Troxerutin Prevents 5-Fluorouracil Induced Morphological Changes in the Intestinal Mucosa: Role of Cyclooxygenase-2 Pathway.

João Antônio Leal De Miranda,Gilberto Santos Cerqueira,Conceição Da Silva Martins,Jefferson Almeida Rocha,Icaro Gusmão Pinto Vieira,Paulo Vitor De Souza Pimentel,Gerly Anne De Castro Brito,Ariel Gustavo Scafuri,Helder Bindá Pimenta,Claudio Silva Teixeira,Francisco Orlando Rafael Freitas,Maria Claudia Dos Santos Luciano,Matheus Da Silva Campelo,Maria Elenir Nobre Pinho Ribeiro,Joabe Lima Araújo,João Erivan Façanha Barreto,Maria Lucianny Lima Barbosa,Lázaro De Sousa Fideles,Nágila Maria Pontes Silva Ricardo

doi:10.3390/ph13010010

João Antônio Leal De Miranda, Gilberto Santos Cerqueira + Show 17 more

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https://doi.org/10.3390/ph13010010

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Abstract

Intestinal mucositis is a common complication associated with 5-fluorouracil (5-FU), a chemotherapeutic agent used for cancer treatment. Troxerutin (TRX), a semi-synthetic flavonoid extracted from Dimorphandra gardneriana, has been reported as a potent antioxidant and anti-inflammatory agent. In the present study, we aimed to evaluate the effect of TRX on 5-FU-induced intestinal mucositis. Swiss mice were randomly divided into seven groups: Saline, 5-FU, TRX-50, TRX-100, TRX-150, Celecoxib (CLX), and CLX + TRX-100. The weight of mice was measured daily. After treatment, the animals were euthanized and segments of the small intestine were collected to evaluate histopathological alterations (morphometric analysis), levels of malondialdehyde (MDA), myeloperoxidase (MPO), glutathione (GSH), mast and goblet cell counts, immunohistochemical analysis, and cyclooxygenase-2 (COX-2) activity. Compared to the saline treatment, the 5-FU treatment induced intense weight loss and reduction in villus height. TRX treatment (100 mg/kg) prevented the 5-FU-induced histopathological changes and decreased oxidative stress by decreasing the MDA levels and increasing GSH concentration. TRX attenuated inflammatory process by decreasing MPO activity, intestinal mastocytosis, and COX-2 expression. TRX also reversed the depletion of goblet cells. Our findings suggest that TRX at a concentration of 100 mg/kg had chemopreventive effects on 5-FU-induced intestinal mucositis via COX-2 pathway.

Highlights

Oral and gastrointestinal mucositis are the most common adverse effects of cancer chemotherapy [1,2]
The pathophysiology of mucositis is more complex than mere direct damage to the intestinal epithelium
Nuclear factor kappa B (NF-kB), proinflammatory cytokines, such as interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α), and apoptotic mediators have been known to be associated with this process

Summary

Introduction

Oral and gastrointestinal mucositis are the most common adverse effects of cancer chemotherapy [1,2]. The pathophysiology of mucositis is more complex than mere direct damage to the intestinal epithelium It includes sequential interaction of events, which leads to generation of reactive oxygen and nitrogen species (ROS/RNS). Nuclear factor kappa B (NF-kB), proinflammatory cytokines, such as interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α), and apoptotic mediators have been known to be associated with this process The interaction of these factors results in oxidative damage, intense infiltration of inflammatory cells, villous atrophy, crypt hypoplasia, edema, necrosis, and cell death, which leads to damage and rupture of the intestinal epithelial barrier [4,9,10,11,12,13,14]

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