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Oxidative stress mediates the apoptosis and epigenetic modification of the Bcl-2 promoter via DNMT1 in a cigarette smoke-induced emphysema model
Yan Chen
the Second Xiangya Hospital, Central South University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-7713-6913
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Respiratory Research.
Background: Emphysema is a crucial pathological characteristic of chronic obstructive pulmonary disease (COPD). Oxidative stress, apoptosis and epigenetic mechanisms contribute to the pathogenesis of emphysema. However, an attempt to accurately identify whether these mechanisms interact with each other and how they are triggered has never been conducted.
Method: The total reactive oxygen species (ROS) level, pulmonary apoptosis and B-cell lymphoma/ leukemia-2 (Bcl-2) expression, an apoptosis regulator, were detected in samples from COPD patients. Bisulfite sequencing PCR (BSP) was conducted to observe the alterations in the methylation of the Bcl-2 promoter in specimens. The dysregulation of DNA methyltransferase enzyme 1 (DNMT1), a vital DNA methyltransferase enzyme, in the lungs of patients was confirmed through western blotting. To find out interactions between oxidative stress and DNA methylation in emphysema, mouse models were built with antioxidant treatment and DNMT1 silencing, and were examined with the pulmonary apoptosis, Bcl-2 and DNMT1 expression, and epigenetic alterations of Bcl-2.
Results: Higher reactive oxygen species (ROS) levels and pulmonary apoptosis were observed in COPD patients than in healthy controls. Downregulated Bcl-2 expression with increased promoter methylation and DNMT1 protein expression was found in COPD patients. Antioxidant treatment reduced the level of ROS and dysregulation of DNMT1 expression and emphysematous progression in the smoking models. Following DNMT1 blockage, smoking models showed improved lung function, pulmonary apoptosis, emphysematous progression, and increased Bcl-2 protein expression with less promoter methylation than emphysema mice.
Conclusion: Cigarette-induced oxidative stress mediates pulmonary apoptosis and hypermethylation of the Bcl-2 promoter in emphysema models through DNMT1.
Keywords
Oxidative stress, apoptosis, hypermethylation, Bcl-2, DNMT1
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CURRENT STATUS: Published
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Posted 13 Aug, 2020
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On 03 Sep, 2020
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Received 24 Aug, 2020
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Received 24 Aug, 2020
Editorial decision: Accept
On 24 Aug, 2020
Reviewer #2 agreed
On 23 Aug, 2020
Reviewers invited
Invitations sent on 18 Aug, 2020
Reviewer #1 agreed
On 18 Aug, 2020
Editor assigned
On 09 Aug, 2020
Submission checks complete
On 08 Aug, 2020
Editor invited
On 08 Aug, 2020
No comments provided
Editorial decision: Major revision
On 13 Jul, 2020
Review #3 received
Received 11 Jul, 2020
Review #2 received
Received 01 Jul, 2020
Review #1 received
Received 29 Jun, 2020
Reviewer #3 agreed
On 28 Jun, 2020
Reviewer #2 agreed
On 24 Jun, 2020
Reviewer #1 agreed
On 13 Jun, 2020
Reviewers invited
Invitations sent on 12 Jun, 2020
Editor assigned
On 01 May, 2020
First submitted
On 30 Apr, 2020
Submission checks complete
On 30 Apr, 2020
Editor invited
On 30 Apr, 2020
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Subject Areas
Pulmonology
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This preprint is under consideration at Respiratory Research. A preprint is 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.
Learn more about In Review
Research
Oxidative stress mediates the apoptosis and epigenetic modification of the Bcl-2 promoter via DNMT1 in a cigarette smoke-induced emphysema model
Yan Chen
the Second Xiangya Hospital, Central South University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-7713-6913
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 2
Posted 13 Aug, 2020
Published
On 03 Sep, 2020
No community comments so far
Review #1 received
Received 24 Aug, 2020
Review #2 received
Received 24 Aug, 2020
Editorial decision: Accept
On 24 Aug, 2020
Reviewer #2 agreed
On 23 Aug, 2020
Reviewers invited
Invitations sent on 18 Aug, 2020
Reviewer #1 agreed
On 18 Aug, 2020
Editor assigned
On 09 Aug, 2020
Submission checks complete
On 08 Aug, 2020
Editor invited
On 08 Aug, 2020
No comments provided
Editorial decision: Major revision
On 13 Jul, 2020
Review #3 received
Received 11 Jul, 2020
Review #2 received
Received 01 Jul, 2020
Review #1 received
Received 29 Jun, 2020
Reviewer #3 agreed
On 28 Jun, 2020
Reviewer #2 agreed
On 24 Jun, 2020
Reviewer #1 agreed
On 13 Jun, 2020
Reviewers invited
Invitations sent on 12 Jun, 2020
Editor assigned
On 01 May, 2020
First submitted
On 30 Apr, 2020
Submission checks complete
On 30 Apr, 2020
Editor invited
On 30 Apr, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Pulmonology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Respiratory Research.
Background: Emphysema is a crucial pathological characteristic of chronic obstructive pulmonary disease (COPD). Oxidative stress, apoptosis and epigenetic mechanisms contribute to the pathogenesis of emphysema. However, an attempt to accurately identify whether these mechanisms interact with each other and how they are triggered has never been conducted.
Method: The total reactive oxygen species (ROS) level, pulmonary apoptosis and B-cell lymphoma/ leukemia-2 (Bcl-2) expression, an apoptosis regulator, were detected in samples from COPD patients. Bisulfite sequencing PCR (BSP) was conducted to observe the alterations in the methylation of the Bcl-2 promoter in specimens. The dysregulation of DNA methyltransferase enzyme 1 (DNMT1), a vital DNA methyltransferase enzyme, in the lungs of patients was confirmed through western blotting. To find out interactions between oxidative stress and DNA methylation in emphysema, mouse models were built with antioxidant treatment and DNMT1 silencing, and were examined with the pulmonary apoptosis, Bcl-2 and DNMT1 expression, and epigenetic alterations of Bcl-2.
Results: Higher reactive oxygen species (ROS) levels and pulmonary apoptosis were observed in COPD patients than in healthy controls. Downregulated Bcl-2 expression with increased promoter methylation and DNMT1 protein expression was found in COPD patients. Antioxidant treatment reduced the level of ROS and dysregulation of DNMT1 expression and emphysematous progression in the smoking models. Following DNMT1 blockage, smoking models showed improved lung function, pulmonary apoptosis, emphysematous progression, and increased Bcl-2 protein expression with less promoter methylation than emphysema mice.
Conclusion: Cigarette-induced oxidative stress mediates pulmonary apoptosis and hypermethylation of the Bcl-2 promoter in emphysema models through DNMT1.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8