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Chicoric acid enhances the antioxidative defense system and protects against inflammation and apoptosis associated with the colitis model induced by dextran sulfate sodium in rats

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Abstract

Although several anticolitic drugs are available, their application is associated with numerous side effects. Chicoric acid (CA) is a hydroxycinnamic acid found naturally in chicory (Cichorium intybus), purple coneflower (Echinacea purpurea), and basil with numerous health benefits, such as antioxidative and anti-inflammatory activities. Here, the potential anticolitic efficiency of CA against dextran sulfate sodium (DSS)-induced colitis in rats was examined in rats. Animals were randomly assigned to the following five groups: control, CA (100 mg/kg body weight), DSS [(DSS); 4% w/v], CA + DSS (100 mg/kg), and the 5-aminosalicylic acid (100 mg/kg) + DSS group. The obtained data revealed that CA significantly prevented the shortening of colon length. Meanwhile, the oxidative stress-related enzymes were increased, while malondialdehyde and nitric oxide, were markedly decreased significantly by CA. The results also indicated that CA administration decreased significantly the pro-apoptogenic indices (Bax and caspase-3) and enhanced significantly Bcl-2, the anti-apoptogenic protein. Moreover, DSS caused a significant elevation of pro-inflammatory mediators, including interleukin-1β, tumor necrosis factor-α, myeloperoxidase, cyclooxygenase II, prostaglandin E2, and peroxisome proliferator-activated receptor gamma. Interestingly, these changes were significantly decreased following the CA administration. At the molecular level, CA supplementation has increased significantly the expression level of nuclear factor erythroid 2-related factor-2 (Nrf2) and decreased the expressions of nitric oxide synthase and mitogen-activated protein kinase 14. CA has been determined to significantly lessen DSS-induced colitis by activating Nrf2 and its derived antioxidant molecules and suppressing inflammation and apoptosis cascades associated with the development of colitis; suggesting that CA could be used as an alternative naturally-derived anticolitic agent.

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References

  • Abdel Moneim AE (2016) Indigofera oblongifolia prevents lead acetate-induced hepatotoxicity, oxidative stress, fibrosis and apoptosis in rats. PLoS One 11(7):e0158965

    Article  Google Scholar 

  • Abdel-Ghany R, Rabia I, El-Ahwany E, Saber S, Gamal R, Nagy F et al (2015) Blockade of Pge2, Pgd2 Receptors Confers Protection against Prepatent Schistosomiasis Mansoni in Mice. J Egypt Soc Parasitol 45(3):511–20. https://doi.org/10.12816/0017911

    Article  Google Scholar 

  • Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  Google Scholar 

  • Almeer RS, Mahmoud SM, Amin HK, Abdel Moneim AE (2018) Ziziphus spina-christi fruit extract suppresses oxidative stress and p38 MAPK expression in ulcerative colitis in rats via induction of Nrf2 and HO-1 expression. Food Chem Toxicol. https://doi.org/10.1016/j.fct.2018.03.002

    Article  Google Scholar 

  • Almeer RS, Hammad SF, Leheta OF, Abdel Moneim AE, Amin HK (2019) Anti-Inflammatory and Anti-Hyperuricemic Functions of Two Synthetic Hybrid Drugs with Dual Biological Active Sites. Int J Mol Sci 20(22):5635. https://doi.org/10.3390/ijms20225635

    Article  CAS  Google Scholar 

  • Andaloussi S, Mager I, Breakefield XO, Wood MJ (2013) Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 12(5):347–57. https://doi.org/10.1038/nrd3978

    Article  CAS  Google Scholar 

  • Bewtra M, Newcomb CW, Wu Q, Chen L, Xie F, Roy JA et al (2015) Mortality associated with medical therapy versus elective colectomy in ulcerative colitis: a cohort study. Ann Intern Med 163(4):262–70. https://doi.org/10.7326/M14-0960

    Article  Google Scholar 

  • Bradley PP, Priebat DA, Christensen RD, Rothstein G (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78(3):206–9

    Article  CAS  Google Scholar 

  • Byrav DSP, Medhi B, Prakash A, Chakrabarti A, Vaiphei K, Khanduja KL (2013) Comparative evaluation of different doses of PPAR-gamma agonist alone and in combination with sulfasalazine in experimentally induced inflammatory bowel disease in rats. Pharmacol Rep 65(4):951–9. https://doi.org/10.1016/s1734-1140(13)71076-4

    Article  Google Scholar 

  • Carlberg I, Mannervik B (1985) Glutathione reductase. Methods Enzymol 113:484–490

    Article  CAS  Google Scholar 

  • Chen L, Huang G, Gao M, Shen X, Gong W, Xu Z et al (2017) Chicoric acid suppresses BAFF expression in B lymphocytes by inhibiting NF-κB activity. Int Immunopharmacol 44:211–215

    Article  CAS  Google Scholar 

  • Choo J, Lee Y, Yan XJ, Noh TH, Kim SJ, Son S et al (2015) A Novel Peroxisome Proliferator-activated Receptor (PPAR)gamma Agonist 2-Hydroxyethyl 5-chloro-4,5-didehydrojasmonate Exerts Anti-Inflammatory Effects in Colitis. J Biol Chem 290(42):25609–19. https://doi.org/10.1074/jbc.M115.673046

    Article  CAS  Google Scholar 

  • Dalar A, Konczak I (2014) Cichorium intybus from Eastern Anatolia: Phenolic composition, antioxidant and enzyme inhibitory activities. Ind Crops Prod 60:79–85

    Article  CAS  Google Scholar 

  • Desreumaux P, Ghosh S (2006) Review article: mode of action and delivery of 5-aminosalicylic acid – new evidence. Aliment Pharmacol Ther 24(s1):2–9. https://doi.org/10.1111/j.1365-2036.2006.03069.x

    Article  CAS  Google Scholar 

  • Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA (2013) Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 13(11):759–71. https://doi.org/10.1038/nrc3611

    Article  CAS  Google Scholar 

  • Fumery M, Singh S, Dulai PS, Gower-Rousseau C, Peyrin-Biroulet L, Sandborn WJ (2018) Natural History of Adult Ulcerative Colitis in Population-based Cohorts: A Systematic Review. Clin Gastroenterol Hepatol 16(3):343-356.e3. https://doi.org/10.1016/j.cgh.2017.06.016

    Article  Google Scholar 

  • Gao C, Liu L, Zhou Y, Bian Z, Wang S, Wang Y (2019) Novel drug delivery systems of Chinese medicine for the treatment of inflammatory bowel disease. Chin Med 14:23. https://doi.org/10.1186/s13020-019-0245-x245[pii]

    Article  Google Scholar 

  • Gerstgrasser A, Melhem H, Leonardi I, Atrott K, Schafer M, Werner S et al (2017) Cell-specific Activation of the Nrf2 Antioxidant Pathway Increases Mucosal Inflammation in Acute but Not in Chronic Colitis. J Crohns Colitis 11(4):485–499. https://doi.org/10.1093/ecco-jcc/jjw172

    Article  Google Scholar 

  • Goel V, Chang C, Slama JV, Barton R, Bauer R, Gahler R et al (2002) Echinacea stimulates macrophage function in the lung and spleen of normal rats. J Nutr Biochem 13(8):487–492

    Article  CAS  Google Scholar 

  • Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids (Research Support, U.S. Gov’t, P.H.S.). Anal Biochem 126(1):131–8

    Article  CAS  Google Scholar 

  • Ighodaro OM, Akinloye OA (2018) First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defence grid. Alexandria J Med 54(4):287–293. https://doi.org/10.1016/j.ajme.2017.09.001

    Article  Google Scholar 

  • Jena G, Trivedi PP, Sandala B (2012) Oxidative stress in ulcerative colitis: an old concept but a new concern. Free Radic Res 46(11):1339–1345. https://doi.org/10.3109/10715762.2012.717692

    Article  CAS  Google Scholar 

  • Jia L, Xue K, Liu J, Habotta OA, Hu L, Abdel Moneim AE (2020) Anticolitic effect of berberine in rat experimental model: Impact of PGE2/p38 MAPK pathways. Mediators Inflamm 2020:9419085

    Article  Google Scholar 

  • Kassab RB, Elbaz M, Oyouni AAA, Mufti AH, Theyab A, Al-Brakati A et al (2022) Anticolitic activity of prodigiosin loaded with selenium nanoparticles on acetic acid-induced colitis in rats. Environ Sci Pollut Res Int 29(37):55790–55802. https://doi.org/10.1007/s11356-022-19747-1[pii]10.1007/s11356-022-19747-1

    Article  CAS  Google Scholar 

  • Kobayashi E, Suzuki T, Yamamoto M (2013) Roles nrf2 plays in myeloid cells and related disorders. Oxid Med Cell Longev 2013:529219. https://doi.org/10.1155/2013/529219

    Article  CAS  Google Scholar 

  • Kour K, Bani S, Sangwan PL, Singh A (2016) Upregulation of Th1 polarization by Taraxacum officinale in normal and immune suppressed mice. Curr Sci 111(4):671–685

    Article  CAS  Google Scholar 

  • Li X, Song P, Li J, Tao Y, Li G, Yu Z (2017) The Disease Burden and Clinical Characteristics of Inflammatory Bowel Disease in the Chinese Population: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health 14(3):238. https://doi.org/10.3390/ijerph14030238

    Article  Google Scholar 

  • Li Z, Feng H, Han L, Ding L, Shen B, Tian Y et al (2020) Chicoric acid ameliorate inflammation and oxidative stress in Lipopolysaccharide and d-galactosamine induced acute liver injury. J Cell Mol Med 24(5):3022–3033. https://doi.org/10.1111/jcmm.14935

    Article  CAS  Google Scholar 

  • Liu Q, Chen Y, Shen C, Xiao Y, Wang Y, Liu Z et al (2017a) Chicoric acid supplementation prevents systemic inflammation-induced memory impairment and amyloidogenesis via inhibition of NF-κB. FASEB J 31(4):1494–1507

    Article  CAS  Google Scholar 

  • Liu Q, Hu Y, Cao Y, Song G, Liu Z, Liu X (2017b) Chicoric acid ameliorates lipopolysaccharide-induced oxidative stress via promoting the Keap1/Nrf2 transcriptional signaling pathway in BV-2 microglial cells and mouse brain. J Agric Food Chem 65(2):338–347

    Article  CAS  Google Scholar 

  • Lu MC, Ji JA, Jiang YL, Chen ZY, Yuan ZW, You QD et al (2016) An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis. Sci Rep 6:26585. https://doi.org/10.1038/srep26585

    Article  CAS  Google Scholar 

  • Ma C, Sandborn WJ, D’Haens GR, Zou G, Stitt LW, Singh S, Ananthakrishnan AN, Dulai PS, Khanna R, Jairath V, Feagan BG (2020) Discordance between patient-reported outcomes and mucosal inflammation in patients with mild to moderate ulcerative colitis. Clin Gastroenterol Hepatol 18(8):1760–1768.e1. https://doi.org/10.1016/j.cgh.2019.09.021

  • Masoodi I, Kochhar R, Dutta U, Vaishnavi C, Prasad KK, Vaiphei K et al (2012) Evaluation of fecal myeloperoxidase as a biomarker of disease activity and severity in ulcerative colitis. Dig Dis Sci 57(5):1336–1340. https://doi.org/10.1007/s10620-012-2027-5

    Article  CAS  Google Scholar 

  • Mateus V, Estarreja J, Silva I, Goncalves F, Teixeira-Lemos E, Pinto R (2022) Effect of Aqueous Extract of Phenolic Compounds Obtained from Red Wine in Experimental Model of Colitis in Mice. Curr Issues Mol Biol 44(6):2745–2758. https://doi.org/10.3390/cimb44060188

    Article  CAS  Google Scholar 

  • Matthias A, Banbury L, Stevenson L, Bone K, Leach D, Lehmann R (2007) Alkylamides from Echinacea modulate induced immune responses in macrophages. Immunol Invest 36(2):117–130

    Article  CAS  Google Scholar 

  • Matthias A, Banbury L, Bone KM, Leach DN, Lehmann RP (2008) Echinacea alkylamides modulate induced immune responses in T-cells. Fitoterapia 79(1):53–58

    Article  CAS  Google Scholar 

  • Moon Y (2014) Ribosomal alteration-derived signals for cytokine induction in mucosal and systemic inflammation: noncanonical pathways by ribosomal inactivation. Mediators Inflamm 2014:708193. https://doi.org/10.1155/2014/708193

    Article  CAS  Google Scholar 

  • Neurath MF, Travis SP (2012) Mucosal healing in inflammatory bowel diseases: a systematic review. Gut 61(11):1619–35. https://doi.org/10.1136/gutjnl-2012-302830

    Article  CAS  Google Scholar 

  • Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI et al (2018) Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390(10114):2769–2778. https://doi.org/10.1016/S0140-6736(17)32448-0

    Article  Google Scholar 

  • Nishikimi M, Appaji N, Yagi K (1972) The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun 46(2):849–854

    Article  CAS  Google Scholar 

  • Oh YC, Jeong YH, Cho WK, Gu MJ, Ma JY (2014) Inhibitory effects of palmultang on inflammatory mediator production related to suppression of NF-kappaB and MAPK pathways and induction of HO-1 expression in macrophages. Int J Mol Sci 15(5):8443–57. https://doi.org/10.3390/ijms15058443

    Article  CAS  Google Scholar 

  • Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358

    Article  CAS  Google Scholar 

  • Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70(1):158–169

    CAS  Google Scholar 

  • Park DK, Park HJ (2013) Ethanol extract of Cordyceps militaris grown on germinated soybeans attenuates dextran-sodium-sulfate- (DSS-) induced colitis by suppressing the expression of matrix metalloproteinases and inflammatory mediators. Biomed Res Int 2013:102918. https://doi.org/10.1155/2013/102918

    Article  Google Scholar 

  • Park CM, Jin K-S, Lee Y-W, Song YS (2011) Luteolin and chicoric acid synergistically inhibited inflammatory responses via inactivation of PI3K-Akt pathway and impairment of NF-κB translocation in LPS stimulated RAW 264.7 cells. Eur J Pharmacol 660(2):454–459. https://doi.org/10.1016/j.ejphar.2011.04.007

    Article  CAS  Google Scholar 

  • Peng Y, Sun Q, Park Y (2019) The bioactive effects of chicoric acid as a functional food ingredient. J Med Food 22(7):645–652

    Article  Google Scholar 

  • Qian Z, Wu Z, Huang L, Qiu H, Wang L, Li L et al (2015) Mulberry fruit prevents LPS-induced NF-kappaB/pERK/MAPK signals in macrophages and suppresses acute colitis and colorectal tumorigenesis in mice. Sci Rep 5:17348. https://doi.org/10.1038/srep17348

    Article  CAS  Google Scholar 

  • Qin M, Long F, Wu W, Yang D, Huang M, Xiao C et al (2019) Hydrogen sulfide protects against DSS-induced colitis by inhibiting NLRP3 inflammasome. Free Radic Biol Med 137:99–109. https://doi.org/10.1016/j.freeradbiomed.2019.04.025

    Article  CAS  Google Scholar 

  • Rodriguez-Canales M, Jimenez-Rivas R, Canales-Martinez MM, Garcia-Lopez AJ, Rivera-Yanez N, Nieto-Yanez O et al (2016) Protective Effect of Amphipterygium adstringens Extract on Dextran Sulphate Sodium-Induced Ulcerative Colitis in Mice. Mediators Inflamm 2016:8543561. https://doi.org/10.1155/2016/8543561

    Article  CAS  Google Scholar 

  • Schlernitzauer A, Oiry C, Hamad R, Galas S, Cortade F, Chabi B et al (2013) Chicoric acid is an antioxidant molecule that stimulates AMP kinase pathway in L6 myotubes and extends lifespan in Caenorhabditis elegans. PLoS One 8(11):e78788

    Article  CAS  Google Scholar 

  • Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25(1):192–205

    Article  CAS  Google Scholar 

  • Su CG, Wen X, Bailey ST, Jiang W, Rangwala SM, Keilbaugh SA et al (1999) A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J Clin Invest 104(4):383–389. https://doi.org/10.1172/JCI7145

    Article  CAS  Google Scholar 

  • Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW et al (2006) Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest 116(4):984–995. https://doi.org/10.1172/JCI25790

    Article  CAS  Google Scholar 

  • Tsai KL, Kao CL, Hung CH, Cheng YH, Lin HC, Chu PM (2017) Chicoric acid is a potent anti-atherosclerotic ingredient by anti-oxidant action and anti-inflammation capacity. Oncotarget 8(18):29600–29612. https://doi.org/10.18632/oncotarget.16768

    Article  Google Scholar 

  • Waetzig GH, Seegert D, Rosenstiel P, Nikolaus S, Schreiber S (2002) p38 mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease. J Immunol 168(10):5342–5351. https://doi.org/10.4049/jimmunol.168.10.5342

    Article  CAS  Google Scholar 

  • Wang Y, Wang H, Qian C, Tang J, Zhou W, Liu X et al (2016) 3-(2-Oxo-2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(1 1bH)-one (compound 1), a novel potent Nrf2/ARE inducer, protects against DSS-induced colitis via inhibiting NLRP3 inflammasome. Biochem Pharmacol 101:71–86. https://doi.org/10.1016/j.bcp.2015.11.015

    Article  CAS  Google Scholar 

  • Wang Y, Diao Z, Li J, Ren B, Zhu D, Liu Q et al (2017) Chicoric acid supplementation ameliorates cognitive impairment induced by oxidative stress via promotion of antioxidant defense system. RSC Adv 7(57):36149–36162

    Article  CAS  Google Scholar 

  • Wang N, Wu T, Du D, Mei J, Luo H, Liu Z et al (2022) Transcriptome and gut microbiota profiling revealed the protective effect of Tibetan Tea on ulcerative colitis in mice. Front Microbiol 12:748594

  • Xue C-H, A S-X, Wang M-J, Wu Q, Liu J-H, Zhang L-F et al (2021) extract (cichoric acid) exerts an anti-inflammatory effect on yak PBMCs and regulates the TLR4 signalling pathway. J Vet Res 65(1):109–115. https://doi.org/10.2478/jvetres-2021-0016

    Article  CAS  Google Scholar 

  • Yamamoto-Furusho JK (2018) Inflammatory bowel disease therapy: blockade of cytokines and cytokine signaling pathways. Curr Opin Gastroenterol 34(4):187–193. https://doi.org/10.1097/MOG.0000000000000444

    Article  CAS  Google Scholar 

  • Yue B, Ren Y-J, Zhang J-J, Luo X-P, Yu Z-L, Ren G-Y, Sun A-N, Deng C, Wang Z-T, Dou W et al (2018) Anti-inflammatory effects of fargesin on chemically induced inflammatory bowel disease in mice. Molecules 23(6):1380

    Article  Google Scholar 

  • Zhang J, Dou W, Zhang E, Sun A, Ding L, Wei X, Chou G, Mani S, Wang Z et al (2014) Paeoniflorin abrogates DSS-induced colitis via a TLR4-dependent pathway. Am J Physiol Gastrointest Liver Physiol 306(1):G27–36

    Article  CAS  Google Scholar 

  • Zhao X, Kang B, Lu C, Liu S, Wang H, Yang X et al (2011) Evaluation of p38 MAPK pathway as a molecular signature in ulcerative colitis. J Proteome Res 10(5):2216–2225. https://doi.org/10.1021/pr100969w

    Article  CAS  Google Scholar 

  • Zhu X, Huang F, Xiang X, Fan M, Chen T (2018) Evaluation of the potential of chicoric acid as a natural food antioxidant. Exp Ther Med 16(4):3651–3657. https://doi.org/10.3892/etm.2018.6596

    Article  CAS  Google Scholar 

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Acknowledgements

The author is deeply grateful to and acknowledge the Deanship of Scientific Research in Taif University, Saudi Arabia, for its financial support for Project (1-443-18).

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Fahad Alharthi has performed all the research items.

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Alharthi, F. Chicoric acid enhances the antioxidative defense system and protects against inflammation and apoptosis associated with the colitis model induced by dextran sulfate sodium in rats. Environ Sci Pollut Res 30, 119814–119824 (2023). https://doi.org/10.1007/s11356-023-30742-y

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