5-Fluorouracil Induces Enteric Neuron Death and Glial Activation During Intestinal Mucositis via a S100B-RAGE-NFκB-Dependent Pathway

Costa, Deiziane Viana da Silva; Bon-Frauches, Ana Carina; Silva, Angeline M. H. P.; Lima-Júnior, Roberto César Pereira; Martins, Carla Adriano; Leitão, Renata F. C.; Freitas, Gutierrez B.; Castelucci, Patrícia; Bolick, David T.; Guerrant, Richard L.; Warren, Cirle A.; Moura‐Neto, Vivaldo; Brito, Gerly Anne de Castro

doi:10.1038/s41598-018-36878-z

Cited by 69 publications

(56 citation statements)

References 53 publications

(70 reference statements)

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“…Several studies have described the histopathological and morphometric alterations promoted by 5-FU, such as reduction and vacuolization of intestinal villi, crypt necrosis, inflammatory cell infiltration, edema, loss of cell architecture, and decrease in villus/crypt ratio [34][35][36][37][38][39]. Our findings are consistent with those presented in these studies.…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 92%

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

et al. 2020

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“…It should also be noted that the inflammatory cytokines that we observed here to be affected by PTM administration are also known to be influenced by S100B [28,31,33]. Furthermore, S100B expression is reduced after PTM administration, as we have shown here in the present experimental MS animal model, also confirming what was observed in other pathological conditions where PTM exerts a protective role [39,40].…”

Section: Discussionsupporting

confidence: 91%

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Sante

Amadio

Sampaolese³

et al. 2020

Cells

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S100B is an astrocytic protein acting either as an intracellular regulator or an extracellular signaling molecule. A direct correlation between increased amount of S100B and demyelination and inflammatory processes has been demonstrated. The aim of this study is to investigate the possible role of a small molecule able to bind and inhibit S100B, pentamidine, in the modulation of disease progression in the relapsing–remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the central nervous system, we observed that pentamidine is able to delay the acute phase of the disease and to inhibit remission, resulting in an amelioration of clinical score when compared with untreated relapsing–remitting experimental autoimmune encephalomyelitis mice. Moreover, we observed a significant reduction of proinflammatory cytokines expression levels in the brains of treated versus untreated mice, in addition to a reduction of nitric oxide synthase activity. Immunohistochemistry confirmed that the inhibition of S100B was able to modify the neuropathology of the disease, reducing immune infiltrates and partially protecting the brain from the damage. Overall, our results indicate that pentamidine targeting the S100B protein is a novel potential drug to be considered for multiple sclerosis treatment.

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“…Then, the membranes were washed in TSBT, incubated in enhanced chemiluminescent (ECL, BioRad, Hercules, CA, USA) detection, and the image was captured with Chemi Doc MP (Bio-Rad). The Image J software (NIH, Bethesda, MD, USA) was used for densitometric quantification of the bands [31].…”

Section: Western Blot For Tgf-β and Smad 2/3mentioning

confidence: 99%

Effect of Gold Nanoparticle on 5-Fluorouracil-Induced Experimental Oral Mucositis in Hamsters

et al. 2020

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Background: Oral mucositis (OM) is a severe inflammation of the oral mucosal cells associated with chemotherapy and/or radiotherapy-induced toxicity, resulting in epithelial ulcers and higher risk of death from sepsis. The aim of the present study was to evaluate the nanoparticle (AuNp) effect on OM induced in hamsters. Materials and methods: 5-fluorouracil (5FU) was used on the first and second day of the experimental model in Golden sirian hamsters, and on the fourth day, mechanical trauma was applied to induce OM. The animals were divided into groups, i.e., polyvinylpyrrolidone (PVP), mechanical trauma (MT), 5FU, and groups treated with gold nanoparticles (AuNps) (62.5, 125, and 250 μg/kg). On the 10th day, animals were euthanized for macroscopic, histopathological, immunohistochemical, western blot, quantitative polymerase chain reaction (qRT-PCR), and AuNp quantification. Results: AuNp (250 μg/kg) reduced TNF-α, IL-1β, COX-2, NF-κB, TGF-β, and SMAD 2/3; increased glutathione levels; decreased the expression of Kelch ECH-associated protein 1 (KEAP1); and induced heme oxygenase 1 (HMOX-1) and NAD (P) H quinone oxidoreductase 1 (NQO1) genes. Conclusions: AuNp (250 μg/kg) prevented 5-FU-induced OM in hamsters and improved the parameters of inflammation and oxidative stress.

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5-Fluorouracil Induces Enteric Neuron Death and Glial Activation During Intestinal Mucositis via a S100B-RAGE-NFκB-Dependent Pathway

Cited by 69 publications

References 53 publications

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

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

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Effect of Gold Nanoparticle on 5-Fluorouracil-Induced Experimental Oral Mucositis in Hamsters

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