Skip to main content
SpringerLink
Log in

Therapeutic effects of genistein in experimentally induced ulcerative colitis in rats via affecting mitochondrial biogenesis

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Ulcerative colitis (UC) is an inflammatory bowel disease that affects the mucosa of the colon, resulting in severe inflammation and ulcers. Genistein is a polyphenolic isoflavone present in several vegetables, such as soybeans and fava beans. Therefore, we conducted the following study to determine the therapeutic effects of genistein on UC in rats by influencing antioxidant activity and mitochondrial biogenesis and the subsequent effects on the apoptotic pathway. UC was induced in rats by single intracolonic administration of 2 ml of 4% acetic acid. Then, UC rats were treated with 25-mg/kg genistein. Colon samples were obtained to assess the gene and protein expression of nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptor-gamma coactivator (PGC-1), mitochondrial transcription factor A (TFAM), B-cell lymphoma 2 (BCL2), BCL2-associated X (BAX), caspase-3, caspase-8, and caspase-9. In addition, colon sections were stained with hematoxylin/eosin to investigate the cell structure. The microimages of UC rats revealed inflammatory cell infiltration, hemorrhage, and the destruction of intestinal glands, and these effects were improved by treatment with genistein. Finally, treatment with genistein significantly increased the expression of PGC-1, TFAM, Nrf2, HO-1, and BCL2 and reduced the expression of BAX, caspase-3, caspase-8, and caspase-9. In conclusion, genistein exerted therapeutic effects against UC in rats. This therapeutic activity involved enhancing antioxidant activity and increasing mitochondrial biogenesis, which reduced cell apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Adams SM, Bornemann PH (2013) Ulcerative colitis. Am Fam Physician 87:699–705

    PubMed  Google Scholar 

  2. Ordas I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ (2012) Ulcerative colitis. Lancet 380:1606–1619. https://doi.org/10.1016/S0140-6736(12)60150-0

    Article  PubMed  Google Scholar 

  3. Armuzzi A, Liguori G (2021) Quality of life in patients with moderate to severe ulcerative colitis and the impact of treatment: A narrative review. Dig Liver Dis 53:803–808. https://doi.org/10.1016/j.dld.2021.03.002

    Article  PubMed  Google Scholar 

  4. Colombel JF, Mahadevan U (2017) Inflammatory bowel disease 2017: innovations and changing paradigms. Gastroenterology 152:309–312. https://doi.org/10.1053/j.gastro.2016.12.004

    Article  PubMed  Google Scholar 

  5. Gardiner LJ, Carrieri AP, Bingham K, Macluskie G, Bunton D, McNeil M, Pyzer-Knapp EO (2022) Combining explainable machine learning, demographic and multi-omic data to inform precision medicine strategies for inflammatory bowel disease. PLoS ONE 17:e0263248. https://doi.org/10.1371/journal.pone.0263248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Billmeier U, Dieterich W, Neurath MF, Atreya R (2016) Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World J Gastroenterol 22:9300–9313. https://doi.org/10.3748/wjg.v22.i42.9300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vermeire S, O’Byrne S, Keir M, Williams M, Lu TT, Mansfield JC, Lamb CA, Feagan BG, Panes J, Salas A, Baumgart DC, Schreiber S, Dotan I, Sandborn WJ, Tew GW, Luca D, Tang MT, Diehl L, Eastham-Anderson J, De Hertogh G, Perrier C, Egen JG, Kirby JA, van Assche G, Rutgeerts P (2014) Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 384:309–318. https://doi.org/10.1016/S0140-6736(14)60661-9

    Article  CAS  PubMed  Google Scholar 

  8. Zurba Y, Gros B, Shehab M (2023) Exploring the pipeline of novel therapies for inflammatory bowel disease; state of the art review. Biomedicines. https://doi.org/10.3390/biomedicines11030747

    Article  PubMed  PubMed Central  Google Scholar 

  9. Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RG, Hu C, Stevens RM, Day RM, Gordon KB, Korman NJ, Griffiths CE (2015) Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol 73:37–49. https://doi.org/10.1016/j.jaad.2015.03.049

    Article  CAS  PubMed  Google Scholar 

  10. Fernandez-Clotet A, Castro-Poceiro J, Panes J (2018) Tofacitinib for the treatment of ulcerative colitis. Expert Rev Clin Immunol 14:881–892. https://doi.org/10.1080/1744666X.2018.1532291

    Article  CAS  PubMed  Google Scholar 

  11. El-Far YM, Khodir AE, Emarah ZA, Ebrahim MA, Al-Gayyar MMH (2022) Chemopreventive and hepatoprotective effects of genistein via inhibition of oxidative stress and the versican/PDGF/PKC signaling pathway in experimentally induced hepatocellular carcinoma in rats by thioacetamide. Redox Rep 27:9–20. https://doi.org/10.1080/13510002.2022.2031515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tanideh N, Sadeghi F, Amanat S, Firoozi D, Noorafshan A, Iraji A, Koohi-Hosseinabadi O (2020) Protection by pure and genistein fortified extra virgin olive oil, canola oil, and rice bran oil against acetic acid-induced ulcerative colitis in rats. Food Funct 11:860–870. https://doi.org/10.1039/c9fo01951k

    Article  CAS  PubMed  Google Scholar 

  13. Alattar A, Alshaman R, Al-Gayyar MMH (2022) Therapeutic effects of sulforaphane in ulcerative colitis: effect on antioxidant activity, mitochondrial biogenesis and DNA polymerization. Redox Rep 27:128–138. https://doi.org/10.1080/13510002.2022.2092378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Albalawi GA, Albalawi MZ, Alsubaie KT, Albalawi AZ, Elewa MAF, Hashem KS, Al-Gayyar MMH (2023) Curative effects of crocin in ulcerative colitis via modulating apoptosis and inflammation. Int Immunopharmacol 118:110138. https://doi.org/10.1016/j.intimp.2023.110138

    Article  CAS  PubMed  Google Scholar 

  15. Bagalagel A, Diri R, Noor A, Almasri D, Bakhsh HT, Kutbi HI, Al-Gayyar MMH (2022) Curative effects of fucoidan on acetic acid induced ulcerative colitis in rats via modulating aryl hydrocarbon receptor and phosphodiesterase-4. BMC Complement Med Ther 22:196. https://doi.org/10.1186/s12906-022-03680-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bagalagel A, Diri R, Noor A, Almasri D, Bakhsh HT, Kutbi HI, Al-Gayyar MMH (2022) The therapeutic effects of cycloastragenol in ulcerative colitis by modulating SphK/MIP-1alpha/miR-143 signalling. Basic Clin Pharmacol Toxicol 131:406–419. https://doi.org/10.1111/bcpt.13788

    Article  CAS  PubMed  Google Scholar 

  17. Bagalagel A, Diri R, Noor A, Almasri D, Bakhsh H, Kutbi HI, Al-Gayyar MM (2022) Evaluating the anticancer activity of blocking TNF type 1 receptors in thioacetamide-induced hepatocellular carcinoma in a rat model. Cureus 14:e32519. https://doi.org/10.7759/cureus.32519

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hassan HM, El-Kannishy SMH, Alattar A, Alshaman R, Hamdan AM, Al-Gayyar MMH (2021) Therapeutic effects of blocking beta-catenin against hepatocellular carcinoma-induced activation of inflammation, fibrosis and tumor invasion. Biomed Pharmacother. https://doi.org/10.1016/j.biopha.2021.111216

    Article  PubMed  Google Scholar 

  19. Sherif IO, Al-Gayyar MMH (2018) Oleuropein potentiates anti-tumor activity of cisplatin against HepG2 through affecting proNGF/NGF balance. Life Sci 198:87–93. https://doi.org/10.1016/j.lfs.2018.02.027

    Article  CAS  PubMed  Google Scholar 

  20. Xu Y, Shen J, Ran Z (2020) Emerging views of mitophagy in immunity and autoimmune diseases. Autophagy 16:3–17. https://doi.org/10.1080/15548627.2019.1603547

    Article  CAS  PubMed  Google Scholar 

  21. Keshavarzian A, Banan A, Farhadi A, Komanduri S, Mutlu E, Zhang Y, Fields JZ (2003) Increases in free radicals and cytoskeletal protein oxidation and nitration in the colon of patients with inflammatory bowel disease. Gut 52:720–728. https://doi.org/10.1136/gut.52.5.720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Du L, Ha C (2020) Epidemiology and Pathogenesis of Ulcerative Colitis. Gastroenterol Clin North Am 49:643–654. https://doi.org/10.1016/j.gtc.2020.07.005

    Article  PubMed  Google Scholar 

  23. Cagin YF, Parlakpinar H, Vardi N, Polat A, Atayan Y, Erdogan MA, Tanbek K (2016) Effects of dexpanthenol on acetic acid-induced colitis in rats. Exp Ther Med 12:2958–2964. https://doi.org/10.3892/etm.2016.3728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cunningham KE, Vincent G, Sodhi CP, Novak EA, Ranganathan S, Egan CE, Stolz DB, Rogers MB, Firek B, Morowitz MJ, Gittes GK, Zuckerbraun BS, Hackam DJ, Mollen KP (2016) Peroxisome Proliferator-activated Receptor-gamma Coactivator 1-alpha (PGC1alpha) Protects against Experimental Murine Colitis. J Biol Chem 291:10184–10200. https://doi.org/10.1074/jbc.M115.688812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reifen R, Levy E, Berkovich Z, Tirosh O (2015) Vitamin A exerts its antiinflammatory activities in colitis through preservation of mitochondrial activity. Nutrition 31:1402–1407. https://doi.org/10.1016/j.nut.2015.05.011

    Article  CAS  PubMed  Google Scholar 

  26. Shi Y, Dierckx A, Wanrooij PH, Wanrooij S, Larsson NG, Wilhelmsson LM, Falkenberg M, Gustafsson CM (2012) Mammalian transcription factor A is a core component of the mitochondrial transcription machinery. Proc Natl Acad Sci U S A 109:16510–16515. https://doi.org/10.1073/pnas.1119738109

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  27. Alizadeh R, Salehi O, Rezaeinezhad N, Hosseini SA (2023) The effect of high intensity interval training with genistein supplementation on mitochondrial function in the heart tissue of elderly rats. Exp Gerontol 171:112039. https://doi.org/10.1016/j.exger.2022.112039

    Article  CAS  PubMed  Google Scholar 

  28. Yao K, Zhang WW, Yao L, Yang S, Nie W, Huang F (2016) Carvedilol promotes mitochondrial biogenesis by regulating the PGC-1/TFAM pathway in human umbilical vein endothelial cells (HUVECs). Biochem Biophys Res Commun 470:961–966. https://doi.org/10.1016/j.bbrc.2016.01.089

    Article  CAS  PubMed  Google Scholar 

  29. Baskol G, Baskol M, Yurci A, Ozbakir O, Yucesoy M (2006) Serum paraoxonase 1 activity and malondialdehyde levels in patients with ulcerative colitis. Cell Biochem Funct 24:283–286. https://doi.org/10.1002/cbf.1224

    Article  CAS  PubMed  Google Scholar 

  30. Kurutas EB (2016) The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. Nutr J 15:71. https://doi.org/10.1186/s12937-016-0186-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. El-Fadl IA, HM and Mohamed MFA, (2022) Targeting endoplasmic reticulum stress, Nrf-2/HO-1, and NF-kappaB by myristicin and its role in attenuation of ulcerative colitis in rats. Life Sci 311:121187. https://doi.org/10.1016/j.lfs.2022.121187

    Article  CAS  Google Scholar 

  32. Deng L, Guo H, Wang S, Liu X, Lin Y, Zhang R, Tan W (2022) The attenuation of chronic ulcerative colitis by (R)-salbutamol in repeated DSS-induced mice. Oxid Med Cell Longev 2022:9318721. https://doi.org/10.1155/2022/9318721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mei Y, Wang Z, Zhang Y, Wan T, Xue J, He W, Luo Y, Xu Y, Bai X, Wang Q, Huang Y (2019) FA-97, a New synthetic caffeic acid phenethyl ester derivative, ameliorates DSS-induced colitis against oxidative stress by activating Nrf2/HO-1 pathway. Front Immunol 10:2969. https://doi.org/10.3389/fimmu.2019.02969

    Article  CAS  PubMed  Google Scholar 

  34. Tan Y, Zheng C (2018) Effects of alpinetin on intestinal barrier function, inflammation and oxidative stress in dextran sulfate sodium-induced ulcerative colitis mice. Am J Med Sci 355:377–386. https://doi.org/10.1016/j.amjms.2018.01.002

    Article  PubMed  Google Scholar 

  35. Li Y, Pan X, Yin M, Li C, Han L (2021) preventive effect of lycopene in dextran sulfate sodium-induced ulcerative colitis mice through the regulation of TLR4/TRIF/NF-kappaB signaling pathway and tight junctions. J Agric Food Chem 69:13500–13509. https://doi.org/10.1021/acs.jafc.1c05128

    Article  CAS  PubMed  Google Scholar 

  36. Holmes EW, Yong SL, Eiznhamer D, Keshavarzian A (1998) Glutathione content of colonic mucosa: evidence for oxidative damage in active ulcerative colitis. Dig Dis Sci 43:1088–1095. https://doi.org/10.1023/a:1018899222258

    Article  CAS  PubMed  Google Scholar 

  37. Vanden Braber NL, Novotny Nunez I, Bohl L, Porporatto C, Nazar FN, Montenegro MA, Correa SG (2018) Soy genistein administered in soluble chitosan microcapsules maintains antioxidant activity and limits intestinal inflammation. J Nutr Biochem 62:50–58. https://doi.org/10.1016/j.jnutbio.2018.08.009

    Article  CAS  PubMed  Google Scholar 

  38. Pool H, Campos-Vega R, Herrera-Hernandez MG, Garcia-Solis P, Garcia-Gasca T, Sanchez IC, Luna-Barcenas G, Vergara-Castaneda H (2018) Development of genistein-PEGylated silica hybrid nanomaterials with enhanced antioxidant and antiproliferative properties on HT29 human colon cancer cells. Am J Transl Res 10:2306–2323

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang P, Zhang X, Xiong P, Zhong C, Zhou Z, Jia B, Liu X (2022) Renshen Baidu powder attenuated intestinal inflammation and apoptosis in ulcerative colitis rats through the inhibition of PI3K/AKT/NF-kappaB signaling pathway. Evid Based Complement Alternat Med 2022:5234025. https://doi.org/10.1155/2022/5234025

    Article  PubMed  PubMed Central  Google Scholar 

  40. Dudzinska E, Szymona K, Gil-Kulik P, Chomik P, Swistowska M, Gryzinska M, Kocki J (2019) Imbalance of controlled death in peripheral blood lymphocytes in crohn’s disease and ulcerative colitis. Medicina (Kaunas). https://doi.org/10.3390/medicina55060231

    Article  PubMed  Google Scholar 

  41. Kinra P, Turlapati S, Mehta A, Rai R (2005) Study of p53 and bcl-2 oncoproteins in ulcerative colitis with dysplasia. Med J Armed Forces India 61:125–129. https://doi.org/10.1016/S0377-1237(05)80006-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sun J, Zhang H, Guan L, Zhou H, Sun M (2015) Alpha-lipoic acid attenuates trinitrobenzene sulfonic acid-induced ulcerative colitis in mice. Int J Clin Exp Med 8:358–367

    PubMed  PubMed Central  Google Scholar 

  43. Siriviriyakul P, Werawatganon D, Phetnoo N, Somanawat K, Chatsuwan T, Klaikeaw N, Chayanupatkul M (2020) Genistein attenuated gastric inflammation and apoptosis in helicobacter pylori-induced gastropathy in rats. BMC Gastroenterol 20:410. https://doi.org/10.1186/s12876-020-01555-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu Y, Wei W, Liang S, Fang H, Cao J (2022) Esculentoside A could attenuate apoptosis and inflammation in TNBS-induced ulcerative colitis via inhibiting the nuclear translocation of NF-kappaB. Ann Transl Med 10:771. https://doi.org/10.21037/atm-22-2675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Becker C, Watson AJ, Neurath MF (2013) Complex roles of caspases in the pathogenesis of inflammatory bowel disease. Gastroenterology 144:283–293. https://doi.org/10.1053/j.gastro.2012.11.035

    Article  CAS  PubMed  Google Scholar 

  46. Leal RF, Ayrizono Mde L, Milanski M, Fagundes JJ, Moraes JC, Meirelles LR, Velloso LA, Coy CS (2010) Detection of epithelial apoptosis in pelvic ileal pouches for ulcerative colitis and familial adenomatous polyposis. J Transl Med 8:11. https://doi.org/10.1186/1479-5876-8-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Michael McClain R, Wolz E, Davidovich A, Pfannkuch F, Edwards JA, Bausch J (2006) Acute, subchronic and chronic safety studies with genistein in rats. Food Chem Toxicol 44:56–80. https://doi.org/10.1016/j.fct.2005.05.021

    Article  CAS  PubMed  Google Scholar 

  48. Kim IS (2021) Current perspectives on the beneficial effects of soybean isoflavones and their metabolites for humans. Antioxidants (Basel). https://doi.org/10.3390/antiox10071064

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

None

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. PharmD Program, Faculty of Pharmacy, University of Tabuk, Tabuk, 71491, Saudi Arabia

    Talal S. Alharbi, Ziyad S. Alshammari, Ziyad N. Alanzi & Fahad Althobaiti

  2. Biochemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, 33516, Egypt

    Mohammed A. F. Elewa

  3. Biochemistry Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt

    Khalid S. Hashem

  4. Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Mohammed M. H. Al-Gayyar

  5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, 71491, Saudi Arabia

    Mohammed M. H. Al-Gayyar

Authors
  1. Talal S. Alharbi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ziyad S. Alshammari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ziyad N. Alanzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fahad Althobaiti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammed A. F. Elewa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Khalid S. Hashem
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohammed M. H. Al-Gayyar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TSA, ZSA, ZNA, and FA were responsible for performing the biochemical analysis. MFE and KSH were responsible for performing the animal experiments. MFE and KSH performed pathological and immunohistochemistry analysis. TSA, ZSA, ZNA, and FA performed the statistical analysis. MMHA came up with the concept for the study and supervised the work. TSA, ZSA, ZNA, FA, MFE, and KSH helped develop and design the present study. All authors contributed to the writing of the manuscript and approved the final version.

Corresponding author

Correspondence to Mohammed M. H. Al-Gayyar.

Ethics declarations

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

The work protocol was approved by Institutional Animal Care and Use Committee, Beni-Suef University (BSU-IACUC-022-356).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alharbi, T.S., Alshammari, Z.S., Alanzi, Z.N. et al. Therapeutic effects of genistein in experimentally induced ulcerative colitis in rats via affecting mitochondrial biogenesis. Mol Cell Biochem 479, 431–444 (2024). https://doi.org/10.1007/s11010-023-04746-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-023-04746-8

Keywords

Search

Navigation