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Current Gene Therapy

Author(s): Zhiwei Miao, Mingjia Gu, Faisal Raza*, Hajra Zafar, Jianyi Huang, Yuhang Yang, Muhammad Sulaiman, Jing Yan* and Yi Xu*

DOI: 10.2174/1566523223666230731115236

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Isoliquiritin Ameliorates Ulcerative Colitis in Rats through Caspase 3/HMGB1/TLR4 Dependent Signaling Pathway

Page: [73 - 92] Pages: 20

  • * (Excluding Mailing and Handling)

Abstract

Background: Isoliquiritin belongs to flavanol glycosides and has a strong antiinflammatory activity. This study sought to investigate the anti-inflammatory effect of isoliquiritin and its underlying mechanism.

Methods: The inflammatory (trinitro-benzene-sulfonic acid-TNBS-induced ulcerative colitis (UC)) model was established to ascertain the effect of isoliquiritin on the caspase-3/HMGB1/TLR4 pathway in rats. We also explored its protective effect on intestinal inflammation and its underlying mechanism using the LPS-induced inflammation model of Caco-2 cells. Besides, Deseq2 was used to analyze UCassociated protein levels.

Results: Isoliquiritin treatment significantly attenuated shortened colon length (induced by TNBS), disease activity index (DAI) score, and body weight loss in rats. A decrease in the levels of inflammatory mediators (IL-1β, I IL-4, L-6, IL-10, PGE2, and TNF-α), coupled with malondialdehyde (MDA) and superoxide dismutase (SOD), was observed in colon tissue and serum of rats after they have received isoliquiritin. Results of techniques (like western blotting, real-time PCR, immunohistochemistry, and immunofluorescence-IF) demonstrated the potential of isoliquiritin to decrease expressions of key genes in the TLR4 downstream pathways, viz., MyD88, IRAK1, TRAF6, NF-κB, p38, and JNK at mRNA and protein levels as well as inhibit HMGB1 expression, which is the upstream ligand of TLR4. Bioinformational analysis showed enteritis to be associated with a high expression of HMGB1, TLR4, and caspase-3.

Conclusion: Isoliquiritin could reduce intestinal inflammation and mucosal damage of TNBS-induced colitis in rats with a certain anti-UC effect. Meanwhile, isoliquiritin treatment also inhibited the expression of HMGB1, TLR4, and MyD88 in LPS-induced Caco-2 cells. These results indicated that isoliquiritin could ameliorate UC through the caspase-3/HMGB1/TLR4-dependent signaling pathway.

Graphical Abstract

[1]
Lee HJ, Song HJ, Jeong JH, Kim HU, Boo SJ, Na SY. Ophthalmologic manifestations in patients with inflammatory bowel disease. Intest Res 2017; 15(3): 380-7.
[http://dx.doi.org/10.5217/ir.2017.15.3.380] [PMID: 28670235]
[2]
Czompa L, Barta Z, Ziad H, et al. Corneal manifestations of inflammatory bowel disease. Semin Ophthalmol 2019; 34(7-8): 543-50.
[http://dx.doi.org/10.1080/08820538.2019.1684525] [PMID: 31657260]
[3]
Ciobica A, Balmus IM, Trifan A, Stanciu C. The implications of oxidative stress and antioxidant therapies in Inflammatory Bowel Disease: Clinical aspects and animal models. Saudi J Gastroenterol 2016; 22(1): 3-17.
[http://dx.doi.org/10.4103/1319-3767.173753] [PMID: 26831601]
[4]
Su H, Kang Q, Wang H, et al. Changes in expression of p53 and inflammatory factors in patients with ulcerative colitis. Exp Ther Med 2019; 17(4): 2451-6.
[PMID: 30906432]
[5]
Gilmour SM, Chait P, Phillips MJ, Roberts EA. Ulcerative colitis, autoimmune hemolytic anemia and primary sclerosing cholangitis in a child. Can J Gastroenterol 1996; 10(5): 301-3.
[http://dx.doi.org/10.1155/1996/762589]
[6]
Guinet-Charpentier C, Champigneulle J, Williet N, Peyrin-Biroulet L, Morali A. The association of autoimmune diseases with pediatric ulcerative colitis does not influence its disease course. Scand J Gastroenterol 2016; 51(1): 33-40.
[http://dx.doi.org/10.3109/00365521.2015.1058415] [PMID: 26152794]
[7]
Sung J, Sim C, Ock M, Oh I, Jeong K, Yoo C. Comparison of a 10-year cumulative age-standardized incidence rate of lung cancer among metropolitan cities in Korea (During the 2000–2009 period): Review of occupational and environmental hazards associated with lung cancer. Int J Environ Res Public Health 2018; 15(6): 1259.
[http://dx.doi.org/10.3390/ijerph15061259] [PMID: 29899316]
[8]
Turhal NS. Savaş B, Çoşkun Ö, et al. Prevalence of K-Ras mutations in hepatocellular carcinoma: A Turkish Oncology Group pilot study. Mol Clin Oncol 2015; 3(6): 1275-9.
[http://dx.doi.org/10.3892/mco.2015.633] [PMID: 26807232]
[9]
Wang YY, Zhao SH, Zheng CX, et al. Research progress of Huangqin Decoction in the treatment of ulcerative colitis. Elect J Clinic Med Literat 2019; 6(85): 69-70.
[10]
Casas R, Sacanella E, Estruch R. The immune protective effect of the Mediterranean diet against chronic low-grade inflammatory diseases. Endocr Metab Immune Disord Drug Targets 2014; 14(4): 245-54.
[http://dx.doi.org/10.2174/1871530314666140922153350] [PMID: 25244229]
[11]
Yang X. Relationship between Helicobacter pylori and Rosacea: Review and discussion. BMC Infect Dis 2018; 18(1): 318.
[http://dx.doi.org/10.1186/s12879-018-3232-4] [PMID: 29996790]
[12]
Enyuan HU, Min Z, Jianming X, et al. The relationship between chronic stress and cortisol levels in patients with coronary heart disease. Adv Cardiovas Dis 2017; 38(01): 94-7.
[13]
Taylor KD, Rotter JI, Elson CO, et al. Characterization of the CBir1 antigenic response for diagnosis and treatment of Crohn’s disease. WO2008141148A3, 2013.
[14]
Yanai H, Ben-Shachar S, Baram L, et al. P655 Gene expression alterations suggest that ulcerative colitis patients after restorative proctocolectomy have ileal disease. J Crohn’s Colitis 2014; 8(5): S343-4.
[http://dx.doi.org/10.1016/S1873-9946(14)60774-1]
[15]
Zhao WC, Liu YD, Sha L. Progress in researches on immune mechanism of ulcerative colitis. Medical Recapitulate 2018; 24(22): 7.
[16]
Van Deventer SJH. Review article: Targeting TNFα as a key cytokine in the inflammatory processes of Crohn’s disease - the mechanisms of action of infliximab. Aliment Pharmacol Ther 1999; 13(4) (Suppl. 4): 3-8.
[http://dx.doi.org/10.1046/j.1365-2036.1999.00024.x] [PMID: 10597333]
[17]
Sohun M, Shen H. The implication and potential applications of high-mobility group box 1 protein in breast cancer. Ann Transl Med 2016; 4(11): 217.
[http://dx.doi.org/10.21037/atm.2016.05.36] [PMID: 27386491]
[18]
Zherebiatiev A, Kamyshnyi A. Expression levels of proinflammatory cytokines and NLRP3 inflammasome in an experimental model of oxazolone-induced colitis. Iran J Allergy Asthma Immunol 2016; 15(1): 39-45.
[PMID: 26996110]
[19]
Chi Z, Wang Z, Liang Q, Zhu Y, Du Q. Induction of cytokine production in cholesteatoma keratinocytes by extracellular high-mobility group box chromosomal protein 1 combined with DNA released by apoptotic cholesteatoma keratinocytes. Mol Cell Biochem 2015; 400(1-2): 189-200.
[http://dx.doi.org/10.1007/s11010-014-2275-0] [PMID: 25416861]
[20]
Li Y, Gan C, Zhang S, et al. FIP200 is involved in murine pseudomonas infection by regulating HMGB1 intracellular translocation. Cell Physiol Biochem 2014; 33(6): 1733-44.
[http://dx.doi.org/10.1159/000362954] [PMID: 24923305]
[21]
Tracey K, Parrish W. Methods for treating conditions mediated by the inflammatory cytokine cascade using GAPDH inhibitors. US8715658B2, 2012.
[22]
Sevindik HG, Güvenalp Z. Karadayı M. Antimutagenic potentials of flavonoids from Achillea millefolium L. subsp. millefolium. Planta Medica 2016; 81(S 01): S1-S381.
[23]
Zhang XD, Zhou S, Yin YC, et al. Analysis on the correlation between chalcone synthase gene polymorphism and content of liquiritin in licorice. Yao Xue Xue Bao 2018; 53(4): 13.
[24]
Lee BH, Choi HS, Hong J. Roles of anti- and pro-oxidant potential of cinnamic acid and phenylpropanoid derivatives in modulating growth of cultured cells. Food Sci Biotechnol 2022; 31(4): 463-73.
[http://dx.doi.org/10.1007/s10068-022-01042-x] [PMID: 35464248]
[25]
Kuang PX, Bu YY. Anti-tumor effect and apoptosis mechanism of isoliquiritin. Central South Pharmacy 2015; 8: 5.
[26]
Yu C, Zhang Y, Gao KX, et al. Serotonergically dependent antihyperalgesic and antiallodynic effects of isoliquiritin in a mouse model of neuropathic pain. Eur J Pharmacol 2020; 881: 173184.
[http://dx.doi.org/10.1016/j.ejphar.2020.173184] [PMID: 32417324]
[27]
Liu Y, Xu X, Xu R, Zhang S. Renoprotective effects of isoliquiritin against cationic bovine serum albumin-induced membranous glomerulonephritis in experimental rat model through its anti-oxidative and anti-inflammatory properties. Drug Des Devel Ther 2019; 13: 3735-51.
[http://dx.doi.org/10.2147/DDDT.S213088] [PMID: 31802848]
[28]
Quaglio AEV, Castilho ACS, Di Stasi LC. Experimental evidence of heparanase, Hsp70 and NF-κB gene expression on the response of anti-inflammatory drugs in TNBS-induced colonic inflammation. Life Sci 2015; 141: 179-87.
[http://dx.doi.org/10.1016/j.lfs.2015.09.023] [PMID: 26434698]
[29]
Piovezani RG, Kane S. Alcohol use in patients with inflammatory bowel disease. Gastroenterol Hepatol 2021; 17(5): 211-25.
[PMID: 34924888]
[30]
Cannon AR, Kuprys PV, Cobb AN, et al. Alcohol enhances symptoms and propensity for infection in inflammatory bowel disease patients and a murine model of DSS-induced colitis. J Leukoc Biol 2018; 104(3): 543-55.
[http://dx.doi.org/10.1002/JLB.4MA1217-506R] [PMID: 29775230]
[31]
Suzuki T, Mizoshita T, Tanida S, et al. The efficacy of maintenance therapy after remission induction with tacrolimus in ulcerative colitis with and without previous tumor necrosis factor‐α inhibitor. JGH Open 2019; 3(3): 217-23.
[http://dx.doi.org/10.1002/jgh3.12140] [PMID: 31276039]
[32]
Wu YP, Meng XS, Bao YR, Wang S. Pharmacokinetic study of four flavones of Glycyrrhiza in rat plasma using HPLC–MS. J Ethnopharmacol 2013; 148(1): 266-70.
[http://dx.doi.org/10.1016/j.jep.2013.04.024] [PMID: 23643543]
[33]
Li YY, Jiang ZZ, Zhang L, et al. Characterization of metabolites of liquirtigenin in rats by uplc-q-tof/ms. Tianjin J Tradit Chin Med 2015; 32: 757-62.
[34]
Oteiza PI, Fraga CG, Mills DA, Taft DH. Flavonoids and the gastrointestinal tract: Local and systemic effects. Mol Aspects Med 2018; 61: 41-9.
[http://dx.doi.org/10.1016/j.mam.2018.01.001] [PMID: 29317252]
[35]
Li Y, Song W, Tong Y, et al. Isoliquiritin ameliorates depression by suppressing NLRP3-mediated pyroptosis via miRNA-27a/SYK/NF-κB axis. J Neuroinflammation 2021; 18(1): 1.
[http://dx.doi.org/10.1186/s12974-020-02040-8] [PMID: 33402173]
[36]
Li W, Zhao T, Wu D, et al. Colorectal cancer in ulcerative colitis: mechanisms, surveillance and chemoprevention. Curr Oncol 2022; 29(9): 6091-114.
[http://dx.doi.org/10.3390/curroncol29090479] [PMID: 36135048]
[37]
Tang Q, Tang QL. Effect of isoliquiritin on wound healing in scalded rats. Pak J Zool 2013; 53(3): 1161-4.
[38]
Nakase H, Sato N, Mizuno N, Ikawa Y. The influence of cytokines on the complex pathology of ulcerative colitis. Autoimmun Rev 2022; 21(3): 103017.
[http://dx.doi.org/10.1016/j.autrev.2021.103017] [PMID: 34902606]
[39]
Moradi-Marjaneh R, Hassanian SM, Hasanzadeh M, et al. Therapeutic potential of toll‐like receptors in treatment of gynecological cancers. IUBMB Life 2019; 71(5): 549-64.
[http://dx.doi.org/10.1002/iub.2011] [PMID: 30729633]
[40]
Katare PB, Nizami HL, Paramesha B, Dinda AK, Banerjee SK. Activation of toll like receptor 4 (TLR4) promotes cardiomyocyte apoptosis through SIRT2 dependent p53 deacetylation. Sci Rep 2020; 10(1): 19232.
[http://dx.doi.org/10.1038/s41598-020-75301-4] [PMID: 33159115]
[41]
Cari L, Rosati L, Leoncini G, et al. Association of GILZ with MUC2, TLR2, and TLR4 in Inflammatory Bowel Disease. Int J Mol Sci 2023; 24(3): 2235.
[http://dx.doi.org/10.3390/ijms24032235] [PMID: 36768553]
[42]
Donaldson GP, Lee SM, Mazmanian SK. Gut biogeography of the bacterial microbiota. Nat Rev Microbiol 2016; 14(1): 20-32.
[http://dx.doi.org/10.1038/nrmicro3552] [PMID: 26499895]
[43]
Yang A, Fan H, Zhao Y, et al. An immune-stimulating proteoglycan from the medicinal mushroom Huaier up-regulates NF-κB and MAPK signaling via Toll-like receptor 4. J Biol Chem 2019; 294(8): 2628-5268.
[http://dx.doi.org/10.1074/jbc.RA118.005477] [PMID: 30602571]
[44]
Feng Y, Cui Y, Gao JL, et al. Resveratrol attenuates neuronal autophagy and inflammatory injury by inhibiting the TLR4/NF-κB signaling pathway in experimental traumatic brain injury. Int J Mol Med 2016; 37(4): 921-30.
[http://dx.doi.org/10.3892/ijmm.2016.2495] [PMID: 26936125]
[45]
Aldapa-Vega G, Moreno-Eutimio MA, Berlanga-Taylor AJ, et al. Structural variants of Salmonella Typhimurium lipopolysaccharide induce less dimerization of TLR4/MD-2 and reduced pro-inflammatory cytokine production in human monocytes. Mol Immunol 2019; 111: 43-52.
[http://dx.doi.org/10.1016/j.molimm.2019.03.003] [PMID: 30959420]
[46]
Dunne A, Carpenter S, Brikos C, et al. IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). J Biol Chem 2010; 285(24): 18276-82.
[http://dx.doi.org/10.1074/jbc.M109.098137] [PMID: 20400509]
[47]
O’Neill LAJ, Golenbock D, Bowie AG. The history of Toll-like receptors — redefining innate immunity. Nat Rev Immunol 2013; 13(6): 453-60.
[http://dx.doi.org/10.1038/nri3446] [PMID: 23681101]
[48]
Park JS, Svetkauskaite D, He Q, et al. Involvement of TLR2 and TLR4 in cellular activation by high mobility group box 1 protein (HMGB1). J Biol Chem 2004; 279(9): 7370-7.
[http://dx.doi.org/10.1074/jbc.M306793200] [PMID: 14660645]
[49]
Vitali R, Palone F, Cucchiara S, et al. Dipotassium glycyrrhizate inhibits HMGB1-dependent inflammation and ameliorates colitis in mice. PLoS One 2013; 8(6): e66527.
[http://dx.doi.org/10.1371/journal.pone.0066527] [PMID: 23840500]
[50]
Ding HS, Yang J, Chen P, et al. The HMGB1–TLR4 axis contributes to myocardial ischemia/reperfusion injury via regulation of cardiomyocyte apoptosis. Gene 2013; 527(1): 389-93.
[http://dx.doi.org/10.1016/j.gene.2013.05.041] [PMID: 23727604]