Trillium tschonoskii maxim saponin mitigates D-galactose-induced brain aging of rats through rescuing dysfunctional autophagy mediated by Rheb-mTOR signal pathway

Wang, Lingjie; Du, Jun-Long; Zhao, Fangyu; Chen, Zonghai; Chang, Jingru; Lai, Yanqing; Wang, Zili; Wang, Fengjie; Chen, Xianbing; Chen, Ning

doi:10.1016/j.biopha.2017.12.046

Cited by 34 publications

(26 citation statements)

References 33 publications

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“…Moreover, the learning and memory capacity of Compound 2 derived from Trillium tschonoskii Maxim has been investigated in aging rats induced by D-gal with impaired cognitive function using the Morris water maze test. Treatment with Compound 2 improved the learning and memory capacity in aging rats induced by D-gal and the mechanism might be associated with rescuing dysfunctional autophagy via the upregulation of Rheb and the downregulation of mTOR signaling, suggesting that Compound 2 has potential in health promotion and aging-related disease therapy [79]. Cumulative evidence has suggested that microglial activation is an early and ongoing stage in neurodegenerative disorders.…”

Section: Pharmacological Activity and Mechanism Of Diosgenin And Its mentioning

confidence: 99%

Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances

Cai

Zhang

Wang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Diosgenin (DG), a well-known steroidal sapogenin, is present abundantly in medicinal herbs such as Dioscorea rhizome, Dioscorea villosa, Trigonella foenum-graecum, Smilax China, and Rhizoma polgonati. DG is utilized as a major starting material for the production of steroidal drugs in the pharmaceutical industry. Due to its wide range of pharmacological activities and medicinal properties, it has been used in the treatment of cancers, hyperlipidemia, inflammation, and infections. Numerous studies have reported that DG is useful in the prevention and treatment of neurological diseases. Its therapeutic mechanisms are based on the mediation of different signaling pathways, and targeting these pathways might lead to the development of effective therapeutic agents for neurological diseases. The present review mainly summarizes recent progress using DG and its derivatives as therapeutic agents for multiple neurological disorders along with their various mechanisms in the central nervous system. In particular, those related to therapeutic efficacy for Parkinson’s disease, Alzheimer’s disease, brain injury, neuroinflammation, and ischemia are discussed. This review article also critically evaluates existing limitations associated with the solubility and bioavailability of DG and discusses imperatives for translational clinical research. It briefly recapitulates recent advances in structural modification and novel formulations to increase the therapeutic efficacy and brain levels of DG. In the present review, databases of PubMed, Web of Science, and Scopus were used for studies of DG and its derivatives in the treatment of central nervous system diseases published in English until December 10, 2019. Three independent researchers examined articles for eligibility. A total of 150 articles were screened from the above scientific literature databases. Finally, a total of 46 articles were extracted and included in this review. Keywords related to glioma, ischemia, memory, aging, cognitive impairment, Alzheimer, Parkinson, and neurodegenerative disorders were searched in the databases based on DG and its derivatives.

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Section: Pharmacological Activity and Mechanism Of Diosgenin And Its mentioning

confidence: 99%

Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances

Cai

Zhang

Wang

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…This drug may inhibit dopamine reuptake as a dopamine transporter inhibitor (Greenblatt & Adams, 2018;Loland et al, 2012), thereby increasing synaptic dopamine levels exciting dopamine receptors and adrenoceptors (Wisor, 2013). Meanwhile, dopamine receptor subtypes have been demonstrated to differentially regulate autophagy (Wang, Du, et al, 2018;Wang, Ji, et al, 2018) as D 1 -like receptors act as negative regulators, whereas D 2 -like receptors work as positive regulators. However, in the present study, we do not know which receptors in hippocampus were modulated by modafinil in the process of the alleviation of excessive autophagy induced by sleep deprivation.…”

Section: Figurementioning

confidence: 99%

“…Basal autophagy is essential in the mammalian nervous system for the maintenance of normal function and homeostasis against neurodegeneration (Menzies et al, 2017). Learning and memory deficits have been closely associated with aberrant autophagy and modulation, and augmentation of autophagy may benefit impaired memory in rodents (Hylin et al, 2018;Wang, Du, et al, 2018;Wang, Ji, Liu, Li, & Zhang, 2018). Learning and memory deficits have been closely associated with aberrant autophagy and modulation, and augmentation of autophagy may benefit impaired memory in rodents (Hylin et al, 2018;Wang, Du, et al, 2018;Wang, Ji, Liu, Li, & Zhang, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Dysfunctional autophagy disrupts neuronal intracellular homeostasis and predisposes individuals to neurodegenerative or neuropsychiatric disorders (Polajnar & Zerovnik, 2014). Learning and memory deficits have been closely associated with aberrant autophagy and modulation, and augmentation of autophagy may benefit impaired memory in rodents (Hylin et al, 2018;Wang, Du, et al, 2018;Wang, Ji, Liu, Li, & Zhang, 2018). Although sleep deprivation is thought to contribute to memory deficits, the relationships between sleep deprivation, hippocampal autophagy, and memory impairment remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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Modafinil protects hippocampal neurons by suppressing excessive autophagy and apoptosis in mice with sleep deprivation

Cao

Liu

et al. 2019

British J Pharmacology

113

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Background and Purpose: Sleep deprivation compromises learning and memory in both humans and animals, and can be reversed by administration of modafinil, a drug promoting wakefulness. Dysfunctional autophagy increases activation of apoptotic cascades, ultimately leading to increased neuronal death, which can be alleviated by autophagy inhibitors. This study aimed to investigate the alleviative effect and mechanism of modafinil on the excessive autophagy occurring in the hippocampus of mice with deficiency of learning and memory induced by sleep deprivation. Experimental Approach: The Morris water maze was used to assess the effects of modafinil on male C57BL/6Slac mice after 48-hr sleep deprivation. The HT-22 hippocampal neuronal cell line was also used. Nissl staining, transmission electron microscope, immunofluorescence, Western blot, transient transfection, and autophagy inducer were used to study the effect and mechanism of modafinil on hippocampal neurons with excessive autophagy and apoptosis. Key Results: Modafinil improved learning and memory in sleep-deprived mice, associated with the inhibition of excessive autophage and apoptosis and an enhanced activation of the PI3K/Akt/mTOR/P70S6K signalling pathway in hippocampal neurons. These effects of modafinil were abolished by rapamycin. In addition, modafinil suppressed the aberrant autophagy and apoptosis induced by rapamycin and reactivated PI3K/Akt/mTOR/P70S6K signals in HT-22 cells. Conclusions and Implications: These results suggested that modafinil alleviated impaired learning and memory of sleep-deprived mice potentially by suppressing excessive autophagy and apoptosis of hippocampal neurons. This novel mechanism may add to our knowledge of modafinil in the clinical treatment of impaired memory caused by sleep loss.Abbreviations: DG, dentate gyrus; 3-MA, 3-methyladenine; mTOR, mammalian target of rapamycin; MWM, Morris water maze; p62, ubiquitin-binding protein p62 or sequestosome-1; P70S6K, ribosomal protein S6 kinase; p-Akt, phosphorylated PKB; p-P70S6K, phosphorylated ribosomal protein S6 kinase; p-PI3K, phosphorylated PI3K

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“…[22], with anti-cancer, anti-inflammatory, analgesic, immune-enhancing, cardiovascular function-promoting, blood pressure-reducing, and anti-aging functions [23,24,25]. Moreover, DG has also been shown to have a protective role in SCI through the up-regulation of ciliary neurotrophic factor (CNTF) and CNTF receptor α (CNTF-Rα) expression in spinal cord tissue [26], and can rescue dysfunctional autophagy to execute anti-aging through up-regulating Rheb and down-regulating mTOR [27] in our previous studies. However, it’s unclear whether DG treatment could protect against SCI through Rheb/mTOR signal pathways in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Diosgenin Glucoside Protects against Spinal Cord Injury by Regulating Autophagy and Alleviating Apoptosis

Chen

Wang

Yang

et al. 2018

IJMS

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Spinal cord injury (SCI) is a severe traumatic lesion of central nervous system (CNS) with only a limited number of restorative therapeutic options. Diosgenin glucoside (DG), a major bioactive ingredient of Trillium tschonoskii Max., possesses neuroprotective effects through its antioxidant and anti-apoptotic functions. In this study, we investigated the therapeutic benefit and underlying mechanisms of DG treatment in SCI. We found that in Sprague-Dawley rats with traumatic SCI, the expressions of autophagy marker Light Chain 3 (LC3) and Beclin1 were decreased with concomitant accumulation of autophagy substrate protein p62 and ubiquitinated proteins, indicating an impaired autophagic activity. DG treatment, however, significantly attenuated p62 expression and upregulated the Rheb/mTOR signaling pathway (evidenced as Ras homolog enriched in brain) due to the downregulation of miR-155-3p. We also observed significantly less tissue injury and edema in the DG-treated group, leading to appreciable functional recovery compared to that of the control group. Overall, the observed neuroprotection afforded by DG treatment warrants further investigation on its therapeutic potential in SCI.

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Trillium tschonoskii maxim saponin mitigates D-galactose-induced brain aging of rats through rescuing dysfunctional autophagy mediated by Rheb-mTOR signal pathway

Cited by 34 publications

References 33 publications

Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances

Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances

Modafinil protects hippocampal neurons by suppressing excessive autophagy and apoptosis in mice with sleep deprivation

Diosgenin Glucoside Protects against Spinal Cord Injury by Regulating Autophagy and Alleviating Apoptosis

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