Zhi mu

Scientific Name(s): Anemarrhena asphodeloides Bunge. Family: Liliaceae.

Common Name(s): Anemarrhena rhizome or zhi mu

Uses

Numerous in vitro and animal studies on the anti-inflammatory, antimicrobial, antiplatelet, antidiabetic, and anticancer activity of A. asphodeloides and its application for improved learning and memory have been published.

Dosing

Zhi mu is available from commercial manufacturers. The most common dosage forms are the whole herb, capsules, and teas for treating “cold and bitter” conditions. Manufacturers suggest using three to six 500 mg capsules two to three times daily as a tea. However, some capsule formulations are a proprietary blend of herbs and are available in several strengths.

Contraindications

Avoid use in patients with known allergy or hypersensitivity reactions to A. asphodeloides or its constituents.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Information regarding adverse reactions with A. asphodeloides is limited.

Toxicology

Limited clinical studies are available on the toxicology of A. asphodeloides . There were no effects on mortality, body weight, or organ systems in rats receiving a 5 g/kg dose of WIN-34B (2 kg of dried Lonicera japonica flowers and 1 kg of A. asphodeloides root). Long-term toxicity studies in rats receiving WIN-34B at 1,000 or 2,000 mg/kg for 13 weeks resulted in no notable abnormalities.

Botany

A. asphodeloides belongs to the family Liliaceae and is an evergreen perennial native to China, Korea, and Japan. The plant grows to a height of 0.5 m and a width of 1 m, and the thin leaves grow up to 70 cm long. The clusters of small, white to light-purple flowers are hermaphroditic (having both male and female organs) and blossom from August to September. 1 , 2 , 3

History

A. asphodeloides is listed in the Pharmacopoeia of the People's Republic of China and used medicinally to remove heat, quench fire, support the production of body fluid, and alleviate dryness syndrome. 4 In Korea, mainland China, and Japan, the rhizomes have been traditionally used for their anodyne, antidiabetic, anti-inflammatory, antipyretic, diuretic, antidepressant, antiplatelet aggregator, and sedative properties. 5 , 6 , 7 The most commonly prescribed triple-drug Chinese herbal formula in Taiwan for insomnia in 2002 contained A. asphodeloides . 8 In traditional Chinese medicine, the rhizomes are also used for the treatment of lung disease. 9

Chemistry

The rhizome's medicinal activity is primarily associated with mangiferin and steroidal saponins, such as sarasapogenin and timosaponin AII and BII. 10 The foaming properties of the saponins have commercial applications and are added to shampoos, liquid detergents, toothpastes, and beverages. 11 Additional studies review the known chemical components of the rhizome. 5 , 7 , 12 A pharmacokinetics study in rats on the intravenous (IV) and oral administration of the pharmacologically active constituent timosaponin B-II document oral bioavailability of only 1.1%. 13

Uses and Pharmacology

Numerous in vitro and animal studies on the anti-inflammatory, antimicrobial, antiplatelet, antidiabetic, and anticancer activity of A. asphodeloides and its application for improved learning and memory have been published.

Anti-inflammatory
In vitro and animal data

Anemasaponin B, a steroidal saponin isolated from the rhizomes of A. asphodeloides , exhibited anti-inflammatory activity in a macrophage cell line stimulated by LPS. 6 Anemasaponin B also attenuated production of pro-inflammatory mediators and inhibited inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-alfa, and interleukin-6 expression by downregulating their transcript. WIN-34B, an herbal formulation containing A. asphodeloides , inhibited carrageenan-induced paw edema and croton oil-induced ear edema in mice at 400 mg/kg, similar to the anti-inflammatory effects of celecoxib 100 mg/kg. 7 WIN-34B also exhibited more effective antinociceptive and anti-inflammatory activity than that of celecoxib in osteoarthritic animal models. No adverse GI or cardiac effects were documented. 7 , 14

Antimicrobial
In vitro data

A methanol extract of A. asphodeloides rhizome containing nysal exhibited strong antifungal activity against the plant pathogenic fungi Magnaphothe grisea and Rhizoctonia solani , and the plant pathogenic oomycete Phytophthora capsici . Nyasol also inhibited the mycelial growth of Colletotrichum orbiculare , P. capsici , Pythium ultimum , R. solani , and Cladosporium cucumerinum . 2 An isolated compound similar to nyasol from an ethyl acetate A. asphodeloides rhizome extract inhibited the growth of 38 strains of fungi and 5 strains of bacteria. 15 An herbal preparation containing A. asphodeloides may improve immune system functioning through the production of various cytokines. 16

Antiplatelet
In vitro data

Six steroidal saponins isolated from the rhizome of A. asphodeloides inhibited platelet aggregation in human blood and activated partial thromboplastin times. 12 Timosaponin A-III exhibited the strongest effect on hemolysis, anemarrhenasaponin IA had a slight effect, and the other saponins had no effect.

In vivo data

Timosaponin B-II inhibited blood coagulation and formation of a thrombus in rabbits, but had no thrombolytic effect in a rabbit arteriovenous shunt model. 17 Timosaponin B-II may enhance fibrinolytic activity and accelerate thrombolysis at higher doses.

Diabetes
In vitro data

A. asphodeloides inhibited alpha-glucosidase (reducing the impact of carbohydrates on blood glucose) and angiotensin-converting enzyme. 3

In vivo data

A rhizome hot water extract of A. asphodeloides reduced blood glucose levels in alloxan-induced diabetic mice. The hypoglycemic mechanism may involve inhibition of hepatic gluconeogenesis or glucogenolysis. 18 Oral administration of a rhizome water extract (90 mg/kg) of A. asphodeloides reduced blood glucose levels and serum insulin levels in KK-Ay mice. 19 The active components of the extract were mangiferin and its glucoside, which may exert antidiabetic activity by increasing insulin sensitivity. 20 Mangiferin prevented progression of diabetic nephropathy in streptozotocin-induced diabetic rats by decreasing urinary albumin excretion and improving creatinine clearance. 21 The mechanism involved inhibition of several key pathological pathways, thus reducing progression of diabetic nephropathy.

Cancer
In vitro data

Timosaponin A-III, a saponin isolated from the rhizome of A. asphodeloides , is an autophagy- and apoptosis-inducing agent to cancer cells. Timosaponin A-III exhibited cytotoxicity to several carcinoma cell lines, including hepatocellular carcinoma cells (HepG2), human breast carcinoma cells (MCF-7), human nasopharyngeal carcinoma cells (SUNE-1), and human cervical epithelioid carcinoma cells (HeLa). 22 Its mechanism of action may include inducing apoptosis through caspase-4 activation, induction of transcriptional changes in breast cancer cells, and inhibition of mammalian target of rapamycin C1 in cancer cells, which has negative consequences for protein translation and cell growth, often leading to activation of autophagy. 23 The rhizomes of A. asphodeloides directly inhibited the growth of 2 gastric cancer cell lines, MKN45 and KATO-III cells, in a dose-dependent manner. 24 A. asphodeloides induced apoptosis by activating caspase 3 or a caspase 3–like protease. A traditional Chinese medicine prescription, which contains A. asphodeloides 14.3 g, inhibited the growth of MCF-7 and MDA-MB-231 human breast cancer cells by inducing apoptosis, blocking cell cycle progression by regulating cell cycle–related factor, activating the mitochondrial pathway, and modulating the Bcl-2 family of proteins in mice. 25 Sarsasapogenin inhibits growth of human 1547 osteosarcoma cells and HepG2 human hepatoma cells by inducing cell apoptosis through cell cycle arrest in G2/M phase. 9 Sarsasapogenin-induced apoptosis may involve activation of key signaling molecules regulating mitochondrial dysfunction. 26

Learning and memory
In vivo data

Mangiferin reversed scopolamine-induced learning deficits in mice by acetylcholine esterase inhibition, cholinergic receptor stimulation, and anti-inflammatory activity. 10 Scopolamine reduced acetylcholine levels, and mice treated with oral mangiferin 20 mg/kg recovered the reduced acetylcholine levels by 75%. Timosaponins may also protect against learning and memory impairment caused by amyloid beta-peptide in rats by promoting scavenging of free radicals. 27 Timosaponin A-III improved scopolamine-induced learning and memory deficits in mice by inhibiting activation of proinflammatory cytokines and acetylcholinesterase. 28 Several compounds isolated from A. asphodeloides also improved learning and memory impairment by upregulating neurotrophic factors that promote neural cell survival, neuronal differentiation, and prevention of neuronal apoptosis in the central and peripheral nervous systems. 29 , 30 , 31

Other pharmacologic activity
Antioxidant

The effect of 3 sapogenins was examined on induced superoxide production in human neutrophils. 32 The effect of the antioxidant activity was in the order of sarsasapogenin > tigogenin > hecogenin. A rhizome water extract of A. asphodeloides exhibited free-radical scavenging activity. 33 , 34

Cardiovascular system

Saponins from the rhizome of A. asphodeloides saponin may modulate the function of vein endothelial cells. 35 Timosaponin A-III induced relaxation of phenylephrine-induced vascular contraction by enhancing release of nitric oxide from endothelial cells. 36 , 37

Chronic fatigue syndrome

A review article on traditional Chinese medicine documents the use of the rhizome of A. asphodeloides to treat chronic fatigue syndrome. 38

Corneal opacity

One clinical study documents the therapeutic use of traditional Chinese herbs (including A. asphodeloides ) combined with subconjunctiva injection of sodium iodide to effectively treat corneal opacity. 39 A pharmacokinetic study found that mangiferin passes the blood-retina barrier after a single IV administration; therefore, its antioxidant activity may be beneficial in treating eye diseases. 40

Depression

At a dose of 50 mg/kg, sarsasapogenin inhibited monoamine oxidase (MAO)-A activity (17%) and MAO-B activity (15%) in mouse brains and increased noradrenaline and serotonin levels. 41

Estrogenic activity

Ethanol extracts of A. asphodeloides have documented estrogen modulatory activity. 42 Additional studies also document estrogen-like activity. 43 , 44

Hyperlipidemia

Saponins may reduce total cholesterol, triglycerides, and low-density lipoproteins and may improve microcirculation. 5 , 45 , 46

Osteoporosis

Saponins stimulated osteoblast reproduction and alkaline phosphatase activity. Mangiferin and neomangiferin inhibited tartrate-resistant acid phosphatase, a biochemical marker of osteoclast function and bone resorption. 47

Prostatitis

No difference was found in patients being treated with minocycline versus a Chinese herbal combination, which included the rhizome of A. asphodeloides , for prostatitis. The Chinese herbal combination enhanced the vitality of sperm more effectively than minocycline. 48

Testosterone

A rhizome diethyl ether extract of A. asphodeloides exhibited testosterone 5 alpha-reductase inhibitory activity. 49

Dosage

Zhi mu is available from commercial manufacturers. The most common dosage forms are the whole herb, capsules, and teas for treating “cold and bitter” conditions. Manufacturers often suggest using 3 to six 500 mg capsules 2 to 3 times daily as a tea. However, some capsule formulations are a proprietary blend of herbs and are available in several strengths.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

Caution is advisable in patients taking A. asphodeloides –containing products and anticancer, anti-inflammatory, antidepressant, antipsychotic, antibacterial, or hormone replacement therapy because limited information is available on potential drug-herb interactions with these medications.

Adverse Reactions

Information regarding adverse reactions with the use of A. asphodeloides is limited.

Toxicology

Limited clinical studies are available on the toxicology of A. asphodeloides . There were no effects on mortality, body weight, or organ systems in rats receiving a 5 g/kg dose of WIN-34B (2 kg of dried L. japonica flowers and 1 kg of A. asphodeloides root). Long-term toxicity studies in rats receiving WIN-34B at 1,000 or 2,000 mg/kg for 13 weeks resulted in no notable abnormalities.

Bibliography

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2. Park HJ, Lee JY, Moon SS, Hwang BK. Isolation and anti-oomycete activity of nyasol from Anemarrhena asphodeloides rhizomes. Phytochemistry . 2003;64(5):997-1001.
3. He K, Li X, Chen X, et al. Evaluation of antidiabetic potential of selected traditional Chinese medicines in STZ-induced diabetic mice. J Ethnopharmacol . 2011;137(3):1135-1142.
4. Zhou T, Zhu Z, Wang C, et al. On-line purity monitoring in high-speed counter-current chromatography: application of HSCCC-HPLC-DAD for the preparation of 5-HMF, neomangiferin and mangiferin from Anemarrhena asphodeloides Bunge. J Pharm Biomed Anal . 2007;44(1):96-100.
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6. Kim JY, Shin JS, Ryu JH, et al. Anti-inflammatory effect of anemarsaponin B isolated from the rhizomes of Anemarrhena asphodeloides in LPS-induced RAW 264.7 macrophages is mediated by negative regulation of the nuclear factor-kappaB and p38 pathways. Food Chem Toxicol . 2009;47(7):1610-1617.
7. Kang M, Jung I, Hur J, et al. The analgesic and anti-inflammatory effect of WIN-34B, a new herbal formula for osteoarthritis composed of Lonicera japonica Thunb and Anemarrhena asphodeloides BUNGE in vivo. J Ethnopharmacol . 2010;131(2):485-496.
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11. Chen YF, Yang CH, Chang MS, Ciou YP, Huang YC. Foam properties and detergent abilities of the saponins from Camellia oleifera . Int J Mol Sci . 2010;11(11):4417-4425.
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18. Nakashima N, Kimura I, Kimura M, Matsuura H. Isolation of pseudoprototimosaponin AIII from rhizomes of Anemarrhena asphodeloides and its hypoglycemic activity in streptozotocin-induced diabetic mice. J Nat Prod . 1993;56(3):345-350.
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25. Hsu YL, Yen MH, Kuo PL, et al. San-Zhong-Kui-Jian-Tang, a traditional Chinese medicine prescription, inhibits the proliferation of human breast cancer cell by blocking cell cycle progression and inducing apoptosis. Biol Pharm Bull . 2006;29(12):2388-2394.
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29. Tsukamoto S, Wakana T, Koimaru K, Yoshida T, Sato M, Ohta T. 7-hydroxy-3-(4-hydroxybenzyl)chroman and broussonin b: neurotrophic compounds, isolated from Anemarrhena asphodeloides BUNGE, function as proteasome inhibitors. Biol Pharm Bull . 2005;28(9):1798-1800.
30. Zhong L, Tan J, Ouyang S, Xu JP. Effects of Saponin B from Anemarrhena asphodeloides Bunge on tau hyperphosphorylation induced by beta-amyloid peptide (25-35) in rats. Nan Fang Yi Ke Da Xue Xue Bao . 2006;26(8):1106-1109.
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37. Lim H, Nam JW, Seo EK, Kim YS, Kim HP. (-)-Nyasol (cis-hinokiresinol), a norneolignan from the rhizomes of Anemarrhena asphodeloides , is a broad spectrum inhibitor of eicosanoid and nitric oxide production. Arch Pharm Res . 2009;32(11):1509-1514.
38. Chen R, Moriya J, Yamakawa J, Takahashi T, Kanda T. Traditional Chinese medicine for chronic fatigue syndrome. Evid Based Complement Alternat Med . 2010;7(1):3-10.
39. Zhang R-J, Zhao Y-W, Tang F-C, Hu S-S, Zhou Y-Y. Clinical effect of traditional Chinese herbs combined with sodium iodide in treating corneal opacity. Int J Ophthal . 2007;7(1):217-219.
40. Hou Y, Fan S, Zhang H, Gu Y, Yu X, Li B. Pharmacokinetic study of mangiferin in rat plasma and retina using high-performance liquid chromatography. Mol Vis . 2010;16:1659-1668.
41. Ren LX, Luo YF, Li X, Zuo DY, Wu YL. Antidepressant-like effects of sarsasapogenin from Anemarrhena asphodeloides BUNGE (Liliaceae). Biol Pharm Bull . 2006;29(11):2304-2306.
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43. Jeong SJ, Higuchi R, Ono M, Kuwano M, Kim YC, Miyamoto T. cis-hinokiresinol, a norlignan from Anemarrhena asphodeloides , inhibits angiogenic response in vitro and in vivo. Biol Pharm Bull . 2003;26(12):1721-1724.
44. Paruthiyil S, Cvoro A, Zhao X, et al. Drug and cell type-specific regulation of genes with different classes of estrogen receptor beta-selective agonists. PLoS One . 2009;4(7):e6271.
45. Li C, Liu Z, Han B, Liu K. Effect of saponins from Anemarrhena asphodeloides bunge on blood lipid concentration of hyperlipemia quail. J Mol Cell Card . 2006;40(6):884.
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47. Qin L, Han T, Zhang Q, et al. Antiosteoporotic chemical constituents from Er-Xian Decoction, a traditional Chinese herbal formula. J Ethnopharmacol . 2008;118(2):271-279.
48. Chen ZX, Luo YJ. Prescription of common Anemarrhena rhizome and amur corktree bark in the treatment of prostatitis in M. urealyticum accompanied by asthenospermia. Chin J Clin Rehabil . 2006;10(43):76-78.
49. Matsuda H, Sato N, Yamazaki M, Naruto S, Kubo M. Testosterone 5alpha-reductase inhibitory active constituents from Anemarrhenae Rhizoma. Biol Pharm Bull . 2001;24(5):586-587.

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