fraxetin and Fibrosis

Chronic pancreatitis is considered a common gastrointestinal disorder, with significant morbidity and mortality. Fluoride is an important agent for the development of our body systems, especially for bone and teeth, however on its excess consumption, it deposits in different body tissues, especially the pancreas, causing its chronic inflammation and destruction. Fraxetin proved to possess versatile activities including; antioxidant, anti-inflammatory, antifibrotic, and anti-apoptotic activities. In the present study, we have evaluated the fraxetin potentiality to prevent fluoride-induced chronic pancreatitis in rats, by evaluating animal body weights and body weight gain rate, serum amylase, and lipase activities, pancreatic oxidative stress markers, cytokines, apoptotic markers, myeloperoxidase, and hydroxyproline levels, and histopathological changes. Nine-weeks-old male Wistar rats drank distilled water containing 500 ppm sodium fluoride (NaF) for 60 days to induce chronic pancreatitis. Oral fraxetin (20, 40, and 80 mg/kg/day) received simultaneously to prevent chronic pancreatitis development. Fraxetin in a dose-dependent manner alleviated chronic pancreatitis induced by NaF, as it restored the decreased body weight and weight gain rate, decreased the elevated serum amylase and lipase activities, pancreatic IL-6, TNF-α, MDA, caspase-3, MPO and hydroxyproline levels, and Bax/Bcl-2 ratio, enhanced pancreatic CAT and SOD activities, and GSH levels, besides it augmented the elevated IL-10 level, with the restoration of normal pancreatic architecture. Therefore, fraxetin could be a promising agent recommended for the prevention of fluoride-induced chronic pancreatitis in endemic areas.

Topics: Amylases; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Coumarins; Cytokines; Fibrosis; Lipase; Male; Pancreas; Pancreatitis, Chronic; Peroxidase; Rats, Wistar; Sodium Fluoride

Fraxetin, a natural derivative of coumarin, is known to have anti-inflammatory, anti-oxidant, and hepatoprotective effects in multiple diseases and in liver fibrosis. Whether fraxetin exerts similar effects against renal fibrosis is unknown. In a Unilateral Ureteral Obstruction (UUO) mouse model of renal fibrosis, fraxetin decreased UUO-induced renal dysfunction with a marked reduction in renal interstitial collagen fibers as detected by Masson's Trichrome staining. Fraxetin treatment also inhibited the expression of α-SMA, Collagen I, Collagen IV, fibronectin, N-cadherin, vimentin, phosphorylated-ERK, and increased the expression of E-cadherin in UUO mice, as shown by immunohistochemical staining and western blot analysis. In vitro studies showed that fraxetin and indoxyl sulfate had no cytotoxic effects on MES13 kidney cells, but that fraxetin significantly decreased IS-induced cell motility and decreased protein expression of α-SMA, N-cadherin, vimentin, and Collagen IV via the ERK-mediated signaling pathway. These findings provide insight into the mechanism underlying fraxetin-induced inhibition of fibrogenesis in renal tissue and suggest that fraxetin treatment may be beneficial for slowing CKD progression.

Topics: Animals; Antifibrotic Agents; Cadherins; Coumarins; Fibronectins; Fibrosis; Kidney; Kidney Diseases; MAP Kinase Signaling System; Mice; Signal Transduction; Transforming Growth Factor beta1; Ureteral Obstruction; Urinary Tract