scholarly journals Transcription factor EB agonists from natural products for treating human diseases with impaired autophagy-lysosome pathway

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Jie Xu ◽  
Xiao-Qi Zhang ◽  
Zaijun Zhang
Keyword(s):  
Transcription Factor ◽  
Natural Products ◽  
Chinese Medicine ◽  
Degradation Process ◽  
Human Diseases ◽  
Lysosomal Storage ◽  
Toxic Protein ◽  
Intracellular Proteins ◽  
Transcription Factor Eb ◽  
Storage Disorders

AbstractAutophagy is a highly conserved degradation process for long-lived intracellular proteins and organelles mediated by lysosomes. Deficits in the autophagy-lysosome pathway (ALP) have been linked to a variety of human diseases, including neurodegenerative diseases, lysosomal storage disorders, and cancers. Transcription factor EB (TFEB) has been identified as a major regulator of autophagy and lysosomal biogenesis. Increasing evidence has demonstrated that TFEB activation can promote the clearance of toxic protein aggregates and regulate cellular metabolism. Traditional Chinese medicine (TCM)-derived natural products as important sources for drug discovery have been widely used for the treatment of various diseases associated with ALP dysfunction. Herein, we review (1) the regulation of TFEB and ALP; (2) TFEB and ALP dysregulation in human diseases; (3) TFEB activators from natural products and their potential uses.

scholarly journals Chloroquine and bafilomycin A mimic lysosomal storage disorders and impair mTORC1 signalling

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Anthony O. Fedele ◽  
Christopher G. Proud
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Lysosomal Proteolysis ◽  
Degradative Enzymes ◽  
Transcription Factor Eb ◽  
Autophagic Process ◽  
Protein Components ◽  
The Impact ◽  
Storage Disorders

Abstract Autophagy is dependent upon lysosomes, which fuse with the autophagosome to complete the autophagic process and whose acidic interior permits the activity of their intraluminal degradative enzymes. Chloroquine (CQ) and bafilomycin A1 (BafA) each cause alkalinisation of the lumen and thus impair lysosomal function, although by distinct mechanisms. CQ diffuses into lysosomes and undergoes protonation, while BafA inhibits the ability of the vacuolar type H+-ATPase (v-ATPase) to transfer protons into the lysosome. In the present study, we examine the impact of CQ and BafA on the activity of mammalian target of rapamycin complex 1 (mTORC1), inhibition of which is an early step in promoting autophagy. We find each compound inhibits mTORC1 signalling, without affecting levels of protein components of the mTORC1 signalling pathway. Furthermore, these effects are not related to these agents’ capacity to inhibit autophagy or the reduction in amino acid supply from lysosomal proteolysis. Instead, our data indicate that the reduction in mTORC1 signalling appears to be due to the accumulation of lysosomal storage material. However, there are differences in responses to these agents, for instance, in their abilities to up-regulate direct targets of transcription factor EB (TFEB), a substrate of mTORC1 that drives transcription of many lysosomal and autophagy-related genes. Nonetheless, our data imply that widely used agents that alkalinise intralysosomal pH are mimetics of acute lysosomal storage disorders (LSDs) and emphasise the importance of considering the result of CQ and BafA on mTORC1 signalling when interpreting the effects of these agents on cellular physiology.

scholarly journals Genistein Activates Transcription Factor EB and Corrects Niemann–Pick C Phenotype

2021 ◽  
Vol 22 (8) ◽  
pp. 4220
Author(s):  
Graciela Argüello ◽  
Elisa Balboa ◽  
Pablo J. Tapia ◽  
Juan Castro ◽  
María José Yañez ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Culture Media ◽  
Autophagic Flux ◽  
Lysosomal Storage ◽  
Cholesterol Accumulation ◽  
Activation Of Transcription ◽  
Genistein Treatment ◽  
Transcription Factor Eb ◽  
Function Regulator ◽  
Niemann Pick

Niemann–Pick type C disease (NPCD) is a lysosomal storage disease (LSD) characterized by abnormal cholesterol accumulation in lysosomes, impaired autophagy flux, and lysosomal dysfunction. The activation of transcription factor EB (TFEB), a master lysosomal function regulator, reduces the accumulation of lysosomal substrates in LSDs where the degradative capacity of the cells is compromised. Genistein can pass the blood–brain barrier and activate TFEB. Hence, we investigated the effect of TFEB activation by genistein toward correcting the NPC phenotype. We show that genistein promotes TFEB translocation to the nucleus in HeLa TFEB-GFP, Huh7, and SHSY-5Y cells treated with U18666A and NPC1 patient fibroblasts. Genistein treatment improved lysosomal protein expression and autophagic flux, decreasing p62 levels and increasing those of the LC3-II in NPC1 patient fibroblasts. Genistein induced an increase in β-hexosaminidase activity in the culture media of NPC1 patient fibroblasts, suggesting an increase in lysosomal exocytosis, which correlated with a decrease in cholesterol accumulation after filipin staining, including cells treated with U18666A and NPC1 patient fibroblasts. These results support that genistein-mediated TFEB activation corrects pathological phenotypes in NPC models and substantiates the need for further studies on this isoflavonoid as a potential therapeutic agent to treat NPCD and other LSDs with neurological compromise.

scholarly journals The Role and Regulatory Mechanism of Transcription Factor EB in Health and Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Sheng-yu Zhu ◽  
Ren-qi Yao ◽  
Yu-xuan Li ◽  
Peng-yue Zhao ◽  
Chao Ren ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Structural Integrity ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Human Diseases ◽  
Host Responses ◽  
Beneficial Effects ◽  
Metabolism Regulation ◽  
Transcription Factor Eb ◽  
Multiple Drugs

Transcription factor EB (TFEB) is a member of the microphthalmia-associated transcription factor/transcription factor E (MiTF/TFE) family and critically involved in the maintenance of structural integrity and functional balance of multiple cells. In this review, we described the effects of post-transcriptional modifications, including phosphorylation, acetylation, SUMOylation, and ubiquitination, on the subcellular localization and activation of TFEB. The activated TFEB enters into the nucleus and induces the expressions of targeted genes. We then presented the role of TFEB in the biosynthesis of multiple organelles, completion of lysosome-autophagy pathway, metabolism regulation, immune, and inflammatory responses. This review compiles existing knowledge in the understanding of TFEB regulation and function, covering its essential role in response to cellular stress. We further elaborated the involvement of TFEB dysregulation in the pathophysiological process of various diseases, such as the catabolic hyperactivity in tumors, the accumulation of abnormal aggregates in neurodegenerative diseases, and the aberrant host responses in inflammatory diseases. In this review, multiple drugs have also been introduced, which enable regulating the translocation and activation of TFEB, showing beneficial effects in mitigating various disease models. Therefore, TFEB might serve as a potential therapeutic target for human diseases. The limitation of this review is that the mechanism of TFEB-related human diseases mainly focuses on its association with lysosome and autophagy, which needs deep description of other mechanism in diseases progression after getting more advanced information.

scholarly journals Remedying the Mitochondria to Cure Human Diseases by Natural Products

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
Jian-Kang Mu ◽  
Yan-Qin Li ◽  
Ting-Ting Shi ◽  
Li-Ping Yu ◽  
Ya-Qin Yang ◽  
...  
Keyword(s):  
Natural Products ◽  
Mitochondrial Dysfunction ◽  
Mechanism Of Action ◽  
Current Knowledge ◽  
Human Diseases ◽  
Mitochondrial Regulation ◽  
The Relationship

Mitochondria are the ‘engine’ of cells. Mitochondrial dysfunction is an important mechanism in many human diseases. Many natural products could remedy the mitochondria to alleviate mitochondria-involved diseases. In this review, we summarized the current knowledge of the relationship between the mitochondria and human diseases and the regulation of natural products to the mitochondria. We proposed that the development of mitochondrial regulators/nutrients from natural products to remedy mitochondrial dysfunction represents an attractive strategy for a mitochondria-involved disorder therapy. Moreover, investigating the mitochondrial regulation of natural products can potentiate the in-depth comprehension of the mechanism of action of natural products.

scholarly journals Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders

2021 ◽  
Author(s):  
Daniel Erskine ◽  
David Koss ◽  
Viktor I. Korolchuk ◽  
Tiago F. Outeiro ◽  
Johannes Attems ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Mitochondrial Diseases ◽  
Model Systems ◽  
Lipid Homeostasis ◽  
Lysosomal Storage ◽  
Iron Storage ◽  
Monogenic Disorders ◽  
Storage Disorders

AbstractAccumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.

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