Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: Implications for Alzheimer's disease therapy

Yang, Chonglin; Su, Cheng-Fu; Iyaswamy, Ashok; Krishnamoorthi, Senthil Kumar; Zhu, Zhou; Yang, Sichang; Tong, Benjamin Chun‐Kit; Liu, Jia; Sreenivasmurthy, Sravan Gopalkrishnashetty; Guan, Xiaodong; Kan, Yuxuan; Wu, Aston Jiaxi; Huang, Alexis Shiying; Tan, Jieqiong; Cheung, King‐Ho; Song, Ju‐Xian; Yang, Chuanbin

doi:10.1016/j.apsb.2022.01.017

Cited by 65 publications

(55 citation statements)

References 75 publications

(116 reference statements)

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“…Though we found that piceatannol effectively enhanced TFEB/TFE3-mediated autophagy, future studies to dissect the role of the upstream signaling pathways such as calcium/calcineurin ( 18 , 38 ), or mTORC1 signaling ( 19 , 39 ) in mediating the synergistic effect of piceatannol with OXA is fundamentally required. It is possible that piceatannol activates TFEB/TFE3 via mTORC1 inhibition since previous studies have shown that piceatannol inhibits PI3k/Akt/mTOR signaling ( 40 ).…”

Section: Discussionmentioning

confidence: 79%

“…Briefly, intracellular total proteins were extracted with RIPA lysis buffer (CST 9806) containing protease inhibitor mixture and phosphatase inhibitor. The cytoplasm and the nuclear proteins were extracted as previously described ( 18 , 19 ). SDS-PAGE (10 to 15%) was used for separation of protein samples, followed by transferring of membrane and blotting with indicated primary antibodies and relevant secondary antibodies.…”

Section: Methodsmentioning

confidence: 99%

“…For tf-LC3, CALR, TFEB, and TFE3 staining, cells were transfected with tf-LC3 (Addgene 21074), Flag-TFEB ( 19 ), GFP-TFE3 (Addgene, 38120), and Calreticulin-RFP-KDEL ( 21 ) plasmids using Lipofectamine 3000 (Thermo, L3000015) for 48 h, followed by treating cells with indicated drugs for another 24 h. After fixation, cells were stained with indicated antibodies, and nucleus was stained with DAPI. The images were captured utilizing a Leica TCS SP8 STED microscope.…”

Section: Methodsmentioning

confidence: 99%

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Autophagy activation by dietary piceatannol enhances the efficacy of immunogenic chemotherapy

Wang

Wang²,

Wu³

et al. 2022

Front. Immunol.

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Immunogenic cell death (ICD) promotes the immune antitumor response via releasing damage-associated molecular patterns (DAMPs) from dying tumor cells. The induction of autophagy improves the efficacy of multiple immunogenic chemotherapies. Here, we show that piceatannol, a dietary phenolic compound that is widely distributed in multiple fruits and vegetables such as grapes, blueberries, and mushrooms, induces autophagy and enhances oxaliplatin (OXA)-induced anticancer immune response. Specifically, piceatannol enhanced OXA-induced release of DAMPs, several key hallmarks of ICD including ATP release, cell surface exposure of calreticulin, and high-mobility group box 1 (HMGB1) release. Mechanistically, piceatannol promoted autophagy via activating TFEB/TFE3, two key transcription factors of the autophagy-lysosome pathway, and inhibiting autophagy attenuated piceatannol plus OXA-induced ATP release. Furthermore, piceatannol induced endoplasmic reticulum stress, which is critical for its role in enhancing OXA-induced cell surface exposure of calreticulin, another key hallmark of ICD. Consistently, the combination of piceatannol with OXA promoted the anticancer effects in immunocompetent mice. Taken together, our results indicate the importance and great potential of dietary piceatannol in cancer immunotherapy. Therefore, piceatannol may be used as an ICD enhancer that improves the efficacy of chemotherapeutics such as OXA in cancer treatment with minimized toxicity.

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Section: Discussionmentioning

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Autophagy activation by dietary piceatannol enhances the efficacy of immunogenic chemotherapy

Wang

Wang²,

Wu³

et al. 2022

Front. Immunol.

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“…Cocoa is known to contain many phytochemicals such as polyphenols, flavanols such as epicatechin and catechin, as well as procyanidins [ 43 ]. In fact, several evidence have confirmed that such natural compounds have not only antioxidant but also anti-neuroinflammatory activity and are able to attenuate neurological disorders [ 54 , 67 , 68 , 69 , 70 ]. However, it is reported that cocoa compounds can induce neuronal protection mostly for their efficacy on endothelial cells, in which they stimulate NO synthesis enhancing cerebrovascular circulation [ 44 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

Cocoa Extract Provides Protection against 6-OHDA Toxicity in SH-SY5Y Dopaminergic Neurons by Targeting PERK

et al. 2022

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Parkinson’s disease (PD) represents one of the most common neurodegenerative disorders, characterized by a dopamine (DA) deficiency in striatal synapses and misfolded toxic α-synuclein aggregates with concomitant cytotoxicity. In this regard, the misfolded proteins accumulation in neurodegenerative disorders induces a remarkable perturbations of endoplasmic reticulum (ER) homeostasis leading to persistent ER stress, which in turn, effects protein synthesis, modification, and folding quality control. A large body of evidence suggests that natural products target the ER stress signaling pathway, exerting a potential action in cancers, diabetes, cardiovascular and neurodegenerative diseases. This study aims to assess the neuroprotective effect of cocoa extract and its purified fractions against a cellular model of Parkinson’s disease represented by 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y human neuroblastoma. Our findings demonstrate, for the first time, the ability of cocoa to specifically targets PERK sensor, with significant antioxidant and antiapoptotic activities as both crude and fractioning extracts. In addition, cocoa also showed antiapoptotic properties in 3D cell model and a notable ability to inhibit the accumulation of α-synuclein in 6-OHDA-induced cells. Overall, these results indicate that cocoa exerts neuroprotective effects suggesting a novel possible strategy to prevent or, at least, mitigate neurodegenerative disorders, such as PD.

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“…A current mechanistic understanding of how autophagy is impaired in aging and AD were beautifully summarized in two review articles 5 , 6 . In addition, two original research articles 7 , 8 describe promising novel small molecules that either directly target A β or activate a transcriptional program that boosts autophagy–lysosomal degradation of A β and tau aggregates. Overall, we believe that this timely special issue will advance our understanding AD and provide mechanistic insights into its pathogenesis, as well as novel drug development efforts.…”

mentioning

confidence: 99%

Editorial of special column on Drug targets and drug development for Alzheimer's disease

Ding

Swerdlow

2022

Acta Pharmaceutica Sinica B

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Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: Implications for Alzheimer's disease therapy

Cited by 65 publications

References 75 publications

Autophagy activation by dietary piceatannol enhances the efficacy of immunogenic chemotherapy

Autophagy activation by dietary piceatannol enhances the efficacy of immunogenic chemotherapy

Cocoa Extract Provides Protection against 6-OHDA Toxicity in SH-SY5Y Dopaminergic Neurons by Targeting PERK

Editorial of special column on Drug targets and drug development for Alzheimer's disease

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