Stilbene glycoside upregulates SIRT3/AMPK to promotes neuronal mitochondrial autophagy and inhibit apoptosis in ischemic stroke

Li, Yuxian; Hu, Ke; Liang, Ming-Hua; Yan, Qing; Huang, Mengxi; Jin, Ling; Chen, Yuefu; Yang, Xirong; Li, Xiaobo

doi:10.17219/acem/130608

Cited by 16 publications

(13 citation statements)

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“…Sirtuins are known to be involved in various cellular processes, including hypoxic and ischemic injury; however, their specific roles are only partially recognized. For example, Sirt3 knockout male mice are less vulnerable to ischemia/reperfusion or stroke injury [ 39 ], and upregulation of SIRT3 inhibits apoptosis in ischemia-challenged PC12 cells [ 40 ]. Intriguingly, in patients with acute cerebrovascular stroke, blood levels of SIRT1 are lower than those in control volunteers [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Post-Treatment with Amorfrutin B Evokes PPARγ-Mediated Neuroprotection against Hypoxia and Ischemia

et al. 2021

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In this study, we demonstrate for the first time that amorfrutin B, a selective modulator of peroxisome proliferator-activated receptor gamma—PPARγ, can protect brain neurons from hypoxia- and ischemia-induced degeneration when applied at 6 h post-treatment in primary cultures. The neuroprotective effect of amorfrutin B suggests that it promotes mitochondrial integrity and is capable of inhibiting reactive oxygen species—ROS activity and ROS-mediated DNA damage. PPARγ antagonist and Pparg mRNA silencing abolished the neuroprotective effect of amorfrutin B, which points to agonistic action of the compound on the respective receptor. Interestingly, amorfrutin B stimulated the methylation of the Pparg gene, both during hypoxia and ischemia. Amorfrutin B also increased the protein level of PPARγ during hypoxia but decreased the mRNA and protein levels of PPARγ during ischemia. Under ischemic conditions, amorfrutin B-evoked hypermethylation of the Pparg gene is in line with the decrease in the mRNA and protein expression of PPARγ. However, under hypoxic conditions, amorfrutin B-dependent hypermethylation of the Pparg gene does not explain the amorfrutin B-dependent increase in receptor protein expression, which suggests other regulatory mechanisms. Other epigenetic parameters, such as HAT and/or sirtuins activities, were affected by amorfrutin B under hypoxic and ischemic conditions. These properties position the compound among the most promising anti-stroke and wide-window therapeutics.

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Section: Discussionmentioning

confidence: 99%

Post-Treatment with Amorfrutin B Evokes PPARγ-Mediated Neuroprotection against Hypoxia and Ischemia

et al. 2021

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“…Stilbene glycoside treatment facilitates mitophagy and cell survival and reduces apoptosis; however, SIRT3 knockdown reduces ΔΨm, cell viability, and LC3II/I and Bcl-2 levels, while markedly increasing apoptosis, and Bax and caspase 3 protein expression in ischemic PC12 cells ( 45 ). SIRT3-knockout macrophages exhibit autophagy dysfunction, as well as enhanced NLRP3 inflammasome expression and vascular inflammation, whereas SIRT3 overexpression induces autophagosome maturation and inhibits NLRP3 inflammasome activation ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

SIRT3 expression alleviates microglia activation‑induced dopaminergic neuron injury through the mitochondrial pathway

et al. 2022

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The mitochondrial protein sirtuin 3 (SIRT3) can counteract cell damage caused by oxidative stress and inflammation, and contribute to cell survival primarily by improving mitochondrial function. However, the effects of SIRT3 in dopaminergic neuronal cells (DACs) remain unclear. In our previous studies, microglia activation-associated cytotoxicity was observed to promote the apoptosis of DACs, along with the decrease of SIRT3 expression. The aim of the present study was to explore the potential neuroprotective effect of SIRT3 expression against dopaminergic neuron injury caused by microglia activation, and clarify its possible mechanisms. SIRT3 overexpression in DACs reduced the production of intracellular reactive oxygen species (ROS), cell apoptosis rate, mitochondrial membrane potential (ΔΨm) depolarization, opening of mitochondrial permeability transition pore (mPTP) and cyclophilin D (CypD) protein level, and promoted cell cycle progression. However, SIRT3 siRNA-mediated knockdown further aggravated microglia activation-mediated cytotoxicity, including ROS accumulation, increased cell apoptosis and mPTP opening, elevated the CypD level, enhanced mitochondrial ΔΨm depolarization, concomitant to cell cycle arrest at G 0 /G 1 phase. The mechanisms of SIRT3 mitigated microglia activation-induced DAC dysfunction, which included decreased mPTP opening and Bax/Bcl-2 ratio, inhibition of mitochondrial cytochrome c release to the cytoplasm, reduced caspase-3/9 activity, increased LC3II/LC3I and beclin-1 protein expression levels, and decreased nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing protein 3 (NLRP3), caspase-1, IL-1β and IL-18 protein expression. In conclusion, these results indicated that SIRT3 expression attenuated cell damage caused by microglia activation through the mitochondrial apoptosis pathway in DACs. The mitophagy-NLRP3 inflammasome pathway may also be associated with this neuroprotection. These findings may provide new intervention targets for the survival of dopaminergic neurons and the prevention and treatment of Parkinson's disease.

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“…SIRT3 can deacetylate and activate LKB1 (liver kinase B1), and active LKB1 can phosphorylate AMPK to activate AMPK ( Liu et al, 2020 ). In ischemic-injured PC12 cells, promoting SIRT3/AMPK pathway significantly increased cell survival, decreased apoptosis rate and increased the mitochondrial autophagy ( Li et al, 2021 ). It has been reported that increased SIRT3 providing neuroprotective effects via enhancing mitochondrial function, increase neuron survival and decrease the number of apoptotic neurons in cerebral ischemia rat through activation of the SIRT3/AMPK/mTOR pathway ( Liu et al, 2020 ).…”

Section: Sirt2 In Central Nervous System Cellsmentioning

confidence: 99%

Sirtuins functions in central nervous system cells under neurological disorders

et al. 2022

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The sirtuins (SIRTs), a class of NAD+ -dependent deacylases, contain seven SIRT family members in mammals, from SIRT1 to SIRT7. Extensive studies have revealed that SIRT proteins regulate virous cell functions. Central nervous system (CNS) decline resulted in progressive cognitive impairment, social and physical abilities dysfunction. Therefore, it is of vital importance to have a better understanding of potential target to promote homeostasis of CNS. SIRTs have merged as the underlying regulating factors of the process of neurological disorders. In this review, we profile multiple functions of SIRT proteins in different cells during brain function and under CNS injury.

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Stilbene glycoside upregulates SIRT3/AMPK to promotes neuronal mitochondrial autophagy and inhibit apoptosis in ischemic stroke

Cited by 16 publications

References 0 publications

Post-Treatment with Amorfrutin B Evokes PPARγ-Mediated Neuroprotection against Hypoxia and Ischemia

Post-Treatment with Amorfrutin B Evokes PPARγ-Mediated Neuroprotection against Hypoxia and Ischemia

SIRT3 expression alleviates microglia activation‑induced dopaminergic neuron injury through the mitochondrial pathway

Sirtuins functions in central nervous system cells under neurological disorders

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