دورية أكاديمية
أعرض في EDS

Harmine inhibits pulmonary fibrosis through regulating DNA damage repair-related genes and activation of TP53-Gadd45α pathway.

التفاصيل البيبلوغرافية
العنوان: Harmine inhibits pulmonary fibrosis through regulating DNA damage repair-related genes and activation of TP53-Gadd45α pathway.
المؤلفون: Gong Y; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China; Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Key Laboratory of Clinical Drug Research, Urumqi, Xinjiang 830011, China., Wang J; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China; Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Key Laboratory of Clinical Drug Research, Urumqi, Xinjiang 830011, China., Pan M; Department of Pharmacognosy, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China., Zhao Y; Department of Pharmacognosy, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China., Zhang H; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China; Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Key Laboratory of Clinical Drug Research, Urumqi, Xinjiang 830011, China., Zhang F; Department of Medicine, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China., Liu J; Soochow Univ, College of Pharmaceutic Science, Suzhou 215123, China., Yang J; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China; Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Key Laboratory of Clinical Drug Research, Urumqi, Xinjiang 830011, China. Electronic address: yjh_yfy@163.com., Hu J; Department of Pharmacognosy, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China. Electronic address: hjp_yxy@163.com.
المصدر: International immunopharmacology [Int Immunopharmacol] 2024 Sep 10; Vol. 138, pp. 112542. Date of Electronic Publication: 2024 Jun 25.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 100965259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1705 (Electronic) Linking ISSN: 15675769 NLM ISO Abbreviation: Int Immunopharmacol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Amsterdam ; New York : Elsevier Science, c2001-
مواضيع طبية MeSH: Pulmonary Fibrosis*/drug therapy , Pulmonary Fibrosis*/genetics , Tumor Suppressor Protein p53*/metabolism , Tumor Suppressor Protein p53*/genetics , Harmine*/pharmacology , Harmine*/therapeutic use , Bleomycin* , DNA Repair*/drug effects , Signal Transduction*/drug effects , Cell Cycle Proteins*/genetics , Cell Cycle Proteins*/metabolism , DNA Damage*/drug effects , Fibroblasts*/drug effects, Animals ; Humans ; Mice ; Cell Line ; Mice, Inbred C57BL ; Transforming Growth Factor beta1/metabolism ; Transforming Growth Factor beta1/genetics ; Male ; Apoptosis/drug effects ; Disease Models, Animal ; Lung/drug effects ; Lung/pathology ; GADD45 Proteins
مستخلص: Background: Harmine has many pharmacological activities and has been found to significantly inhibit the fibrosis of keloid fibroblasts. DNA damage repair (DDR) is essential to prevent fibrosis. This study aimed to investigate the effects of harmine on pulmonary fibrosis and its underlying mechanisms.
Methods: Bleomycin and TGF-β1 were used to construct pulmonary fibrosis models in vivo and in vitro, then treated with harmine to explore harmine's effects in treating experimental pulmonary fibrosis and its related mechanisms. Then, RNA sequencing was applied to investigate further the crucial DDR-related genes and drug targets of harmine against pulmonary fibrosis. Finally, the expression levels of DDR-related genes were verified by real-time quantitative PCR (RT-qPCR) and western blot.
Results: Our in vivo experiments showed that harmine treatment could improve weight loss and lung function and reduce tissue fibrosis in mice with pulmonary fibrosis. The results confirmed that harmine could inhibit the viability and migration of TGF-β1-induced MRC-5 cells, induce their apoptosis, and suppress the F-actin expression, suggesting that harmine could suppress the phenotypic transition from lung fibroblasts to lung myoblasts. In addition, RNA sequencing identified 1692 differential expressed genes (DEGs), and 10 DDR-related genes were screened as critical DDR-related genes. RT-qPCR and western blotting showed that harmine could down-regulate the expression of CHEK1, ERCC1, ERCC4, POLD1, RAD51, RPA1, TOP1, and TP53, while up-regulate FEN1, H2AX and GADD45α expression.
Conclusions: Harmine may inhibit pulmonary fibrosis by regulating DDR-related genes and activating the TP53-Gadd45α pathway.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: DNA damage repair; Harmine; Lung function; Pulmonary fibrosis; TP53-Gadd45α pathway
المشرفين على المادة: 0 (Tumor Suppressor Protein p53)
4FHH5G48T7 (Harmine)
11056-06-7 (Bleomycin)
0 (Cell Cycle Proteins)
0 (Transforming Growth Factor beta1)
0 (GADD45A protein, human)
0 (TP53 protein, human)
0 (GADD45 Proteins)
تواريخ الأحداث: Date Created: 20240626 Date Completed: 20240730 Latest Revision: 20240730
رمز التحديث: 20240730
DOI: 10.1016/j.intimp.2024.112542
PMID: 38924867
قاعدة البيانات: MEDLINE
الوصف
تدمد:1878-1705
DOI:10.1016/j.intimp.2024.112542