Mammalian Target of Rapamycin: Is It Relevant to COPD Pathogenesis or Treatment?

Pasini, Evasio; Flati, Vincenzo; Comini, Laura; Olivares, Adriana; Bertella, Enrica; Corsetti, Giovanni; Vitacca, Michele

doi:10.1080/15412555.2019.1583726

Cited by 5 publications

(3 citation statements)

References 28 publications

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“…COPD patients with low muscle mass exhibit an increase in phosphorylation of the downstream targets 4E-BP1 and p70S6K, explained by an attempt to compensate for the loss of muscle mass through increased protein synthesis compared to patients with normal muscle mass [193,200]. The relationship between COPD and mTOR activation has been identified as a new therapeutic target in COPD [201]. Furthermore, it has been reported that the 5 -UTR of the IGF-1 receptor mRNA is translated by IRES-dependent translation, providing additional control for its expression under stress conditions that downregulate eIF4E/mTORC1-dependent canonical mRNA translation [202].…”

Section: The Mtorc1 Signaling Pathway In Metabolic and Inflammatory Dmentioning

confidence: 99%

Translation Regulation by eIF2α Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs)

Rios-Fuller

Mahé

Walters

et al. 2020

IJMS

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Non-communicable diseases (NCDs) are medical conditions that, by definition, are non-infectious and non-transmissible among people. Much of current NCDs are generally due to genetic, behavioral, and metabolic risk factors that often include excessive alcohol consumption, smoking, obesity, and untreated elevated blood pressure, and share many common signal transduction pathways. Alterations in cell and physiological signaling and transcriptional control pathways have been well studied in several human NCDs, but these same pathways also regulate expression and function of the protein synthetic machinery and mRNA translation which have been less well investigated. Alterations in expression of specific translation factors, and disruption of canonical mRNA translational regulation, both contribute to the pathology of many NCDs. The two most common pathological alterations that contribute to NCDs discussed in this review will be the regulation of eukaryotic initiation factor 2 (eIF2) by the integrated stress response (ISR) and the mammalian target of rapamycin complex 1 (mTORC1) pathways. Both pathways integrally connect mRNA translation activity to external and internal physiological stimuli. Here, we review the role of ISR control of eIF2 activity and mTORC1 control of cap-mediated mRNA translation in some common NCDs, including Alzheimer’s disease, Parkinson’s disease, stroke, diabetes mellitus, liver cirrhosis, chronic obstructive pulmonary disease (COPD), and cardiac diseases. Our goal is to provide insights that further the understanding as to the important role of translational regulation in the pathogenesis of these diseases.

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Section: The Mtorc1 Signaling Pathway In Metabolic and Inflammatory Dmentioning

confidence: 99%

Translation Regulation by eIF2α Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs)

Rios-Fuller

Mahé

Walters

et al. 2020

IJMS

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“…Therefore, this study highlighted the possibility of developing a specific inhibitor against mTOR to improve the phagocytic capacity of macrophages and reduce the frequency of acute exacerbations in patients with COPD. Moreover, the complex and heterogenic enzymatic pathway of mTOR and the use of mTOR inhibitors for COPD therapy need a more in-depth knowledge of mTOR signaling (35).…”

Section: Discussionmentioning

confidence: 99%

Relationship between PI3K/mTOR/RhoA pathway-regulated cytoskeletal rearrangements and phagocytic capacity of macrophages

Bao

Chen

et al. 2020

Braz J Med Biol Res

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The objective of this study was to investigate the relationship between PI3K/mTOR/RhoA signaling regulated cytoskeletal rearrangements and phagocytic capacity of macrophages. RAW264.7 macrophages were divided into four groups; blank control, negative control, PI3K-RNAi, and mTOR-RNAi. The cytoskeletal changes in the macrophages were observed. Furthermore, the phagocytic capacity of macrophages against Escherichia coli is reported as mean fluorescence intensity (MFI) and percent phagocytosis. Transfection yielded 82.1 and 81.5% gene-silencing efficiencies against PI3K and mTOR, respectively. The PI3K-RNAi group had lower mRNA and protein expression levels of PI3K, mTOR, and RhoA than the blank and negative control groups (Po0.01). The mTOR-RNAi group had lower mRNA and protein levels of mTOR and RhoA than the blank and the negative control groups (Po0.01). Macrophages in the PI3K-RNAi group exhibited stiff and inflexible morphology with short, disorganized filopodia and reduced number of stress fibers. Macrophages in the mTOR-RNAi group displayed pronounced cellular deformations with long, dense filopodia and an increased number of stress fibers. The PI3K-RNAi group exhibited lower MFI and percent phagocytosis than blank and negative control groups, whereas the mTOR-RNAi group displayed higher MFI and percent phagocytosis than the blank and negative controls (Po0.01). Before and after transfection, the mRNA and protein levels of PI3K were both positively correlated with mTOR and RhoA (Po0.05), but the mRNA and protein levels of mTOR were negatively correlated with those of RhoA (Po0.05). Changes in the phagocytic capacity of macrophages were associated with cytoskeletal rearrangements and were regulated by the PI3K/mTOR/RhoA signaling pathway.

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“…Another study suggested that particulate matter (PM) may inactivate mTOR signaling and promote the subsequent autophagy-mediated epithelial injury in PM-induced airway inflammation 57 . This apparent discrepancy may be due to the complex and heterogenic enzymatic pathway of mTOR signaling, implying that translation on the use of mTOR inhibitors to COPD therapy requires a more in-depth knowledge of mTOR signaling 58 .…”

Section: Mtor Signalingmentioning

confidence: 99%

Recent Advances in Molecular Basis of Lung Aging and Its Associated Diseases

Kang

2020

Tuberc Respir Dis

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Aging is often viewed as a progressive decline in fitness due to cumulative deleterious alterations of biological functions in the living system. Recently, our understanding of the molecular mechanisms underlying aging biology has significantly advanced. Interestingly, many of the pivotal molecular features of aging biology are also found to contribute to the pathogenesis of chronic lung disorders such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, for which advanced age is the most crucial risk factor. Thus, an enhanced understanding of how molecular features of aging biology are intertwined with the pathobiology of these aging-related lung disorders has paramount significance and may provide an opportunity for the development of novel therapeutics for these major unmet medical needs. To serve the purpose of integrating molecular understanding of aging biology with pulmonary medicine, in this review, recent findings obtained from the studies of aging-associated lung disorders are summarized and interpreted through the perspective of molecular biology of aging.

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Mammalian Target of Rapamycin: Is It Relevant to COPD Pathogenesis or Treatment?

Cited by 5 publications

References 28 publications

Translation Regulation by eIF2α Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs)

Translation Regulation by eIF2α Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs)

Relationship between PI3K/mTOR/RhoA pathway-regulated cytoskeletal rearrangements and phagocytic capacity of macrophages

Recent Advances in Molecular Basis of Lung Aging and Its Associated Diseases

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