Antiobesity-, and glucose metabolism -, and lipid metabolism-improving effects and active components in the mycelia and fruiting bodies of Cordyceps militaris (Vuill.) Fr. fermented on pupae of silkworms (Bombyx mori)

Wada, Mikiyo; Mitushima, Yuta; Sasaki, Tomoki; Sadahiro, Yusaku; Kawahara, Teppei; Hitora, Yuki; Murata, Yuki; Nishi, Oumi; Hino, Masato; Kusakabe, Takahiro

doi:10.51094/jxiv.733

##article.authors##

Wada, Mikiyo Graduate School of Pharmaceutical Sciences, Kumamoto University https://orcid.org/0000-0001-8126-6692
Mitushima, Yuta Graduate School of Pharmaceutical Sciences, Kumamoto University
Sasaki, Tomoki Department of Bioresource Sciences Faculty of Agriculture, Kyushu University
Sadahiro, Yusaku Graduate School of Pharmaceutical Sciences, Kumamoto University
Kawahara, Teppei Graduate School of Pharmaceutical Sciences, Kumamoto University
Hitora, Yuki Graduate School of Pharmaceutical Sciences, Kumamoto University
Murata, Yuki Graduate School of Pharmaceutical Sciences, Kumamoto University
Nishi, Oumi Department of Bioresource Sciences Faculty of Agriculture, Kyushu University
Hino, Masato Department of Bioresource Sciences Faculty of Agriculture, Kyushu University
Kusakabe, Takahiro Department of Bioresource Sciences Faculty of Agriculture, Kyushu University

DOI:

https://doi.org/10.51094/jxiv.733

キーワード:

Cordyceps militaris、 silkworm pupae、 obesity、 liver fat、 hyperglycemia、 hyperlipidemia

抄録

Cordyceps militaris (Vuill.) Fr. (CM) is an entomopathogenic fungus that has traditionally been used as a herbal medicine, particularly as a tonic, throughout Asia. In this study, we show for the first time that not only the fruiting body (FB) but also mycelia (pupa part; PM) of C. militaris fermented in silkworm (Bombyx mori) pupa (SPCM) can reduce body weight, visceral fat, liver fat, blood glucose, cholesterol, insulin, and leptin levels in a high-fat diet-induced obese mouse model. Pair-feeding examination revealed that appetite suppression somewhat contributed to the effectiveness of SPCM. Ultraperformance liquid chromatography–high-resolution tandem mass spectrometry analysis and feature-based molecular networking analysis revealed that the PM contained a molecular network of beauveriolides, including beauveriolides I and III, that are potent inhibitors of cholesterol synthesis, whereas the FB contained a network of spermidines that exhibit antiobesity effects and improve glucose and lipid metabolism.

利益相反に関する開示

Mikiyo Wada received recearch funding for this study from KAICO Ltd, Tomoki Sasaki is employee of KAICO Ltd,The other authors declare no conflicts of interest associated with this manuscript

ダウンロード *前日までの集計結果を表示します

ダウンロード実績データは、公開の翌日以降に作成されます。

引用文献

An, Y., Li, Y., Wang, X., Chen. Z., Xu, H., Wu, L., ...Yu, L. (2018). Cordycepin reduces weight through regulating gut microbiota in

high-fat diet-induced obese rats. Lipids in Health and Disease, 17(1), 276. https://doi. org/10.1186/s12944-018-0910-6.

Aron, A.T., Gentry, E.C., McPhail, K.L., Nthias, L.F., Nothias-Esposito, M., Bouslimani, A., …Dorrestein, P.C. (2020). Reproducible molecular networking of untargeted mass spectrometry data using GNPS. Nature Protocols, 15(6), 1954-1991. https://doi.org/10.1038/s41596-020-0317-5.

Blight, E.D. & Dyer, W.J. (1959). A rapid method of total lipid extraction and purification. Canadian Journal of Biochemistry and Physiology, 37(8), 911-7. https://doi.org/10.1139/o59-099

Brandfon, S., Eylon, A., Khanna, D., & Parmar, M.S. (2023). Advances in Anti-obesity Pharmacotherapy: Current Treatments, Emerging Therapies, and Challenges. Cureus, 15(10), e46623. https://doi.org/10.7759/cureus.46623

Choi, H., Kang, M., Jeong, S., Seo, M.J, Kang, B. W., Jeong, Y. K., & Kim, J. (2012). Effect of Dongchunghacho (Cordyceps militaris) on Hyperglycemia and Dyslipidemia in Type 2 Diabetic db/db Mice. Food Science and Biotechnology, 21(4), 1157-1162. https://doi.org/10.1007/s10068-012-0151-9

Choi, H., Jang, Y., Kim, M., Seo M. J., Won, B. K., Jeong, Y. K & Kim, J. (2014). Cordyceps militaris alleviates non-alcoholic fatty liver disease in ob/ob mice. Nutrition Research and Practice, 8(2), 172-176. https://doi.org/10.4162/nrp.2014.8.2.172.

Das, M. & G. Kumar, S. (2021). Potential role of mycosterols in hyperlipidemia – A review. Steroids, 166, 108775. https://doi.org/10.1016/j.steroids.2020.108775.

Das, S. K., Masuda, M., Sakurai, A. & Sakakibara, M. (2010). Medicinal uses of the mushroom Cordyceps militaris: Current state and prospects. Fitoterapia, 81(8), 961–968.

Druce, M. & Bloom, S. R. The regulation of appetite. (2006). Archives of Disease in Childhood, 91(2), 183-187. https://doi.org/10.1136/adc.2005.073759.

Gao, M., Zhao, W., Li, C., Xie, X., Li, M., Bi, Y., Fang, F., Du, Y. & Liu, Xiaojun. (2018). Spermidine ameliorates non-alcoholic fatty liver disease through regulating lipid metabolism via AMPK. Biochemical and Biophysical Research Communications, 505, 93e98. https://doi.org/10.1016/j.bbrc.2018.09.078

Gong, X., Li, T., Wan, R & Sha, L. (2021). Cordycepin attenuates high-fat diet-induced non-alcoholic fatty liver disease via down-regulation of lipid metabolism and inflammatory responses. International Immunopharmacology, 91, 107173. https://doi.org/10.1016/j.intimp. 2020.107173

Hsieh, W., Hsu, M., Lin, W., Xiao, Y., Lyu, P., Liu, Y., ... Chung, J. (2021). Ergosta-7, 9 (11), 22-trien-3β-ol Interferes with LPS Docking to LBP, CD14, and TLR4/MD-2 Co-Receptors to Attenuate the NF-κB Inflammatory Pathway In Vitro and Drosophila. Int. International Journal of Molecular Sciences, 22(12), 6511. https://doi.org/10.3390/ijms22126511

Huang, R., Zhu, Z., Wu, S., Wang, J., Chen, M., Liu, W., ...Ding, Y. (2022). Polysaccharides from Cordyceps militaris prevent obesity in association with modulating gut microbiota and metabolites in high-fat diet-fed mice. Food Research International, 157, 111197. https://doi.org/10.1016/j.foodres.2022.111197

Huang, S., Zou, Y., Tang, H., Zhuang, J., Ye, Z., Wei, T., ... Zheng, Q. (2023).

Cordyceps militaris polysaccharides modulate gut microbiota and improve metabolic disorders in mice with diet-induced obesity. The Journal of the Science of Food and Agriculture, 103(4), 1885-1894. https://doi.org/10.1002/jsfa.12409

Jang, D., Lee, E., Lee, S., Kwon, Y., Kang, K. S., Kim, C. & Kim, D. (2022). System-level investigation of anti-obesity effects and the potential pathways of Cordyceps militaris in ovariectomized rats. BMC Complementary Medicine and Therapies, 22(1), 132. https://doi.org/10.1186/s12906-022-03608-y.

Jędrejko, K. J., Lazur, J. & Muszyńska, B. (2021). Cordyceps militaris: An Overview of Its Chemical Constituents in Relation to Biological Activity. Foods, 10 (11), 2634. https://doi.org/10.3390/foods10112634.

Jędrejko, K., Kała, K., Sułkowska-Ziaja, K., Krakowska, A., Zięba, P., Marzec, K., ...Muszyńska B. (2022). Cordyceps militaris—Fruiting Bodies, Mycelium, and Supplements: Valuable Component of Daily Diet. Antioxidants (Basel), 11, 1861. https://doi.org/10.3390/antiox11101861.

Kim, S. B., Ahn, B., Kim, M., Ji, H., Shin, S., Hong, I., Kim, C., Hwang, B. & Lee, M. (2014). Effect of Cordyceps militaris extract and active constituents on metabolic parameters of obesity induced by high-fat diet in C58BL/6J mice. Journal of Ethnopharmacology, 151(1), 478-484. https://doi.org/10.1016/j.jep.2013.10.064.

Kimura, I., Hitora, Y., Sadahiro, Y., Kawahara, T. & Tsukamoto, S. (2023) A monoacylglyceryltrimethylhomoserine, 21F121-A, containing a branched acyl group from Penicillium glaucoroseum. Journal of Natural Medicines 77, 992-997. https://doi.org/10.1007/s11418-023-01735-5.

Kontogiannatos. D., Koutrotsios, G., Xekalaki, S & Zervakis, G. I. (2021). Biomass and Cordycepin Production by the Medicinal Mushroom Cordyceps militaris—A Review of Various Aspects and Recent Trends towards the Exploitation of a Valuable Fungus. Journal of Fungi, 7(11), 986. https://doi.org/10.3390/jof7110986.

Lee, B., Chen, C., Hsu, Y., Chuang, P., Shih, M. & Hsu, W. (2021) Polysaccharides Obtained from Cordyceps militaris Alleviate Hyperglycemia by Regulating Gut Microbiota in Mice Fed a High-Fat/Sucrose Diet. Foods,10(8), 1870. https://doi.org/10.3390/foods10081870.

Li, Y., Li, Y., Wang, X., Xu, H., Wang, C., An, Y., …Yu, L. (2018). Cordycepin Modulates Body Weight by Reducing Prolactin Via an Adenosine A1 Receptor. Current Pharmaceutical Design, 24(27), 3240-3249. https://doi.org/10.2174/1381612824666180820144917.

Li, Y., Talbot, C.L., Chandravanshi, B., Ksiazek, A., Sood, A., Chowdhury, K.H., ... Chaurasia, B. (2022). Cordyceps inhibits ceramide biosynthesis and improves insulin resistance and hepatic steatosis. Scientific Reports,12, 7273 https://doi.org/10.1038/s41598-022-11219-3

Namatame, I., Tomoda, H., Si, S., Yamaguchi, Y. Masuma, R. & Omura, S. (1999a). Beauveriolides, specific inhibitors of lipid droplet formation in mouse macrophages, produced by Beauveria sp. FO-6979. The Journal of Antibiotics, 52(1), 1-6. https://doi.org/10.7164/antibiotics.52.1.

Namatame, I., Tomoda, H., Tabata, N., Si, S. & Omura, S. (1999b). Structure Elucidation of Fungal Beauveriolide III, a Novel Inhibitor of Lipid Droplet Formation in Mouse Macrophages. The Journal of Antibiotics, 52 (1), 7-12. https://doi.org/10.7164/antibiotics.52.7.

Namatame I, Tomoda H, Ishibashi S & Omura, S. 2004. Antiatherogenic activity of fungal beauveriolides, inhibitors of lipid droplet accumulation in macrophages. Proceedings of the National Academy of Sciences of the United States of America,101(3), 737–742. https://doi.org/10.1073/pnas.0307757100.

Niu, Y., Tao, R., Liu, Q., Tian, J., Ye, F., Zhu, P. & Zhu, H. (2010). Improvement on lipid metabolic disorder by 3'-deoxyadenosine in high-fat-diet-induced fatty mice.

The American Journal of Chinese Medicine, 38(6), 1065-1075. https://doi.org/10.1142/S0192415X10008470

Nothias, L.F., Petras, D., Schmid, R., Dührkop, K., Rainer, J., Sarvepalli, A., ...Dorrestein, P.C. (2020). Feature-based molecular networking in the GNPS analysis environment. Nature Methods, 17(9), 905–908. https://doi.org/10.1038/s41592-020-0933-6.

Ohshiro, T., Kobayashi, K., Ohba, M., Matsuda, D., Rudel, L.L., Takahashi, T., Doi, T., & Tomoda, H. (2017). Selective inhibition of sterol O-acyltransferase 1 isozyme by beauveriolide III in intact cells. Scientific reports, 7, 4163. https://doi.org/10.1038/s41598-017-04177-8.

Sadasivan, S.K., Vasamsetti, B., Singh, J., Marikunte, V.V., Oommen, A.M., M.R., Jagannath, R., & Rao, P. (2014). Exogenous administration of spermine improves glucose utilization and decreases bodyweight in mice. European Journal of Pharmacology, 729, 94-99. https://doi.org/10.1016/j.ejphar.2014.01.073

Shi, Y., Zhang, J., Wang, Y., Ding, K., Yan, Y., Xia, C., ... Xu, J. (2022). The untapped potential of spermidine alkaloids: Sources, structures, bioactivities and syntheses. European Journal of Medicinal Chemistry, 240, 114600. https://doi.org/10.1016/j.ejmech.2022.114600.

Sung, G., Hywel-Jones, N. L., Sung, J., Luangsa-ard, J. J., Shrestha, B. & Spatafora, J. W. (2007). Phylogenetic classification of Cordyceps and the clavicipitaceous fungi. Studies in Mycology, 57, 5–59. https://doi.org/10.3114/sim.2007.57.01.

Takahashi S., Tamai M., Nakajima, S., Kato H., Johno, H, Nakamura T. & Kitamura, M. (2012). Blockade of adipocyte differentiation by cordycepin. British Journal of Pharmacology,167 (3), 561–575, 2012. https://doi.org/10.1111/j.1476-5381.2012.02005.x

Tomoda, H. & Ōmura, S. (2007). Potential therapeutics for obesity and atherosclerosis: Inhibitors of neutral lipid metabolism from microorganisms. Pharmacology & Therapeutics, 115 (3), 375–389. https://doi.org/10.1016/j.pharmthera.2007.05.008.

Yamazaki, T., Kishimoto, K. & Ezaki, O. (2012). The ddY mouse: a model of postprandial hypertriglyceridemia in response to dietary fat. Journal of Lipid Research, 53(10), 2024-2037. https://doi.org/10.1194/jlr.M023713

Yu, M., Yue, J., Hui, N., Zhi, Y., Hayat, K., Yang X., … Zhou, P. (2021). Anti-Hyperlipidemia and Gut Microbiota Community Regulation Effects of Selenium-Rich Cordyceps militaris Polysaccharides on the High-Fat Diet-Fed Mice Model. Foods, 10(10), 2252. https://doi.org/10.3390/foods10102252.

Yu, S., Chen, S. T., Li, W. Dubey, N.K., Chen, W., Chuu, J., Leu, S. & Deng, W. (2015). Hypoglycemic Activity through a Novel Combination of Fruiting Body and Mycelia of Cordyceps militaris in High-Fat Diet-Induced Type 2 Diabetes Mellitus Mice. Journal of Diabetes Research, 2015, Article ID 723190. https://doi.org/10.1155/2015/723190

Yu, W., Wang, X., Ji, H., Miao, M., Zhang, B., Li, H., ... Guo, S. (2023). International Journal of Biological Macromolecules, 239 (2023), 124293. 124293https://doi.org/10.1016/j.ijbiomac.2023.124293

Yin, Y., Chen, B., Song, S. Li, B. Yang, X. & Wanga, C. (2020). Production of Diverse Beauveriolide Analogs in Closely Related Fungi: a Rare Case of Fungal Chemodiversity. mSphere, 5(5), e00667-20. https://doi.org/10.1128/msphere.00667-20

Wang, X., Gao,Y., Zhang, M., Zhang, H., Huang, J. & Li, L. (2020). Genome mining and biosynthesis of the Acyl-CoA:cholesterol acyltransferase inhibitor beauveriolide I and III in Cordyceps militaris. Journal of Biotechnology, 309,85–91. https://doi.org/10.1016/j.jbiotec.2020.01.002

Zhabinskii, V.N., Drasar, P. & Khripach, V.A. (2022). Structure Biological Activity of Ergostane-Type Steroids from Fungi. Molecules, 27(7), 2103. https://doi.org/10.3390/molecules27072103

Zhao, H., Li. M., Liu, Liang., Li, D., Zhao. L., Wu, Z., Zhou. M., Jia, L. & Yang, F. (2023). Cordyceps militaris polysaccharide alleviates diabetic symptoms by regulating gut microbiota against TLR4/NF-κB pathway. International Journal of Biological Macromolecules, 230 (2023) 123241. https://doi.org/10.1016/j.ijbiomac.2023.123241