Identification of Active Component of Hachimi-jio-gan Ameliorating Diabetic Nephropathy

Chan Hum Park (Institute of New Frontier Research Team, Hallym Clinical and Translational Science Institute, Hallym University, Chuncheon, 24252, Republic of Korea)
Takashi Tanaka (Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, 852-8521, Japan)
Takako Yokozawa (Graduate School of Science and Engineering for Research, University of Toyama, Toyama, 930-8555, Japan)

Article ID: 4112



Conventional medicine-based Chinese herbal prescriptions, have fascinatedmuch attention due to their extensive and unique diversity of biologicaleffects without toxicity and/or adverse effects. Treatment with Hachimijio-gan (Ba-Wei-Di-Huang-Wan in Chinese) improved the dysregulatedlevels of hyperglycemic condition-related oxidative stress generation,advanced glycation endproduct generation, and renal function parameters.These results indicate that Hachimi-jio-gan is a prospective therapeuticagent against the pathogenesis of diabetic nephropathy. Cornel iridoidglycosides and polyphenol are the active compounds of Corni Fructus, theactive component of Hachimi-jio-gan, against kidney damage caused bydiabetes. Additionally, major components of the Corni Fructus, morronisideand 7-O-Galloyl-D-sedoheptulose (GS) are considered to be importantcontributors to prevent and/or delay the onset of kidney damage caused bydiabetes. Chief of all, GS is expected to be developed as a novel therapeuticdrug for the diabetes-accelerated kidney damage.


Diabetic nephropathy;Hachimi-jio-gan;Corni Fructus;Morroniside;7-O-Galloyl-D-sedoheptulose

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[1] Zoja, C., Xinaris, C., Macconi, D., 2020. Diabetic nephropathy: novel molecular mechanisms and ther-apeutic targets. Front Pharmacol. 11, 586892.

[2] Wolf, G., 2004. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Invest. 34(12), 785-796.

[3] Lim, A., 2014. Diabetic nephropathy – complications and treatment. Int J Nephrol Renovasc Dis. 7, 361-381.

[4] Heerspink, H.J.L., de Zeeuw, D., 2011. The kidney in type 2 diabetes therapy. Rev Diabet Stud. 8, 392-402.

[5] Fried, L.F., Emanuele, N., Zhang, J.H., Brophy, M., Conner, T.A., Duckworth, W., Leehey, D.J., McCullough, P.A., O’Connor, T.,Palevsky, P.M., Reilly, R.F., Seliger, S.L., Warren, S.R., Watnick, S., Peduzzi, P., Guarino, P., 2013. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 369(20), 1892-1903.

[6] Yamout, H., Lazich, I., Bakris, G.L., 2014. Blood pressure, hypertension, RAAS blockade, and drug therapy in diabetic kidney disease. Adv Chronic Kidney Dis. 21(3), 281-286.

[7] Alicic, R.Z., Neumiller, J.J., Johnson, E.J., Dieter, B., Tuttle, K.R., 2019. Sodium-glucose cotransporter 2 inhibition and diabetic kidney disease. Diabetes. 68(2), 248-257.

[8] Watanabe, K., Matsuura, K., Gao, P., Hottenbacher, L., Tokunaga, H., Nishimura, K., Imazu, Y., Reissenweber, H., Witt, C.M., 2011. Traditional Japanese Kampo medicine: clinical research between modernity and traditional medicine-The state of research and methodological suggestions for the future. Evid Based Complement Alternat Med. Article ID 513842.

[9] Yagi, H., Sato, R., Nishio, K., Arai, G., Soh, S., Okada, H., 2015. Clinical efficacy and tolerability of two Japanese traditional herbal medicines, Hachimijio-gan and Gosha-jinki-gan, for lower urinary tract symptoms with cold sensitivity. J Trad Complement Med. 5, 258-261.

[10] Kondo, T., 2016. Kidneys in Oriental and Occidental medicine. Integr Med Int. 3, 64-67.

[11] Lee, A.L., Chen, B.C., Mou, C.H., Sun, M.F., Yen, H.R., 2016. Association of traditional Chinese medicine therapy and the risk of vascular complications in patients with type II diabetes mellitus. Medicine. 95(3), 1-7.

[12] Yokozawa, T., Yamabe, N., Cho, E.J., Nakagawa, T., Oowada, S., 2004. A study on the effects to diabetic nephropathy of Hachimi-jio-gan in rats. Nephron Exp Nephrol. 97(2), e38-e48.

[13] Yamabe, N., Yokozawa, T., 2006. Activity of the Chinese prescription Hachimi-jio-gan against renal damage in the Otsuka Long-Evans Tokushima Fatty rat: a model of human type 2 diabetes mellitus. J Pharm Pharmacol. 58, 535-545.

[14] Mau, J.L., Chen, C.P., Hsieh, P.C., 2001. Antimicrobial effect of extracts from Chinese chive, cinnamon, and corni fructus. J Agric Food Chem. 49(1), 183-188.

[15] Chang, J.S., Chiang, L.C., Hsu, F.F., Lin, C.C., 2004. Chemoprevention against hepatocellular carcinoma of Cornus officinalis in vitro. Am J Chin Med. 32(5), 717-725.

[16] Liou, S.S., Liu, I.M., Hsu, S.F., Cheng, J.T., 2004. Corni fructus as the major herb of Die-Huang-Wan for lowering plasma glucose in Wistar rats. J Pharm Pharmacol. 56(11), 1443-1447.

[17] Vareed, S.K., Reddy, M.K., Schutzki, R.E., Nair, M.G., 2006. Anthocyanins in Cornus alternifolia, Cornus controversa, Cornus kousa and Cornus florida fruits with health benefits. Life Sci. 78(7), 777-784.

[18] Yamabe, N., Kang, K.S., Goto, E., Tanaka, T., Yokozawa, T., 2007. Beneficial effect of Corni Fructus, a constituent of Hachimi-jio-gan, on advanced glycation end-product-mediated renal injury in streptozotocin-treated diabetic rats. Biol Pharm Bull. 30(3), 520-526.

[19] Yamabe, N., Kang, K.S., Matsuo, Y., Tanaka, T., Yokozawa, T., 2007. Identification of antidiabetic effect of iridoid glycosides and low molecular weight polyphenol fractions of Corni Fructus, a constituent of Hachimi-jio-gan, in streptozotocin-induced diabetic rats. Biol Pharm Bull. 30(7), 1289-1296.

[20] Xu, H.Q., Hao, H.P., 2004. Effects of iridoid total glycoside from Cornus officinalis on prevention of glomerular overexpression of transforming growth factor beta 1 and matrixes in an experimental diabetes model. Biol Pharm Bull. 27(7), 1014-1018.

[21] Xu, H.Q., Hao, H.P., Zhang, X., Pan, Y., 2004. Morroniside protects cultured human umbilical vein endothelial cells from damage by high ambient glucose. Acta Pharmacol Sin. 25(4), 412-415.

[22] Xu, H., Shen, J., Liu, H., Shi, Y., Li, L., Wei, M., 2006. Morroniside and loganin extracted from Cornus officinalis have protective effects on rat mesangial cell proliferation exposed to advanced glycation end products by preventing oxidative stress. Can J Physiol Pharmacol. 84(12), 1267-1273.

[23] Yokozawa, T., Yamabe, N., Kim, H.Y., Kang, K.S., Hur, J.M., Park, C.H., Tanaka, T., 2008. Protective effects of morroniside isolated from Corni Fructus against renal damage in streptozotocin-induced diabetic rats. Biol Pharm Bull. 31(7), 1422-1428.

[24] Yokozawa, T., Kang, K.S., Park, C.H., Noh, J.S., Yamabe, N., Shibahara, N., Tanaka, T., 2010. Bioactive constituents of Corni Fructus: The therapeutic use of morroniside, loganin, and 7-O-galloyl-D-sedoheptulose as renoprotective agents in type 2 diabetes. Drug Discov Ther. 4(4), 223-234.

[25] Yamabe, N., Noh, J.S., Park, C.H., Kang, K.S., Shibahara, N., Tanaka, T., Yokozawa, T., 2010. Evaluation of loganin, iridoid glycoside from Corni Fructus, on hepatic and renal glucolipotoxicity and inflammation in type 2 diabetic db/db mice. Eur J Pharmacol. 648, 179-187.

[26] Landis-Piwowar, K.R., Huo, C., Chen, D., Milacic, V., Shi, G., Chan, T.H., Dou, Q.P., 2007. A novel prodrug of the green tea polyphenol (-)-epigallocatechin-3-gallate as a potential anticancer agent. Cancer Res. 67(9), 4303-4310.

[27] Mandel, S., Weinreb, O., Amit, T., Youdim, M.B.H., 2004. Cell signaling pathways in the neuroprotective actions of the green tea polyphenol (-)-epigallocatechin-3-gallate: implications for neurodegenerative diseases. J Neurochem. 88(6), 1555-1569.

[28] Vinson, J.A., Proch, J., Bose, P., Muchler, S., Taffera, P., Shuta, D., Samman, N., Agbor, G.A., 2006. Chocolate is a powerful ex vivo and in vivo antioxidant, an antiatherosclerotic agent in an animal model, and a significant contributor to antioxidants in the European and American Diets. J Agric Food Chem. 54(21), 8071-8076.

[29] Kowluru, R.A., Kanwar, M., 2007. Effects of curcumin on retinal oxidative stress and inflammation in diabetes. Nutr Metab. 4(8), 1-8.

[30] Baur, J.A., Pearson, K.J., Price, N.L., Jamieson, H.A., Lerin, C., Kalra, A., Prabhu, V.V., Allard, J.S., Lopez-Lluch, G., Lewis, K., Pistell, P.J., Poosala, S., Becker, K.G., Boss, O., Gwinn, D., Wang, M., Ramaswamy, S., Fishbein, K.W., Spencer, R.G., Lakatta, E.G., Couteur, D.L., Shaw, R.J., Navas, P., Puigserver, P., Ingram, D.K., de Cabo, R., Sinclair, D.A., 2006. Resveratrol improves health and survival

[31] of mice on a high-calorie diet. Nature. 444(7117), 337-342.

[32] Yamabe, N., Yokozawa, T., Oya, T., Kim, M., 2006. Therapeutic potential of (-)-epigallocatechin 3-O-gallate on renal damage in diabetic nephropathy model rats. J Pharmacol Exp Ther. 319(1), 228-236.

[33] Yamabe, N., Kang, K.S., Park, C.H., Tanaka, T., Yokozawa, T., 2009. 7-O-Galloyl-D-sedoheptulose is a novel therapeutic agent against oxidative stress and advanced glycation endproducts in the diabetic kidney. Biol Pharm Bull. 32(4), 657-664.


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