α-Cyperone Antagonizes Intestinal Mucosal Inflammatory Response Through Modulation of TLR4/NF-κB Signaling Pathway to Alleviate Crohn's Disease-Like Colitis in Mice

ZHANG Nuo, ZHANG Min, SONG Xue, ZHANG Xiaofeng, GENG Zhijun, WANG Lian, GE Sitang, LI Jing, ZUO Luge

Abstract

To investigate the effect and potential mechanisms of α-cyperone (CYP) on Crohn's disease (CD) -like colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) in mice.

Methods 

The mice were randomly and evenly divided into wild type (WT), TNBS, CYP and 5-aminosalicylic acid (5-ASA) groups, with 10 mice in each group. The symptoms of enteritis, the function and structure of the intestinal barrier, and the expression levels of inflammatory factors, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and gamma-interferon (IFN-γ), in the colon were assessed. The lipopolysaccharide (LPS)-induced inflammation model of Caco2 cells was constructed and the cells were divided into Control, LPS and LPS+CYP groups. The expression levels of tight junction protein and inflammatory factors in each group were assessed. Gene Ontology (GO) functional enrichment analysis was conducted to predict the possible pathways of action and potential molecular mechanisms of CYP, and to verify them in vivo and in vitro.

Results 

In the in vivo study, compared with those of the TNBS group, the body mass and colon length of mice in the CYP group and the 5-ASA group were significantly increased, while the disease activity scores and histological inflammation scores were significantly decreased (P<0.05). The level of lucifcein-glucan isothiocyanate and the bacterial translocation rate (in the liver, the spleen, and mesenteric lymph nodes) were significantly decreased, while the transepithelial electric resistance (TEER) value and the expression levels of zonula occluden protein-1 (ZO-1), and claudin-1 were significantly increased (P<0.05). The expression of inflammatory factors was significantly decreased (P<0.05). In the in vitro study, compared with those of the LPS group, the TEER value and the expression of ZO-1 and claudin-1 in the Caco2 cells in the LPS+CYP group were significantly increased (P<0.05). The expression of inflammatory factors was significantly decreased (P<0.05). Enrichment analysis showed that CYP was correlated with inflammatory response (P<0.001). Western blot results showed that CYP could significantly reduce the expression of key proteins in toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway in vivo and in vitro (P<0.05).

Conclusion 

CYP may protect the intestinal barrier by antagonizing the inflammatory response of the intestinal mucosa through regulating the expression of the TLR4/NF-κB signaling pathway, thereby alleviating TNBS-induced CD-like colitis in mice.

 

Keywords: Crohn's disease, Colitis, α-Cyperone, Intestinal mucosal barrier, TLR4/NF-κB

 

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References


TORRES J, MEHANDRU S, COLOMBEL J F, et al. Crohn's disease. Lancet, 2017, 389(10080): 1741–1755. doi: 10.1016/S0140-6736(16)31711-1.

PETAGNA L, ANTONELLI A, GANINI C, et al. Pathophysiology of Crohn's disease inflammation and recurrence. Biol Direct, 2020, 15(1): 23. doi: 10.1186/s13062-020-00280-5.

DOLINGER M, TORRES J, VERMEIRE S. Crohn's disease. Lancet, 2024, 403(10432): 1177–1191. doi: 10.1016/S0140-6736(23)02586-2.

XU L, HE B, SUN Y, et al. Incidence of inflammatory bowel disease in urban China: a nationwide population-based study. Clin Gastroenterol Hepatol, 2023, 21(13): 3379–3386.e29. doi: 10.1016/j.cgh.2023.08.013.

BRETTO E, RIBALDONE D G, CAVIGLIA G P, et al. Inflammatory bowel disease: emerging therapies and future treatment strategies. Biomedicines, 2023, 11(8): 2249. doi: 10.3390/biomedicines11082249.

WEN H, ZHANG X, LI Q, et al. Ruscogenins improve CD-like enteritis by inhibiting apoptosis of intestinal epithelial cells and activating Nrf2/NQO1 pathway. Oxid Med Cell Longev, 2022, 2022: 4877275. doi: 10.1155/2022/4877275.

HENDRICKSON B A, GOKHALE R, CHO J H. Clinical aspects and pathophysiology of inflammatory bowel disease. Clin Microbiol Rev, 2002, 15(1): 79–94. doi: 10.1128/CMR.15.1.79-94.2002.

QIAO N, WANG Q, TAO Y, et al. α-Cyperone ameliorates depression in mammary gland hyperplasia and chronic unpredictable mild stress rat by regulating hormone, inflammation, and oxidative stress. Immunopharmacol Immunotoxicol, 2023, 45(1): 73–82. doi: 10.1080/ 08923973.2022.2115925.

PAN S, ZHANG Z, FENG Q, et al. An efficient high-speed counter-current chromatography method for the preparative separation of sesquiterpenoids from the rhizomes of Cyperus rotundus L. combined with evaluation of the anti-inflammation activity in vitro and molecular docking. J Sep Sci, 2023, 46(10): e2300042. doi: 10.1002/jssc.202300042.

HUANG B, HE D, CHEN G, et al. α-Cyperone inhibits LPS-induced inflammation in BV-2 cells through activation of Akt/Nrf2/HO-1 and suppression of the NF-κB pathway. Food Funct, 2018, 9(5): 2735–2743. doi: 10.1039/c8fo00057c.

DENG M, XIE P, LIU J, et al. α-Cyperone improves rat spinal cord tissue damage via Akt/Nrf2 and NF-κB pathways. J Surg Res, 2022, 276: 331–339. doi: 10.1016/j.jss.2022.02.006.

HUANG B, HU G, ZONG X, et al. α-Cyperone protects dopaminergic neurons and inhibits neuroinflammation in LPS-induced Parkinson's disease rat model via activating Nrf2/HO-1 and suppressing NF-κB signaling pathway. Int Immunopharmacol, 2023, 115: 109698. doi: 10. 1016/j.intimp.2023.109698.

SPENCER D M, VELDMAN G M, BANERJEE S, et al. Distinct inflammatory mechanisms mediate early versus late colitis in mice. Gastroenterology, 2002, 122(1): 94–105. doi: 10.1053/gast.2002.30308.

YANG Z, ZHAO T H, CHENG Y, et al. 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. J South Med Univ, 2023, 43(3): 474–482. doi: 10.12122/j.issn.1673-4254. 2023.03.19.

KATSANDEGWAZA B, HORSNELL W, SMITH K. Inflammatory bowel disease: a review of pre-clinical murine models of human disease. Int J Mol Sci, 2022, 23(16): 9344. doi: 10.3390/ijms23169344.

TAVARES JUNIOR A G, De ARAÚJO J, MENEGUIN A B, et al. Characteristics, properties and analytical/bioanalytical methods of 5-Aminosalicylic acid: a review. Crit Rev Anal Chem, 2022, 52(5): 1000–1014. doi: 10.1080/10408347.2020.1848516.

LIU X, JIN X, YU D, et al. Suppression of NLRP3 and NF-κB signaling pathways by α-Cyperone via activating SIRT1 contributes to attenuation of LPS-induced acute lung injury in mice. Int Immunopharmacol, 2019, 76: 105886. doi: 10.1016/j.intimp.2019.105886.

WANG K, WU L Y, DOU C Z, et al. Research advance in intestinal mucosal barrier and pathogenesis of Crohn's disease. Gastroenterol Res Pract, 2016, 2016: 9686238. doi: 10.1155/2016/9686238.

ZHOU L, ZHU L, WU X, et al. Decreased TMIGD1 aggravates colitis and intestinal barrier dysfunction via the BANF1-NF-κB pathway in Crohn's disease. BMC Med, 2023, 21(1): 287. doi: 10.1186/s12916-023-02989-2.

YUAN S N, WANG M X, HAN J L, et al. Improved colonic inflammation by nervonic acid via inhibition of NF-κB signaling pathway of DSS-induced colitis mice. Phytomedicine, 2023, 112: 154702. doi: 10.1016/j. phymed.2023.154702.

GHEZZAL S, POSTAL B G, QUEVRAIN E, et al. Palmitic acid damages gut epithelium integrity and initiates inflammatory cytokine production. Biochim Biophys Acta Mol Cell Biol Lipids, 2020, 1865(2): 158530. doi: 10.1016/j.bbalip.2019.158530.

QIU S, LI P, ZHAO H, et al. Maresin 1 alleviates dextran sulfate sodium-induced ulcerative colitis by regulating NRF2 and TLR4/NF-kB signaling pathway. Int Immunopharmacol, 2020, 78: 106018. doi: 10.1016/j.intimp. 2019.106018.

CHEN Z, TANG J, WANG P, et al. GYY4137 attenuates sodium deoxycholate-induced intestinal barrier injury both in vitro and in vivo. Biomed Res Int, 2019, 2019: 5752323. doi: 10.1155/2019/5752323.

DEJBAN P, NIKRAVANGOLSEFID N, CHAMANARA M, et al. The role of medicinal products in the treatment of inflammatory bowel diseases (IBD) through inhibition of TLR4/NF-kappaB pathway. Phytother Res, 2021, 35(2): 835–845. doi: 10.1002/ptr.6866.

WANG J W, PAN Y B, CAO Y Q, et al. Loganin alleviates LPS-activated intestinal epithelial inflammation by regulating TLR4/NF-κB and JAK/STAT3 signaling pathways. Kaohsiung J Med Sci, 2020, 36(4): 257–264. doi: 10.1002/kjm2.12160.

XIN J. Critical signaling pathways governing colitis-associated colorectal cancer: Signaling, therapeutic implications, and challenges. Dig Liver Dis, 2023, 55(2): 169–177. doi: 10.1016/j.dld.2022.08.012.

YU C, WANG D, YANG Z, et al. Pharmacological effects of polyphenol phytochemicals on the intestinal inflammation via targeting TLR4/NF-κB signaling pathway. Int J Mol Sci, 2022, 23(13): 6939. doi: 10.3390/ijms23136939.

LI J, WU H, ZHOU J, et al. Ruscogenin attenuates ulcerative colitis in mice by inhibiting caspase-1-dependent pyroptosis via the TLR4/NF-κB signaling pathway. Biomedicines, 2024, 12(5): 989. doi: 10.3390/biomedicines12050989.


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