC-induced neuroprotection. Thus, IPC enhances the activation of PI3K/AKT signaling pathway and promotes neuronal tolerance by controlling the MDM2–p53 interaction. Our findings provide a new mechanistic pathway involved in IPC-induced neuroprotection via modulation of AKT signaling, suggesting that AKT is a potential therapeutic target against ischemic injury.


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