Identification of the Anti-inflammatory and Wound Healing Effects of Cordyceps militaris Extract in Animal Models

Ouafa Rebai^1, , Nesrine Ouda Amari¹ and Fatiha Missoun¹

¹Department of Biology, University Abdelhamid Ibn Badis, Mostaganem, Algeria

Cite this paper:
Ouafa Rebai, Nesrine Ouda Amari and Fatiha Missoun. Identification of the Anti-inflammatory and Wound Healing Effects of Cordyceps militaris Extract in Animal Models. Journal of Food and Nutrition Research. 2023; 11(8):549-556. doi: 10.12691/jfnr-11-8-5

Abstract

Cordyceps militaris is one of the most well known medicinal entomopathogenic fungi and as such has been widely used for the treatment of various diseases. However, the pharmacological and biochemical activities of C. militaris have not been clearly elucidated. The evaluation of the anti-inflammatory activity of C. militaris was performed by the test for plantar edema induced by injection of carrageenan in mice. The percentage inhibition of edema and the percentage increase in paw edema volume were then evaluated. Wound healing effect of C. militaris extract was studied on an excision wound model in rats. Changes in wound area were measured regularly and the rate of wound contraction calculated, then the histopathological recovery was evaluated. The results in all animals were not shown signs of toxic effects, moribund, and mortality. Oral administration of C. militaris extract reduced significantly after 2 hours the paw edema induced by carrageenan in mice (8.96±2.83%, 6.25±2.70% and 4.92±2.22 % at doses of 100, 200 and 300mg/kg BW respectively); the histological study confirmed the decrease in inflammatory response. Topical application of C. militaris ointments at 5% and 10% showed an enhance rate of contraction and significantly decreased wound area than control group. With histological evidence of more collagen formation in the skin and early epithelization period with low scar area. C. militaris mushrooms definitely deserve to be considered as functional foods and also have great potential for medicinal use.

Keywords:
Cordyceps militaris anti-inflammatory wound healing mice rat

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]	Shweta, S., Komal A., Kumar, A, A brief review on the medicinal uses of Cordyceps militaris, Pharmacological Research Modern Chinese Medicine, (7). 100228. 2023.
[2]	Sung, G.H, Shrestha, B., Han, S.K. and Sung, J.M, Cultural Characteristics of Ophiocordyceps heteropoda Collected from Korea, Mycobiology, 39. 1–6. 2011.
[3]	Wang, Y., Stata, M., Wang, W., Stajich, J.E., White, M.M. and Moncalvo, J.M, Comparative genomics reveals the core gene toolbox for the fungusinsect symbiosis, MBio, 9( 3). 00636–18. 2018.
[4]	Xiang, R.K., Zhen, Y., Xiao, J.Z. and Yong, M.Z, Effects of cordyceps polysaccharides on pasting properties and in vitro starch digestibility of wheat starch, Food Hydrocolloids, 102. 1–8. 2020.
[5]	Cui, J.D, Biotechnological production and applications of Cordyceps militaris, a valued traditional Chinese medicine, Critical Reviews in Biotechnology, 5(4). 475-484. 2015.
[6]	Chan, J.S., Barseghyan, G.S., Asatiani, M.D. and Wasser, S.P, Chemical composition and medicinal value of fruiting bodies and submerged cultured mycelia of caterpillar medicinal fungus Cordyceps militaris CBS-132098 (Ascomycetes), International Journal of Medicinal Mushrooms, 17. 649–659. 2015.
[7]	Phull, A., Ahmed, M. and Park, H.J, Cordyceps militaris as a Bio Functional Food Source: Pharmacological Potential, Anti-Inflammatory Actions and Related Molecular Mechanisms, Microorganisms, 10. 405. 2022.
[8]	Shen, H.S., Shao, S., Chen, J.C. and Zhou, T, Antimicrobials from mushrooms for assuring food safety, Comprehensive Reviews in Food Science and Food Safety, 16(2). 316–329. 2017.
[9]	Meng, X., Li, Y., Li, S., Gan, R.Y. and Li, H.B, Natural products for prevention and treatment of chemical-induced liver injuries, Comprehensive Reviews in Food Science and Food Safety, 17(2). 472–495. 2018.
[10]	Li, P., Qin, X., Yang, H., Wang, Z.Y. and Lu, D, Therapeutic potentialand biological applications of Cordycepin and metabolic mechanisms in Cordycepin-producing fungi, Molecules, 24(12). 2231. 2019.
[11]	Guo, Z., Chen, W., Dai, G. and Huang, Y. Cordycepin suppresses the migration and invasion of human liver cancer cells by downregulating the expression of CXCR4, International Journal of Molecular Medicine, 45(1).141–150. 2020.
[12]	Liu, Y., Guo, Z.J. and Zhou, X.W. Chinese Cordyceps: Bioactive Components, Antitumor Effects and Underlying Mechanism-A Review, Molecules, 27(19). 6576. 2022
[13]	Jo, L.W., Choi, Y.J., Kim, H.J., Lee, J.Y., Nam, B.H., Lee, J.D, et al., The anti-inflammatory effects of water extract from Cordyceps militaris in murine macrophage, Mycobiology, 38(1). 46–51. 2010.
[14]	Rao, Y.K., Fang, S.H., Wu, W.S. and Tzeng, Y.M, Constituents isolated from Cordyceps militaris suppress enhanced inflammatory mediator’s production and human cancer cell proliferation, Journal of Ethnopharmacology, 131. 363–367. 2010.
[15]	Chen, X., Wu, G. and Huang, Z, Structural analysis and antioxidant activities of polysaccharides from cultured Cordyceps militaris, International Journal of Biological Macromolecules, 58. 18–22. 2013.
[16]	Phull, A.R. and Kim, S.J, Fucoidan as bio-functional molecule: Insights into the anti-inflammatory potential and associated molecular mechanisms, Journal of Functional Foods, 38. 415–426. 2017.
[17]	Segal, J.P., Tresidder, K.A., Bhatt, C., Gilron, I. and Ghasemlou, N.J, Circadian control of pain and neuroinflammation, Journal of Neuroscience Research, 96.1002–1020. 2018.
[18]	Jedrejko, K.J., Lazur, J. and Muszynska, B, Cordyceps militaris: An Overview of Its Chemical Constituents in Relation to Biological Activity, Foods, 10. 2634. 2021.
[19]	Das, G., Shin, H.S., Leyva-Gómez, G., Del Prado-Audelo, M.L., Cortes, H., Singh, Y.D., et al. Cordyceps spp.: A Review on Its Immune-Stimulatory and Other Biological Potentials, Frontiers in Pharmacology, 11. 2020.
[20]	Miao, M., Yu, W.Q., Li, Y., Sun, Y.L. and Guo, S.D, Structural Elucidation and Activities of Cordyceps militaris-Derived Polysaccharides: A Review, Frontiers in Nutrition, 31(9). 898674. 2022.
[21]	da Silva, S.M.M., Costa, C.R.R., Gelfuso, G.M., Guerra, E.N.S, Nóbrega, Y.K.M., Gomes, S.M, et al., Wound Healing Effect of Essential Oil Extracted from Eugenia dysenterica DC (Myrtaceae) Leaves, Molecules, 24(2). 2019.
[22]	Sharifi-Rad, J., Butnariu, M., Ezzat, S.M., Adetunji, C.O., Imran, M., Sobhani, S.R;, et al., Mushrooms-Rich Preparations on Wound Healing: From Nutritional to Medicinal Attributes, Frontiers in Pharmacology, 11. 567518. 2020.
[23]	Tottoli, E.M., Dorati, R., Genta, I., Chiesa, E., Pisani, S. and Conti, B, Skin Wound Healing Process and New Emerging Technologies for Skin Wound Care and Regeneration, Pharmaceutics, 12. 735. 2020.
[24]	Alwashli, M., Al Sobarry, Y., Cherrah and Alaoui, K, Anti-inflammatory and analgesic effects of ethanol extract of Dracaena cinnabari balf, as endemic plant in Yemen, International Journal of pharma and biosciences, 3. 96-106. 2012.
[25]	Bignotto, L., Rocha, J., Sepodes, B., Eduardo-Figueira, M., Pinto, R., Chaud, M., et al., Anti-inflammatory effect of lycopene on carrageenan-induced paw oedema and hepatic ischaemia-reperfusion in the rat, British Journal of Nutrition, 102(1). 126-33. 2009.
[26]	Balazs, L., Okolicany, J., Ferrebee, M., Tolley, B. and Tigyi, G, Topical application of the phospholipid growth factor lysophosphatidic acid promotes wound healing in vivo, American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 280(2). 466-72. 2001.
[27]	Fenglin, L., Li, L., Xiaokun,. J, Yan, L. and Hengwei, L, Analysis of seven mineral elements in cultivated fruiting bodies of Cordyceps militaris, E3S Web of Conferences, 185:04019ICEEB. 2020.
[28]	Li, J., Shen, B., Nie, S., Duan, Z. and Chen, K, A combination of selenium and polysaccharides: promising therapeutic potential, Carbohydrate Polymers, 206. 163–173. 2019.
[29]	Long, H., Qiu, X., Cao, L., Liu, G., Rao, Z. and Han, R, Toxicological safety evaluation of the cultivated Chinese cordyceps, Journal of Ethnopharmacology, 268. 113600. 2021.
[30]	Suwannasaroj, K., Srimangkornkaew, P., Yottharat, P. and Sirimontaporn, A, The Acute and Sub-Chronic Oral Toxicity Testing of Cordyceps militaris in Wistar Rats, นิพนธตนฉบับ ว กรมวิทย พ, 63(3). 628-647. 2021.
[31]	De Garde Elion Itou, R., Sanogo, R., Ossibi, A.W.E., Ntandou, F.G.N., Ondelé, R., Pénemé, B.M., et al., Anti-inflammatory and analgesic effects of aqueous extract of stem bark of Ceiba pentandra Gaertn, Pharmacology and Pharmacy, 5(12). 2014-512121. 2014.
[32]	Jeong, J.W., Jin, C.Y., Kim, G.Y., Lee, J.D., Park, C., Kim, G.D., et al., Anti-Inflammatory Effects of Cordycepin via Suppression of Inflammatory Mediators in BV2 Microglial Cells, International Immunopharmacology, 10. 1580–1586. 2010.
[33]	Ye, H., Wang, Y., Jenson, A.B. and Yan, J, Identification of inflammatory factor TNFα inhibitor from medicinal herbs, Experimental and Molecular Pathology, 100(2). 307-311. 2016.
[34]	Smiderle, F.R., Baggio, C.H., Borato, D.G., Santana-Filho, A.P., Sassaki, G.L., Iacomini, M., et al., Anti-Inflammatory Properties of the Medicinal Mushroom Cordyceps militaris Might Be Related to Its Linear (1→3)-β-D-Glucan, Plos One, 9(10):e110266. 2014.
[35]	Jo, W.S., Choi, Y.J., Mm, H.J., Lee, J.Y., Nam, B.H., Lee, J.D., et al., The Anti-Inflammatory Effects of Water Extract from Cordyceps militaris in Murine Macrophage, Mycobiology, 38. 46–51. 2010.
[36]	Chiu, C.P., Liu, S.C., Tang, C.H., Chan, Y., El-Shazly, M., Lee, C.L., et al., Anti-inflammatory Cerebrosides from Cultivated Cordyceps militaris, Journal of Agricultural and Food Chemistry, 64(7). 1540-8. 2016.
[37]	Ernest, D., Yimta, F., Stéphanie, M.K. and Théophile, D, Activité cicatrisante d’une pomade à base des feuilles de Kalanchoe crenata, International Journal of Research and Analytical Reviews, 6(4). 2349-5138. 2019.
[38]	Bahramikia, S. and Yazdanparast, R, Phytochemistry and medicinal properties of Teucrium polium L. (Lamiaceae), Phytotherapy Research, 26(11). 1581-93. 2012.
[39]	Lin, W.H., Tsai, M.T., Chen, Y.S., Hou, R.C.W., Hung, H.F., Li, C.H., et al., Improvement of sperm production in subfertile boars by Cordyceps militaris supplement, American Journal of Chinese Medicin, 35(4). 631-41. 2007.
[40]	Pooja, P. and Anand, S, Studies on the biology of Cordyceps militaris: A medicinal mushroom from North West Himalaya, KAVAKA, 43. 35-40. 2014.
[41]	Misset, B. and Desport, J.C, Nutrition et cicatrisation, Actualités Pharmaceutiques, 59. 20-22. 2020.
[42]	Fontaine, J. and Raynaud-Simon, A, Pressure sores in geriatric medicine: the role of nutrition, La Presse Médicale, 37(7-8). 1150-7. 2008.
[43]	Ellinger, S. and Stehle, P, Efficacy of vitamin supplementation in situations with wound healing disorders: results from clinical intervention studies, Current Opinion in Clinical Nutrition and Metabolic Care, 12(6). 588-95. 2009.
[44]	Wang, X., Liu, B., Xu, Q., Sun, H., Shi, M., Wang, D., et al., Feng GHK-Cu-liposomes accelerate scald wound healing in mice by promoting cell proliferation and angiogenesis, Journal of Tissue Repair and Regeneration, 25(2). 270-278. 2017.
[45]	Jahromi, M.A.M., Zangabad, P.S., Basri, S.M.M., Zangabad, K.S., Ghamarypour, A., Aref, A.R., et al. Nanomedicine and advanced technologies for burns: Preventing infection and facilitating wound healing, Advanced Drug Delivery Reviews, 123. 33-64. 2018.
[46]	Chow, O. and Barbul, A, Immunonutrition: Role in Wound Healing and Tissue Regeneration, Advanced wound care (New Rochelle), 3(1). 46-53. 2014
[47]	Borkow, G., Okon-Levy, N. and Copper, J.G, Oxide impregnated wound dressing: biocidal and safety studies, Wounds, 22(12). 301-10. 2010.
[48]	Jedrejko, K., Kała, K., Ziaja, K.S., Krakowska,. A, Zieba, P., Marzec, K., et al., Improvement of sperm production in subfertile boars by Cordyceps militaris supplement, Antioxidants, 11. 1861. 2022.