1. Chrysin-loaded calixarene-cyclodextrin ternary drug delivery system inhibits TGF-β and galectin-1 mediated pathways in diabetic liver fibrosis.
- Author
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Balta C, Herman H, Ciceu A, Lepre CC, Mladin B, Rosu M, Oatis D, Russo M, Peteu VE, Gherghiceanu M, Fenyvesi F, Cotoraci C, Trotta MC, D'Amico M, and Hermenean A
- Subjects
- Animals, Male, Mice, Drug Delivery Systems methods, Transforming Growth Factor beta metabolism, Signal Transduction drug effects, Cyclodextrins chemistry, Cyclodextrins administration & dosage, Calixarenes administration & dosage, Calixarenes chemistry, Flavonoids administration & dosage, Flavonoids pharmacology, Liver Cirrhosis drug therapy, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental metabolism, Galectin 1 metabolism, Galectin 1 antagonists & inhibitors
- Abstract
This study investigated the efficacy of a new chrysin-loaded calixarene-cyclodextrin ternary drug delivery system (DDS) in reversing liver fibrosis in a mouse model of chronic diabetes. The system was designed to enhance the solubility and bioavailability of chrysin (CHR) and calixarene 0118 (OTX008). Adult male CD1 mice received streptozotocin (STZ) injections to induce diabetes. After 20 weeks, they underwent intraperitoneal treatments twice weekly for a two-week period. Histological analyses revealed that long-term hyperglycaemia increased liver fibrosis and altered hepatic ultrastructure, characterized by lipid accumulation, hepatic stellate cell activation, and collagen deposition. The treatment with the chrysin-loaded DDS restored liver structure closely to normal levels, as opposed to the minimal impact observed with sulfobutylated β-cyclodextrin (SBECD) alone. The treatment significantly decreased serum activities of alanine /aspartate transaminases and reduced the gene expression of collagen type I (Col-I). It also modulated the transforming growth factor beta 1 (TGF-β1)/Smad signalling pathway, inhibiting the activation and proliferation of hepatic stellate cells. The treatment led to a downregulation of the TGF-β1 gene and its receptors TGFβR1 and TGFβR2, together with a decrease in Smad 2 and 3 mRNA levels. Conversely, Smad 7 mRNA expression was increased by the DDS. Furthermore, it downregulated galectin-1 (Gal-1) gene and protein levels, which correlated with fibrotic markers. In conclusion, the chrysin-loaded calixarene-cyclodextrin ternary DDS presents a promising therapeutic approach for diabetic liver fibrosis, effectively targeting fibrotic pathways and restoring hepatic function and structure., 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. Published by Elsevier Inc.)
- Published
- 2024
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