[Effect of IL-18BP on Fractalkine chemokine expression in the kidney tissue of rats with renal fibrosis].

OBJECTIVE: To study the expression of Fractalkine (FKN) in the kidney tissue of rats with renal fibrosis and the effect of IL-18BP on FKN. METHODS: Male Wister rats were randomly assigned to sham-operation (n=24), unilatral ureteral obstruction (UUO, n=22), and IL-18 binding protein (IL-18BP) treatment groups (n=23). The UUO model was prepared by unilateral ureteral ligation in the later two groups. The IL-18BP treatment group received an intraperitoneal injection of IL-18BP (0.1 mg/kg) every other day after UUO inducement, for 7 times, while normal saline was administered in the other two groups. Seven or eight rats of every group were sacrificed at 3, 7 or 14 days after IL-18BP or normal saline injections. FKN levels at various times were detected by immunohistochemistry and Western blot. RESULTS: Compared with the sham-operation group, FKN levels in the kidney tissue of the untreated UUO group increased significantly at all time points (P<0.01). IL-18BP treatment decreased significantly FKN levels in the kidney tissue at all time points compared with the untreated UUO group (P<0.01). CONCLUSIONS: IL-18BP treatment may down-regulate the increased FKN levels of the rat kidney tissue caused by UUO, possibly thus delays the occurrence and development of renal fibrosis.

Isolation and Biological Evaluation of Alfa-Mangostin as Potential Therapeutic Agents against Liver Fibrosis.

The increased proliferation and activation of hepatic stellate cells (HSCs) are associated with liver fibrosis development. To date, there are no FDA-approved drugs for the treatment of liver cirrhosis. Augmentation of HSCs apoptosis is one of the resolutions for liver fibrosis. In this study, we extracted α-mangostin (1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methyl-2-butenyl)-9H-xanthen-9-one) from the fruit waste components of mangosteen pericarp. The isolated α-mangostin structure was determined and characterized with nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) and compared with those known compounds. The intracellular signaling pathway activities of α-mangostin on Transforming growth factors-beta 1 (TGF-ß1) or Platelet-derived growth factor subunit B (PDGF-BB) induced HSCs activation and were analyzed via Western blot and Real-time Quantitative Polymerase Chain Reaction (Q-PCR). α-Mangostin-induced mitochondrial dysfunction and apoptosis in HSCs were measured by seahorse assay and caspase-dependent cleavage. The in vivo anti-fibrotic effect of α-mangostin was assessed by carbon tetrachloride (CCl4) treatment mouse model. The data showed that α-mangostin treatment inhibited TGF-ß1-induced Smad2/3 phosphorylation and alpha-smooth muscle actin (α-SMA) expression in HSCs in a dose-dependent manner. Regarding the PDGF-BB-induced HSCs proliferation signaling pathways, α-mangostin pretreatment suppressed the phosphorylation of extracellular-signal-regulated kinase (ERK) and p38. The activation of caspase-dependent apoptosis and dysfunction of mitochondrial respiration (such as oxygen consumption rate, ATP production, and maximal respiratory capacity) were observed in α-mangostin-treated HSCs. The CCl4-induced liver fibrosis mouse model showed that the administration of α-mangostin significantly decreased the expression of the fibrosis markers (α-SMA, collagen-a2 (col1a2), desmin and matrix metalloproteinase-2 (MMP-2)) as well as attenuated hepatic collagen deposition and liver damage. In conclusion, this study demonstrates that α-mangostin attenuates the progression of liver fibrosis through inhibiting the proliferation of HSCs and triggering apoptosis signals. Thus, α-mangostin may be used as a potential novel therapeutic agent against liver fibrosis.