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Norcantharidin attenuates amiodarone-induced pulmonary fibrosis via modulating miRNA-30a/GSK-3β/β-catenin and
Ahmed G Abd Elhameed1,2, Eman H Yousef2, Muhammed M Salahuddin2
1Pharmacology and Toxicology Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Abstract:
Amiodarone-induced pulmonary fibrosis (AIPF) is characterized by inflammation, oxidative stress, microRNA dysregulation, fibroblast activation, and excessive extracellular matrix deposition. Norcantharidin (NCTD), a small-molecule compound with reported anti-inflammatory, antioxidant, and antifibrotic properties, has attracted attention as a potential therapeutic agent. To investigate the protective effects of NCTD against AIPF in rats. Eighteen rats were randomly divided into three groups (n = 6 each): a negative control group receiving vehicle, an amiodarone group, and an NCTD-treated group receiving 0.1 mg/kg intraperitoneally for six weeks. Pulmonary fibrosis was induced by oral administration of 50 mg/kg amiodarone for five weeks. Lung injury was assessed using hematoxylin and eosin staining and semi-quantitative scoring, collagen deposition was evaluated by Masson's trichrome staining, and immunohistochemistry was performed for fibronectin and α-smooth muscle actin (α-SMA). Molecular and biochemical markers including tumor necrosis factor (TNF)-α, β-catenin, interleukin (IL)-1β, malondialdehyde (MDA), and glutathione (GSH) were measured, while glycogen synthase kinase (GSK)-3β was assessed by Western blot, and miRNA-30a by quantitative PCR. Amiodarone significantly increased lung injury scores, collagen deposition, α-SMA, fibronectin, TNF-α, IL-1β, MDA, GSK-3β, and β-catenin, while reducing GSH and miRNA-30a levels. NCTD treatment markedly reversed these alterations, restoring α-SMA, fibronectin, TNF-α, IL-1β, MDA, GSK-3β, and β-catenin, while increasing GSH and miRNA-30a toward normal. Histologically, NCTD preserved alveolar architecture, reduced peribronchiolar inflammation, and normalized collagen distribution. These results demonstrate that NCTD exerts potent antifibrotic, anti-inflammatory, and antioxidant effects in AIPF, likely through modulation of oxidative stress, inflammatory cytokines, microRNA expression, and the GSK-3β/β-catenin signaling pathway, highlighting its potential as a therapeutic agent for drug-induced lung injury.
Insights
Norcantharidin (NCTD) shows promise in treating amiodarone-induced pulmonary fibrosis (AIPF). NCTD reversed lung injury, inflammation, and fibrosis in rats by modulating oxidative stress and key signaling pathways.
Area of Science:
- Pharmacology
- Toxicology
- Pulmonology
Background:
- Amiodarone-induced pulmonary fibrosis (AIPF) involves inflammation, oxidative stress, and fibrosis.
- Norcantharidin (NCTD) possesses anti-inflammatory, antioxidant, and antifibrotic properties.
Purpose of the Study:
- To investigate the protective effects of NCTD against amiodarone-induced pulmonary fibrosis in a rat model.
- To elucidate the underlying mechanisms of NCTD's therapeutic action.
Main Methods:
- Rats were administered amiodarone to induce pulmonary fibrosis and treated with NCTD.
- Lung injury, collagen deposition, and fibrotic markers were assessed histologically and biochemically.
- Levels of inflammatory cytokines (TNF-α, IL-1β), oxidative stress markers (MDA, GSH), and signaling pathway components (GSK-3β, β-catenin) were quantified.
- MicroRNA-30a expression was analyzed using quantitative PCR.
Main Results:
- Amiodarone induced significant lung injury, increased fibrosis markers (collagen, α-SMA, fibronectin), elevated inflammatory cytokines and oxidative stress, and altered GSK-3β/β-catenin and miRNA-30a levels.
- NCTD treatment markedly attenuated lung injury, reduced fibrosis, suppressed inflammation and oxidative stress, and normalized the expression of GSK-3β, β-catenin, and miRNA-30a.
- Histological analysis showed NCTD preserved alveolar structure and reduced inflammation and collagen deposition.
Conclusions:
- NCTD demonstrates potent antifibrotic, anti-inflammatory, and antioxidant effects in AIPF.
- NCTD likely acts by modulating oxidative stress, inflammatory cytokines, microRNA expression, and the GSK-3β/β-catenin pathway.
- NCTD holds potential as a therapeutic agent for drug-induced lung injury.
