Galantamine inhibits β‐amyloid‐induced cytostatic autophagy in <scp>PC</scp>12 cells through decreasing <scp>ROS</scp> production

Jiang, Sheng; Zhao, Ye; Zhang, Tao; Lan, Jingbin; Yang, Jing; Yuan, Longhui; Zhang, Qiyu; Pan, Kehou; Zhang, Kun

doi:10.1111/cpr.12427

Cited by 42 publications

(25 citation statements)

References 40 publications

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“… 36 In contrast, cytotoxic autophagy results in autophagic cell death or promotes apoptosis, 37 whereas cytostatic autophagy inhibits cell growth in an apoptosis-independent way. 38 In this study, we confirmed that IBP-induced autophagy inhibited the proliferation of lung cancer cells in an apoptosis-independent way ( Figures 1 D and S1 A). In addition, no significant apoptosis was observed even in IBP-treated lung cancer cells when IBP-mediated autophagy was interrupted by siRNA against Atg5 or Beclin1 ( Figures S4 A and S4B), further suggesting that IBP treatment induces cytostatic autophagy, which is not related to apoptosis in lung cancer cells.…”

Section: Discussionsupporting

confidence: 77%

Therapeutic potential of IBP as an autophagy inducer for treating lung cancer via blocking PAK1/Akt/mTOR signaling

Tan

Yuan

et al. 2021

Molecular Therapy - Oncolytics

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Lung cancer is the most frequent and fatal malignancy in humans worldwide, yet novel successful drugs for control of this disease are still lacking. Ipomoea batatas polysaccharides (IBPs) have been implicated in inhibiting diverse cancer types, but their functions in mitigating lung cancer are largely unknown. In this study, we identify a role of IBP in inhibiting lung cancer proliferation. We found that IBP significantly impedes the proliferation of lung cancer cells by inducing cytostatic macroautophagy both in vitro and in vivo . Mechanistically, IBP specifically promotes ubiquitination-mediated degradation of PAK1 (p21-activated kinase 1) and blocks its downstream Akt1/mTOR signaling pathway, leading to increased autophagic flux. In lung cancer xenografts in mice, IBP-induced cytostatic autophagy suppresses tumor development. Through site-directed mutational analysis, the underlying signaling augments ubiquitination via PAK1-ubiquitin interaction. Collectively, this work unravels the molecular mechanism underpinning IBP-induced cytostatic autophagy in lung cancer and characterizes IBP as a potential therapeutic agent for lung cancer treatment.

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Section: Discussionsupporting

confidence: 77%

Therapeutic potential of IBP as an autophagy inducer for treating lung cancer via blocking PAK1/Akt/mTOR signaling

Tan

Yuan

et al. 2021

Molecular Therapy - Oncolytics

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“…In our study, autophagy was maintained at a low level in normal cells, a finding consistent with previous studies ( López-Pérez et al, 2019 ). In PC12 cells damaged by Aβ due to overexpression of APPswe, increased expression of Beclin-1 may represent the stress response of cells, as they attempt to increase the number of autophagosomes to eliminate excess Aβ 1-42 ( Jiang et al, 2018 ). High expression levels of LC3-Ⅱ indicates that the number of autophagosomes has increased, which may be caused by the stress-induced response of autophagy, the blocked fusion of autophagosomes and lysosomes, or the inability of autophagosomes to degrade substrates, among other causes ( Shen et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

β-Asarone Attenuates Aβ-Induced Neuronal Damage in PC12 Cells Overexpressing APPswe by Restoring Autophagic Flux

Zhongsheng

et al. 2021

Front. Pharmacol.

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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory damage and cognitive dysfunction. Studies have shown that defective autophagic flux is associated with neuronal dysfunction. Modulating autophagic activity represents a potential method of combating AD. In Chinese medicine, Acori Tatarinowii Rhizoma is used to treat dementia and amnesia. β-Asarone, an active component of this rhizome can protect PC12 cells from Aβ-induced injury and modulate expression of autophagy factors. However, its cytoprotective mechanisms have yet to be discerned. It is unclear whether β-asarone affects autophagic flux and, if it does, whether this effect can alleviate Aβ cell damage. In the present study, we constructed APPswe-overexpressing PC12 cell line as a cell model of Aβ-induced damage and assessed expression of autophagic flux-related proteins as well as the number and morphology of autophagosomes and autolysosomes. Our results show that β-asarone decreases the expression levels of Beclin-1, p62, LC3-Ⅱ, and Aβ1-42. β-Asarone reduced the number of autophagosomes and increased the number of autolysosomes, as determined by confocal laser scanning microscopy and transmission electron microscopy. Our results suggest that β-asarone can protect PC12 cells from Aβ-induced damage by promoting autophagic flux, which may be achieved by enhancing autophagosome-lysosome fusion and/or lysosome function.

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“…Aβ42 can also act as seeds to initiate Aβ40 aggregation [ 2 ]. Protein oxidation caused by ROS leads to polymerization, thereby forming protein aggregation, such as Aβ deposition [ 36 ]. Consequently, the aggregated Aβ reduces mitochondrial respiration in neurons and astrocytes, and induces mitochondrial dysfunction and energy failure [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Basis for the Use of Evodiamine in Alzheimer’s Disease: Antioxidation and Antiapoptosis

Zhang

Wang

et al. 2018

IJMS

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Evodiamine (Evo), a major alkaloid compound isolated from the dry unripened fruit of Evodia fructus, has a wide range of pharmacological activities. The present study sought to explore the neuroprotective effects of Evo in l-glutamate (l-Glu)-induced apoptosis of HT22 cells, and in a d-galactose and aluminum trichloride-developed Alzheimer’s disease (AD) mouse model. Evo significantly enhanced cell viability, inhibited the accumulation of reactive oxygen species, ameliorated mitochondrial function, increased the B-cell lymphoma-2 protein content, and inhibited the high expression levels of Bax, Bad, and cleaved-caspase-3 and -8 in l-Glu-induced HT22 cells. Evo also enhanced the phosphorylation activities of protein kinase B and the mammalian target of rapamycin in the l-Glu-induced HT22 cells. In the AD mouse model, Evo reduced the aimless and chaotic movements, reduced the time spent in the central area in the open field test, and decreased the escape latency time in the Morris water maze test. Evo reduced the deposition of amyloid beta 42 (Aβ42) in the brain, and increased the serum level of Aβ42, but showed no significant effects on Aβ40. In addition, six weeks of Evo administration significantly suppressed oxidative stress by modulating the related enzyme levels. In the central cholinergic system of AD mice, Evo significantly increased the serum levels of acetylcholine and choline acetyltransferase and decreased the level of acetylcholinesterase in the serum, hypothalamus, and brain. Our results provide experimental evidence that Evo can serve as a neuroprotective candidate for the prevention and/or treatment of neurodegenerative diseases.

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Galantamine inhibits β‐amyloid‐induced cytostatic autophagy in PC12 cells through decreasing ROS production

Abstract: Galantamine inhibits Aβ-induced cytostatic autophagy through decreasing ROS accumulation, providing new insights into deep understanding of AD progression and molecular basis of galantamine in neuroprotection.

Cited by 42 publications

References 40 publications

Therapeutic potential of IBP as an autophagy inducer for treating lung cancer via blocking PAK1/Akt/mTOR signaling

Therapeutic potential of IBP as an autophagy inducer for treating lung cancer via blocking PAK1/Akt/mTOR signaling

β-Asarone Attenuates Aβ-Induced Neuronal Damage in PC12 Cells Overexpressing APPswe by Restoring Autophagic Flux

Pharmacological Basis for the Use of Evodiamine in Alzheimer’s Disease: Antioxidation and Antiapoptosis

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