Gamma-Secretase Inhibitor (DAPT), a potential therapeutic target drug, caused neurotoxicity in planarian regeneration by inhibiting Notch signaling pathway

Dong, Zimei; Huo, Jinrui; Liang, Ang; Chen, Jinzi; Chen, Guangwen; Liu, Dezeng

doi:10.1016/j.scitotenv.2021.146735

Cited by 34 publications

(18 citation statements)

References 47 publications

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“…Enrichment of the BPs related to negative regulation of peptidase activity by the upregulated genes in Yap1_KD samples was noteworthy. Our results are in accordance with earlier investigations which showed that peptidase activity is required for an appropriate regeneration process in both invertebrates and vertebrates (Dolmatov et al, 2019;Dong et al, 2021;Enos et al, 2019;Pasten et al, 2012;Rinkevich et al, 2007).…”

Section: Decreased Osteogenic and Collagen-related Gene Expression As...supporting

confidence: 94%

Downregulation of Yap1 During Limb Regeneration Results in Defective Bone Formation in Axolotl

Bay

Öztürk

Emekli

et al. 2022

Preprint

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The Hippo pathway plays an imperative role in cellular processes such as differentiation, regeneration, cell migration, organ growth, apoptosis, and cell cycle. Transcription coregulator component of Hippo pathway, YAP1, promotes transcription of genes involved in cell proliferation, migration, differentiation, and suppressing apoptosis. However, its role in epimorphic regeneration has not been fully explored. The axolotl is a well-established model organism for developmental biology and regeneration studies. By exploiting its remarkable regenerative capacity, we investigated the role of Yap1 in the early blastema stage of limb regeneration. Depleting Yap1 using gene-specific morpholinos attenuated the competence of axolotl limb regeneration evident in bone formation defects. To explore the affected downstream pathways from Yap1 down-regulation, the gene expression profile was examined by employing LC-MS/MS technology. Based on the generated data, we provided a new layer of evidence on the putative roles of increased protease inhibition and immune system activities and altered ECM composition in diminished bone formation capacity during axolotl limb regeneration upon Yap1 deficiency. We believe that new insights into the roles of the Hippo pathway in complex structure regeneration were granted in this study.

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Section: Decreased Osteogenic and Collagen-related Gene Expression As...supporting

confidence: 94%

Downregulation of Yap1 During Limb Regeneration Results in Defective Bone Formation in Axolotl

Bay

Öztürk

Emekli

et al. 2022

Preprint

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“…Next, we aimed to investigate whether the activation of Notch signal is related to M1 polarization of macrophages caused by AGEs. As a new type of γ-secretase inhibitor, DAPT is one of the commonly used inhibitors of Notch signaling pathway, which has a strong blocking effect on the transduction of Notch signal [33]. It should be noted that the target of DAPT is γ-secretase, a proteolytic enzyme that can dissociate NICD from Notch [34].…”

Section: Discussionmentioning

confidence: 99%

Notch/NICD/RBP-J Signaling Axis Regulates M1 Polarization of Macrophages Mediated by Advanced Glycation End Products

Tan¹,

Xu²,

Ding³

et al. 2021

Preprint

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Advanced glycation end products (AGEs) aggregation and macrophages polarization both play essential roles in degenerative bone diseases caused by aging or diabetes, such as senile or diabetic osteoporosis. Here, we aimed to understand the involvement and potential mechanism of AGEs in macrophages polarization and osteoclastogenesis. We found that RAW264.7 macrophages treated with AGEs highly expressed M1-associated genes and surface antigen markers CD86, and released a large amount of NO to the extracellular environment. Through the detection of osteoclast-related markers and TRAP staining, we revealed that the osteoclastogenesis of M1 macrophages could be markedly enhanced by AGEs. To explore the potential mechanisms of AGEs-mediated M1 polarization, we first demonstrated that AGEs effectively activated the transduction of Notch signaling pathway, including nuclear translocation of NICD1. Subsequently, it was observed that the M1 polarization effects induced by AGEs were significantly mitigated, when γ-secretase inhibitor DAPT and siRNA targeting silencing RBP-J were applied to block the signal transduction of Notch. In conclusion, our findings revealed a series of phenomena that AGEs induce macrophage M1 polarization and enhance its osteoclastogenesis ability, and Notch/NICD/RBP-J signaling axis is involved in the regulation of this polarization process.

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“…Recent advances in molecular and cellular biology techniques, behavioral imaging, and quantitative computational methods have reignited the excitement about planarians for studying chemical toxicity. The application of these tools has allowed planarian toxicology studies to evolve from primarily qualitative observations to quantitative analyses of specific phenotypes, which can be anchored to their molecular mechanisms (such as in Balestrini et al., 2014; Dong et al., 2021; Hagstrom et al., 2018; Ireland, Zhang, et al., 2022). The wide array of stereotypical behaviors exhibited by these worms has been exploited in neurotoxicology studies to uncover the effects of chemicals on brain function (reviewed in Hagstrom et al., 2016; Wu and Li, 2018).…”

Section: Brief History Of Freshwater Planarians In Toxicology Researchmentioning

confidence: 99%

New Worm on the Block: Planarians in (Neuro)Toxicology

Ireland

Collins

2022

Current Protocols

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Traditional mammalian testing is too time‐ and cost‐intensive to keep up with the large number of environmental chemicals needing assessment. This has led to a dearth of information about the potential adverse effects of these chemicals, especially on the developing brain. Thus, there is an urgent need for rapid and cost‐effective neurotoxicity and developmental neurotoxicity testing. Because of the complexity of the brain, metabolically competent organismal models are necessary to understand the effects of chemicals on nervous system development and function on a systems level. In this overview, we showcase asexual freshwater planarians as an alternative invertebrate (“non‐animal”) organismal model for neurotoxicology research. Planarians have long been used to study the effects of chemicals on regeneration and behavior. But they have only recently moved back into the spotlight because modern molecular and computational approaches now enable quantitative high‐content and high‐throughput toxicity studies. Here, we present a short history of the use of planarians in toxicology research, highlight current techniques to measure toxicity qualitatively and quantitatively in planarians, and discuss how to further promote this non‐animal organismal system into mainstream toxicology research. The articles in this collection will help work towards this goal by providing detailed protocols that can be adopted by the community to standardize planarian toxicity testing. © 2022 Wiley Periodicals LLC.

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Gamma-Secretase Inhibitor (DAPT), a potential therapeutic target drug, caused neurotoxicity in planarian regeneration by inhibiting Notch signaling pathway

Cited by 34 publications

References 47 publications

Downregulation of Yap1 During Limb Regeneration Results in Defective Bone Formation in Axolotl

Downregulation of Yap1 During Limb Regeneration Results in Defective Bone Formation in Axolotl

Notch/NICD/RBP-J Signaling Axis Regulates M1 Polarization of Macrophages Mediated by Advanced Glycation End Products

New Worm on the Block: Planarians in (Neuro)Toxicology

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