Chrysin-loaded calixarene-cyclodextrin ternary drug delivery system inhibits TGF-β and galectin-1 mediated pathways in diabetic liver fibrosis

• Published in: Biochemical pharmacology 2024-11, Vol.229, p.116474, Article 116474
• Main Authors: Balta, Cornel, Herman, Hildegard, Ciceu, Alina, Lepre, Caterina Claudia, Mladin, Bianca, Rosu, Marcel, Oatis, Daniela, Russo, Marina, Peteu, Victor Eduard, Gherghiceanu, Mihaela, Fenyvesi, Ferenc, Cotoraci, Coralia, Trotta, Maria Consiglia, D’Amico, Michele, Hermenean, Anca
• Format: Article
• Language: English
• Subjects: Animals; Calixarene; Calixarenes - administration & dosage; Calixarenes - chemistry; Chronic diabetes; Chrysin; Cyclodextrin; Cyclodextrins - administration & dosage; Cyclodextrins - chemistry; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Drug delivery system; Drug Delivery Systems - methods; Flavonoids - administration & dosage; Flavonoids - pharmacology; Galectin 1 - antagonists & inhibitors; Galectin 1 - metabolism; Liver Cirrhosis - drug therapy; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver fibrosis; Male; Mice; Signal Transduction - drug effects; Transforming Growth Factor beta - metabolism
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2024.116474

[Display omitted] 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.