Glycyrrhizic acid prevents enteritis through reduction of NF‑κB p65 and p38MAPK expression in rat

Wang,Yi‑Ming; Du,Guo‑Qiang

doi:10.3892/mmr.2016.4981

Glycyrrhizic acid prevents enteritis through reduction of NF‑κB p65 and p38MAPK expression in rat

Authors:
- Yi‑Ming Wang
- Guo‑Qiang Du
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Affiliations: Department of Pediatric Surgery, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
Published online on: March 7, 2016 https://doi.org/10.3892/mmr.2016.4981
Pages: 3639-3646

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Abstract

Glycyrrhizic acid has a variety of biological properties, including a protective function in the liver, and anti‑inflammatory, anti‑ulcer, anti‑anaphylaxis, anti‑oxidant, immunoregulatory, antiviral and anticancer activities. The efficacy of glycyrrhizic acid can be increased when combined with other medicines. In the present study, the potential protective effects of glycyrrhizic acid against enteritis in rats, and its role in regulating anti‑inflammation, anti‑oxidation, angiogenic and apoptotic mechanisms were investigated using enzyme‑linked immunosorbent and bicinchoninic acid assays, and reverse transcription‑quantitative polymerase chain reaction and western blotting analyses. Adult male Sprague‑Dawley rats were injected with 20 mg/kg methotrexate (MTX) to establish enteritis. Additionally, rats with MTX‑induced enteritis were peritoneally injected with 200 mg glycyrrhizic acid for 9 weeks. The current study demonstrated that glycyrrhizic acid could alleviate MTX‑induced increases of tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6 levels, and raise IL‑10 levels, in rats with enteritis. Treatment with glycyrrhizic acid significantly reduced D‑lactate and intercellular adhesion molecule‑1 gene expression (P<0.01), but did not inhibit diamine oxidase activity in MTX‑induced enteritis. Pretreatment with glycyrrhizic acid significantly suppressed the promotion of p38 mitogen‑activated protein kinase (p38MAPK), nuclear factor‑κB p65 (NF‑κB p65) protein expression, interferon‑γ protein concentration, and caspase‑3 and cycloxygenase‑2 activity in MTX‑induced enteritis (P<0.01). The findings of the current study suggest that glycyrrhizic acid may prevent enteritis by reducing NF‑κB p65 and p38MAPK expression levels, which may inform future therapeutic strategies for the treatment of enteritis.

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1	Takagi T, Naito Y, Okada H, Takaoka M, Oya-Ito T, Yamada S, Hirai Y, Mizushima K, Yoshida N, Kamada K, et al: Hemopexin is upregulated in rat intestinal mucosa injured by indomethacin. J Gastroenterol Hepatol. 27(Suppl 3): 70–75. 2012. View Article : Google Scholar : PubMed/NCBI
2	Kim H, Song MJ, Brian H and Choi K: A comparative analysis of ethnomedicinal practices for treating gastrointestinal disorders used by communities living in three national parks (Korea). Evid Based Complement Alternat Med. 2014:1080372014. View Article : Google Scholar : PubMed/NCBI
3	Stoidis CN, Misiakos EP, Patapis P, Fotiadis CI and Spyropoulos BG: Potential benefits of pro- and prebiotics on intestinal mucosal immunity and intestinal barrier in short bowel syndrome. Nutr Res Rev. 24:21–30. 2011. View Article : Google Scholar
4	Vandenbroucke RE, Dejonckheere E, Van Hauwermeiren F, Lodens S, De Rycke R, Van Wonterghem E, Staes A, Gevaert K, López-Otin C and Libert C: Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF. EMBO Mol Med. 5:932–948. 2013. View Article : Google Scholar : PubMed/NCBI
5	Zhang XP, Zhang J, Song QL and Chen HQ: Mechanism of acute pancreatitis complicated with injury of intestinal mucosa barrier. J Zhejiang Univ Sci B. 8:888–895. 2007. View Article : Google Scholar
6	Lin JE, Snook AE, Li P, Stoecker BA, Kim GW, Magee MS, Garcia AV, Valentino MA, Hyslop T, Schulz S and Waldman SA: GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity. PLoS One. 7:e316862012. View Article : Google Scholar : PubMed/NCBI
7	Vetrano S, Ploplis VA, Sala E, Sandoval-Cooper M, Donahue DL, Correale C, Arena V, Spinelli A, Repici A, Malesci A, et al: Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation. Proc Natl Acad Sci USA. 108:19830–19835. 2011. View Article : Google Scholar : PubMed/NCBI
8	Talukder JR, Boyd B, Griffin A, Jaima A and Rajendran VM: Inflammatory cytokine TNF-α inhibits Na(+)-glutamine cotransport in intestinal epithelial cells. Can J Physiol Pharmacol. 91:275–284. 2013. View Article : Google Scholar : PubMed/NCBI
9	Gao X, Wang W, Wei S and Li W: Review of pharmacological effects of Glycyrrhiza radix and its bioactive compounds. Zhongguo Zhong Yao Za Zhi. 34:2695–2700. 2009.In Chinese.
10	Asl MN and Hosseinzadeh H: Review of pharmacological effects of Glycyrrhiza sp and its bioactive compounds. Phytother Res. 22:709–724. 2008. View Article : Google Scholar : PubMed/NCBI
11	Isbrucker RA and Burdock GA: Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. Regul Toxicol Pharmacol. 46:167–192. 2006. View Article : Google Scholar : PubMed/NCBI
12	Shin EM, Zhou HY, Guo LY, Kim JA, Lee SH, Merfort I, Kang SS, Kim HS, Kim S and Kim YS: Anti-inflammatory effects of glycyrol isolated from Glycyrrhiza uralensis in LPS-stimulated RAW264.7 macrophages. Int Immunopharmacol. 8:1524–1532. 2008. View Article : Google Scholar : PubMed/NCBI
13	Franceschelli S, Pesce M, Vinciguerra I, Ferrone A, Riccioni G, Patruno A, Grilli A, Felaco M and Speranza L: Licocalchone-C extracted from Glycyrrhiza glabra inhibits lipopolysaccharide-interferon-γ inflammation by improving antioxidant conditions and regulating inducible nitric oxide synthase expression. Molecules. 16:5720–5734. 2011. View Article : Google Scholar : PubMed/NCBI
14	Sun D, Zhou M, Ying X, Cheng B, Han Y, Nie Y, Hou Y and Bai G: Identification of nuclear factor-kappaB inhibitors in the folk herb Rhizoma Menispermi via bioactivity-based ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry analysis. BMC Complement Altern Med. 14:3562014. View Article : Google Scholar
15	Mi Wi S, Park J, Shim JH, Chun E and Lee KY: Ubiquitination of ECSIT is crucial for the activation of p65/p50 NF-kappaBs in Toll-like receptor 4 signaling. Mol Biol Cell. 26:151–160. 2015. View Article : Google Scholar :
16	Chen R, Li M, Zhang Y, Zhou Q and Shu HB: The E3 ubiquitin ligase MARCH8 negatively regulates IL-1β-induced NF-κB activation by targeting the IL1RAP coreceptor for ubiquitination and degradation. Proc Natl Acad Sci USA. 109:14128–14133. 2012. View Article : Google Scholar
17	Yin H, Liu Z, Li F, Ni M, Wang B, Qiao Y, Xu X, Zhang M, Zhang J, Lu H and Zhang Y: Ginsenoside-Rg1 enhances angio-genesis and ameliorates ventricular remodeling in a rat model of myocardial infarction. J Mol Med (Berl). 89:363–375. 2011. View Article : Google Scholar
18	Park KR, Nam D, Yun HM, Lee SG, Jang HJ, Sethi G, Cho SK and Ahn KS: β-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Lett. 312:178–188. 2011. View Article : Google Scholar : PubMed/NCBI
19	Kim CK, Choi YK, Lee H, Ha KS, Won MH, Kwon YG and Kim YM: The farnesyltransferase inhibitor LB42708 suppresses vascular endothelial growth factor-induced angiogenesis by inhibiting ras-dependent mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signal pathways. Mol Pharmacol. 78:142–150. 2010. View Article : Google Scholar : PubMed/NCBI
20	Institute of Laboratory Animal Resources (US); Committee on Care Use of Laboratory Animals National Institutes of Health (US); Division of Research Resources: Guide for the care and use of laboratory animals. 8th edition. National Academies Press; Washington, DC: 2011
21	Wang ZH, Hsieh CH, Liu WH and Yin MC: Glycyrrhizic acid attenuated glycative stress in kidney of diabetic mice through enhancing glyoxalase pathway. Mol Nutr Food Res. 58:1426–1435. 2014. View Article : Google Scholar : PubMed/NCBI
22	Khan R, Khan AQ, Lateef A, Rehman MU, Tahir M, Ali F, Hamiza OO and Sultana S: Glycyrrhizic acid suppresses the development of precancerous lesions via regulating the hyper-proliferation, inflammation, angiogenesis and apoptosis in the colon of Wistar rats. PLoS One. 8:e560202013. View Article : Google Scholar
23	Wang ZX, Huang CY, Hua YP, Huang WQ, Deng LH and Liu KX: Dexmedetomidine reduces intestinal and hepatic injury after hepatectomy with inflow occlusion under general anaesthesia: A randomized controlled trial. Br J Anaesth. 112:1055–1064. 2014. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-tie quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
25	Best SM, Wolfinbarger JB and Bloom ME: Caspase activation is required for permissive replication of Aleutian mink disease parvovirus in vitro. Virology. 292:224–234. 2002. View Article : Google Scholar : PubMed/NCBI
26	Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, Bifulco G, Baldelli F, Donini A and Fiorucci S: The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS One. 6:e256372011. View Article : Google Scholar : PubMed/NCBI
27	Reynolds JM, Martinez GJ, Nallaparaju KC, Chang SH, Wang YH and Dong C: Cutting edge: Regulation of intestinal inflammation and barrier function by IL-17C. J Immunol. 189:4226–4230. 2012. View Article : Google Scholar : PubMed/NCBI
28	Bhattacharjee S, Bhattacharjee A, Majumder S, Majumdar SB and Majumdar S: Glycyrrhizic acid suppresses Cox-2-mediated anti-inflammatory responses during Leishmania donovani infection. J Antimicrob Chemother. 67:1905–1914. 2012. View Article : Google Scholar : PubMed/NCBI
29	Orazizadeh M, Fakhredini F, Mansouri E and Khorsandi L: Effect of glycyrrhizic acid on titanium dioxide nanoparticles-induced hepatotoxicity in rats. Chem Biol Interact. 220:214–221. 2014. View Article : Google Scholar : PubMed/NCBI
30	Lord JD, Chen J and Kozarek RA: A case of fatal idiopathic enteritis and multiple opportunistic infections associated with dendritic cell deficiencies. J Gastrointestin Liver Dis. 22:87–91. 2013.PubMed/NCBI
31	Miner P, Wedel M, Bane B and Bradley J: An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis. Aliment Pharmacol Ther. 19:281–286. 2004. View Article : Google Scholar : PubMed/NCBI
32	Huang CF, Wu TC, Wu CC, Lee CC, Lo WT, Hwang KS, Hsu ML and Peng HJ: Sublingual vaccination with sonicated Salmonella proteins and mucosal adjuvant induces mucosal and systemic immunity and protects mice from lethal enteritis. APMIS. 119:468–478. 2011. View Article : Google Scholar : PubMed/NCBI
33	Feng L, Zhu MM, Zhang MH, Wang RS, Tan XB, Song J, Ding SM, Jia XB and Hu SY: Protection of glycyrrhizic acid against AGEs-induced endothelial dysfunction through inhibiting RAGE/NF-κB pathway activation in human umbilical vein endothelial cells. J Ethnopharmacol. 148:27–36. 2013. View Article : Google Scholar : PubMed/NCBI
34	Wu Q, Tang Y, Zhang J, Hu X, Wang Q and Huang J: Therapeutic effects of glycyrrhizic acid on asthma airway inflammation in mice and its mechanism. Zhonghua Yi Xue Za Zhi. 94:3338–3344. 2014.In Chinese.
35	Jorge E, Vergara P and Martin MT: Ileal inducible nitric oxide synthase mRNA expression in response to stress is modified in Sprague-Dawley rats exposed to a previous intestinal inflammation. Stress. 15:62–73. 2012. View Article : Google Scholar
36	Li J, Feng G, Liu J, Rong R, Luo F, Guo L, Zhu T, Wang G and Chu Y: Renal cell carcinoma may evade the immune system by converting CD4⁺Foxp3⁻ T cells into CD4⁺CD25⁺Foxp3⁺ regulatory T cells: Role of tumor COX-2-derived PGE2. Mol Med Rep. 3:959–963. 2010.
37	Sun L, Liu J, Cui D, Li J, Yu Y, Ma L and Hu L: Anti-inflammatory function of Withangulatin A by targeted inhibiting COX-2 expression via MAPK and NF-kappaB pathways. J Cell Biochem. 109:532–541. 2010.
38	Cherng JM, Tsai KD, Yu YW and Lin JC: Molecular mechanisms underlying chemopreventive activities of glycyrrhizic acid against UVB-radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis. Radiat Res. 176:177–186. 2011. View Article : Google Scholar : PubMed/NCBI
39	Wang Y, Fu Y, Xue S, Ai A, Chen H, Lyu Q and Kuang Y: The M2 polarization of macrophage induced by fractalkine in the endometriotic milieu enhances invasiveness of endometrial stromal cells. Int J Clin Exp Pathol. 7:194–203. 2014.PubMed/NCBI
40	Zhang X, Li C, Li J, Xu Y, Guan S and Zhao M: Protective effects of protocatechuic acid on acute lung injury induced by lipopolysaccharide in mice via p38MAPK and NF-κB signal pathways. Int Immunopharmacol. 26:229–236. 2015. View Article : Google Scholar : PubMed/NCBI
41	Bredeson S, Papaconstantinou J, Deford JH, Kechichian T, Syed A, Saade GR and Menon R: HMGB1 promotes a p38MAPK associated non-infectious inflammatory response pathway in human fetal membranes. PLoS One. 9:e1137992014. View Article : Google Scholar : PubMed/NCBI
42	Akiho H, Tokita Y, Nakamura K, Satoh K, Nishiyama M, Tsuchiya N, Tsuchiya K, Ohbuchi K, Iwakura Y, Ihara E, et al: Involvement of interleukin-17A-induced hypercontractility of intestinal smooth muscle cells in persistent gut motor dysfunction. PLoS One. 9:e929602014. View Article : Google Scholar : PubMed/NCBI
43	Wojcik M, Zieleniak A, Zurawska-Klis M, Cypryk K and Wozniak LA: Increased expression of immune-related genes in leukocytes of patients with diagnosed gestational diabetes mellitus (GDM). Exp Biol Med (Maywood). 2015.