Chrysin promotes oral ulcer healing via modulating matrix metalloproteinases and vascular endothelial growth factor in rats

Articles in Press

Document Type : Original Article

Authors

1 Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre (NRC), 33 El Buhouth St., Dokki, Cairo 12622, Egypt

2 Narcotics, Ergogenics and Poisons Department, Medical Research and Clinical Studies Institute, National Research Centre (NRC), 33 El Buhouth St., Dokki, Cairo 12622, Egypt

10.22038/ijbms.2025.86895.18772

Abstract

Objective(s): Oral ulcers are a common inflammatory condition affecting the mucosal lining, often causing pain and discomfort. Chrysin is a natural flavonoid with well-documented anti-oxidant and anti-inflammatory properties. This study investigates the therapeutic effect of chrysin in an experimental model of acetic acid-induced oral ulcers in rats.
Materials and Methods: To establish an oral ulcerative mucositis model, 50% acetic acid was administered to the labial fornix of the inferior incisors. Chrysin gel (1% and 2%) was applied to the oral mucosa of rats with aggravated oral ulcerative mucositis that had developed after seven days of acetic acid application.
Results: Chrysin gel after 7 days reduced buccal ulcer and inhibited inflammation and degradation of collagen induced by acetic acid via suppression of MDA, TNF-α, NF-κβ, IL-6, and matrix metalloproteinases (MMP9) as well as stimulation of GSH and vascular endothelial growth factor (VEGF) enhancing healing effect. Histopathological results exhibited that chrysin alleviated the muscle bundle degeneration in the tongue and the acinar lining epithelium degeneration of submandibular salivary glands. 
Conclusion: Chrysin gel can be used as an oral gel via its anti-inflammatory activity and induction of VEGF. It can also be tested clinically in oral human ulcers. 

Keywords

Main Subjects

References

1. Hitomi S, Nodai T, Kokabu S, Shikayama T, Sago-Ito M,   Nakatomi Ch, et al. Hepcidin expression in the trigeminal ganglion and the oral mucosa in an oral ulcerative mucositis rat model. PloS One 2023; 18: e0284617-284638.
2. Donnelly JP, Bellm LA, Epstein JB, Sonis ST, Symonds RP. Antimicrobial therapy to prevent or treat oral mucositis. Lancet Infect Dis 2003; 3: 405-412.
3. Cheng H, Tian G, Liu H, Bai D, Zhang Y, Wang Q, et al. A molybdenum sulfide based nitric oxide controlled release oral gel for rapid healing of oral mucosal ulcers. J Colloid Interface Sci 2025; 678: 560-571.
4. Minhas S, Sajjad A, Kashif M, Taj F, Al Waddani H, Khurshid Z. Oral ulcers presentation in systemic diseases: An update. Open Access Maced J Med Sci 2019; 7: 3341-3348.
5. Hitomi S, Ono K, Terawaki K, Matsumoto Ch, Mizuno K, Yamaguchi K, et al. [6]-gingerol and [6]-shogaol, active ingredients of the traditional Japanese medicine hangeshashinto, relief oral ulcerative mucositis-induced pain via action on Na+ channels. Pharmacol Res 2017; 117: 288-302.
6. Dou X, Li G, Wang S, Shao D, Wang D, Deng X, et al. Probiotic-loaded calcium alginate/fucoidan hydrogels for promoting oral ulcer healing. Int J Biol Macromol 2023; 244: 125273.
7. Chen Y, Lei K, Li Y, Mu Zh, Chu T, Hu J, et al. Synergistic effects of NO/H2S gases on antibacterial, anti-inflammatory, and analgesic properties in oral ulcers using a gas-releasing nanoplatform. Acta Biomater 2025; 194: 288-304.
8. Siu A, Landon K, Ramos DM. Differential diagnosis and management of oral ulcers. Semin Cutan Med Surg 2015; 34: 171-177.
9. Susanto H, Saraswati ARM, Nugraha AP, Wicaksono S, Nur’aeny N, Ernawati DS. Topical adipose mesenchymal stem cell metabolites regulate the expression of MMP-1, MMP-9, EGF, TGF-β in oral mucosa ulcer rat model. Saudi Dent J 2024; 36: 932-939.
10. Salama A, EL-Kassaby MI, Refaat A, Mohasib RM. GC-MS and molecular docking analyses of phytochemicals from Calendula officinalis L. Hexane extract and evaluation of its antioxidant and wound healing properties in rats. Egypt J Chem 2024; 67: 1037-1058.
11. Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Sci STKE 2001; 2001: re21.
12. Anwar MA, El Gedaily RA, Salama A, Aboulthana WM, Kandil ZA, Abdel-dayem SI. Phytochemical analysis and wound healing properties of Malva parviflora L. ethanolic extract. J Ethnopharmacol 2024; 337: 118983.
13. Caley MP, Martins VLC, O’Toole EA. Metalloproteinases and wound healing. Adv Wound Care 2015; 4: 225-234.
14. Lim H, Heo MY, Kim HP. Flavonoids: Broad-spectrum agents on chronic inflammation. Biomol Ther 2019; 27: 241-253.
15. Salama AA, Allam RM. Promising targets of chrysin and daidzein in colorectal cancer: Amphiregulin, CXCL1, and MMP-9. Eur J Pharmacol 2021; 892: 173763.
16. Salama A, Elgohary R, Kassem AA, Asfour MH. Chrysin-phospholipid complex-based solid dispersion for improved anti-aging and neuroprotective effects in mice. Pharm Dev Technol 2023; 28: 109-123.
17. Salama A, Salama AH, Asfour MH. Tannic acid coated nanosuspension for oral delivery of chrysin intended for anti-schizophrenic effect in mice. Int J Pharm 2024; 656: 124085.
18. Yu C-H, Suh B, Shin I, Kim E-H, Kim D, Shin Y-J, et al. Inhibitory effects of a novel chrysin-derivative, CPD 6, on acute and chronic skin inflammation. Int J Mol Sci 2019; 20: 2607-2624.
19. Ayoub N, Badr N, Al-Ghamdi SS, Alsanosi S, Alzahrani AR, Abdel-Naim AB, et al. HPLC/MSn profiling and healing activity of a muco-adhesive formula of Salvadora persica against acetic acid-induced oral ulcer in rats. Nutrients 2021; 14: 28-45.
20. Ali MT, Al-Mahdy DA, El Fishawy AM, Salama A, Al‐Karmalawy AA, Otify AM. Phytochemical investigation, role in wound healing process and cytotoxicity of Sphagneticola trilobata: In vitro, in vivo and in silico approach. J Ethnopharmacol 2025; 342: 119394.
21. Meguellati H, Ouafi S, Saad S, Djemouai N. Evaluation of acute, subacute oral toxicity and wound healing activity of mother plant and callus of Teucrium polium L. subsp. geyrii Maire from Algeria. S Afr J Bot 2019;127:25-34.
22. Salama AAA, Mostafa RE, Elgohary R. Effect of L-carnitine on potassium dichromate-induced nephrotoxicity in rats: modulation of PI3K/AKT signaling pathway. Res Pharm Sci 2022;17: 153-163.
23. Salama A, Elgohary R. L-carnitine and Co Q10 ameliorate potassium dichromate-induced acute brain injury in rats targeting AMPK/AKT/NF-κβ. Int Immunopharmacol 2021; 101: 107867.
24. Bancroft JD, Layton C, Suvarna SK. Bancroft’s theory and practice of histological techniques. Churchill Livingstone Elsevier; 8 th ed. 2013.
25. Porter S, Leao J. Oral ulcers and its relevance to systemic disorders. Aliment Pharmacol Ther 2005; 21: 295-306.
26. Altenburg A, El-Haj N, Micheli C, Puttkammer M, Abdel-Naser MB, Zouboulis CC. The treatment of chronic recurrent oral aphthous ulcers. Deutsch Ärztebl Int 2014; 111: 665-673.
27. Riordain RN, Hodgson T. Content and quality of website information on the treatment of oral ulcers. Br Dent J 2014; 217: E15-E15.
28. Muñoz‐Corcuera M, Esparza‐Gómez G, González‐Moles M, Bascones‐Martínez A. Oral ulcers: Clinical aspects. A tool for dermatologists. Part I. Acute ulcers. Clin Exp Dermatol 2009; 34: 289-294.
29. Pu S, Liu Q, Li Y, Li R, Wu T, Zhang Z, et al. Montelukast prevents mice against acetaminophen-induced liver injury. Front Pharmacol 2019; 10: 1070-1080.
30. Kumar B, Vijayakumar M, Govindarajan R, Pushpangadan P. Ethnopharmacological approaches to wound healing—exploring medicinal plants of India. J Ethnopharmacol 2007; 114: 103-113.
31. Chokpaisarn J, Chusri S, Amnuaikit T, Udomuksorn W, Voravuthikunchai SP. Potential wound healing activity of Quercus infectoria formulation in diabetic rats. PeerJ 2017; 5: e3608-3624.
32. Fagundes FL, de Morais Piffer G, Périco LL, Rodrigues VP, Hiruma-Lima CA, Dos Santos RC. Chrysin modulates genes related to inflammation, tissue remodeling, and cell proliferation in the gastric ulcer healing. Int J Mol Sci 2020; 21: 760-772.
33. Kesarwala AH, Krishna MC, Mitchell JB. Oxidative stress in oral diseases. Oral Dis 2016; 22: 9-18.
34. Mohammadi Z, Sharif Zak M, Majdi H, et al. The effect of chrysin-curcumin-loaded nanofibres on the wound-healing process in male rats. Artif Cells Nanomed Biotechnol 2019; 47: 1642-1652.
35. Naz S, Imran M, Rauf A, Orhan IE, Shariati MA, Ul-Haq I, et al. Chrysin: Pharmacological and therapeutic properties. Life Sci 2019; 235: 116797.
36. Comino-Sanz IM, López-Franco MD, Castro B, Pancorbo-Hidalgo PL. The role of antioxidants on wound healing: A review of the current evidence. J Clin Med 2021; 10: 3558-3580.
37. Koc F, Tekeli MY, Kanbur M, Karayigit M, Liman BC. The effects of chrysin on lipopolysaccharide-induced sepsis in rats. J Food Biochem 2020; 44: e13359.
38. Schinella G, Tournier H, Prieto J, De Buschiazzo PM, Rıos J. Antioxidant activity of anti-inflammatory plant extracts. Life Sci 2002; 70: 1023-1033.
39. de Souza Farias SA, da Costa KS, Martins JBL. Analysis of conformational, structural, magnetic, and electronic properties related to antioxidant activity: Revisiting flavan, anthocyanidin, flavanone, flavonol, isoflavone, flavone, and flavan-3-ol. ACS Omega 2021; 6: 8908-8918.
40. Rabkin SW. Chapter Seven - The Role Matrix Metalloproteinases in the Production of Aortic Aneurysm. In: Khalil RA, ed. Progress in Molecular Biology and Translational Science. Vol 147. Academic Press; 2017: 239-265.
41. Liu L, Mai Y, Liang Y, Zhou X, Chen K. Experimental study on the effect of chrysin on skin injury induced by amiodarone extravasation in rats. Microvasc Res 2022; 139: 104257.
42. Jiang Y, Gong F-L, Zhao G-B, Li J. Chrysin suppressed inflammatory responses and the inducible nitric oxide synthase pathway after spinal cord injury in rats. Int J Mol Sci 2014; 15: 12270-12279.
43. Salama A, Asaad GF, Shaheen A. Chrysin ameliorates STZ-induced diabetes in rats: possible impact of modulation of TLR4/NF-κβ pathway. Res Pharm Sci 2022; 17: 1-11.
44. Raziyeva K, Kim Y, Zharkinbekov Z, Kassymbek K, Jimi S, Saparov A. Immunology of acute and chronic wound healing. Biomolecules 2021; 11: 700-725.
45. Hariono M, Yuliani SH, Istyastono EP, Riswanto FDO, Adhipandito CF. Matrix metalloproteinase 9 (MMP9) in wound healing of diabetic foot ulcer: Molecular target and structure-based drug design. Wound Med 2018; 22: 1-13.
46. Miao M, Peng M, Xing Z, Liu D. Effect of Shuangjinlian mixture on oral ulcer model in rat. Saudi J Biol Sci 2019; 26: 790-794.
47. Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res 2009; 153: 347-358.
48. Salama A, Elgohary R. Influence of chrysin on D‐galactose induced‐aging in mice: Up regulation of AMP kinase/liver kinase B1/peroxisome proliferator‐activated receptor‐γ coactivator 1‐α signaling pathway. Fundam Clin Pharmacol 2023; 37: 947-959.
Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 28 June 2025

Files

Share

How to cite

Statistics