Pseudoginsenoside‐F11 attenuates cerebral ischemic injury by alleviating autophagic/lysosomal defects

Liu, Yueyang; Zhang, Tianyu; Xue, Xue; Li, Dongmei; Zhang, Haotian; Yuan, Linlin; Liu, Yinglu; Yang, Hanlin; Sun, Shibo; Zhang, Cheng; Xu, He-Song; Wu, Chunfu; Yang, Jingyu

doi:10.1111/cns.12702

Cited by 35 publications

(16 citation statements)

References 53 publications

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“…In a 2vessel occlusion (2-VO) ischemic stroke model, treatment with chloroquine (CQ) does not further change the LC3-II levels, suggesting that ALP is impaired [8]. In our latest study, impaired ALP function is also observed at 24 h in a model of permanent cerebral ischemia [9]. Additionally, lysosomal dysfunction, as reflected by cytosolic acidification and rupture/ permeabilization, is detected after ischemic insult [10][11][12].…”

Section: Introductionmentioning

confidence: 79%

“…Mounting evidence strongly indicates that ALP is induced in multiple ischemic stroke models as reflected by the accumulation of autophagosomes and activation of lysosomal function [1,2,6,7]. However, it is noteworthy that ischemic injury can trigger a defect in ALP by causing lysosomal dysfunction, thus resulting in the abnormal accumulation of autophagosomes and substrates [8][9][10][11][12]. In a 2vessel occlusion (2-VO) ischemic stroke model, treatment with chloroquine (CQ) does not further change the LC3-II levels, suggesting that ALP is impaired [8].…”

Section: Introductionmentioning

confidence: 99%

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Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia

et al. 2018

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Mounting attention has been focused on defects in macroautophagy/autophagy and the autophagylysosomal pathway (ALP) in cerebral ischemia. TFEB (transcription factor EB)-mediated induction of ALP has been recently considered as the common mechanism in ameliorating the pathological lesion of myocardial ischemia and neurodegenerative diseases. Here we explored the vital role of TFEB in permanent middle cerebral artery occlusion (pMCAO)-mediated dysfunction of ALP and ischemic insult in rats. The results showed that ALP function was first enhanced in the early stage of the ischemic process, especially in neurons of the cortex, and this was accompanied by increased TFEB expression and translocation to the nucleus, which was mediated at least in part through activation by PPP3/ calcineurin. At the later stages of ischemia, a gradual decrease in the level of nuclear TFEB was coupled with a progressive decline in lysosomal activity, accumulation of autophagosomes and autophagy substrates, and exacerbation of the ischemic injury. Notably, neuron-specific overexpression of TFEB significantly enhanced ALP function and rescued the ischemic damage, starting as early as 6 h and even lasting to 48 h after ischemia. Furthermore, neuron-specific knockdown of TFEB markedly reversed the activation of ALP and further aggravated the neurological deficits and ischemic outcome at the early stage of pMCAO. These results highlight neuronal-targeted TFEB as one of the key players in the pMCAO-mediated dysfunction of ALP and ischemic injury, and identify TFEB as a promising target for therapies aimed at neuroprotection in cerebral ischemia.

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Section: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia

et al. 2018

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“…Although the benefits of autophagy in acute ischemic brains have been documented, few compounds were known to rescue ischemic brain injury by targeting autophagy . Uro‐A activates autophagy in several types of cell, yet it has been undetermined whether Uro‐A also activates autophagy in ischemic neuronal cells and mice brain.…”

Section: Discussionmentioning

confidence: 99%

Urolithin A‐activated autophagy but not mitophagy protects against ischemic neuronal injury by inhibiting ER stress in vitro and in vivo

Ahsan

Zheng

et al. 2019

CNS Neurosci Ther

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Aim Mitochondrial autophagy (mitophagy) clears damaged mitochondria and attenuates ischemic neuronal injury. Urolithin A (Uro‐A) activates mitophagy in mammal cells and Caenorhabditis elegans. We explored neuroprotection of Uro‐A against ischemic neuronal injury. Methods Mice were subjected to middle cerebral artery occlusion. The brain infarct and neurological deficit scores were measured. The N2a cells and primary cultured mice cortical neurons were subjected to oxygen‐glucose deprivation and reperfusion (OGD/R). Uro‐A was incubated during OGD/R, and cell injury was determined by MTT and LDH. Autophagosomes were visualized by transfecting mCherry‐microtubule‐associated protein 1 light chain 3 (LC3). The protein levels of LC3‐II, p62, Translocase Of Inner Mitochondrial Membrane 23 (TIMM23), and cytochrome c oxidase subunit 4 isoform 1 (COX4I1) were detected by Western blot. The ER stress markers, activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP), were determined by reverse transcription‐polymerase chain reaction (RT‐PCR). Results Urolithin A alleviated OGD/R‐induced injury in N2a cells and neurons and reduced ischemic brain injury in mice. Uro‐A reinforced ischemia‐induced autophagy. Furthermore, Uro‐A‐conferred protection was abolished by 3‐methyladenine, suggesting the requirement of autophagy for neuroprotection. However, mitophagy was not further activated by Uro‐A. Instead, Uro‐A attenuated OGD/R‐induced ER stress, which was abolished by 3‐methyladenosine. Additionally, neuroprotection was reversed by ER stress inducer. Conclusion Urolithin A protected against ischemic neuronal injury by reinforcing autophagy rather than mitophagy. Autophagy activation by Uro‐A attenuated ischemic neuronal death by suppressing ER stress.

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“…It was capable of improving lysosomal function and lysosome/autophagosome fusion following pMCAO. This change was reversed by the lysosomal inhibitor chloroquine, which, in turn reversed improvement in ischemic outcome and the antiapoptotic effect [ 115 ].…”

Section: Pharmacological Potential Of Active Ginseng Constituents In mentioning

confidence: 99%

Active ginseng components in cognitive impairment: Therapeutic potential and prospects for delivery and clinical study

et al. 2018

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Cognitive impairment is a state that affects thinking, communication, understanding, and memory, and is very common in various neurological disorders. Among many factors, age-related cognitive decline is an important area in mental health research. Research to find therapeutic medications or supplements to treat cognitive deficits and maintain cognitive health has been ongoing. Ginseng and its active components may have played a role in treating chronic disorders. Numerous preclinical studies have confirmed that ginseng and its active components such as ginsenosides, gintonin, and compound K are pharmacologically efficacious in different models of and are linked to cognitive impairment. Among their several roles, they act as an anti-neuroinflammatory and help fight against oxidative stress and modulate the cholinergic signal. These roles may be involved in enhancing cognition and attenuating impairment. There have been some clinical studies on the activity of ginseng in cognitive impairment, but many ginseng species and active compounds remain to be investigated. In addition, new formulations of active ginseng components such as nanoparticles and liposomes could be used for preclinical and clinical models of cognitive impairment. Here, we discuss the therapeutic potential of active ginseng components in cognitive impairment and their chemistry and pharmacokinetics and consider prospects for their delivery and clinical study with respect to cognitive impairment.

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Pseudoginsenoside‐F11 attenuates cerebral ischemic injury by alleviating autophagic/lysosomal defects

Abstract: These findings indicate that the autophagic flux is impaired in a rat model of pMCAO, and that PF11 exerts an excellent protective effect against ischemic stroke by alleviating autophagic/lysosomal defects.

Cited by 35 publications

References 53 publications

Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia

Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia

Urolithin A‐activated autophagy but not mitophagy protects against ischemic neuronal injury by inhibiting ER stress in vitro and in vivo

Active ginseng components in cognitive impairment: Therapeutic potential and prospects for delivery and clinical study

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