RESUMO
Cholestasis is a hepatobiliary condition that manifests as acute or chronic and results from disruptions in the bile flow, formation, or secretion processes. The Farnesoid X receptor (FXR) is a vital target for the therapy of cholestasis since it regulates BA homeostasis. Despite the discovery of multiple active FXR agonists, there are still no effective treatments for cholestasis. Papaverine is identified as an FXR agonist.This study investigates papaverine's efficacy and probable mechanism in protecting against alpha naphthylisothiocyanate (ANIT) induced cholestasis. Thirty male albino rats were divided into three groups, each with ten rats. Group I (control) rats were administered 1 mL/kg corn oil 48 h before sacrifice; group II rats were orally administered 100 mg/kg ANIT. Group III received a 200 mg/kg dosage of papaverine over seven consecutive days. A single dose of ANIT at a concentration of 100 mg/kg was orally administered on the fifth day; group II and III animals were euthanized 48 h after inducing cholestasis, and serum concentrations of liver function tests and total bile acid (TBA) were measured. Besides measuring the inflammatory mediator's tumor necrosis factor-alpha (TNF-α) and interleukin 1 (IL-1ß), antioxidant markers such as superoxide dismutase (SOD) and glutathione (GSH) were also assessed. The findings indicated the enhancement in the liver function test and total bile acids, as well as in liver histology; papaverine significantly lowered TNF-α and IL-1ß while SOD and GSH significantly increased. Additionally, papaverine upregulates Fxr gene expression, bile salt export pump (Besp), small heterodimer partner (shp), hepatocyte nuclear factor 1α (Hnfα), nuclear factor erythroid 2-related factor (Nrf2), heme oxygenase (Ho-1), NAD(P)H quinone oxidoreductase 1 (Nqo1). Furthermore, papaverine increased protein expressions of Sirtuin1. (SIRT 1), FXR, HO-1, and BSEP levels in the rats' livers. The protective effects of papaverine may be attributed to the activation of FXR signaling pathways. These findings revealed that papaverine protects against ANIT-induced Cholestasis.
RESUMO
Intestinal mucositis (IM) is a common side effect of several anticancer medications, including 5-fluorouracil (5-FU), and can lead to treatment disruptions and compromised outcomes. IM has severe clinical effects such as diarrhea, erythematous mucosal lesions, and the development of ulcers accompanied by excruciating pain. This study aimed to evaluate the mucoprotective effects of ellagic acid on 5-FU-induced IM in mice. Mice were administered normal saline intraperitoneally for six days, followed by intraperitoneal injection of 5-FU for four days at a dose of 50 mg per kilogram. Ellagic acid was orally administered to the mice in groups III and IV in two doses (5 mg and 10 mg), with a one-hour time separation from 5-FU for ten days. At the end of the experiment, small intestine tissue was collected to measure the levels of antioxidant enzymes superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and inflammatory cytokines (IL-6, IL-B, TNF) using ELISA assay. Pre-treatment with ellagic acid led to a significant decrease in pro-inflammatory cytokines and improved antioxidant enzyme levels compared to the 5-FU group. Histopathological analysis demonstrated the mucoprotective effect of ellagic acid against 5-FU-induced intestinal changes, including villi atrophy, damage to stem cells, infiltration of inflammatory cells in the mucosal layer, edema, damage to muscular mucosa, and decreased oxidative stress production, such as MDA. These results suggest that ellagic acid may be a potential candidate for treating IM induced by antineoplastic drugs.
