Salidroside protects against intestinal barrier dysfunction in septic mice by regulating IL‑17 to block the NF‑κB and p38 MAPK signaling pathways

Abstract

Sepsis is a systemic inflammatory response syndrome, mainly caused by infection or suspected infectious factors. The intestine is not only one of the most easily involved organs in the course of sepsis, but also the dynamic organ for the course of sepsis. The present study investigated the protective effect and mechanism of salidroside on intestinal barrier dysfunction of septic mice. Briefly, C57BL/6 mice were used to establish a septic model and then administered with salidroside. The ileum tissues of mice were examined by histopathological examination. Fluorescein isothiocyanate-dextran concentration was measured. IL-17, IL-6, IL-13 and TNF-α levels in ileum tissues and NF-κB and p38 MAPK activations were detected by ELISA and the expressions of NF-κB p65 and p38 MAPK protein with their phosphorylation and intestinal tight junction proteins were gauged by western blotting. The above assays were performed again to investigate the effect of anti-IL-17A and salidroside (160 mg/kg) alone or in combination. The septic model induced the ileum tissue injury, increased intestinal permeability and TNF-α, IL-17 and IL-6 levels, activated NF-κB and p38 MAPK pathways, promoted the expressions of NF-κB p65 and p38 MAPK and their phosphorylation, while suppressing the levels of IL-13 and intestinal tight junction proteins. Salidroside and anti-IL-17A partially reversed the above effects of septic model, which in combination further strengthened the reversing effect. Collectively, salidroside protected against intestinal barrier dysfunction in septic mice by downregulating IL-17 level to inhibit NF-κB and p38 MAPK signaling pathways, thus providing a new treatment direction.

Salidroside ameliorated the pulmonary inflammation induced by cigarette smoke via mitigating M1 macrophage polarization by JNK/c‐Jun

“…Salidroside treatment inhibited the activation of M1 polarization of AMs and decreased the phosphorylation level of JNK caused by CSE, which might indicate that salidroside ameliorated the M1 polarization via JNK. However, JNK might not be the only target of salidroside to improve COPD, which could be reflected by the following aspects: (1) Compared with the CSE + salidroside group, anisomycin treatment only partly offset the effects of salidroside on decreasing M1 polarization markers (Jiang et al, 2022); (2) It was reported that salidroside could modulate some classical inflammatory pathways, like NF‐κB and P38 (Liao et al, 2023). To verify our speculation, we knocked down JNK in Raw264.7 cells, and found that salidroside treatment could still inhibit M1 polarization by CSE when JNK was knocked down, whereas knocking down JNK could not further inhibit M1 polarization induced by CSE under the treatment of salidroside.…”

Identifying the active compounds and mechanism of action of TongFu XieXia Decoction for treating intestinal obstruction using network pharmacology combined with ultra‐high performance liquid chromatography‐quadrupole‐orbitrap mass spectrometry

“…The PI3K/Akt signaling pathway, a master regulator of downstream substrates such as NF‐κB, CREB, P53, and mTOR, plays a crucial role in regulating inflammation, metabolism, and immunity 44 . Recent studies have demonstrated that activation of the PI3K/Akt pathway can reduce intestinal inflammation severity while promoting the proliferation of intestinal epithelial cells 45,46 . This effect is mediated by upstream activators such as IGF1, EGFR, and AKT2.…”

“…In summary, the active components of TFXXD may exert their effects through anti‐inflammatory and antioxidative stress, regulation of GI motility, and protection of the intestinal mucosa, among other mechanisms 38–51 …”

“…44 Recent studies have demonstrated that activation of the PI3K/Akt pathway can reduce intestinal inflammation severity while promoting the proliferation of intestinal epithelial cells. 45,46 This effect is mediated by upstream activators as IGF1, EGFR, and AKT2.…”

Effects of salidroside on atherosclerosis: potential contribution of gut microbiota

“…This reversal of protein expression helps to prevent intestinal damage and protect the intestinal mucosal barrier during sepsis. The mechanism by which Salidroside achieves this protective effect is through regulating IL-17 levels, which in turn blocks the NF-κB and p38 MAPK signaling pathways ( Liao et al, 2023 ). In LPS-activated intestinal epithelial cells, salidroside could suppress the secretion of pro-inflammatory cytokine IL-6 through attenuating the NF-κB, MAPK, and JAK-STAT3 signaling pathways ( Wang et al, 2019 ).…”