[Diosmetin regulates intestinal immune balance by inhibiting PI3K/AKT signaling to relieve 2, 4, 6-trinitrobenzene sulfonic acid-induced Crohn's disease-like colitis in mice].

Abstract

OBJECTIVE:

To investigate the therapeutic mechanism of diosmetin on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced Crohn's disease (CD)-like colitis in mice.

METHODS:

Wild-type C57BL/6 mice were randomized into control group, TNBS-induced CD-like colitis group (TNBS group) and 50 mg·kg-1·d-1 diosmetin-treated group (n=8). Disease activity (DAI) scores, body weight changes, histological scores, colon lengths and colon mucosal levels of TNF-α, IFN-γ, and IL-17A were measured to evaluate the severity of colitis. The changes of T lymphocyte subsets (Th1/Th2 and Th17/Treg) in the mesenteric lymph nodes were analyzed by flow cytometry. Network pharmacology and molecular docking were used to analyze the effect of diosmetin on PI3K/AKT pathway.

RESULTS:

Compared with TNBS group, diosmetin treatment significantly lowered DAI scores, histological scores, body weight loss and colon mucosal levels of TNF-α, IFN-γ, and IL-17A (P < 0.05) and increased the colon length of the rat models, but these improvements did not reach the control levels (P < 0.05). Diosmetin significantly lowered the percentages of Th1/Th17 cells in the mesenteric lymph nodes in TNBS-treated mice, which remained higher than the control levels (P < 0.05); The percentages of Th2/Treg cells were significantly higher in diosmetin group than in TNBS group (P < 0.05) and the control group (P < 0.05). Network pharmacologic analysis identified 46 intersection targets of diosmetin and CD, and among them AKT1, EGFR, SRC, ESR1, MMP9 and PTGS2 were the top 6 core targets. GO and KEGG analyses showed that the PI3K/AKT signaling pathway was closely related with the therapeutic effect of diosmetin on CD-like colitis. Molecular docking suggested strong binding of diosmetin to the key core targets. Diosmetin significantly reduced the levels of p-PI3K and p-AKT in the colon mucosa in TNBS-treated mice (P < 0.05), but their levels remained higher than those in the control group (P < 0.05).

CONCLUSION:

Diosmetin ameliorates TNBS-induced CDPlike colitis in mice possibly by regulating Th1/Th2 and Th17/Treg balance to improve intestinal immune disorder through inhibition of PI3K/AKT signaling.

• Authors: Z Yang, T Zhao, Y Cheng, Y Zhou, Y Li, X Wang, X Zhang, L Zuo, S Ge
• Journal: Nan fang yi ke da xue xue bao = Journal of Southern Medical University (Nan Fang Yi Ke Da Xue Xue Bao) Vol. 43 Issue 3 Pg. 474-482 (Mar 20 2023) ISSN: 1673-4254 [Print] China
• PMID: 37087594 (Publication Type: English Abstract, Journal Article)

Chemical References

• Cytokines
• diosmetin
• Interleukin-17
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Trinitrobenzenesulfonic Acid
• Tumor Necrosis Factor-alpha
• Flavonoids

Topics

• Animals
• Mice
• Rats
• Colitis (chemically induced, drug therapy)
• Colon (metabolism)
• Crohn Disease (drug therapy)
• Cytokines (metabolism)
• Disease Models, Animal
• Interleukin-17 (metabolism)
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Molecular Docking Simulation
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Trinitrobenzenesulfonic Acid (adverse effects, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Flavonoids (pharmacology)
• Intestines (immunology)