Gastrodin Regulates the Notch Signaling Pathway and Sirt3 in Activated Microglia in Cerebral Hypoxic-Ischemia Neonatal Rats and in Activated BV-2 Microglia

Guo, Jing; Zhang, Xiao‐Li‐Na; Bao, Zhang-Rui; Yang, Xueke; Li, Ling-Shuang; Zi, Yu; Li, Fan; Wu, Cheng-Shong; Li, Juanjuan; Yun, Yuan

doi:10.1007/s12017-020-08627-x

Cited by 37 publications

(36 citation statements)

References 43 publications

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“…Therefore, we cannot ignore the importance of hypoxia-induced neuroinflammatory responses. In our study, we found that GAS could downregulate the expression of inflammatory factors (IL-1β and TNF-α) in astrocytes after OGD model, which was in line with our expectations and previous studies (22). Hence, it is indicated that GAS can improve the neuroinflammatory response in HIBD.…”

Section: Discussionsupporting

confidence: 92%

“…However, whether GAS has protective effect in HIBD and the underlying mechanism have not yet been elucidated. Our previous studies have confirmed that ischemia and hypoxia after HIBD induce the activation of the Notch signaling pathway, and inhibition of the Notch signaling pathway can improve neurological deficits after HIBD (22). The Notch pathway , as an evolutionarily conserved signaling pathway, has a prominent role in regulating the proliferation, differentiation and apoptosis of neural progenitor cells (23).…”

Section: Introductionmentioning

confidence: 81%

“…Based on our data, GAS can significantly promote the expression of Sirt3, which reveals the potential mechanism of GAS's neuroprotective effect. Given previous studies have suggested that Sirt3 may be related to the Notch signaling pathway (22,39), we further explored the role of Notch pathway in reactive astrocytes. The Notch pathway is conserved as an evolutionarily critical signaling mechanism regulating the proliferation and differentiation of neural stem cells (40), and promoting the differentiation of astrocytes with hypoxia exposure (41,42).…”

Section: Discussionmentioning

confidence: 99%

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Gastrodin exerts protective effects in reactive TNC1 astrocytes via regulation of the Notch signaling pathway

Zhang¹,

Yang²,

Wu³

et al. 2021

Ann Transl Med

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Background: Gastrodin (GAS) has been proven to play a therapeutic role in a variety of neurological diseases by affecting activated astrocytes, however, the underlying mechanisms have not been fully illustrated.This study aimed to investigate if GAS exerts the neuroprotective effect through regulating the Notch signaling pathway involved in reactive astrocytes.Methods: Astrocyte cell lines (TNC1 cells) were cultured in vitro. The hypoxic-ischemic cell model was prepared using the oxygen-glucose deprivation (OGD) method, GAS's pretreatment concentration was 0.34 mM, intervention for 1 hour. Cell counting kit-8 (CCK-8) assay, Transwell migration assay, immunofluorescent staining (double staining), and Western blotting were used to observe the effects of OGD or GAS interference on the function of astrocytes, and the changes of key protein expressions in the Notch signaling pathway were analyzed.Results: GAS had no obvious toxic effect on TNC1 astrocytes under physiological conditions. Following OGD, GAS can not only improve cell viability and migration, but also regulate the production of inflammatory mediators. We also found that OGD significantly increased the expression of key proteins related to the Notch signaling pathway, Notch-1, intracellular Notch receptor domain (NICD), recombining binding protein suppressor of hairless (RBP-JK), transcription factor hairy and enhancer of split-1 (Hes-1) in TNC1 astrocytes, which was significantly inhibited by GAS. In addition, GAS inhibited the OGD-induced expression of TNC1 astrocyte tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β), and enhanced the expression of nutrient factors, including brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1). The Notch signaling pathway specific inhibitor, N-[N-(3,5-Difluorophenacetyl)-1-alany1]-S-phenyglycine t-butylester (DAPT), could significantly enhance the effect of GAS on TNC1 astrocytes after OGD, such as the inhibition of inflammatory factors and the up-regulation of neurotrophic factors.Conclusions: GAS exerts dual effects on astrocytes via regulation of the Notch signaling pathway. We found that it could inhibit the pro-inflammatory factors mediated by astrocytes, and also promote the secretion of neurotrophic factors by astrocytes. These results provide a new biological mechanism for the treatment of neuroinflammatory diseases by GAS.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Gastrodin exerts protective effects in reactive TNC1 astrocytes via regulation of the Notch signaling pathway

Zhang¹,

Yang²,

Wu³

et al. 2021

Ann Transl Med

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“…Attenuated OGD/R-Induced Pyroptosis of BV-2 Cells. Previous studies demonstrated that microglial pyroptosis is an important cause of neuronal injury under I/R conditions [13,14]. To investigate the effect of MSCexos on OGD/R-induced pyroptosis, BV-2 cells were cultured in OGD conditions for 4 h and then cocultured with MSC-exos in the 24 h reperfusion phase.…”

Section: Msc-exosmentioning

confidence: 99%

“…As the resident immune cells in the central nervous system, microglia play an important role in the occurrence and development of HIBD [12][13][14][15][16]. Previous studies have demonstrated that inhibition of microglial pyroptosis in neonatal HIBD mice could promote neuronal survival and improve brain injury [12,16].…”

Section: Introductionmentioning

confidence: 99%

Human Umbilical Cord Mesenchymal Stem Cell‐Derived Exosomes Attenuate Oxygen‐Glucose Deprivation/Reperfusion‐Induced Microglial Pyroptosis by Promoting FOXO3a‐Dependent Mitophagy

Yuan

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Background. Mesenchymal stem cell-derived exosomes (MSC-exos) have been recognized as a promising therapeutic strategy for neonatal hypoxic-ischemic brain damage (HIBD). Recently, microglial pyroptosis was shown to play a vital role in the progression of neonatal HIBD. However, whether MSC-exos improve HIBD by regulating microglial pyroptosis remains unknown. Methods. Exosomes were isolated from human umbilical cord mesenchymal stem cells (huMSCs) and identified by transmission electron microscopy (TEM), western blot, and nanoparticle tracking analysis (NTA). BV-2 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to induce microglial ischemia/reperfusion (I/R) in vitro. CCK-8, ELISA, western blot, and Hoechst 33342/PI double staining were performed to detect the pyroptosis of BV-2 cells. Conditioned medium (CM) from BV-2 cells exposed to different treatments was used to investigate its effect on neuronal injury. Moreover, 3-methyladenine (3-MA) and mitochondrial division inhibitor-1 (mdi-1) were used to verify the involvement of mitophagy in the protection of MSC-exos against OGD/R-induced pyroptosis in BV-2 cells. Finally, FOXO3a siRNA was used to investigate the involvement of FOXO3a in MSC-exo-induced mitophagy and pyroptosis inhibition. Results. Exosomes from huMSCs were successfully extracted. In OGD/R-exposed BV-2 cells, MSC-exos increased cell viability and decreased the expression of NLRP3, cleaved caspase-1, and GSDMD-N as well as the release of IL-1β and IL-18. Compared with CM from OGD/R-exposed BV-2 cells treated with PBS, CM from OGD/R-exposed BV-2 cells treated with MSC-exos significantly increased the viability of SH-SY5Y cells and decreased LDH release. MSC-exos also increased the expression of TOM20 and COX IV in OGD/R-exposed BV-2 cells. Additionally, 3-MA and mdi-1 attenuated the inhibition of pyroptosis with MSC-exo treatment. Furthermore, FOXO3a siRNA partially abolished the neuroprotective effect of MSC-exos and attenuated mitophagy and pyroptosis inhibition induced by MSC-exo treatment. Conclusions. Our findings demonstrated that MSC-exos increased FOXO3a expression to enhance mitophagy, therefore protecting microglia from I/R-induced pyroptosis and alleviating subsequent neuronal injury.

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Sirtuin 3 regulates astrocyte activation by reducing Notch1 signaling after status epilepticus

Zhu,

Park,

Kim

et al. 2024

Glia

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Sirtuin3 (Sirt3) is a nicotinamide adenine dinucleotide enzyme that contributes to aging, cancer, and neurodegenerative diseases. Recent studies have reported that Sirt3 exerts anti‐inflammatory effects in several neuropathophysiological disorders. As epilepsy is a common neurological disease, in the present study, we investigated the role of Sirt3 in astrocyte activation and inflammatory processes after epileptic seizures. We found the elevated expression of Sirt3 within reactive astrocytes as well as in the surrounding cells in the hippocampus of patients with temporal lobe epilepsy and a mouse model of pilocarpine‐induced status epilepticus (SE). The upregulation of Sirt3 by treatment with adjudin, a potential Sirt3 activator, alleviated SE‐induced astrocyte activation; whereas, Sirt3 deficiency exacerbated astrocyte activation in the hippocampus after SE. In addition, our results showed that Sirt3 upregulation attenuated the activation of Notch1 signaling, nuclear factor kappa B (NF‐κB) activity, and the production of interleukin‐1β (IL1β) in the hippocampus after SE. By contrast, Sirt3 deficiency enhanced the activity of Notch1/NF‐κB signaling and the production of IL1β. These findings suggest that Sirt3 regulates astrocyte activation by affecting the Notch1/NF‐κB signaling pathway, which contributes to the inflammatory response after SE. Therefore, therapies targeting Sirt3 may be a worthy direction for limiting inflammatory responses following epileptic brain injury.

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Gastrodin Regulates the Notch Signaling Pathway and Sirt3 in Activated Microglia in Cerebral Hypoxic-Ischemia Neonatal Rats and in Activated BV-2 Microglia

Cited by 37 publications

References 43 publications

Gastrodin exerts protective effects in reactive TNC1 astrocytes via regulation of the Notch signaling pathway

Gastrodin exerts protective effects in reactive TNC1 astrocytes via regulation of the Notch signaling pathway

Human Umbilical Cord Mesenchymal Stem Cell‐Derived Exosomes Attenuate Oxygen‐Glucose Deprivation/Reperfusion‐Induced Microglial Pyroptosis by Promoting FOXO3a‐Dependent Mitophagy

Sirtuin 3 regulates astrocyte activation by reducing Notch1 signaling after status epilepticus

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