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Research
Yaqing Li
Cancer Hospital of the University of Chinese Academy of Sciences
Corresponding Author
ORCiD: https://orcid.org/0000-0002-7379-8151
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Chronic obstructive pulmonary disease (COPD) is often associate with cigarette smoke extract (CSE)-introduced bronchial epithelial cell senescence, mitochondrial fragmentation. Sirtuin-1(Sirt1) has been reported to play a crucial role in mitochondrial homeostasis and confers a protective role against the onset and development of CSE introduced bronchial epithelial cell senescence in COPD although the precise mechanism(s) remain elusive. Here we hypothesized that SRT1720, a pharmacological SIRT1720 activator, exerts protect against COPD by activating PINK1 mediated mitophagy, en route to preserved mitochondrial homeostasis.
Methods
COPD rats model was established by CS exposure. During 6 months of SRT1720 treatment, airway resistance, cellular senescence and mitochondrial injury, mitophagy in the lung tissues of model rats were examined by western blot(WB) and histochemical and immunofluorescence staining. Transmission electron microscopy was also carried to elucidate the effects of SRT1720.Human bronchial epithelial cells(HBEC) were used to clarify the underlying molecular mechanisms.
Result
During the introduction of CSE in cellular or rats, administration of SRT1720 improved airway resistance, cellular senescence and mitochondrial injury, accompanied with suppressed autophagy and mitophagy. Mitochondrial damage, cellular senescence and lung injury under contrast exposure were more severe in FOXO3 or Pink1 deficient cells and mice than in SRT1720 groups. Activation of Sirt1 by treating with SRT1720 induces autophagy enhanced. A Decrease in sirt1 expression caused by selisistat treatment promotes senescence.
Conclusions
Taken together, our data suggested that suppressed SIRT1/FOXO3/Pink1 signaling mediated mitophagy played a protective role in COPD by reducing mitochondrial reactive oxygen species (ROS).
Keywords
Sirt1, SRT1720, selisistat, COPD, mitophagy, Foxo3A, PINK1
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Yaqing Li
Cancer Hospital of the University of Chinese Academy of Sciences
Corresponding Author
ORCiD: https://orcid.org/0000-0002-7379-8151
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 13 May, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Internal Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Chronic obstructive pulmonary disease (COPD) is often associate with cigarette smoke extract (CSE)-introduced bronchial epithelial cell senescence, mitochondrial fragmentation. Sirtuin-1(Sirt1) has been reported to play a crucial role in mitochondrial homeostasis and confers a protective role against the onset and development of CSE introduced bronchial epithelial cell senescence in COPD although the precise mechanism(s) remain elusive. Here we hypothesized that SRT1720, a pharmacological SIRT1720 activator, exerts protect against COPD by activating PINK1 mediated mitophagy, en route to preserved mitochondrial homeostasis.
Methods
COPD rats model was established by CS exposure. During 6 months of SRT1720 treatment, airway resistance, cellular senescence and mitochondrial injury, mitophagy in the lung tissues of model rats were examined by western blot(WB) and histochemical and immunofluorescence staining. Transmission electron microscopy was also carried to elucidate the effects of SRT1720.Human bronchial epithelial cells(HBEC) were used to clarify the underlying molecular mechanisms.
Result
During the introduction of CSE in cellular or rats, administration of SRT1720 improved airway resistance, cellular senescence and mitochondrial injury, accompanied with suppressed autophagy and mitophagy. Mitochondrial damage, cellular senescence and lung injury under contrast exposure were more severe in FOXO3 or Pink1 deficient cells and mice than in SRT1720 groups. Activation of Sirt1 by treating with SRT1720 induces autophagy enhanced. A Decrease in sirt1 expression caused by selisistat treatment promotes senescence.
Conclusions
Taken together, our data suggested that suppressed SIRT1/FOXO3/Pink1 signaling mediated mitophagy played a protective role in COPD by reducing mitochondrial reactive oxygen species (ROS).
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
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