[8] and [10]-Gingerol reduces urothelial damage in ifosfamide-induced hemorrhagic cystitis via JAK/STAT/FOXO signaling pathway via IL-10

Abstract

Acrolein is the main toxic metabolite of Ifosfamide (IFO) that causes urothelial damage by oxidative stress and in ammation. Here we investigate the molecular mechanism of action of gingerols, Zingiber o cinale 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 minutes before, 4 and 8 hours after IFO (400mg/kg, i.p.).Gingerols (25 mg/Kg, p.o.) were given 1 hour before and 4 and 8 hours after IFO. Animals were euthanized 12 hours after IFO injection. Bladders were submitted to macroscopic and histological evaluation. Oxidative stress and in ammation 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-in ammatory agent stimulating the production of IL-10, which intracellularly activated JAK/STAT/FOXO signaling pathway.

Chronic Critical Illness-Induced Muscle Atrophy: Insights From a Trauma Mouse Model and Potential Mechanism Mediated via Serum Amyloid A

“…5A). Among the 10 activated pathways, previous studies have shown that JAK2/STAT3 could activate the FOXO signaling pathway (43–45), and JAK2/STAT3 could be activated via RAGE (46). In addition, the FOXO signaling pathway has been proved to induce muscle atrophy in previous studies (47,48).…”

“…The above study identified the RAGE ligand, S100B, as a novel factor able to induce muscle atrophy via a p38 mitogen-activated protein kinase/myogenin axis and STAT3-dependent myoblast determination protein 1 degradation. Previous study has also shown that the activation of JAK2/STAT3 could induce muscle wasting (53), and previous studies also proved that JAK2/STAT3 was able to activate FOXO, thus leading to a series of subsequent biological processes, including muscle wasting (43), age-related disease (44), or reduction of urothelial damage in ifosfamide-induced hemorrhagic cystitis (45). Notably, as we have mentioned previously, RAGE is also one of important receptors for SAA (41,42).…”