Qibai Pingfei Capsule ameliorated inflammation in chronic obstructive pulmonary disease (COPD) via HIF-1 α/glycolysis pathway mediated of BMAL1

• Published in: International immunopharmacology 2025-01, Vol.144, p.113636, Article 113636
• Main Authors: Luan, Xuejing, Zhu, Dandan, Hao, Yifei, Xie, Jinghui, Wang, Xiu, Li, Yan, Zhu, Jie
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; BMAL1; Capsules; Cell Line; COPD; Disease Models, Animal; Glycolysis; Glycolysis - drug effects; Hexokinase - genetics; Hexokinase - metabolism; HIF-1α; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Lung - drug effects; Lung - metabolism; Lung - pathology; Male; Molecular Docking Simulation; Pulmonary Disease, Chronic Obstructive - drug therapy; Pulmonary Disease, Chronic Obstructive - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113636

•The disorder of HIF-1 α/glycolysis pathway is involved in the pathological process of COPD.•Confirmed the negative feedback regulation between the expression of circadian rhythm gene BMAL1 and HIF-1 α in COPD.•Identification BMAL1 has a close functional relationship with HIF-1 α via molecular docking and co-immunoprecipitation.•QBPF can alleviate lung inflammation through regulating circadian rhythm genes BMAL1 and imbalance of glycolysis. Chronic obstructive pulmonary disease (COPD) is characterized for the persistent inflammation. The brain and muscle arnt-like 1 (BMAL1), as a crucial clock gene, is associated with the expression level of upstream factor hypoxia-inducible factor (HIF)-1α in glycolysis, which may affect the occurrence of inflammatory reactions in COPD. However, the moderation effect of Qibai Pingfei Capsule (QBPF) capsule is still unknown on BMAL1 and HIF-1α/glycolytic pathway. The aim of this study is to investigate the modulatory effects of QBPF capsules on BMAL1 and the HIF-1α/glycolytic pathway in COPD. The multifactorial approach were used to construct the COPD rat model, including forced swimming, hypoxia, and inhalation of cigarette smoke with four weeks. Nextly, the rats received a two-week course of gavage treatment with medicant. Finally, tissue samples were collected for comprehensive analysis using various molecular biology techniques. These methods included molecular docking, immunoprecipitation, small interfering RNA (siRNA), hematoxylin and eosin (HE) staining, western blot (WB), and immunofluorescence etc. to elucidate the modulatory effects of QBPF for treating COPD in vitro and in vivo. The expression levels in mRNA and protein of BMAL1 decreased in COPD, while the content in mRNA and protein of HIF-1α increased. At the same time, the concentration in glycolytic metabolites of hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), lactate dehydrogenase (LDH), and lactate (LD) increased, and ATP decreased. The QBPF capsule can reverse the imbalance between BMAL1 and HIF-1α, improve disorders of glycolytic pathway, and alleviate the inflammation response. Notably, in vivo experiments, the interaction between BMAL1 and HIF-1α were confirmed via molecular docking and immunoprecipitation. In rescue experiments, intervention with siRNA BMAL1 in 16HBE cells revealed a significant decrease in BMAL1 levels and the therapeutic effect of QBPF was also affected. QBPF could up-regulate the expression level of clock gene B