Top

Published in:

Open Access 30-10-2023 | Ulcerative Colitis | Original Article

Management of ulcerative colitis by dichloroacetate: Impact on NFATC1/NLRP3/IL1B signaling based on bioinformatics analysis combined with in vivo experimental verification

Authors: Esraa Abdel-Nassir Abdel-Razek, Heba M. Mahmoud, Amany A. Azouz

Published in: Inflammopharmacology | Issue 1/2024

Abstract

The inflammatory response in ulcerative colitis (UC) could be relieved by the conventional immunomodulatory agents; 5-aminosalicylic acid, corticosteroids, or azathioprine. However, the low remission rates and the intolerance to these agents necessitate investigation of gene expression signature in UC that could influence the therapeutic efficacy of drugs, as well as the interference with persistence genes by novel therapeutic option. Three microarray datasets (GSE66407, GSE38713 and GSE14580) from the NCBI-GEO database were utilized. Differentially expressed genes between samples of patients with UC and healthy ones were analyzed using R software. In addition, in vivo study using oxazolone-induced UC in BALB/c mice was carried out to investigate the proposed therapeutic efficacy of dichloroacetate (DCA). The bioinformatics analysis revealed the persistence of NLRP3, NFATC1, and IL1B in UC despite treatment with common therapeutic agents. DCA administration to oxazolone-treated mice showed remarkable interference with those persistence genes. Western blotting analysis for NLRP3, NFATC1, nuclear/total NF-κB, and cleaved caspase-1 revealed the ability of DCA to reduce the expression levels of these proteins in oxazolone-treated mice. Additionally, the inflammatory cytokines IL-1β and IL-13 were reduced in colonic tissue by DCA treatment. The therapeutic efficacy of DCA was further confirmed by the apparent reduction in histopathological scoring, disease activity index, and the normalization of colon length. Therefore, DCA could be suggested as a novel and promising therapeutic option in UC based on its ability to interfere with the persistence of NFATC1/NLRP3/IL1B signaling. That merits further safety/toxicological pre-clinical assessment and update of bioavailability/metabolism data prior to clinical investigation.

Available only for authorised users

Abdelmalak M, Lew A, Ramezani R, Shroads AL, Coats BS, Langaee T, Shankar MN, Neiberger RE, Subramony S, Stacpoole PW (2013) Long-term safety of dichloroacetate in congenital lactic acidosis. Mol Genet Metab 109:139–143PubMedPubMedCentralCrossRef

Agbenyega T, Planche T, Bedu-Addo G, Ansong D, Owusu-Ofori A, Bhattaram VA, Nagaraja NV, Shroads AL, Henderson GN, Hutson AD (2003) Population kinetics, efficacy, and safety of dichloroacetate for lactic acidosis due to severe malaria in children. J Clin Pharmacol 43:386–396PubMedCrossRef

Atreya I, Atreya R, Neurath M (2008) Nf-κb in inflammatory bowel disease. J Intern Med 263:591–596PubMedCrossRef

Axelrad JE, Lichtiger S, Yajnik V (2016) Inflammatory bowel disease and cancer: the role of inflammation, immunosuppression, and cancer treatment. World J Gastroenterol 22:4794PubMedPubMedCentralCrossRef

Bancroft JD, Gamble M (2008) Theory and practice of histological techniques. Elsevier Health Sciences

Bauer C, Duewell P, Lehr H-A, Endres S, Schnurr M (2012) Protective and aggravating effects of Nlrp3 inflammasome activation in ibd models: influence of genetic and environmental factors. Dig Dis 30:82–90PubMedCrossRef

Baydi Z, Limami Y, Khalki L, Zaid N, Naya A, Mtairag EM, Oudghiri M, Zaid Y (2021) An update of research animal models of inflammatory bowel disease. Sci World J. https://doi.org/10.1155/2021/7479540CrossRef

Berg M (2020) Immunometabolic regulation of atherosclerosis. Karolinska Institutet

Bian L, Josefsson E, Jonsson I-M, Verdrengh M, Ohlsson C, Bokarewa M, Tarkowski A, Magnusson M (2009) Dichloroacetate alleviates development of collagen ii-induced arthritis in female Dba/1 mice. Arthritis Res Ther 11:1–10CrossRef

Boirivant M, Fuss IJ, Chu A, Strober W (1998) Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med 188:1929–1939PubMedPubMedCentralCrossRef

Chami B, Ahmad G, Schroder A, San Gabriel P, Witting P (2021) The role of myeloperoxidase and neutrophil extracellular traps in the pathogenesis of inflammatory bowel disease. Gastroenterology 160:S5–S6CrossRef

Chen Y, Wang P, Zhang Y, Du X-Y, Zhang Y-J (2022) Comparison of effects of aminosalicylic acid, glucocorticoids and immunosuppressive agents on the expression of multidrug-resistant genes in ulcerative colitis. Sci Rep 12:20656ADSPubMedPubMedCentralCrossRef

Cottone M, Renna S, Modesto I, Orlando A (2011) Is 5-asa still the treatment of choice for ulcerative colitis? Curr Drug Targets 12:1396–1405PubMedCrossRef

Cross RK, Wilson KT (2003) Nitric oxide in inflammatory bowel disease. Inflamm Bowel Dis 9:179–189PubMedCrossRef

Do Nascimento RS, Nagamine MK, De Toledo GF, Chaible LM, Tedardi MV, Murilo P, Da Fonseca II, Dagli ML (2021) Sodium dichloroacetate attenuates the growth of B16–F10 melanoma in vitro and in vivo: an opportunity for drug repurposing. Anticancer Drugs 32:111–116PubMedCrossRef

Dohi T, Fujihashi K, Rennert PD, Iwatani K, Kiyono H, Mcghee JR (1999) Hapten-induced colitis is associated with colonic patch hypertrophy and T helper cell 2–Type responses. J Exp Med 189:1169–1180PubMedPubMedCentralCrossRef

Elloumi HZ, Maharshak N, Rao KN, Kobayashi T, Ryu HS, Mühlbauer M, Li F, Jobin C, Plevy SE (2012) A cell permeable peptide inhibitor of nfat inhibits macrophage cytokine expression and ameliorates experimental colitis. PLoS ONE 7:E34172ADSPubMedPubMedCentralCrossRef

Erben U, Loddenkemper C, Doerfel K, Spieckermann S, Haller D, Heimesaat MM, Zeitz M, Siegmund B, Kühl AA (2014) A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exper Pathol 7:4557

Feng X, Wang H, Ye S, Guan J, Tan W, Cheng S, Wei G, Wu W, Wu F, Zhou Y (2012) Up-regulation of Microrna-126 may contribute to pathogenesis of ulcerative colitis via regulating nf-kappab inhibitor iκbα. PLoS ONE 7:E52782ADSPubMedPubMedCentralCrossRef

Forteza MJ, Berg M, Edsfeldt A, Sun J, Baumgartner R, Kareinen I, Casagrande FB, Hedin U, Zhang S, Vuckovic I (2023) Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk. Cardiovasc Res. https://doi.org/10.1093/cvr/cvad038CrossRefPubMedPubMedCentral

Garrity-Park M, Loftus EV Jr, Sandborn WJ, Smyrk TC (2012) Myeloperoxidase immunohistochemistry as a measure of disease activity in ulcerative colitis: association with ulcerative colitis-colorectal cancer, tumor necrosis factor polymorphism and Runx3 methylation. Inflamm Bowel Dis 18:275–283PubMedCrossRef

Giustarini D, Rossi R, Milzani A, Dalle-Donne I (2008) Nitrite and nitrate measurement by griess reagent in human plasma: evaluation of interferences and standardization. Methods Enzymol 440:361–380PubMedCrossRef

Goyette P, Labbé C, Trinh TT, Xavier RJ, Rioux JD (2007) Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine. Ann Med 39:177–199PubMedCrossRef

Guignabert C, Tu L, Izikki M, Dewachter L, Zadigue P, Humbert M, Adnot S, Fadel E, Eddahibi S (2009) Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with Sm22α-targeted overexpression of the serotonin transporter. FASEB J 23:4135–4147PubMedCrossRef

Guo H, Callaway JB, Ting JP (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21:677–687PubMedPubMedCentralCrossRef

He T, Wang K, Zhao P, Zhu G, Yin X, Zhang Y, Zhang Z, Zhao K, Wang Z, Wang K (2022) Integrative computational approach identifies immune-relevant biomarkers in ulcerative colitis. FEBS Open Bio 12:500–515PubMedPubMedCentralCrossRef

Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by Il-13-producing nk-T cells. Immunity 17:629–638PubMedCrossRef

Hoving JC, Cutler AJ, Leeto M, Horsnell WG, Dewals BG, Nieuwenhuizen NE, Brombacher F (2017) Interleukin 13-mediated colitis in the absence of il-4rα signalling. Gut 66:2037–2039PubMedCrossRef

Huang R, Yao J, Zhou L, Li X, Zhu J, Hu Y, Liu J (2023) Protective effect and mechanism insight of purified Antarctic kill phospholipids against mice ulcerative colitis combined with bioinformatics. Nat Prod Bioprospect 13:11PubMedPubMedCentralCrossRef

Itani S, Watanabe T, Nadatani Y, Sugimura N, Shimada S, Takeda S, Otani K, Hosomi S, Nagami Y, Tanaka F (2016) Nlrp3 inflammasome has a protective effect against oxazolone-induced colitis: a possible role in ulcerative colitis. Sci Rep 6:39075ADSPubMedPubMedCentralCrossRef

Jena G, Trivedi PP, Sandala B (2012) Oxidative stress in ulcerative colitis: an old concept but a new concern. Free Radical Res 46:1339–1345CrossRef

Kan P-C, Chang Y-J, Chien C-S, Su C-Y, Fang H-W (2018) Coupling dichloroacetate treatment with curcumin significantly enhances anticancer potential. Anticancer Res 38:6253–6261PubMedCrossRef

Kanneganti T-D, Lamkanfi M (2007) Intracellular nod-like receptors in host defense and disease. Immunity 27:549–559PubMedCrossRef

Khan A, Marier D, Marsden E, Andrews D, Eliaz I (2014) A novel form of dichloroacetate therapy for patients with advanced cancer: a report of 3 cases. Altern Ther Health Med 20:21–28PubMed

Kucharzik T, Koletzko S, Kannengiesser K, Dignass A (2020) Ulcerative colitis—diagnostic and therapeutic algorithms. Dtsch Arztebl Int 117:564PubMedPubMedCentral

Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, Hayee BH, Lomer MC, Parkes GC, Selinger C (2019) British society of gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 68:S1–S106PubMedCrossRef

Li T, Li S, Feng Y, Zeng X, Dong S, Li J, Zha L, Luo H, Zhao L, Liu B (2020) Combination of dichloroacetate and atorvastatin regulates excessive proliferation and oxidative stress in pulmonary arterial hypertension development via P38 signaling. Oxid Med Cell Longev. https://doi.org/10.1155/2020/6973636CrossRefPubMedPubMedCentral

Lin Y, Zhou Z, Xie L, Huang Y, Qiu Z, Ye L, Cui C (2022) Effects of Mir-939 and Mir-376a on ulcerative colitis using a decoy strategy to inhibit Nf-Κb and Nfat expression. Eur J Histochem Ejh. https://doi.org/10.4081/ejh.2022.3316CrossRefPubMed

Lu P-D, Zhao Y-H (2020) Targeting nf-κb pathway for treating ulcerative colitis: comprehensive regulatory characteristics of Chinese medicines. Chin Med 15:1–25CrossRef

Manktelow A, Meyer AA (1986) Lack of correlation between decreased chemotaxis and susceptibility to infection in burned rats. J Trauma 26:143–148PubMedCrossRef

Martínez-Martínez S, Rodríguez A, López-Maderuelo MD, Ortega-Pérez I, Vázquez JS, Redondo JM (2006) Blockade of nfat activation by the second calcineurin binding site. J Biol Chem 281:6227–6235PubMedCrossRef

Masoodi I, Kochhar R, Dutta U, Vaishnavi C, Prasad K, Vaiphei K, Hussain S, Singh K (2012) Evaluation of fecal myeloperoxidase as a biomarker of disease activity and severity in ulcerative colitis. Dig Dis Sci 57:1336–1340PubMedCrossRef

Mcmurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED (2004) Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95:830–840PubMedCrossRef

Mercken EM, Calvert LD, Singh SJ, Hageman GJ, Schols AM, Steiner MC (2009) Dichloroacetate modulates the oxidative stress and inflammatory response to exercise in copd. Chest 136:744–751PubMedCrossRef

Mikami Y, Tsunoda J, Suzuki S, Mizushima I, Kiyohara H, Kanai T (2023) Significance of 5-aminosalicylic acid intolerance in the clinical management of ulcerative colitis. Digestion 104:58–65PubMedCrossRef

Öhman L, Simrén M (2010) Pathogenesis of ibs: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol 7:163–173PubMedCrossRef

Ostroukhova M, Goplen N, Karim MZ, Michalec L, Guo L, Liang Q, Alam R (2012) The role of low-level lactate production in airway inflammation in asthma. Am J Physiol-Lung Cell Mol Physiol 302:L300–L307PubMedCrossRef

Pan M-G, Xiong Y, Chen F (2013) Nfat gene family in inflammation and cancer. Curr Mol Med 13:543–554PubMedPubMedCentralCrossRef

Perera AP, Sajnani K, Dickinson J, Eri R, Körner H (2018) Nlrp3 inflammasome in colitis and colitis-associated colorectal cancer. Mamm Genome 29:817–830PubMedCrossRef

Petrilli V, Papin S, Tschopp J (2005) The inflammasome. Curr Biol 15:R581PubMedCrossRef

Rana SV, Sharma S, Kaur J, Prasad KK, Sinha SK, Kochhar R, Malik A, Morya RK (2014) Relationship of cytokines, oxidative stress and gi motility with bacterial overgrowth in ulcerative colitis patients. J Crohn’s Colitis 8:859–865CrossRef

Saed GM, Fletcher NM, Jiang ZL, Abu-Soud HM, Diamond MP (2011) Dichloroacetate induces apoptosis of epithelial ovarian cancer cells through a mechanism involving modulation of oxidative stress. Reprod Sci 18:1253–1261PubMedCrossRef

Saghir SA, Schultz IR (2002) Low-dose pharmacokinetics and Oral bioavailability of dichloroacetate in naive and GST-zeta-depleted rats. Environ Health Perspect 110:757–763PubMedPubMedCentralCrossRef

Shi L, Han X, Li J-X, Liao Y-T, Kou F-S, Wang Z-B, Shi R, Zhao X-J, Sun Z-M, Hao Y (2020a) Identification of differentially expressed genes in ulcerative colitis and verification in a colitis mouse model by bioinformatics analyses. World J Gastroenterol 26:5983PubMedPubMedCentralCrossRef

Shi Y, Liu Z, Cui X, Zhao Q, Liu T (2020b) Intestinal vitamin D receptor knockout protects from oxazolone-induced colitis. Cell Death Dis 11:1–11

Shih T-C, Hsieh S-Y, Hsieh Y-Y, Chen T-C, Yeh C-Y, Lin C-J, Lin D-Y, Chiu C-T (2008) Aberrant activation of nuclear factor of activated T cell 2 in lamina propria mononuclear cells in ulcerative colitis. World J Gastroenterol WJG 14:1759PubMedCrossRef

Siregar R, Widyawati T (2021) Chemically-induced colitis models in animal. Sumatera Med J 4:10–17CrossRef

Soufli I, Toumi R, Rafa H, Touil-Boukoffa C (2016) Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases. World J Gastrointestinal Pharmacol Therapeutics 7:353CrossRef

Stacpoole PW, Wright EC, Baumgartner TG, Bersin RM, Buchalter S, Curry SH, Duncan CA, Harman EM, Henderson GN, Jenkinson S (1992) A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. N Engl J Med 327:1564–1569PubMedCrossRef

Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS (1997) Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child 77:535–541PubMedPubMedCentralCrossRef

Stacpoole PW, Henderson GN, Yan Z, James MO (1998) Clinical pharmacology and toxicology of dichloroacetate. Environ Health Perspect 106:989–994PubMedPubMedCentral

Taku K, Britta S, Chen WS, Ferrante M, Shen B, Bernstein CN, Silvio D, Laurent P-B, Toshifumi H (2020) Ulcerative colitis (primer). Nat Rev Dis Primers. https://doi.org/10.1038/s41572-020-0205-xCrossRef

Tataranni T, Piccoli C (2019) Dichloroacetate (Dca) and cancer: an overview towards clinical applications. Oxid Med Cell Longev. https://doi.org/10.1155/2019/8201079CrossRefPubMedPubMedCentral

Torres-Cavazos Z, Franco-Molina MA, Santana-Krímskaya SE, Rodríguez-Padilla C, Kawas-Garza JR, Hernández-Vidal G, Moreno-Degollado G, Zamora-Ávila DE (2020) In vivo evaluation of the antitumor and immunogenic properties of silver and sodium dichloroacetate combination against melanoma. J Nanomater 2020:1–8CrossRef

Tourkochristou E, Aggeletopoulou I, Konstantakis C, Triantos C (2019) Role of Nlrp3 inflammasome in inflammatory bowel diseases. World J Gastroenterol 25:4796PubMedPubMedCentralCrossRef

Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci 76:4350–4354ADSPubMedPubMedCentralCrossRef

Ullah HA, Saba E, Lee YY, Hong S-B, Hyun S-H, Kwak Y-S, Park C-K, Kim SD, Rhee MH (2022) Restorative effects of Rg3-enriched korean red ginseng and Persicaria tinctoria extract on oxazolone-induced ulcerative colitis in mice. J Ginseng Res 46:628–635PubMedCrossRef

Wang S, Abouzied M, Smith D (1996) Proteins as potential endpoint temperature indicators for ground beef patties. J Food Sci 61:5–7CrossRef

Wang Z-Y, Kusam S, Munugalavadla V, Kapur R, Brutkiewicz RR, Dent AL (2006) Regulation of Th2 cytokine expression in nkt cells: unconventional use of Stat6, Gata-3, and Nfat2. J Immunol 176:880–888PubMedCrossRef

Wang S, Lin Y, Yuan X, Li F, Guo L, Wu B (2018) Rev-erbα integrates colon clock with experimental colitis through regulation of nf-Κb/Nlrp3 Axis. Nat Commun 9:4246ADSPubMedPubMedCentralCrossRef

Wirtz S, Neufert C, Weigmann B, Neurath MF (2007) Chemically induced mouse models of intestinal inflammation. Nat Protoc 2:541–546PubMedCrossRef

Yang J, Zhou W-W, Shi D-D, Pan F-F, Sun W-W, Yang P-L, Li X-M (2023) The interaction between oxidative stress biomarkers and gut microbiota in the antioxidant effects of extracts from Sonchus brachyotus Dc. in oxazolone-induced intestinal oxidative stress in adult zebrafish. Antioxidants 12:192PubMedPubMedCentralCrossRef

Zhang L, Cao N, Wang Y, Wang Y, Wu C, Cheng X, Wang C (2019) Improvement of oxazolone-induced ulcerative colitis in rats using andrographolide. Molecules 25:76PubMedPubMedCentralCrossRef

Zhang J, Wang X, Xu L, Zhang Z, Wang F, Tang X (2020) Investigation of potential genetic biomarkers and molecular mechanism of ulcerative colitis utilizing bioinformatics analysis. Biomed Res Int. https://doi.org/10.1155/2020/4921387CrossRefPubMedPubMedCentral

Zhao X, Li S, Mo Y, Li R, Huang S, Zhang A, Ni X, Dai Q, Wang J (2021) Dca protects against oxidation injury attributed to cerebral ischemia-reperfusion by regulating glycolysis through Pdk2-Pdh-Nrf2 axis. Oxid Med Cell Longev. https://doi.org/10.1155/2021/5173035CrossRefPubMedPubMedCentral

Zherebiatiev A, Kamyshnyi A (2016) Expression levels of proinflammatory cytokines and Nlrp3 inflammasome In An experimental model of oxazolone-induced colitis. Iran J Allergy Asthma Immunol 15:39–45PubMed

Zhou J, Li M, Chen Q, Li X, Chen L, Dong Z, Zhu W, Yang Y, Liu Z, Chen Q (2022) Programmable probiotics modulate inflammation and gut microbiota for inflammatory bowel disease treatment after effective Oral delivery. Nat Commun 13:3432ADSPubMedPubMedCentralCrossRef

Zhu H, Cao X (2017) Nlr members in inflammation-associated carcinogenesis. Cell Mol Immunol 14:403–405PubMedPubMedCentralCrossRef

Title: Management of ulcerative colitis by dichloroacetate: Impact on NFATC1/NLRP3/IL1B signaling based on bioinformatics analysis combined with in vivo experimental verification
Authors: Esraa Abdel-Nassir Abdel-Razek
Heba M. Mahmoud
Amany A. Azouz
Publication date: 30-10-2023
Publisher: Springer International Publishing
Keyword: Ulcerative Colitis
Published in: Inflammopharmacology / Issue 1/2024
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-023-01362-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Management of ulcerative colitis by dichloroacetate: Impact on NFATC1/NLRP3/IL1B signaling based on bioinformatics analysis combined with in vivo experimental verification

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2024

Linking NLRP3 inflammasome and pulmonary fibrosis: mechanistic insights and promising therapeutic avenues

Erythropoietin alleviates astrocyte pyroptosis by targeting the miR-325-3p/Gsdmd axis in rat spinal cord injury

Resveratrol protects against Schistosoma mansoni-induced liver fibrosis by targeting the Sirt-1/NF-κB axis

Osteoarthritis

Using aspirin to prevent and treat cancer

Nigella sativa and its chemical constituents: pre-clinical and clinical evidence for their potential anti-SARS-CoV-2 effects