xanthohumol and Fibrosis

Fibrosis has various biological processes and affects almost every organ, especially in patients with inflammatory bowel disease, including Crohn's disease, who experience discomfort caused by intestinal fibrosis, which is a problem that needs to be resolved. TGF-β signaling is known to act as a key regulator of intestinal fibrosis, and its modulation could be an excellent candidate for fibrosis therapy. Xanthohumol (XN) has various effects, including anti-inflammation and anti-cancer; however, the detailed mechanism of TGF-β signaling has not yet been studied. The purpose of this study was to investigate the mechanism underlying the anti-fibrotic effect of XN on TGF-β1-induced intestinal fibrosis using primary human intestinal fibroblasts (HIFs). In this study, to check the anti-fibrotic effects of XN on intestinal fibrosis, we assessed the expression of fibrosis-related genes in TGF-β1-stimulated HIFs by qPCR, immunoblotting, and immunofluorescence staining. As a result, XN showed the ability to reduce the expression of fibrosis-associated genes increased by TGF-β1 treatment in HIFs and restored the cell shape altered by TGF-β1. In particular, XN repressed both NF-κB- and Smad-binding regions in the α-SMA promoter, which is important in fibrosis. In addition, XN inhibited NF-κB signaling, including phosphorylated-IkBα and cyclooxygenase-2 expression, and TNF-α-stimulated transcriptional activity of NF-κB. XN attenuated TGF-β1-induced phosphorylation of Smad2 and Smad3, and the transcriptional activity of CAGA. Particularly, XN interfered with the binding of TGF-Receptor I (TβRI) and Smad3 by binding to the kinase domain of the L45 loop of TβRI, thereby confirming that the fibrosis mechanism did not proceed further. In conclusion, XN has an inhibitory effect on TGF-β1-induced intestinal fibrosis in HIFs, significantly affecting TGF-β/Smad signaling.

Topics: Fibrosis; Humans; NF-kappa B; Signal Transduction; Transforming Growth Factor beta1

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fatty Liver; Fibrosis; Flavonoids; Hypoglycemic Agents; Injections, Intraperitoneal; Male; NF-E2-Related Factor 2; NF-kappa B; Propiophenones; Rats; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Signal Transduction; Streptozocin

Emerging evidence suggests the cardiovascular protective effects of Xanthohumol (Xn), a prenylated flavonoid isolated from the hops (Humulus lupulus L.). However, the cardioprotective effect of Xn remains unclear. Present study aimed to investigate the protective role of Xn against isoprenaline (ISO)-induced cardiac hypertrophy and fibrosis, and elucidate the underlying mechanism. The cardiac hypertrophy and fibrosis model were established via subcutaneously administration of ISO. ISO reduced the left ventricular contractile function and elevated myocardial enzyme levels, suggesting cardiac dysfunction. Moreover, the increased cardiac myocyte area, heart weight/body weight (HW/BW) ratio and ANP/BNP expressions indicated the ISO-induced hypertrophy, while the excessive collagen-deposition and up-regulation of fibrosis marker protein (α-SMA, Collagen-I/III) expression indicated the ISO-induced fibrosis. The ISO-induced cardiac dysfunction, hypertrophy and fibrosis were significantly attenuated by oral administrated with Xn. PTEN/AKT/mTOR pathway has been reported to involve in pathogenesis of cardiac hypertrophy and fibrosis. We found that Xn administration up-regulated PTEN expression and inhibited the phosphorylation of AKT/mTOR in ISO-treated mice. Moreover, treating with VO-ohpic, a specific PTEN inhibitor, abolished the cardioprotective effect of Xn. Collectively, these results suggested that Xn attenuated ISO-induced cardiac hypertrophy and fibrosis through regulating PTEN/AKT/mTOR pathway.

Topics: Animals; Disease Models, Animal; Fibrosis; Flavonoids; Hypertrophy, Left Ventricular; Isoproterenol; Male; Mice, Inbred C57BL; Myocytes, Cardiac; Phosphorylation; Propiophenones; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; TOR Serine-Threonine Kinases; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling