Trehalose promotes the survival of random-pattern skin flaps by TFEB mediated autophagy enhancement

Wu, Hongqiang; Chen, Huanwen; Zheng, Zhilong; Li, Jiafeng; Ding, Jian; Huang, Zihuai; Jia, Chang; Shen, Zitong; Bao, Guodong; Wu, Lingyun; Mamun, Abdullah Al; Xu, Huazi; Gao, Weiyang; Zhou, Kailiang

doi:10.1038/s41419-019-1704-0

Cited by 50 publications

(39 citation statements)

References 54 publications

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“…Autophagy is defined as a highly regulated process involved in the turnover of long-lived proteins, cytosolic components, or damaged organelles 36 . Autophagy generates energy through a lysosome-dependent degeneration pathway for cells under nutrient-poor conditions or during starvation to maintain cellular homeostasis 37 .…”

Section: Discussionmentioning

confidence: 99%

TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress

et al. 2020

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Background and Aim: Increasing evidence suggests that spinal cord injury (SCI)-induced defects in autophagic flux may contribute to an impaired ability for neurological repair following injury. Transcription factor E3 (TFE3) plays a crucial role in oxidative metabolism, lysosomal homeostasis, and autophagy induction. Here, we investigated the role of TFE3 in modulating autophagy following SCI and explored its impact on neurological recovery. Methods: Histological analysis via HE, Nissl and Mason staining, survival rate analysis, and behavioral testing via BMS and footprint analysis were used to determine functional recovery after SCI. Quantitative real-time polymerase chain reaction, Western blotting, immunofluorescence, TUNEL staining, enzyme-linked immunosorbent assays, and immunoprecipitation were applied to examine levels of autophagy flux, ER-stress-induced apoptosis, oxidative stress, and AMPK related signaling pathways. In vitro studies using PC12 cells were performed to discern the relationship between ROS accumulation and autophagy flux blockade. Results: Our results showed that in SCI, defects in autophagy flux contributes to ER stress, leading to neuronal death. Furthermore, SCI enhances the production of reactive oxygen species (ROS) that induce lysosomal dysfunction to impair autophagy flux. We also showed that TFE3 levels are inversely correlated with ROS levels, and increased TFE3 levels can lead to improved outcomes. Finally, we showed that activation of TFE3 after SCI is partly regulated by AMPK-mTOR and AMPK-SKP2-CARM1 signaling pathways. Conclusions: TFE3 is an important regulator in ROS-mediated autophagy dysfunction following SCI, and TFE3 may serve as a promising target for developing treatments for SCI.

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Section: Discussionmentioning

confidence: 99%

TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress

et al. 2020

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“…Previous studies showed that Tre could augment lysosomal biogenesis and autophagic flux to ameliorate various disease phenotypes [23,36,[39][40][41]. These effects were accompanied by the activation and nuclear translocation of TFEB.…”

Section: Tre Activates Tfeb and Relieves Cs-induced Lysosomes Damagementioning

confidence: 97%

Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages

Shi

et al. 2020

Cells

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Silicosis is an occupational lung disease characterized by persistent inflammation and irreversible fibrosis. Crystalline silica (CS) particles are mainly phagocytized by alveolar macrophages (AMs), which trigger apoptosis, inflammation, and pulmonary fibrosis. Previously, we found that autophagy-lysosomal system dysfunction in AMs was involved in CS-induced inflammation and fibrosis. Induction of autophagy and lysosomal biogenesis by transcription factor EB (TFEB) nuclear translocation can rescue fibrotic diseases. However, the role of TFEB in silicosis is unknown. In this study, we found that CS induced TFEB nuclear localization and increased TFEB expression in macrophages both in vivo and in vitro. However, TFEB overexpression or treatment with the TFEB activator trehalose (Tre) alleviated lysosomal dysfunction and enhanced autophagic flux. It also reduced apoptosis, inflammatory cytokine levels, and fibrosis. Both pharmacologically inhibition of autophagy and TFEB knockdown in macrophages significantly abolished the antiapoptotic and anti-inflammatory effects elicited by either TFEB overexpression or Tre treatment. In conclusion, these results uncover a protective role of TFEB-mediated autophagy in silicosis. Our study suggests that restoration of autophagy-lysosomal function by Tre-induced TFEB activation may be a novel strategy for the treatment of silicosis.

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“…Random-pattern skin flap is a technique used in tissue reconstruction, and is not limited in flap position and direction due to the lack of axial vasculature 1,2 . Therefore, this technique is particularly popular in various clinical specialties such as plastic, trauma, and hand surgery 3,4 . However, due to the lack of axial blood vessels, the skin flap’s blood supply mainly depends on the microvascular network at the pedicle of the flap, and the blood flow at the distal end of the flap is often poor and inadequate, often leading to ischemic necrosis 5,6 .…”

Section: Introductionmentioning

confidence: 99%

FGF21 augments autophagy in random-pattern skin flaps via AMPK signaling pathways and improves tissue survival

et al. 2019

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Random-pattern skin flap is commonly used for surgical tissue reconstruction due to its ease and lack of axial vascular limitation. However, ischemic necrosis is a common complication, especially in distal parts of skin flaps. Previous studies have shown that FGF21 can promote angiogenesis and protect against ischemic cardiovascular disease, but little is known about the effect of FGF21 on flap survival. In this study, using a rat model of random skin flaps, we found that the expression of FGF21 is significantly increased after establishment skin flaps, suggesting that FGF21 may exert a pivotal effect on flap survival. We conducted experiments to elucidate the role of FGF21 in this model. Our results showed that FGF21 directly increased the survival area of skin flaps, blood flow intensity, and mean blood vessel density through enhancing angiogenesis, inhibiting apoptosis, and reducing oxidative stress. Our studies also revealed that FGF21 administration leads to an upregulation of autophagy, and the beneficial effects of FGF21 were reversed by 3-methyladenine (3MA), which is a well-known inhibitor of autophagy, suggesting that autophagy plays a central role in FGF21's therapeutic benefit on skin flap survival. In our mechanistic investigation, we found that FGF21-induced autophagy enhancement is mediated by the dephosphorylation and nuclear translocation of TFEB; this effect was due to activation of AMPK-FoxO3a-SPK2-CARM1 and AMPK-mTOR signaling pathways. Together, our data provides novel evidence that FGF21 is a potent modulator of autophagy capable of significantly increasing random skin flap viability, and thus may serve as a promising therapy for clinical use.

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Trehalose promotes the survival of random-pattern skin flaps by TFEB mediated autophagy enhancement

Cited by 50 publications

References 54 publications

TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress

TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress

Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages

FGF21 augments autophagy in random-pattern skin flaps via AMPK signaling pathways and improves tissue survival

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