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- Title
Diacerein ameliorates cholestasis-induced liver fibrosis in rat via modulating HMGB1/RAGE/NF-κB/JNK pathway and endoplasmic reticulum stress.
- Authors
Abdelfattah, Amira Mohammed; Mahmoud, Shireen Sami; EL-wafaey, Dalia Ibrahim; Abdelgeleel, Heba Mahmoud; Abdelhamid, Amira Mohamed
- Abstract
Diacerein is an interleukin (IL)-1β inhibitor approved for osteoarthritis. This study aimed to investigate the potential anti-fibrotic effect of diacerein against bile duct ligation (BDL)-induced liver fibrosis. Forty male Wistar rats were divided into: sham-operated group, BDL group, and BDL groups treated with diacerein at 10, 30, and 50 mg/kg/day starting two days before surgery and continued for 4 weeks. Diacerein decreased the hepatic injury markers and alleviated oxidative stress triggered by BDL by reducing hepatic malondialdehyde (MDA) and increasing hepatic superoxide dismutase (SOD) levels. Diacerein mitigated BDL-induced inflammation via lowering hepatic levels and mRNA expression of high mobility group box 1 (HMGB1), nuclear factor-κB (NF-κB), and IL-1β. The hepatic gene expression of Advanced Glycation End products Receptor (RAGE) gene and immunohistochemical expression of some ER stress markers, e.g., glucose-regulated protein 78 (GRP78), inositol-requiring enzyme 1 (IRE1α), protein kinase RNA-like endoplasmic reticulum kinase (PERK), CCAAT/enhancer-binding protein homologous protein (CHOP), and phosphorylated c-Jun N-terminal kinase protein contents were lowered by diacerein. Furthermore, diacerein suppressed the hepatic levels of fibrogenic mediators, e.g., Transforming growth factor β1 (TGF˗β1), α- smooth muscle actin (α-SMA), collagen 1, and hydroxyproline, as well as the apoptotic caspase 3 and BAX immunostaining in BDL rats. The histopathological abnormalities induced by BDL significantly improved. Our study demonstrated that diacerein exhibited an antifibrotic effect by inhibiting HMGB1/RAGE/NF-κB/JNK pathway, and ER stress. Better protection was observed with increasing the dose.
- Subjects
RECEPTOR for advanced glycation end products (RAGE); GLUCOSE-regulated proteins; HEPATIC fibrosis; ENDOPLASMIC reticulum; ADVANCED glycation end-products; TRANSFORMING growth factors; PROTEIN kinases
- Publication
Scientific Reports, 2023, Vol 13, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-023-38375-4