Intestinal mucositis, characterized by inflammatory and/or ulcerative processes in the gastrointestinal tract, occurs due to cellular and tissue damage following treatment with 5-fluorouracil (5-FU). Rutin (RUT), a natural flavonoid extracted from Dimorphandra gardneriana, exhibits antioxidant, anti-inflammatory, cytoprotective, and gastroprotective properties. However, the effect of RUT on inflammatory processes in the intestine, especially on mucositis promoted by antineoplastic agents, has not yet been reported. In this study, we investigated the role of RUT on 5-FU-induced experimental intestinal mucositis. Swiss mice were randomly divided into seven groups: Saline, 5-FU, RUT-50, RUT-100, RUT-200, Celecoxib (CLX), and CLX + RUT-200 groups. The mice were weighed daily. After treatment, the animals were euthanized and segments of the small intestine were collected to evaluate histopathological alterations (morphometric analysis); malondialdehyde (MDA), myeloperoxidase (MPO), and glutathione (GSH) concentrations; mast and goblet cell counts; and cyclooxygenase-2 (COX-2) activity, as well as to perform immunohistochemical analyses. RUT treatment (200 mg/kg) prevented 5-FU-induced histopathological changes and reduced oxidative stress by decreasing MDA concentrations and increasing GSH concentrations. RUT attenuated the inflammatory response by decreasing MPO activity, intestinal mastocytosis, and COX-2 expression. These results suggest that the COX-2 pathway is one of the underlying protective mechanisms of RUT against 5-FU-induced intestinal mucositis.
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.
Intestinal mucositis was induced by the administration of 5‐FU in a single dose of 450mg/kg on the first day of the protocol in Swiss mice, and groups of animals that received dosages of angico branco were treated between the second and the fifth day, culminating in euthanasia and removal of intestinal segments for further analysis. Initially, through histopathological and morphometric findings, the severity of mucositis was demonstrated in this study, through aspects related to tissue architecture, focusing on the reduction and vacuolization of intestinal villi, crypt necrosis, infiltration of inflammatory cells, loss of inflammation cell architecture, decreased villus/crypt ratio, caused in the group of animals that received the 5‐FU dose. However, the group of animals that were treated with angico branco gum at a dose of 400mg/kg, after induction of intestinal mucositis, attenuation of these deleterious effects promoted by 5‐FU was observed, among which we can mention: less inflammatory infiltrate, maintenance of cellular architecture, attenuation of villus shortening and crypt depth, decrease of crypt necrosis, also evidenced by the better villus/crypt ratio. These effects, however, were not seen in the ileum. Treatment with white angelic gum at doses of 100 mg/kg; 200 mg/kg and 400 mg/kg promoted a statistically significant reduction (p <0.05) in the number of mast cells when confronted with the 5‐FU group in the duodenum and jejunum. In contrast, treatment with white angico gum reversed the mastocytosis observed by the increase in mast cell count in the intestinal segments of animals submitted to mucositis. In addition, the saline group did not show an increase in mast cells when compared to the group with 5‐FU. Studies that evaluated the role of mast cells in mucositis also revealed the participation of these substances in the course of intestinal mucositis (PEREIRA JUNIOR, 2017; MIRANDA, 2018). The study by Nogueira et al. (2017) also demonstrated a significant increase in the number of total and degranulated mast cells in the intestinal segments of animals subjected to irinotecan‐induced intestinal mucositis, with a release of pro‐inflammatory mediators in the inflammatory condition. Through the results found in this study it can be concluded that the gum of angico reduced the mast cell count and preserved the number of goblet cells after induction of intestinal mucositis induced by 5‐FU in mice. White angico gum reduces the mast cell count in the duodenum, jejunum of mice subjected to intestinal mucositis induced by 5‐FU.
The enzyme nitric oxide synthase (iNOS) is responsible for the synthesis of NO which is complemented by the conversion of L‐arginine and oxygen to L‐citrulline and NO. There are three forms of NOS identified: nitric oxide endothelial synthase (eNOS) found in the vascular endothelium, the neuronal nitric oxide synthase (nNOS) that regulates neuronal transmission, and inducible nitric oxide, first identified in macrophages. The first two are constitutive, and the last is related to tissue damage and present in inflammation and cell apoptosis (LIAUDET; SORIANO; SZABÓ, 2000; DAVIS et al., 2001). The mechanism of action of NO can occur in two ways: when there is interaction directly with the molecule of the target system and when there is a reaction with intermediates of reactive oxygen species, which can lead to the formation of reactive nitrogen species (RNA) such as peroxynitrite. (FANG, 1997; DAVIS et al., 2001; VALKO et al., 2007). Intestinal mucositis was induced in mice with the administration of 5 FU, according to the methodology described by Carneiro‐Filho et al. (2004), adapted. The treatment was done using three doses of angico branco gum (100, 200, 400 mg/kg) one day after i.p. of 5‐FU, the choice of doses being based on the study by Santos et al. (2013). The other groups received saline. Suppression of NO is an essential indicator for the development of an anti‐inflammatory agent, since NO is a mediator of inflammation derived from pro‐inflammatory cytokines and produced in various inflammatory conditions resulting from cytokine cytotoxicity (KHAN et al., 2015; TOSUN et al., 2014; CHUN et al., 2012). It has also been shown that NO negatively regulates the expression of adhesion molecules in the vascular endothelium, thus decreasing neutrophil trafficking in inflamed tissues (LEITÃO et al., 2006). When investigating the possible involvement of nitric oxide in the protective effect of white angico gum on morphometric and histopathological changes in mice submitted to intestinal mucositis by 5‐FU, it was evaluated that the administration of L‐NAME with white angico gum, as well as the separate administration of the two compounds prevented the villus shortening caused by 5‐FU, and increased the villus/crypt ratio. Thus, it can be said that both individual, and acting synergistically blocked the effects of NO and, consequently, can be used to treat intestinal mucositis. In conclusion, we observed that the angico gum at a concentration of 400 mg/kg had a protective effect on the intestinal mucosa, after inducing injury by chemotherapy, by decreasing the immunostaining for the enzyme iNOS, demonstrating the role of antiinflammatory. GAB = 400mg/kg white angico gum. Values were expressed as mean ± SEM of the percentage of the immunostained area for INOS.
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Physical exercise prior to myocardial infarction (MI) protects against the IM scar, prevents cardiac remodeling and attenuates systolic dysfunction and diastolic activity in rats. Evaluate the influence of physical training by swimming, performed prior to MI, on the growth of cardiac masses, pulmonary and hepatic water content. Characterize the echocardiographic changes indicative of cardioprotection induced by physical training prior to myocardial infarction. Young rats weighing between 170 and 190 grams, from the Experimental Models Development Center (CEDEME) of the Federal University of São Paulo, were used. The animals were kept in boxes with water and rations in a temperature controlled environment. They were distributed in four experimental groups: non‐infarcted sedentary (SS); Sedentary infarcted (IMS); Trained non‐infarcted (SE); Infarcted Training (IME) The animals were submitted to a period of adaptation to the swimming exercise, later those belonging to the SE and IME groups swam for 90 minutes, this time was maintained until five weeks were completed. After this period the maximum physical capacity (MCF) was again evaluated and then the rats were submitted to myocardial infarction (MI) surgery. The method of production of IM was based on the work of Johns and Olson (1954). After three weeks of infarction the animals were submitted to Doppler echocardiography and were sacrificed for the analysis of the wet and dry weight of the heart, lungs and liver. The data were statistically evaluated, one‐way ANOVA followed by Tukey's test, and significant values of (p<0,05) were considered. After the training period prior to MI, the animals exercised SE (2,317 ± 275 seconds) and IME (3,104 ± 281 seconds) had an increase (p ≤ 0.001) in MCF compared to SS sedentary animals (378 ± 43 seconds) and IMS (341 ± 25 seconds), respectively. These results indicate that the protocol was effective in increasing the cardiorespiratory capacity of the exercised animals. The atrial masses of the infarcted animals were higher than those of the non‐infarcted animals (p ≤ 0.001). The right ventricular (RV) mass values of SE, IMS and IME animals were higher than the values for the SS group (p ≤ 0.001). There was hypertrophy (12%) of the left ventricle (LV) of the SE rats in relation to the SS (p = 0.008). The results of the IMS and IME groups related to the cardiac morphology indicated significant LV dilation and decreased LV wall thickness (p ≤ 0.001) in relation to SS and SE animals. No significant differences were observed in the comparisons of aortic diameters, left atrial and LV posterior wall thickness between groups. The water contents of the lungs and liver did not differ significantly between the four experimental groups. The results related to the systolic function indicated that there was a significant loss (p ≤ 0.001) of the shortening fraction and the shortening fraction of the transverse area indicating clear systolic dysfunction, not prevented by physical exercise. Values for diastolic function in infarcted animals were significantly worse than those recorded in non‐infarcted animals (p<0,05). The protocol of physical training per swimming, imposed prior to MI, did not prevent the cardiac remodeling of infarcted rats and does not prevent cardiac remodeling or systolic and diastolic dysfunction evaluated by Doppler echocardiography.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Intestinal mucositis (MI), characterized by inflammation and ulceration of the intestinal mucosa, is one of the main causes of morbidity and mortality in chemotherapy patients (LEE et al., 2014).GOALSTo evaluate the action of the white angico polysaccharide on the histological changes in villi and crypts induced by 5‐FU in the intestinal mucosa;To verify the role of the white angico polysaccharide in the involvement of the cyclooxygenase‐2 (COX‐2) pathway in the 5‐FU induced intestinal mucositis model;METHODSThe experimental protocol was forwarded and approved by the Ethics Committee for Animal Use (CEUA) of UFC (3463140518). Intestinal mucositis was induced in mice with administration of 5‐FU, according to the methodology described by Carneiro‐Filho et al. (2004), in which the mice received on the first day of the experiment a single dose of 5‐FU (450 mg/kg) via intraperitoneal (i.p). The treatment was done using three doses of the white angico polysaccharide (100, 200, 400 mg/kg) one day after the injection of 5‐FU, the doses being based on Santos et al. (2013). The animals were divided into groups: Group I (Saline): saline solution 0.9% (0.1 mL/10g) and intraperitoneal (i.p), in parallel to the other groups treated throughout the study. Group II (5‐FU): on the first day of the experimental protocol will receive a single dose of 5‐FU (450 mg/kg) i.p. and will be treated with 0.9% saline solution (0.1 mL/10g) on the next four days. Group III (Angico best dose): 5‐FU (450 mg/kg) i.p on the first day of the experiment and was treated with angico diluted in distilled water. Group IV (Celecoxib): single dose of 5‐FU (450mg/kg) intraperitoneally (i.p) on the first day. On the following days of the experimental protocol only Celecoxib (7.5 mg/kg, i.p) was administered Group V (Celocoxib + Angico best dose): single dose of 5‐FU (450mg/kg) intraperitoneally (i.p) on the first day. On the second day of protocol, they was received white angico polysaccharide diluted in distilled water, and Celecoxib (7.5 mg/kg, i.p). After the histological processing, the morphometric evaluation was carried out with the aid of the ImageJ software, where the height of the villi and the depth of the crypts were measured. Immunohistochemistry for COX‐2 was then performed using the streptavidin‐biotin‐peroxidase method (HSU; RAINE, 1981)RRESULTSThe white Angico polysaccharide was able to statistically (p <0.05) prevent the shortening of villi and decrease the depth of the crypts caused by 5‐FU (Figure 1). The groups treated with angio 400 mg/kg, CLX and the CLX + angio combination (Figure 2) showed a statistically significant (p <0.05) reduction of the immunolabelled area for COX‐2 when compared to the 5‐FU group.CONCLUSIONThe white angico polysaccharide protected the intestinal mucosa and promoted a decrease in COX‐2 expression in the 5‐FU induced intestinal mucositis model.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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