Evaluating the effects of mitochondrial autophagy flux on ginsenoside Rg2 for delaying D-galactose induced brain aging in mice

Zhang, Junjie; Chen, Ke-cheng; Zhou, Yue; Wei, Heng; Qi, Meng-han; Wang, Zi; Zheng, Yajuan; Chen, Rixin; Liu, Shuang; Li, Wei

doi:10.1016/j.phymed.2022.154341

Cited by 34 publications

(15 citation statements)

References 45 publications

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“…In the current investigation on FRGs, autophagy was enriched in KEGG pathway analysis of the modular genes ( Figure 4(c) ). And in 10 hub DEFRGs, Prkaa2 [ 15 ], Arntl [ 17 ], Sesn2 [ 47 ], and Lamp2 [ 48 ] reported the involvement in autophagy, which may indicate a link between autophagy and ferroptosis in sevoflurane-induced hippocampal neuronal injury.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Miao

Wang

Zeng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Sevoflurane is one of the most popular inhalational anesthetics during perioperative period but presenting neurotoxicity among pediatric and aged populations. Recent experiments in vivo and in vitro have indicated that ferroptosis may contribute to the neurotoxicity of sevoflurane anesthesia. However, the exact mechanism is still unclear. Methods. In current study, we explored the differential expressed genes (DEGs) in HT-22 mouse hippocampal neuronal cells after sevoflurane anesthesia using RNA-seq. Differential expressed ferroptosis-related genes (DEFRGs) were screened and analyzed by Gene Ontology (GO) and pathway enrichment analysis. Protein-to-protein interaction (PPI) network was constructed by the Search Tool for the Retrieval of Interacting Genes (STRING). Significant modules and the hub genes were identified by using Cytoscape. The Connectivity Map (cMAP) was used for screening drug candidates targeting the identified DEFRGs. Potential TF-gene network and drug-gene pairs were established towards the hub genes. In final, we validated these results in experiments. Results. A total of 37 ferroptosis-related genes (18 upregulated and 19 downregulated) after sevoflurane exposure in hippocampal neuronal cells were finally identified. These differentially expressed genes were mainly involved into the biological processes of cellular response to oxidative stress. Pathway analysis indicated that these genes were involved in ferroptosis, mTOR signaling pathway, and longevity-regulating pathway. PPI network was constructed. 10 hub genes including Prkaa2, Chac1, Arntl, Tfrc, Slc7a11, Atf4, Mgst1, Lpin1, Atf3, and Sesn2 were found. Top 10 drug candidates, gene-drug networks, and TFs targeting these genes were finally identified. These results were validated in experiments. Conclusion. Our results suggested that ferroptosis-related genes play roles in sevoflurane anesthesia-related hippocampal neuron injury and offered the hub genes and potential therapeutic agents for investigating and treatment of this neurotoxicity after sevoflurane exposure. Finally, therapeutic effect of these drug candidates and function of potential ferroptosis targets should be further investigated for treatment and clarifying mechanisms of sevoflurane anesthesia-induced neuron injury in future research.

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Section: Discussionmentioning

confidence: 99%

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Miao

Wang

Zeng

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…PPT powder was dissolved in 0.05% sodium carboxymethyl cellulose (CMC‐Na). Mice in all groups except the normal group were continuously injected with D‐gal for 8 weeks to simulate the aging process (the normal group was given the same volume of CMC‐Na) (Sha et al, 2019; Zhang et al, 2022). Furthermore, in the D‐gal + PPT groups, all mice were fed PPT at 10 or 20 mg/kg per day by oral gavage after continuous 4‐weeks' D‐gal injection.…”

Section: Methodsmentioning

confidence: 99%

20(S)‐protopanaxatriol inhibited D‐galactose‐induced brain aging in mice via promoting mitochondrial autophagy flow

Zhang

Chen³

et al. 2023

Phytotherapy Research

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Previous reports have confirmed that saponins (ginsenosides) derived from Panax ginseng. C. A. Meyer exerted obvious memory‐enhancing and antiaging effects, and the simpler the structure of ginsenosides, the better the biological activity. In this work, we aimed to explore the therapeutic effect and underlying molecular mechanism of 20(S)‐protopanaxatriol (PPT), the aglycone of panaxatriol‐type ginsenosides, by establishing D‐galactose (D‐gal)‐induced subacute brain aging model in mice. The results showed that PPT treatment (10 and 20 mg/kg) for 4 weeks could significantly restore the D‐gal (800 mg/kg for 8 weeks)‐induced impaired memory function, choline dysfunction, and redox system imbalance in mice. Meanwhile, PPT also significantly reduced the histopathological changes caused by D‐gal exposure. Moreover, PPT could increase TFEB/LAMP2 protein expression to promote mitochondrial autophagic flow. Importantly, the results from molecular docking showed that PPT had good binding ability with LAMP2 and TFEB, suggesting that TFEB/LAMP2 might play an important role in PPT to alleviate D‐gal‐caused brain aging.

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“…33 Ginsenoside Rg2 can reduce β-amyloid deposition by regulating oxidative stress and inhibiting oxidation reaction in the hippocampus. 34 Ginsenoside Rg3 exhibits anti-inflammatory and anti-oxidant activities that could improve neuronal apoptosis and neuroinflammation. 35 Ginsenoside Rd protects nerve cells by activating the AKT ( protein kinase B)/ERK (extracellular regulated protein kinases) signaling pathway of mitochondria, thereby increasing the expression of p-Akt and p-ERK, and reducing the release of cytochrome c. 36 Besides, pseudoginseng-F11 (PF11) did improve neurological function in ischemic stroke by promoting microglia to phagocytize degenerated myelin sheaths that had been caused by ischemic injury while also inhibiting the excessive release of pro-inflammatory factors.…”

Section: Biological Propertiesmentioning

confidence: 99%

“…57 Ginsenoside Rg2 improved mitochondrial dysfunction by promoting the degradation of autophagy substrates and upregulated the expression of lysosomal-associated membrane protein 2/transcription factor EB, thereby improving brain aging. 34 Vina-ginsenoside R4 reduced cellular neurotoxicity by reducing the translation of NF-κB and inhibiting the PI3K/AKT/GSK/3β pathway. 58 The neuroprotective effect of ginsenosides may be related to the MAPK, PI3K/AKT, cyclin-dependent kinase 5, BDNF/ TrkB, protein kinase A/cAMP-response element binding protein (CREB), fibroblast growth factor 2 (FGF2)/AKT, NF-κB, nod-like receptor protein1, N-methyl-D-aspartate receptor 2B/ ERK (extracellular regulated protein kinase)/CREB/BDNF, notch, Wnt/β-catenin, toll-like receptor-3 (TLR3), and TLR4 signaling pathways.…”

Section: Role In Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Ginsenosidesmentioning

confidence: 99%

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Ginsenosides can target brain-derived neurotrophic factor to improve Parkinson's disease

et al. 2023

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Evaluating the effects of mitochondrial autophagy flux on ginsenoside Rg2 for delaying D-galactose induced brain aging in mice

Cited by 34 publications

References 45 publications

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

20(S)‐protopanaxatriol inhibited D‐galactose‐induced brain aging in mice via promoting mitochondrial autophagy flow

Ginsenosides can target brain-derived neurotrophic factor to improve Parkinson's disease

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