Inhibition of MAPK and STAT3-SOCS3 by Sakuranetin Attenuated Chronic Allergic Airway Inflammation in Mice

Abstract

Asthma allergic disease is caused by airway chronic inflammation. Some intracellular signaling pathways, such as MAPK and STAT3-SOCS3, are involved in the control of airway inflammation in asthma. The flavonoid sakuranetin demonstrated an anti-inflammatory effect in different asthma models. Our aim was to clarify how sakuranetin treatment affects MAPK and STAT3-SOCS3 pathways in a murine experimental asthma model. Mice were submitted to an asthma ovalbumin-induction protocol and were treated with vehicle, sakuranetin, or dexamethasone. We assayed the inflammatory profile, mucus production, and serum antibody, STAT3-SOCS3, and MAPK levels in the lungs. Morphological alterations were also evaluated in the liver. LPS-stimulated RAW 264.7 cells were used to evaluate the effects of sakuranetin on nitric oxide (NO) and cytokine production. In vivo, sakuranetin treatment reduced serum IgE levels, lung inflammation (eosinophils, neutrophils, and Th2/Th17 cytokines), and respiratory epithelial mucus production in ovalbumin-sensitized animals. Considering possible mechanisms, sakuranetin inhibits the activation of ERK1/2, JNK, p38, and STAT3 in the lungs. No alterations were found in the liver for treated animals. Sakuranetin did not modify in vitro cell viability in RAW 264.7 and reduced NO release and gene expression of IL-1β and IL-6 induced by LPS in these cells. In conclusion, our data showed that the inhibitory effects of sakuranetin on eosinophilic lung inflammation can be due to the inhibition of Th2 and Th17 cytokines and the inhibition of MAPK and STAT3 pathways, reinforcing the idea that sakuranetin can be considered a relevant candidate for the treatment of inflammatory allergic airway disease.

circRNA‑0006896‑miR1264‑DNMT1 axis plays an important role in carotid plaque destabilization by regulating the behavior of endothelial cells in atherosclerosis

“…Previous studies have documented that DNMT1 is a critical regulator of JNK, STAT, and NF-κB signaling during the development of UA because an increase DNMT1 expression results in CpG island hypermethylation in the promoter region of SOCS3, which downregulates its expression ( 28 ). Low expression of SOCS3 promotes JNK/STAT signaling, thus increasing the proliferation and migration of HUVECs ( 29 ), which in turn leads to plaque destabilization and promotes AS development ( 23 , 30 , 31 ). Thus, functional assays using HUVECs treated with UA or SA-Exos were carried out to explore the role of circRNA-0006896, miR-1264 and DNMT1 in AS development.…”

Pterocarpus mildbraedii(Harms) extract resolves propanil‐induced hepatic injury via repression of inflammatory stress responses in Wistar rats

“…Interestingly, PME alone and in combination with PRP further suppressed p38 MAPK induction, and this is an indication of their anti‐inflammatory effects. Previously, sakuranetin, a flavonoid obtained from Baccharis retusa , had been shown to inhibit the activation of p38MAPK and STAT‐3 in a murine experimental asthma model (Santana et al., 2019). The observed PME‐ mediated decrease in phosphorylation of STAT‐3 seemed to parallel p38 MAPK downregulation, correlating an earlier report that p38 MAPK is an upstream activator of STAT‐3 (Cheng et al., 2017).…”

A Review on Sources and Pharmacological Aspects of Sakuranetin

“…Santana et al clarified how sakuranetin treatment (in a dose of 20 mg/kg −1 / day; 10 µL intranasal) affects mitogen-activated protein kinases MAPKs and STAT3-SOCS3 pathways in a murine experimental asthma model [76]. Mice were submitted to an asthma ovalbumin-induction protocol and were treated with vehicle, sakuranetin, or dexamethasone.…”