Oxidative stress mediates the apoptosis and epigenetic modification of the Bcl-2 promoter via DNMT1 in a cigarette smoke-induced emphysema model

Zeng, Huihui; Li, Tiao; He, Xue; Cai, Sanjun; Luo, Hong; Chen, Ping; Chen, Yan

doi:10.1186/s12931-020-01495-w

Cited by 32 publications

(31 citation statements)

References 48 publications

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“…DNMTs-mediated aberrant methylation is linked to the pathogenesis and development of COPD ( Adcock et al, 2011 ). DNMT1 expression in the lung tissue from COPD patients was higher than that in the lung tissue from non-smokers ( Zeng et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Shema Oral Liquid Ameliorates the Severity of LPS-Induced COPD via Regulating DNMT1

et al. 2022

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Background: Chronic obstructive pulmonary disease (COPD) is the most common respiratory disease with high morbidity and mortality. Shema oral liquid (Shema) is a traditional Chinese medicine (TCM) approved for the treatment of respiratory diseases. Clinical applications have shown that Shema has antitussive, expectorant, and anti-asthmatic effects, but its definite efficacy to COPD is still unclear. This study aimed to explore the therapeutic capacity and potential mechanism of Shema in treatment of COPD.Methods: Network pharmacology was used to investigated the possible pharmacological mechanism of Shema against COPD. A rat model of lipopolysaccharide (LPS)-induced COPD was established to determine pulmonary ventilatory function, serum inflammatory cytokines, and pulmonary pathological change. Subsequently, tandem mass tag (TMT)-based quantitative proteomics was used to further reveal the therapeutic targets related with Shema against COPD. Western blot was finally performed to validate the expression of targeted proteins screened by proteomics research.Results: Network pharmacology analysis indicated that Shema against COPD mainly inhibited the inflammation and affected the immune system. The animal experiment demonstrated that Shema treatment protected the lung tissue from LPS induced injury, inhibited the levels of serum inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, and improved the respiratory ventilatory function by upregulating forced expiratory volume in 0.1 s (FEV0.1), FEV0.3, forced vital capacity (FVC), and the ratios of FEV0.1 (0.3)/FVC. Proteomic analysis and western blot both proved that Shema inhibited the expression of DNA methyltransferase 1 (DNMT1) in the lung tissue.Conclusion: The therapeutic mechanism of Shema in treatment of COPD may involve inhibiting inflammatory response, improving pulmonary ventilatory function, and alleviating LPS-induced lung injury through regulating the expression of DNMT1. This study also shed light on the development of therapeutic strategies in treating COPD by intervening DNMT-related pathways.

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Section: Resultsmentioning

confidence: 99%

Shema Oral Liquid Ameliorates the Severity of LPS-Induced COPD via Regulating DNMT1

et al. 2022

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“…Morphometry was quantified by the values of mean linear intercept (MLI) at a magnification of 100× as previously described. 18 MLI was assessed by dividing the length of a line drawn across the section by the total number of intercepts encountered in 36 lines per sample, and 10 random fields per sample were observed by microscopy. The numbers of apoptotic cells in longitudinal lung sections from control and emphysema mice were quantified by In-situ Apoptosis Detection Kit (Nanjing Keygen Biotech, China).…”

Section: Methodsmentioning

confidence: 99%

Prohibitin Protects Pulmonary Microvascular Endothelial Cells Against Cigarette Smoke Extract-Induced Cell Apoptosis and Inflammation

Peng¹,

Cheng²,

Duan³

et al. 2022

COPD

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Background Prohibitin has been identified to play roles in cell survival and apoptosis. Here, this study aimed to clarify the role of prohibitin in cigarette smoke extract (CSE)-induced endothelial cell apoptosis. Methods The protein level of prohibitin was assessed by Western blot in lung tissues from emphysema and control mice. CSE-induced human pulmonary microvascular endothelial cells (hPMECs) were applied to mimic smoke-related cell apoptosis in vitro. Prohibitin was overexpressed in hPMECs with or without CSE. Mitochondrial function was analyzed by JC-1 staining and ATP assay kits. Oxidative stress was assessed by flow cytometry, fluorescence staining and immunocytochemistry. Apoptosis was analyzed by flow cytometry, Western blot and caspase-3 activity assays. In addition, the expression of inflammatory markers was assessed by Western blot and real-time polymerase chain reaction (PCR). The secretion of inflammatory cytokines was measured by ELISA. Results Prohibitin was downregulated in emphysema mouse tissues compared with control experiments. Consistently, CSE inhibited both the protein and RNA levels of prohibitin in hPMECs in a dose-dependent manner. Gain-of-function experiments indicated that CSE induced collapse of mitochondrial membrane potential (MMP) and loss of ATP, while prohibitin improved mitochondrial function. CSE induced robust ROS production and oxidative DNA damage, while prohibitin decreased this damage. Upregulation of prohibitin protected the apoptosis of hPMECs from CSE. Overexpression of prohibitin significantly reduced the levels of the main proinflammatory cytokines. Finally, prohibitin inhibited nuclear factor-kappa B (NF-κB) p65 accumulation and IκBα degradation induced by CSE. Conclusion The current findings suggest that CSE-mediated mitochondrial dysfunction, oxidative stress, cell apoptosis and inflammation in hPMECs were reduced by overexpression of prohibitin. We identified prohibitin as a novel regulator of endothelial cell apoptosis and survival in the context of CSE exposure.

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“…Venetoclax was the first selective BCL-2 inhibitor to be approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia [186]. Zeng, et al suggested the involvement of BCL-2 in the pathogenesis of COPD [187]. BCL-2 inhibitors may have anti-neoplastic as well as anti-inflammatory and anti-aging properties.…”

Section: B-cell Lymphoma-2 (Bcl-2) Inhibitorsmentioning

confidence: 99%

Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease

et al. 2022

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Chronic obstructive pulmonary disease (COPD) is recognized as a disease of accelerated lung aging. Over the past two decades, mounting evidence suggests an accumulation of senescent cells within the lungs of patients with COPD that contributes to dysregulated tissue repair and the secretion of multiple inflammatory proteins, termed the senescence-associated secretory phenotype (SASP). Cellular senescence in COPD is linked to telomere dysfunction, DNA damage, and oxidative stress. This review gives an overview of the mechanistic contributions and pathologic consequences of cellular senescence in COPD and discusses potential therapeutic approaches targeting senescence-associated signaling in COPD.

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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

Cited by 32 publications

References 48 publications

Shema Oral Liquid Ameliorates the Severity of LPS-Induced COPD via Regulating DNMT1

Shema Oral Liquid Ameliorates the Severity of LPS-Induced COPD via Regulating DNMT1

Prohibitin Protects Pulmonary Microvascular Endothelial Cells Against Cigarette Smoke Extract-Induced Cell Apoptosis and Inflammation

Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease

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