Quercetin Suppresses Apoptosis and Attenuates Intervertebral Disc Degeneration via the SIRT1-Autophagy Pathway

Wang, Dong; He, Xu; Wang, Di; Peng, Pandi; Xu, Xiaolong; Gao, Bo; Zheng, Cuifang; Wang, Han; Jia, Huixian; Shang, Qiliang; Sun, Zhen; Luo, Zhuojing; Liu, Yang

doi:10.3389/fcell.2020.613006

Cited by 62 publications

(55 citation statements)

References 71 publications

(82 reference statements)

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“…These results indicated that Sirt1-induced deacetylation of p53 was able to enhance RTEC autophagy. Two Sirt1 chemical agonists, RSV and QCT, were then applied to clarify the effects of Sirt1 activation on acetylation of p53 and RTEC autophagy (24). First, we verified that both RSV and QCT could reduce the acetylation level of p53 at lysine 379 (Supplementary Figures 5A-F).…”

Section: Activation Of Deacetylase Sirt1 Promotes Autophagy and Reduces Sakimentioning

confidence: 72%

p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy

Sun

Mao

et al. 2021

Front. Immunol.

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Recent studies have shown that autophagy upregulation can attenuate sepsis-induced acute kidney injury (SAKI). The tumor suppressor p53 has emerged as an autophagy regulator in various forms of acute kidney injury (AKI). Our previous studies showed that p53 acetylation exacerbated hemorrhagic shock-induced AKI and lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. However, the role of p53-regulated autophagy in SAKI has not been examined and requires clarification. In this study, we observed the dynamic changes of autophagy in renal tubular epithelial cells (RTECs) and verified the protective effects of autophagy activation on SAKI. We also examined the changes in the protein expression, intracellular distribution (nuclear and cytoplasmic), and acetylation/deacetylation levels of p53 during SAKI following cecal ligation and puncture (CLP) or LPS treatment in mice and in a LPS-challenged human RTEC cell line (HK-2 cells). After sepsis stimulation, the autophagy levels of RTECs increased temporarily, followed by a sharp decrease. Autophagy inhibition was accompanied by an increased renal tubular injury score. By contrast, autophagy agonists could reduce renal tubular damage following sepsis. Surprisingly, the expression of p53 protein in both the renal cortex and HK-2 cells did not significantly change following sepsis stimulation. However, the translocation of p53 from the nucleus to the cytoplasm increased, and the acetylation of p53 was enhanced. In the mechanistic study, we found that the induction of p53 deacetylation, due to either the resveratrol/quercetin -induced activation of the deacetylase Sirtuin 1 (Sirt1) or the mutation of the acetylated lysine site in p53, promoted RTEC autophagy and alleviated SAKI. In addition, we found that acetylated p53 was easier to bind with Beclin1 and accelerated its ubiquitination-mediated degradation. Our study underscores the importance of deacetylated p53-mediated RTEC autophagy in future SAKI treatments.

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Section: Activation Of Deacetylase Sirt1 Promotes Autophagy and Reduces Sakimentioning

confidence: 72%

p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy

Sun

Mao

et al. 2021

Front. Immunol.

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“…Aysa et al [36] reported that QUE alleviates high glucoseinduced damage on umbilical vein endothelial cells by promoting autophagy, although the specific autophagy-related pathways were not analyzed. Recently, QUE has been shown to suppress apoptosis and attenuate IVDD via the SIRT1autophagy pathway [43], while He et al [9] reported that QUE could induce autophagy via the FOXO1-dependent pathways. Taken together, these studies suggest that in addition to the p38 MAPK pathway, QUE may, at least partially, reduce the oxidative stress-induced injury of NPCs through these additional pathways.…”

Section: Discussionmentioning

confidence: 99%

Quercetin Alleviates Intervertebral Disc Degeneration by Modulating p38 MAPK-Mediated Autophagy

Zhang

Abulizi

et al. 2021

BioMed Research International

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Intervertebral disc degeneration (IVDD) is a degenerative and chronic spinal disorder often associated with the older population. Oxidative stress is a major pathogenic factor of aging that results in the apoptosis of nucleus pulposus cells (NPCs) and extracellular matrix (ECM) degradation. Quercetin (QUE), a naturally occurring flavonoid with antioxidant and anti-inflammatory properties, has been studied in research on degenerative diseases. However, the potential effects and mechanisms of action of QUE on IVDD remain unclear. In this study, the effects of QUE on antiapoptosis and ECM metabolism were firstly investigated in TBHP-treated NPCs. Meanwhile, the autophagy inhibitor, 3-MA, and p38 MAPK inhibitor, SB203580, were used in subsequent TBHP-induced NPC experiments to determine whether QUE exerted its protective effects through autophagy and the p38 MAPK/mTOR signaling pathway. Finally, the therapeutic effects of QUE were confirmed in vivo using a rat tail needle puncture-induced model of IVDD. We found that QUE treatment significantly alleviated oxidative stress-decreased cell viability and intracellular ROS levels in NPCs treated with TBHP. Furthermore, treatment with QUE led to a decrease in apoptosis as measured by decreased Bax and increased Bcl-2 expression and PE/7-AAD flow cytometry analysis. QUE also promoted ECM stability as measured by increased collagen II and aggrecan and decreased MMP13 levels. Our results also showed that QUE promoted the expression of autophagy markers beclin-1, LC3-II/I, and decreased p62. Inhibition of autophagy by inhibitor 3-MA may partially reverse the protective effect of QUE on apoptosis and ECM degeneration, indicating that autophagy was involved in the protective effect of QUE in NPCs. Further study confirmed that QUE partially inhibited the p38 MAPK signaling pathway and inhibition of p38 MAPK by SB203580 activated autophagy, indicating that QUE protected NPCs against apoptosis and prevented ECM degeneration via the p38 MAPK-autophagy pathway. Finally, using a rat tail puncture-induced model of IVDD, we confirmed that QUE had a protective effect against IVDD. Our results suggest that QUE could prevent IVDD by modulating p38 MAPK-mediated autophagy and, therefore, is a potential therapeutic strategy in the treatment of IVDD.

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“…However, in contrast with our findings, their study reported that quercetin treatment induced protein aggregation, mostly inside the nucleus [ 29 ]. Induction of autophagy by quercetin has been observed in several tissues and diseases, including diabetic nephropathy [ 30 ], oocytes from aged mice [ 31 ], intervertebral disc degeneration [ 32 ], myelodysplastic bone marrow [ 33 ], and human retinal pigment epithelial cells [ 34 ], while one study reported that quercetin attenuated autophagy in a rat model of traumatic brain injury [ 35 ]. Regardless of these previous studies, here we performed a comprehensive set of autophagy assays that unquestionably proved the effect of quercetin on autophagy for the first time [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Quercetin in Tartary Buckwheat Induces Autophagy against Protein Aggregations

Ikari

Liu³

et al. 2021

Antioxidants

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Tartary buckwheat is used as an ingredient in flour and tea, as well as in traditional Chinese medicine for its antioxidant effects. Here, we found that an ethanol extract of tartary buckwheat (TBE) potently induced autophagy flux in HeLa cells by suppressing mTORC1 activity, as revealed by dephosphorylation of the mTORC1 substrates Ulk1, S6K, and 4EBP, as well as by the nuclear translocation of transcriptional factor EB. In addition to non-selective bulk autophagy, TBE also induced aggrephagy, which is defined as autophagy against aggregated proteins. Quercetin is a flavonol found at high levels in TBE. We showed that quercetin induced both non-selective bulk autophagy and aggrephagy. These effects were also observed in Huh-7 cells derived from hepatocytes. Thus, aggrephagy induction by TBE and quercetin may relieve alcoholic hepatitis, which is closely linked to the accumulation of protein aggregations called Mallory–Denk bodies.

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Quercetin Suppresses Apoptosis and Attenuates Intervertebral Disc Degeneration via the SIRT1-Autophagy Pathway

Cited by 62 publications

References 71 publications

p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy

p53 Deacetylation Alleviates Sepsis-Induced Acute Kidney Injury by Promoting Autophagy

Quercetin Alleviates Intervertebral Disc Degeneration by Modulating p38 MAPK-Mediated Autophagy

Quercetin in Tartary Buckwheat Induces Autophagy against Protein Aggregations

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