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DNA nanoparticles targeting FOXO4 selectively eliminate cigarette smoke-induced senescent lung fibroblasts.

ABSTRACT: The pathogenesis and development of chronic obstructive pulmonary disease (COPD) are significantly related to cellular senescence. Strategies to eliminate senescent cells have been confirmed to benefit several senescence-related diseases. However, there are few reports of senolytic drugs in COPD management. In this study, we demonstrated elevated FOXO4 expression in cigarette smoke-induced senescent lung fibroblasts both in vitro and in vivo. Additionally, self-assembled DNA nanotubes loaded with single-stranded FOXO4 siRNA (siFOXO4-NT) were designed and synthesized to knockdown FOXO4 in senescent fibroblasts. We found that siFOXO4-NT can concentration- and time-dependently enter human lung fibroblasts (HFL-1 cells), thereby reducing FOXO4 levels in vitro. Most importantly, siFOXO4-NT selectively cleared senescent HFL-1 cells by reducing BCLXL expression and the BCL2/BAX ratio, which were increased in CSE-induced senescent HFL-1 cells. The findings from our work present a novel strategy for senolytic drug development for COPD therapy.

SUBMITTER: Han Y

PROVIDER: S-EPMC10597553 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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DNA nanoparticles targeting FOXO4 selectively eliminate cigarette smoke-induced senescent lung fibroblasts.

Han Yaopin Y Wu Yixing Y He Binfeng B Wu Di D Hua Jianlan J Qian Hang H Zhang Jing J

Nanoscale advances 20231005 21

The pathogenesis and development of chronic obstructive pulmonary disease (COPD) are significantly related to cellular senescence. Strategies to eliminate senescent cells have been confirmed to benefit several senescence-related diseases. However, there are few reports of senolytic drugs in COPD management. In this study, we demonstrated elevated FOXO4 expression in cigarette smoke-induced senescent lung fibroblasts both <i>in vitro</i> and <i>in vivo</i>. Additionally, self-assembled DNA nanotu ...[more]

PMID: 37881696

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Project description:BackgroundCigarette smoke is a major risk factor for various lung diseases, such as chronic obstructive pulmonary disease (COPD). Ninjinyoeito (NYT), a traditional Chinese medicine, has been prescribed for patients with post-illness or post-operative weakness, fatigue, loss of appetite, rash, cold limbs, and anemia. In addition to its traditional use, NYT has been prescribed for treating frailty in gastrointestinal, respiratory, and urinary functions. Further, NYT treatment can ameliorate cigarette smoke-induced lung injury, which is a destructive index in mice; however, the detailed underlying mechanism remains unknown. The purpose of this study was to investigate whether NYT ameliorates cigarette smoke-induced cell injury and inflammation in human lung fibroblasts and determine its mechanism of action.MethodsWe prepared a cigarette smoke extract (CSE) from commercially available cigarettes to induce cell injury and inflammation in the human lung fibroblast cell line HFL1. The cells were pretreated with NYT for 24 h prior to CSE exposure. Cytotoxicity and cell viability were measured by lactate dehydrogenase (LDH) cytotoxicity assay and cell counting kit (CCK)-8. IL-8 level in the cell culture medium was measured by performing Enzyme-Linked Immuno Sorbent Assay (ELISA). To clarify the mechanisms of NYT, we used CellROX Green Reagent for reactive oxygen species (ROS) production and western blotting analysis for cell signaling.ResultsExposure of HFL1 cells to CSE for 24 h induced apoptosis and interleukin (IL)-8 release. Pretreatment with NYT inhibited apoptosis and IL-8 release. Furthermore, CSE exposure for 24 h increased the production of ROS and phosphorylation levels of p38 and JNK. Pretreatment with NYT only inhibited CSE-induced JNK phosphorylation, and not ROS production and p38 phosphorylation. These results suggest that NYT acts as a JNK-specific inhibitor.ConclusionNYT treatment ameliorated CSE-induced apoptosis and inflammation by inhibiting the JNK signaling pathway. Finally, these results suggest that NYT may be a promising therapeutic agent for patients with COPD.

Dataset Information

DNA nanoparticles targeting FOXO4 selectively eliminate cigarette smoke-induced senescent lung fibroblasts.

Publications

DNA nanoparticles targeting FOXO4 selectively eliminate cigarette smoke-induced senescent lung fibroblasts.

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