Activation of Nrf2/ARE pathway by Anisodamine (654-2) for Inhibition of cellular aging and alleviation of Radiation-Induced lung injury

Haochun Guo; Jiajia Chen; Hanxu Yu; Lei Dong; Ran Yu; Qingju Li; Jian Song; Haoyu Chen; Haijun Zhang; Juan Pu; Wanpeng Wang

doi:10.1016/j.intimp.2023.110864

Activation of Nrf2/ARE pathway by Anisodamine (654-2) for Inhibition of cellular aging and alleviation of Radiation-Induced lung injury

Int Immunopharmacol. 2023 Nov;124(Pt A):110864. doi: 10.1016/j.intimp.2023.110864. Epub 2023 Sep 7.

Authors

Haochun Guo¹, Jiajia Chen², Hanxu Yu³, Lei Dong¹, Ran Yu⁴, Qingju Li⁴, Jian Song³, Haoyu Chen³, Haijun Zhang⁵, Juan Pu⁶, Wanpeng Wang⁷

Affiliations

¹ Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China.
² Department of Radiotherapy, Lianshui People's Hospital, Kangda College of Nanjing Medical University, Huai'an 223400, China; Jiangsu Nursing Vocational and Technical College, Huai'an 223400, China.
³ Department of Radiotherapy, Lianshui People's Hospital, Kangda College of Nanjing Medical University, Huai'an 223400, China.
⁴ Department of Radiotherapy, Lianshui People's Hospital, Kangda College of Nanjing Medical University, Huai'an 223400, China; Jiangsu Nursing Vocational and Technical College, Huai'an 223400, China; School of Clinical Medicine, Medical College of Yangzhou University, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou 225009, China.
⁵ Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China. Electronic address: haijunzhang@seu.edu.cn.
⁶ Department of Radiotherapy, Lianshui People's Hospital, Kangda College of Nanjing Medical University, Huai'an 223400, China. Electronic address: lianshuipujuan@163.com.
⁷ Department of Radiotherapy, Lianshui People's Hospital, Kangda College of Nanjing Medical University, Huai'an 223400, China; Jiangsu Nursing Vocational and Technical College, Huai'an 223400, China; School of Clinical Medicine, Medical College of Yangzhou University, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou 225009, China. Electronic address: wangwanpeng123@163.com.

PMID: 37678028
DOI: 10.1016/j.intimp.2023.110864

Abstract

Background: Radiation-induced lung injury (RILI) is a common side effect of thoracic tumor radiotherapy, including early-stage radiation-induced lung injury (RP) and late-stage radiation-induced pulmonary fibrosis (RIPF). Currently, it is urgently needed to clarify the pathogenesis of RILI and find safe and effective RILI treatment methods. Irradiation causes DNA damage and oxidative stress in tissues and cells, induces cellular senescence, and promotes the occurrence and development of RILI. In recent years, Anisodamine (654-2) has shown potential therapeutic value in acute lung injury, acute kidney injury, chlamydial pneumonia, and COVID-19. However, there is currently no research on the mechanism of 654-2-mediated cellular senescence and its preventive and therapeutic effects on RILI.

Purpose: This study aimed to investigate the protective effect and mechanism of 654-2 on X-ray-induced RILI.

Methods: In vivo experiments involved a mouse RILI model with 18 Gy X-ray irradiation. Mice were divided into control, model, medication (control + 654-2), and treatment (model + 654-2) groups. And mice in medication and treatment groups were intraperitoneal injection of 5 mg/kg 654-2 every other day until being sacrificed at week 6. In vitro experiments used MLE-12 cells irradiated with 16 Gy and divided into control, model, and model + 654-2（2 μM and 10 μM） groups. Various assays were performed to evaluate lung tissue morphology, fibrosis, apoptosis, cytokine expression, cellular senescence, protein expression, and antioxidant capacity.

Results: 654-2 mitigated pulmonary pathological damage, inflammation, DNA damage, cellular senescence, and apoptosis in RILI mice and MLE-12 cells. It restored epithelial cell proliferation ability and enhanced antioxidant capacity. Additionally, 654-2 activated the Nrf2/ARE pathway, increased Nrf2 phosphorylation, and upregulated antioxidant gene expression. Inhibition of Nrf2 reversed the effects of 654-2 on ROS production, antioxidant capacity, and cell senescence.

Conclusion: 654-2 can activate the Nrf2/ARE pathway, enhance cellular antioxidant capacity, and inhibit cellular senescence, thereby exerting a protective effect against RILI.

Keywords: Anisodamine; Apoptosis; Cellular Senescence; Radiation-induced Lung Injury; Senescence-associated β-galactosidase.