Gliclazide Prevents 5-FU-Induced Oral Mucositis by Reducing Oxidative Stress, Inflammation, and P-Selectin Adhesion Molecules

Mafra, Cristiane Assunção da Costa Cunha; Vasconcelos, Roseane Carvalho; Medeiros, Caroline Addison Carvalho Xavier de; Leitão, Renata Ferreira de Carvalho; Brito, Gerly Anne de Castro; Costa, Deiziane Viana da Silva; Guerra, Gerlane Coelho Bernardo; Araújo, Raimundo Fernandes de; Medeiros, Aldo Cunha; Araújo, Aurigena Antunes de

doi:10.3389/fphys.2019.00327

Cited by 21 publications

(12 citation statements)

References 58 publications

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“…This is because neutrophils secrete a repertoire of proteases and enzymes such as MMPs, elastase, Cathepsin G, and MPO that damage tissue (61,62). MPO is abundantly expressed in neutrophil granules and is associated with severe OM lesions (45,63) and delayed wound healing (64). Neutrophils also produce various MMPs, such as MMP-9, which was detected at elevated levels in Il17ra −/− mice, and is associated with tissue destruction during periodontal disease and OM (65,66).…”

Section: Discussionmentioning

confidence: 99%

Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling

et al. 2021

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Oral mucositis (OM) is a treatment-limiting adverse side effect of radiation and chemotherapy. Approximately 80% of patients undergoing radiotherapy (RT) for head and neck cancers (HNC) develop OM, representing a major unmet medical condition. Our understanding of the immunopathogenesis of OM is limited, due in part to the surprising paucity of information regarding healing mechanisms in the oral mucosa. RNAseq of oral tissue in a murine model that closely mimics human OM, showed elevated expression of IL-17 and related immune pathways in response to head and neck irradiation (HNI). Strikingly, mice lacking the IL-17 receptor (IL-17RA) exhibited markedly more severe OM. Restoration of the oral mucosa was compromised in Il17ra−/− mice and components associated with healing, including matrix metalloproteinase 3, 10 and IL-24 were diminished. IL-17 is typically associated with recruitment of neutrophils to mucosal sites following oral infections. Unexpectedly, in OM the absence of IL-17RA resulted in excessive neutrophil recruitment and immunopathology. Instead, neutrophil activation was IL-1R-driven in Il17ra−/− mice. Blockade of IL-1R and depletion of neutrophils lessened the severity of damage in these mice. Overall, we show IL-17 is protective in OM through multiple mechanisms including restoration of the damaged epithelia and control of the neutrophil response. We also present a clinically relevant murine model of human OM to improve mechanistic understanding and develop rational translational therapeutics.

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Section: Discussionmentioning

confidence: 99%

Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling

et al. 2021

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“…This research was approved by the Ethics Committee on the Use of Animals of the Federal University of Rio Grande do Norte (CEUA-UFRN), permit number 002001/2017. The experimental OM model was induced in golden Syrian hamsters ( Mesocricetus auratus ) males weighing 180 g. They were maintained with rations, water ad libitum, at a temperature of 22 ± 2 °C, and a light/dark cycle of 12 h [ 15 , 36 ]. OM was induced by two intraperitoneal (i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…The goals of mucositis management are to prevent or reduce the severity of toxicity and to manage the associated symptoms, which will, in turn, enable the continued delivery of cancer therapy without interruption or dose reduction and improve the overall prognosis [ 13 ]. Previous research has shown that drugs with anti-inflammatory action can prevent OM [ 14 , 15 , 16 , 17 ]. Recently, it was shown that dexamethasone (DEX) ameliorated OM induced by 5-FU [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of Dexamethasone-Loaded PLGA Nanoparticles on Oral Mucositis Induced by 5-Fluorouracil

et al. 2021

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Oral mucositis (OM) is characterized by the presence of severe ulcers in the oral region that affects patients treated with chemotherapy. It occurs in almost all patients who receive radiotherapy of the head and neck, as well as patients who undergo hematopoietic cell transplantation. The pathophysiology of OM is complex, and there is no effective therapy. The aim of this study was to evaluate the effect of dexamethasone-loaded poly(d,l-Lactic-co-glycolic) nanoparticles (PLGA-DEX NPs) on an OM model induced in hamsters. The NPs were synthesized using the emulsification-solvent evaporation method and were characterized by the size, zeta potential, encapsulation efficiency, atomic force microscopy, physicochemical stability, and the in vitro release. The OM was induced by the administration of 5-FU on the first and second days and mechanical trauma on the 4th day of the experiment. PLGA-DEX NPs were administered to treat OM. The animals were euthanized on the 10th day. Macroscopic and histopathological analyses were performed, measurement of malonaldehyde (MDA) and ELISA was used to determine the levels of IL-1β and TNF-α. Immunoexpressions of NF-κB, COX-2, and TGF-β were determined by immunohistochemistry, and qRT-PCR was used to quantify the gene expression of the GILZ, MKP1, and NF-κB p65. The PLGA-DEX NPs (0.1 mg/kg) significantly reduced macroscopic and histopathological scores, decreased MDA, TNF-α and IL-1β levels, immunostaining for NF-κB, COX-2, TGF-β, and suppressed NF-κB p65 mRNA expression, but increased GILZ and MKP1 expression.

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“…Thalidomide, an NF-κB inhibitor, significantly improved mucosal tissue in irradiated mice, although the underlying mechanism still requires further study ( 63 ). Other drugs, such as amiforstine and gliclazide, reduce oxidative stress and inflammation ( 64 , 65 ). Growth factors and cytokines are also used to treat radiation mucositis.…”

Section: Clinical Intervention For Riom and Malnutrition In Hnc Patiementioning

confidence: 99%

The Effects of Early Nutritional Intervention on Oral Mucositis and Nutritional Status of Patients With Head and Neck Cancer Treated With Radiotherapy

Zheng

Zhao

et al. 2021

Front. Oncol.

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Radiation-induced oral mucositis (RIOM) is a common side effect after radiotherapy (RT) in head and neck cancer (HNC) patients. RIOM patients with severe pain have difficulty in eating, which increases the incidence of malnutrition and affects patients’ quality of life and the process of RT. The mechanism of RIOM is not fully understood, and inflammatory response and oxidative stress appear to be important for RIOM occurrence and development. The nutritional status of patients is very important for their RT tolerance and recovery. Malnutrition, which can lead to anemia, low protein, decreased immunity and other problems, is an important clinical factor affecting tumor progression and treatment. Recent studies have shown that early nutritional intervention can ameliorate oral mucositis and nutritional status of patients with HNC. However, in clinical practice, early nutritional intervention for patients with HNC is not a conventional intervention strategy. Therefore, this review summarized the possible pathogenesis of RIOM, commonly used assessment tools for malnutrition in patients, and recent studies on the effects of early nutritional interventions on RIOM and nutritional status of patients with HNC. We hope to provide the basis and reference for the clinical application of early nutritional intervention models.

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Gliclazide Prevents 5-FU-Induced Oral Mucositis by Reducing Oxidative Stress, Inflammation, and P-Selectin Adhesion Molecules

Cited by 21 publications

References 58 publications

Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling

Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling

Effect of Dexamethasone-Loaded PLGA Nanoparticles on Oral Mucositis Induced by 5-Fluorouracil

The Effects of Early Nutritional Intervention on Oral Mucositis and Nutritional Status of Patients With Head and Neck Cancer Treated With Radiotherapy

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