Development of novel celastrol-ligustrazine hybrids as potent peroxiredoxin 1 inhibitors against lung cancer

Bai, Ying; Liang, Chao; Liu, Yafeng; Wang, F.; Gao, Jian; Wu, Jing; Hu, Dong

doi:10.1016/j.ejmech.2023.115656

Cited by 4 publications

(1 citation statement)

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“…In our preliminary research, we optimized the structure of CSL and discovered compound CEL-07 , which significantly improved water solubility and potential toxicity compared to celastrol ( Figure 1 ) [ 27 , 28 ]. However, the role and mechanism of CEL-07 in the treatment of silicosis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Celastrol Pyrazine Derivative Alleviates Silicosis Progression via Inducing ROS-Mediated Apoptosis in Activated Fibroblasts

Bai,

Liang,

Gao

et al. 2024

Molecules

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Silicosis is a complex occupational disease without recognized effective treatment. Celastrol, a natural product, has shown antioxidant, anti-inflammatory, and anti-fibrotic activities, but the narrow therapeutic window and high toxicity severely limit its clinical application. Through structural optimization, we have identified a highly efficient and low-toxicity celastrol derivative, CEL-07. In this study, we systematically investigated the therapeutic potential and underlying mechanisms of CEL-07 in silicosis fibrosis. By constructing a silicosis mouse model and analyzing with HE, Masson, Sirius Red, and immunohistochemical staining, CEL-07 significantly prevented the progress of inflammation and fibrosis, and it effectively improved the lung respiratory function of silicosis mice. Additionally, CEL-07 markedly suppressed the expression of inflammatory factors (IL-6, IL-1α, TNF-α, and TNF-β) and fibrotic factors (α-SMA, collagen I, and collagen III), and promoted apoptosis of fibroblasts by increasing ROS accumulation. Moreover, bioinformatics analysis combined with experimental validation revealed that CEL-07 inhibited the pathways associated with inflammation (PI3K-AKT and JAK2-STAT3) and the expression of apoptosis-related proteins. Overall, these results suggest that CEL-07 may serve as a potential candidate for the treatment of silicosis.

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Section: Introductionmentioning

confidence: 99%