Abstract
Acrolein is the main toxic metabolite of ifosfamide (IFO) that causes urothelial damage by oxidative stress and inflammation. Here, we investigate the molecular mechanism of action of gingerols, Zingiber officinale bioactive molecules, as an alternative treatment for ifosfamide-induced hemorrhagic cystitis. Female Swiss mice were randomly divided into 5 groups: control; IFO; IFO + Mesna; and IFO + [8]- or [10]-gingerol. Mesna (80 mg/kg, i.p.) was given 5 min before, 4 and 8 h after IFO (400mg/kg, i.p.). Gingerols (25 mg/kg, p.o.) were given 1 h before and 4 and 8 h after IFO. Animals were euthanized 12 h after IFO injection. Bladders were submitted to macroscopic and histological evaluation. Oxidative stress and inflammation were assessed by malondialdehyde (MDA) or myeloperoxidase assays, respectively. mRNA gene expression was performed to evaluate mesna and gingerols mechanisms of action. Mesna was able to protect bladder tissue by activating NF-κB and NrF2 pathways. However, we demonstrated that gingerols acted as an antioxidant and anti-inflammatory agent stimulating the expression of IL-10, which intracellularly activates JAK/STAT/FOXO signaling pathway.
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Funding
Stipend was provided to Francisco C. S. Ferreira funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
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Francisco C. S. Ferreira: conceptualization, data curation, formal analysis, investigation, methodology, project administration, manuscript writing original draft. Marco Clementino: conceptualization, data curation, formal analysis, investigation, manuscript writing original draft, review, and editing. Francisco A. P. Rodrigues, Herlice N. Veras, Dainesy S. Martins, Marcus L. Queiroga, Mikael A. Lima, Dayara O. Silva, Thiago M. de Freitas, Samilly A. Ribeiro, Mario R. L. Mota: formal analysis, methodology, validation, data curation. James A. da Silva, Aldo A. M. Lima: conceptualization, project supervision, investigation, manuscript review and editing. Alexandre Havt: conceptualization, data curation, formal analysis, investigation, methodology, project administration, manuscript writing original draft, review and editing, funding acquisition.
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Experiments were carried out in accordance with the norms of the Brazilian National Council for the Control of Animal Experiments (CONCEA) and approved by the Ethics Committee on Animal of the Federal University of Ceará, Fortaleza, Brazil (protocol 34/2016).
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Ferreira, F.C.S., Clementino, M., Rodrigues, F.A.P. et al. [8] and [10]-Gingerol reduces urothelial damage in ifosfamide-induced hemorrhagic cystitis via JAK/STAT/FOXO signaling pathway via IL-10. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1773–1786 (2023). https://doi.org/10.1007/s00210-023-02436-2
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DOI: https://doi.org/10.1007/s00210-023-02436-2