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

Zhou, Kailiang; Zheng, Zhilong; Li, Yao; Han, Wen; Zhang, Jing; Mao, Yuqin; Chen, Huanwen; Zhang, Wanying; Liu, Mi; Xie, Ling; Zhang, Hongyu; Xu, Huazi; Xiao, Jian

doi:10.7150/thno.46566

Cited by 104 publications

(76 citation statements)

References 66 publications

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“…It is well-known that, following an HI insult, mitochondrial dysfunction results in the production of excess ROS, which rapidly overwhelms neuronal antioxidant capacity 16 . The high levels of ROS induce oxidative damage to cellular macromolecules, which initiates a cycle of ROS production and organelle dysregulation that eventually triggers neuronal apoptosis 1 , 16 , 104 - 107 . We found that prenatal PBM treatment significantly alleviated HI-induced oxidative damage to lipids, proteins, and DNA.…”

Section: Discussionmentioning

confidence: 99%

Effects of prenatal photobiomodulation treatment on neonatal hypoxic ischemia in rat offspring

Yang¹,

Dong²,

Wu³

et al. 2021

Theranostics

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Neonatal hypoxic-ischemic (HI) injury is a severe complication often leading to neonatal death and long-term neurobehavioral deficits in children. Currently, the only treatment option available for neonatal HI injury is therapeutic hypothermia. However, the necessary specialized equipment, possible adverse side effects, and limited effectiveness of this therapy creates an urgent need for the development of new HI treatment methods. Photobiomodulation (PBM) has been shown to be neuroprotective against multiple brain disorders in animal models, as well as limited human studies. However, the effects of PBM treatment on neonatal HI injury remain unclear. Methods: Two-minutes PBM (808 nm continuous wave laser, 8 mW/cm 2 on neonatal brain) was applied three times weekly on the abdomen of pregnant rats from gestation day 1 (GD1) to GD21. After neonatal right common carotid artery ligation, cortex- and hippocampus-related behavioral deficits due to HI insult were measured using a battery of behavioral tests. The effects of HI insult and PBM pretreatment on infarct size; synaptic, dendritic, and white matter damage; neuronal degeneration; apoptosis; mitochondrial function; mitochondrial fragmentation; oxidative stress; and gliosis were then assessed. Results: Prenatal PBM treatment significantly improved the survival rate of neonatal rats and decreased infarct size after HI insult. Behavioral tests revealed that prenatal PBM treatment significantly alleviated cortex-related motor deficits and hippocampus-related memory and learning dysfunction. In addition, mitochondrial function and integrity were protected in HI animals treated with PBM. Additional studies revealed that prenatal PBM treatment significantly alleviated HI-induced neuroinflammation, oxidative stress, and myeloid cell/astrocyte activation. Conclusion: Prenatal PBM treatment exerts neuroprotective effects on neonatal HI rats. Underlying mechanisms for this neuroprotection may include preservation of mitochondrial function, reduction of inflammation, and decreased oxidative stress. Our findings support the possible use of PBM treatment in high-risk pregnancies to alleviate or prevent HI-induced brain injury in the perinatal period.

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Section: Discussionmentioning

confidence: 99%

Effects of prenatal photobiomodulation treatment on neonatal hypoxic ischemia in rat offspring

Yang¹,

Dong²,

Wu³

et al. 2021

Theranostics

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“…We followed the methods of our previous research (Zhou et al, 2020). TFE3-KI/wt mice were generated by the Nanjing Biomedical Research Institute of Nanjing University.…”

Section: Production Of Tfe3-ki/wt Micementioning

confidence: 99%

“…Enzyme-Linked Immunosorbent Assay (ELISA) was performed as previously described (Zhou et al, 2020). At a word, the flap tissue and cell supernatant were homogenized with PBS, and then, they were repeatedly frozen and thawed with liquid nitrogen.…”

Section: Enzyme-linked Immunosorbent Assaymentioning

confidence: 99%

Targeting TFE3 Protects Against Lysosomal Malfunction-Induced Pyroptosis in Random Skin Flaps via ROS Elimination

Lou

et al. 2021

Front. Cell Dev. Biol.

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Increasing evidence indicates that pyroptosis, a new type of programmed cell death, may participate in random flap necrosis and play an important role. ROS-induced lysosome malfunction is an important inducement of pyroptosis. Transcription factor E3 (TFE3) exerts a decisive effect in oxidative metabolism and lysosomal homeostasis. We explored the effect of pyroptosis in random flap necrosis and discussed the effect of TFE3 in modulating pyroptosis. Histological analysis via hematoxylin-eosin staining, immunohistochemistry, general evaluation of flaps, evaluation of tissue edema, and laser Doppler blood flow were employed to determine the survival of the skin flaps. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays were used to calculate the expressions of pyroptosis, oxidative stress, lysosome function, and the AMPK-MCOLN1 signaling pathway. In cell experiments, HUVEC cells were utilized to ensure the relationship between TFE3, reactive oxygen species (ROS)-induced lysosome malfunction and cell pyroptosis. Our results indicate that pyroptosis exists in the random skin flap model and oxygen and glucose deprivation/reperfusion cell model. In addition, NLRP3-mediated pyroptosis leads to necrosis of the flaps. Moreover, we also found that ischemic flaps can augment the accumulation of ROS, thereby inducing lysosomal malfunction and finally initiating pyroptosis. Meanwhile, we observed that TFE3 levels are interrelated with ROS levels, and overexpression and low expression of TFE3 levels can, respectively, inhibit and promote ROS-induced lysosomal dysfunction and pyroptosis during in vivo and in vitro experiments. In conclusion, we found the activation of TFE3 in random flaps is partially regulated by the AMPK-MCOLN1 signal pathway. Taken together, TFE3 is a key regulator of ROS-induced pyroptosis in random skin flaps, and TFE3 may be a promising therapeutic target for improving random flap survival.

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“…Traumatic spinal cord injury (SCI) is a devastating condition that results in long-term disability and death worldwide [ 1 ]. Neuronal cell death is one of the most critical pathological issues caused by direct mechanical impact, followed by a series of secondary molecular cascades, including mitochondrial damage, reactive oxygen species (ROS) and misfolded protein accumulation, and the inflammatory response [ [2] , [3] , [4] ]. Although neural tissue is associated with limited intrinsic regenerative capability, increasing evidence indicates that targeting these secondary molecular processes is a therapeutic method for improving functional recovery after SCI in many animal cases [ [5] , [6] , [7] ].…”

Section: Introductionmentioning

confidence: 99%

Delivery of pOXR1 through an injectable liposomal nanoparticle enhances spinal cord injury regeneration by alleviating oxidative stress

Zhang

Xiong

et al. 2021

Bioactive Materials

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Oxidation resistance 1 (OXR1) is regarded as a critical regulator of cellular homeostasis in response to oxidative stress. However, the role of OXR1 in the neuronal response to spinal cord injury (SCI) remains undefined. On the other hand, gene therapy for SCI has shown limited success to date due in part to the poor utility of conventional gene vectors. In this study, we evaluated the function of OXR1 in SCI and developed an available carrier for delivering the OXR1 plasmid (pOXR1). We found that OXR1 expression is remarkably increased after SCI and that this regulation is protective after SCI. Meanwhile, we assembled cationic nanoparticles with vitamin E succinate-grafted ε-polylysine (VES-g-PLL) (Nps). The pOXR1 was precompressed with Nps and then encapsulated into cationic liposomes. The particle size of pOXR1 was compressed to 58 nm, which suggests that pOXR1 can be encapsulated inside liposomes with high encapsulation efficiency and stability to enhance the transfection efficiency. The agarose gel results indicated that Nps-pOXR1-Lip eliminated the degradation of DNA by DNase I and maintained its activity, and the cytotoxicity results indicated that pOXR1 was successfully transported into cells and exhibited lower cytotoxicity. Finally, Nps-pOXR1-Lip promoted functional recovery by alleviating neuronal apoptosis, attenuating oxidative stress and inhibiting inflammation. Therefore, our study provides considerable evidence that OXR1 is a beneficial factor in resistance to SCI and that Nps-Lip-pOXR1 exerts therapeutic effects in acute traumatic SCI.

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

Cited by 104 publications

References 66 publications

Effects of prenatal photobiomodulation treatment on neonatal hypoxic ischemia in rat offspring

Effects of prenatal photobiomodulation treatment on neonatal hypoxic ischemia in rat offspring

Targeting TFE3 Protects Against Lysosomal Malfunction-Induced Pyroptosis in Random Skin Flaps via ROS Elimination

Delivery of pOXR1 through an injectable liposomal nanoparticle enhances spinal cord injury regeneration by alleviating oxidative stress

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