Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions

Martins, Waleska K.; Silva, Maryana do Nascimento da; Pandey, Kiran; Maejima, Ikuko; Ramalho, Ercília da Silva; Olivon, Vânia C.; Diniz, Susana Nogueira; Grasso, Daniel

doi:10.1016/j.crphar.2021.100033

Cited by 11 publications

(5 citation statements)

References 341 publications

(382 reference statements)

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“…Several existing drugs have been found to modulate autophagy, including rapamycin and rapalogues, metformin and chloroquine, but these drugs all have several other actions so are not specific for autophagy [ 97 ]. Cardiac glycosides, widely used in the treatment of cardiovascular diseases, are activators of autophagy, although under some conditions they may be inhibitory [ 98 ].…”

Section: Conclusion and Future Developmentsmentioning

confidence: 99%

Autophagy in asthma and chronic obstructive pulmonary disease

2022

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Autophagy (or macroautophagy) is a key cellular process that removes damaged molecules (particularly proteins) and subcellular organelles to maintain cellular homeostasis. There is growing evidence that abnormalities in autophagy may contribute to the pathogenesis of many chronic diseases, including asthma and chronic obstructive pulmonary disease (COPD). In asthma, increased autophagy plays a role in promoting type 2 immune responses and eosinophilic inflammation, whereas decreased autophagy may be important in neutrophilic asthma. Acute exposure to cigarette smoke may activate autophagy, resulting in ciliary dysfunction and death of airway epithelial cells, whereas in stable COPD most studies have demonstrated an impairment in autophagy, with reduced autophagic flux and accumulation of abnormal mitochondria (defective mitophagy) and linked to cellular senescence. Autophagy may be increased or decreased in different cell types and depending on the cellular environment, making it difficult to target autophagy therapeutically. Several existing drugs may activate autophagy, including rapamycin, metformin, carbamazepine, cardiac glycosides and statins, whereas others, such as chloroquine, inhibit this process. However, these drugs are nonspecific and more selective drugs are now in development, which may prove useful as novel agents to treat asthma and COPD in the future.

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Section: Conclusion and Future Developmentsmentioning

confidence: 99%

Autophagy in asthma and chronic obstructive pulmonary disease

2022

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“…Dysfunction and dysregulation of autophagy are associated with many human diseases such as metabolic syndrome, lung disease, kidney disease, infectious disease, cardiovascular disease, liver disease, neurodegenerative disease, and cancers. Drugs that modulate autophagic activity have the potential to treat these diseases [ 39 , 41 , 122 , 123 , 124 ]. Autophagy dysfunction increases the accumulation of abnormal proteins in cells and induces oxidative stress and ER stress, leading to genomic instability and tumor progression [ 41 ].…”

Section: Autophagy In Mafldmentioning

confidence: 99%

Autophagy Dysregulation in Metabolic Associated Fatty Liver Disease: A New Therapeutic Target

Chen

Lin

2022

IJMS

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Metabolic associated fatty liver disease (MAFLD) is one of the most common causes of chronic liver disease worldwide. To date, there is no FDA-approved treatment, so there is an urgent need to determine its pathophysiology and underlying molecular mechanisms. Autophagy is a lysosomal degradation pathway that removes damaged organelles and misfolded proteins after cell injury through endoplasmic reticulum stress or starvation, which inhibits apoptosis and promotes cell survival. Recent studies have shown that autophagy plays an important role in removing lipid droplets from hepatocytes. Autophagy has also been reported to inhibit the production of pro-inflammatory cytokines and provide energy for the hepatic stellate cells activation during liver fibrosis. Thyroid hormone, irisin, melatonin, hydrogen sulfide, sulforaphane, DA-1241, vacuole membrane protein 1, nuclear factor erythroid 2-related factor 2, sodium-glucose co-transporter type-2 inhibitors, immunity-related GTPase M, and autophagy-related gene 7 have been reported to ameliorate MAFLD via autophagic induction. Lipid receptor CD36, SARS-CoV-2 Spike protein and leucine aminopeptidase 3 play a negative role in the autophagic function. This review summarizes recent advances in the role of autophagy in MAFLD. Autophagy modulates major pathological changes, including hepatic lipid metabolism, inflammation, and fibrosis, suggesting the potential of modulating autophagy for the treatment of MAFLD.

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“…The idea of enhancing autophagy to counteract neurodegeneration has been explored by many [ 152 ] and in most cases the preferred molecular target for the proposed therapeutic strategies is mTOR, particularly using specific mTOR inhibitors. Despite their efficacy in certain models, they have also proved to have limited capacity of impacting neurodegenerative diseases in certain clinical trials.…”

Section: Mitf/tfe Family Transcription Factors: Putative Therapeutic ...mentioning

confidence: 99%

The Regulation of MiTF/TFE Transcription Factors Across Model Organisms: from Brain Physiology to Implication for Neurodegeneration

et al. 2022

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The microphthalmia/transcription factor E (MiTF/TFE) transcription factors are responsible for the regulation of various key processes for the maintenance of brain function, including autophagy-lysosomal pathway, lipid catabolism, and mitochondrial homeostasis. Among them, autophagy is one of the most relevant pathways in this frame; it is evolutionary conserved and crucial for cellular homeostasis. The dysregulation of MiTF/TFE proteins was shown to be involved in the development and progression of neurodegenerative diseases. Thus, the characterization of their function is key in the understanding of the etiology of these diseases, with the potential to develop novel therapeutics targeted to MiTF/TFE proteins and to the autophagic process. The fact that these proteins are evolutionary conserved suggests that their function and dysfunction can be investigated in model organisms with a simpler nervous system than the mammalian one. Building not only on studies in mammalian models but also in complementary model organisms, in this review we discuss (1) the mechanistic regulation of MiTF/TFE transcription factors; (2) their roles in different regions of the central nervous system, in different cell types, and their involvement in the development of neurodegenerative diseases, including lysosomal storage disorders; (3) the overlap and the compensation that occur among the different members of the family; (4) the importance of the evolutionary conservation of these protein and the process they regulate, which allows their study in different model organisms; and (5) their possible role as therapeutic targets in neurodegeneration.

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Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions

Cited by 11 publications

References 341 publications

Autophagy in asthma and chronic obstructive pulmonary disease

Autophagy in asthma and chronic obstructive pulmonary disease

Autophagy Dysregulation in Metabolic Associated Fatty Liver Disease: A New Therapeutic Target

The Regulation of MiTF/TFE Transcription Factors Across Model Organisms: from Brain Physiology to Implication for Neurodegeneration

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