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Ginseng leaf-stem: bioactive constituents and pharmacological functions

Hongwei Wang1, Dacheng Peng2 and Jingtian Xie2*

Author Affiliations

1 Section of Endocrinology, Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637, USA

2 Ben May Department for Cancer Research, Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637, USA

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Chinese Medicine 2009, 4:20  doi:10.1186/1749-8546-4-20

The electronic version of this article is the complete one and can be found online at: http://www.cmjournal.org/content/4/1/20


Received:30 April 2009
Accepted:22 October 2009
Published:22 October 2009

© 2009 Wang et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Ginseng root is used more often than other parts such as leaf stem although extracts from ginseng leaf-stem also contain similar active ingredients with pharmacological functions. Ginseng's leaf-stems are more readily available at a lower cost than its root. This article reviews the pharmacological effects of ginseng leaf-stem on some diseases and adverse effects due to excessive consumption. Ginseng leaf-stem extract contains numerous active ingredients, such as ginsenosides, polysaccharides, triterpenoids, flavonoids, volatile oils, polyacetylenic alcohols, peptides, amino acids and fatty acids. The extract contains larger amounts of the same active ingredients than the root. These active ingredients produce multifaceted pharmacological effects on the central nervous system, as well as on the cardiovascular, reproductive and metabolic systems. Ginseng leaf-stem extract also has anti-fatigue, anti-hyperglycemic, anti-obesity, anti-cancer, anti-oxidant and anti-aging properties. In normal use, ginseng leaf-stem extract is quite safe; adverse effects occur only when it is over dosed or is of poor quality. Extracts from ginseng root and leaf-stem have similar multifaceted pharmacological activities (for example central nervous and cardiovascular systems). In terms of costs and source availability, however, ginseng leaf-stem has advantages over its root. Further research will facilitate a wider use of ginseng leaf-stem.

Background

Ginseng is cultivated in China, Korea, Japan and Russia, as well as in the United States and Canada. Ginseng is one of the most well-known herbal medicines widely used in East Asia as a tonic, restorative and anti-aging agent in traditional Chinese medicine [1-8]. Ginseng is a slow-growing, deciduous, perennial plant of the Araliaceae family which includes Panax ginseng (Renshen, Chinese or Korean ginseng), Panax japonicus (Japanese ginseng) and Panax quinquefolius (Xiyangshen, American ginseng) [9]. Ginseng is used as a dietary supplement in the United States [10].

In Chinese medicine practice, ginseng root is the most commonly used part of the plant. It contains ginsenosides as the major bioactive components known to have complex and multiple pharmacological effects [2,11].

While ginseng leaf-stem was less studied [12], a recent report indicates that American ginseng leaf contains similar pharmacologically active ingredients more abundantly than ginseng root [13]. Panax ginseng leaf-stem is rich in containing several ginsenosides. Therefore, this article reviews the constituents and pharmacological profile of ginseng leaf-stem, including its chemical components, biological activities, pharmacological properties and adverse effects.

Bioactive constituents

Ginseng leaf-stem extract contains a number of important bioactive constituents [14,15], namely ginsenosides, polysaccharides, triterpenoids and flavonoids [16]. Among other constituents, ginsenosides exert main pharmacological actions of ginseng root, leaf-stem and berry [17]. More than 30 ginsenosides have been isolated and identified [10] in Panax quinquefolius, Panax ginseng and Panax japonicus [11,18-20]. Ginsenoside content in the leaf of Panax quinquefolius is higher than in the root[21]. However, significant variations in content exist between major ginsenosides in the leaf [13,22-24]. Re and Rd are the major ginsenosides in the ginseng leaf [13,21]. Ginseng leaf-stem may be a valuable source for Re, Rd and Rb2 [23].

Seasonal fluctuations, geographical differences and age variations may affect the ginsenoside content in ginseng leaf. According to a study using solid phase extraction and high performance liquid chromatography (HPLC) on American ginseng leaf and [25], Rh1, Rg2, 20(R)-Rg2 and Rg3 accounted for 4.71% in leaf and 5.35% in berry of American. A RP-HPLC (Reversed-Phase High Performance Liquid Chromatography) study on Rh2 saponin of American ginseng leaf studied the transform ratio of 20(S)-ginsenoside Rh2 [26]. Using HPLC with UV detection at 203 nm, Shi et al. found that the seven major ginsenosides (Rg1, Re, Rb1, Rc, Rb2, Rb3 and Rd) were present in various parts of Chinese ginseng of various ages [27]. These results also indicate that ginsenoside content is higher in the leaf and root hair but lower in the stem than that in other parts of the plant and that the total content of ginsenosides in the leaf decreases with age [25-27].

Yan et al. developed a simple and reliable liquid chromatography/electron spray ionization mass spectrometry (LC-ESI/MS) assay to detect Chinese ginseng leaf-stem saponin (GLSS) in methanol and rat plasma and to construct the fingerprints of GLSS reference substances and plasma samples. Thirty-one compounds were detected in GLSS, ten of which were identified in the fingerprints of reference substances and the spiked plasma sample. Twelve compounds in GLSS, including C7, C8, C14, C15, C18, Re, C24, Rb(1), Rc, Rb(2), Rb(3) and Rd were easily absorbed and might be the metabolites of GLSS [28]. Moreover, two new compounds were separated from Panax ginseng leaf [29].

Pharmacological functions

Ginseng leaf-stem extracts exhibit multifaceted pharmacological actions in the central nervous system (CNS), cardiovascular system, growth-metabolism system and immune system [30-32] (Table 1). Ginseng leaf-stem extracts also possess anti-fatigue, anti-hyperglycemic, anti-obesity, anti-cancer, anti-oxidant and anti-aging activities as described below.

Table 1. Major pharmacological effects of ginseng leaf-stem extracts

Effects on the CNS

An early study revealed that ginseng leaf extract caused CNS depression and neuroleptic effects in mice [30-32]. The extract-induced CNS depression was observed along with a reduction of spontaneous and exploratory movements and the potentiation of hypnotic actions of hexobarbital. Analgesic and anticonvulsant activities were also confirmed in this study. Moreover, ginseng leaf extract inhibited conditioned avoidance response in the pole climbing test.

Effects of saponins from Chinese ginseng leaf-stem on memory, learning and biogenic monoamines of the brain were also examined in rats [33]. Results showed that ginseng root saponins improved learning and memory in normal male rats, while the effects of ginseng leaf-stem saponins on anti-electroconvulsive shock-induced impairment of memory consolidation were more intense. Both leaf-stem and root saponins raised the levels of biogenic monoamines significantly in the brains of normal rats. In another study, the effects of ginseng leaf-stem saponins on learning and memory of one-way avoidance were evaluated in shuttle-box rats [34]. The data indicated that ginseng leaf-stem saponins facilitated the acquisition of learning and memory and ameliorated scopolamine and cycloheximide amnesia. Effects of ginseng leaf extract on the CNS were also examined in various species of ginseng [35]. For example, Siberian ginseng leaf extract was found to have anti-fatigue, anti-stress and anti-depressive effects. An In vivo study revealed that a Chinese herbal formula consisting of ginseng leaf, namely Jiannaoning, improved memory function in rats with cerebral ischemia [36] and that Jiannaoning regulated the levels of interleukin-2, interleukin-6 and neuropeptide Y in rat brain. Moreover, ginsenosides from ginseng leaf-stem affected the level of glucocorticoid receptor (GR) in brain cytosol in heat-damaged rats [37]. Binding activities of GR in brain, lung and liver cytosols and the expression levels of GR mRNA in brain and liver cytosols were all higher in the ginsenosides-treated groups than the untreated control group. Ginsenosides reduced GR binding activity in viscera which may have induced the expression of GR mRNA. Another study [38], however, indicated that extract from the aboveground part of Chinese ginseng (including ginseng leaf-stem) had a weaker effect or no effect on the animal behavior compared to ginseng root.

Effects on cardiovascular system

Ginseng leaf extracts had preservative effects on the cardiac and vascular systems and prevented myocardial ischemia in animal experiments [39]. In anaesthetized open-chest dogs treated with American ginseng leaf extract, the myocardial infarct size, activity of serum creatine kinase (CK), lactate dehydrogenase (LDH), the contents of serum free fatty acid (FFA) and lactoperoxidase (LPO) significantly decreased, whereas the activity of serum superoxide dismutase (SOD) and Gtutathione peroxidase (GSH-Px) significantly increased. At the same time, myocardial blood flow was increased and coronary vascular resistance was decreased. The results indicate that the ginseng leaf extract protected against myocardial ischemia by modifying metabolic dysfunction of FFA, inhibiting oxygen free radical-mediated peroxidation of membrane lipids, enhancing endogenous antioxidase activity and increasing myocardial blood supply. Another study [40] confirmed that ginseng leaf-stem extract protects against acute myocardial infarction (AMI) in rats by promoting angiogenesis in the infracted or ischemic area of myocardium.

A previous study demonstrated that Chinese ginseng leaf-stem extracts had beneficial effects on the preservation of cardiac and coronary vascular functions after cold storage for 12 hours in isolated rat hearts. The extracts increased coronary artery dilation and coronary flow in response to an endothelial-dependent vasodilator (ACh), protected the coronary endothelium, prevented coronary vascular dysfunction induced by reperfusion injury after hypothermic heart preservation and attenuated reperfusion damage of vascular smooth muscle cells [41].

Furthermore, American ginseng leaf-stem saponins were reported to antagonize the effects of norepinephrine (NE), potassium chloride and calcium chloride on the isolated aortic strips of rabbits [42]. The saponins inhibited intracellular and extracellular Ca2+-dependent contractions induced by NE in rabbit aortic strips. Another study revealed that American ginseng saponins inhibited the contractility of guinea pig papillary muscle [43]. A randomized controlled trial with double blinding indicated that Shenshao Tongguan Piana, a proprietary Chinese medicine formula containing ginseng leaf-stem extract, effectively treated angina pectoris in coronary heart disease (CHD) with effective rates of 94.7% and 67.0% in the treatment and control groups respectively [44].

Several studies revealed that ginseng leaf-stem extract affected atrial natriuretic peptide (ANP) gene expression in older rats [45,46] and that both ginseng leaf-stem and root extracts increased the ANP mRNA in rats. An in vivo study on American ginseng leaf extracts showed that the expression of vascular endothelial growth factor (VEGF) and mean micro-vessel density were higher in the ginseng leaf saponin groups than in the vehicle model group and that the expression of basic fibroblast growth factor (bFGF) was higher in the ginseng leaf saponin groups than in the vehicle model group [40], suggesting that ginseng leaf-stem extracts may protect myocardium from ischemic injury in rats with AMI by up-regulating VEGF and bFGF in myocardial cells thereby inducing angiogenesis.

Effects on growth and intermediary metabolism

Ginsenosides from Chinese ginseng leaf-stem significantly increased the protein and RNA contents of muscles and liver in rats and that ginsenosides accelerated the growth of young pigs. It was suggested that ginsenosides may have direct influence on RNA and protein synthesis [32].

Ginsenosides from ginseng leaf-stem coupled with aerobic exercise lowered serum lipid, regulated lipid metabolism, promoted antioxidation and enhanced immune activity [47]. Oral administration of ginsenosides extracted from ginseng leaf-stem significantly inhibited the rise of total lipid, cholesterol and triglyceride in rabbits [48].

Anti-hyperglycemic effects

One third of diabetic patients use dietary supplements or alternative medicines [49]. Previous studies indicated that ginseng is an important alternative medicine to treat diabetes and both Chinese and American ginseng roots had anti-hyperglycemic effect [50-53]. Ginseng berry extract reduced hyperglycemia and body weight in C57BL/6J ob/ob mice [54,55] and C57BL/Ks db/db mice [56]. Ginseng leaf-stem extracts also had this anti-diabetic effect [21,57,58]. Ginseng leaf and root extracts increased the basal content and glucose-dependent secretion of insulin in blood [59].

Active ingredients and hypoglycemic properties of American ginseng leaf were examined with high performance liquid chromatography (HPLC) in diabetic ob/ob mice [21]. The results indicated that American ginseng leaf extract significantly reduced blood glucose levels. Intraperitoneal glucose tolerance test showed that the leaf extract significantly improved glucose disposal. Thus, American ginseng leaf extract, with its high ginsenoside yield, may be an inexpensive alternative to the root for diabetic treatment. Similar anti-hyperglycemic activity was observed in a study on total ginsenosides of Chinese ginseng leaf-stem [60].

Anti-obesity effect

Obesity is a serious medical disorder that may cause a myriad of health problems, such as heart disease, hypertension and adult-onset diabetes. Berry, root and leaf extracts of American and Chinese ginseng as well as total ginsenosides of Chinese ginseng leaf-stem had anti-obesity activities in animals and that American ginseng leaf extract significantly reduced body weight in adult ob/ob mice [21,54,56,60,61].

Anti-cancer effect

Anti-cancer effect of ginseng leaf-stem is an important pharmacological function. Anti-cancer effects of Chinese ginseng leaf extract were found after co-administration of acidic polysaccharide from Chinese ginseng leaf enhanced therapeutic effects and reduced hematopoietic complications induced by systemic chemotherapy or radiation therapy [62]. Acidic polysaccharide may be a novel and potent immunotropic agent to improve cellular immunity and an anti-cancer drug to treat urological cancer patients. Extract of Indian ginseng leaf (Ashwagandha) had anti-cancer activities [63]. Total saponins from Panax ginseng leaf-stem protected against cyclophosphamide (a commonly used anti-cancer compound)-induced genotoxicity and apopotosis in bone marrow cells and peripheral lymphocytes in mice [64]. Thus, ginseng leaf extracts can be a new source for anti-cancer drugs.

Kitts et al. also confirmed that ginsenoside Rh2 extracted from American ginseng leaf induced cytotoxity in cultured leukemia THP-1 cells [65]. Flow cytometry of cells stained with annexin V-fluorescein isothiocyanate and propidium iodide showed that the Rh2 from ginseng leaf significantly increased apoptosis at a concentration that inhibited cell viability by 50% (LC50). Ginsenoside (Rh2) may be the active ingredient for anti-cancer activity in ginseng leaf [65].

Anti-oxidant activities

Extracts from American ginseng root and berry possess antioxidant properties [5,13,35,66,67] and so does ginseng leaf extract. In streptozotocin-induced diabetic rats, oral administration of wild ginseng leaf extract (WGLE) effectively suppressed lipid peroxidationin diabetic rats [68]. Similar antioxidant activities were observed in cultivated and wild Korean ginseng leaf extracts [69]. It was confirmed that water, methanol and ethanol extracts form freeze-dried leaves of wild ginseng exhibited scavenging activities towards DPPH (2,2-diphenyl-2-picrylhydrazyl hydrate), superoxide anion and hydroxyl radicals. Among various solvent used to extract wild ginseng leaves, ethanol yielded the highest DPPH, hydroxyl radical scavenging and ferrous ion chelating activity [70].

Not surprisingly, the saponin extracted from American ginseng leaf-stem (0.25-1 mg/ml) also demonstrated antioxidant properties in cultured rat cardiomyocytes [5]. Moreover, Rb1, Rb2 and Rb3 extracted from Panax ginseng leaf-stem restored the action potentials of free radical damaged cells [71].

Other effects

Anti-fatigue effect

Chinese ginseng leaf-stem extract had anti-fatigue effects. In rats, orally administered saponins extracted from Chinese ginseng leaf-stem significantly prolonged swimming time, inhibited the increase of blood lactic acid and reduced liver and rectus femurs muscle glycogen. Ginseng leaf-stem extract also facilitated the synthesis of protein and expression of mRNA in liver and muscle tissues [72].

Anti-ulcer effect

Panax ginseng root is used in Chinese medicine to treat gastrointestinal disorders. Research showed that the crude polysaccharide fraction from ginseng leaf exhibited potent anti-ulcer activity against acute gastric lesions in mice [3].

Anti-diuretic effect

Anti-diuresis was another pharmacological property of ginsenoside from Panax ginseng leaf-stem. Total ginsenosides from the leaf-stem helped retain water and Na+, increased K+ excretion and reduced the ratio of urinary Na+/K+ in rats [73].

Anti-aging effects

A clinical trial showed that Tongbu No.1, a proprietary Chinese medicine formula containing ginseng leaf, improved various some symptoms related to aging, improved immune and endocrinal functions, scavenged free radicals and adjusted intestinal flora [74].

Inductive differentiation effect

Ginsenosides from Panax ginseng leaf-stem induced the differentiation of all types of acute nonlymphocytic leukemia cells in primary culture [75].

Saponins, as well as the combination of saponins and oil, significantly enhanced the immune response in mice to vaccination against foot-and-mouth disease (FMDV) [76]. Co-administered with the saponins, FMDV antigen induced a significantly higher IgG response than FMDV antigen used alone.

Potential adverse effects

Both animal experiments and clinical trials have shown that normal use of ginseng is safe [50,76]. Asian ginseng is classified as a generally safe herb along with feverfew, garlic, ginkgo, saw palmetto, St. John's wort and valerian [77]. Ginseng, including ginseng root and leaf-stem, may exhibit minor adverse effects [78]. A systematic review of adverse effects of ginseng suggested that Panax ginseng monopreparations are rarely associated with adverse events or drug interactions [79]. The adverse effects in clinical trials or toxic effects in animal experiments were attributed to improper use or poor quality of ginseng [80-83].

Acute toxic effects

Toxicity of ginsenosides from Panax ginseng leaf-stem was determined in mice. When mice were given ginsenosides per oral, no death occurred [31,32]. Another report [84] indicated that the LD50 values of crude saponin fraction and saponins of ginseng leaves were 381 mg/kg and 299 mg/kg respectively.

Subacute toxic effects

Ginseng leaf-stem extracts did not affect the number of erythrocytes, leukocytes, thrombocytes, the amount of hemoglobin or renal function in subacute toxic experiments in rats [32]. Body weight, food consumption and liver weight of rats increased [32]. Brain, heart, lungs, liver, spleen, kidneys, stomach, testes and ovaries were normal on gross examination and histopathological study. These findings suggested that high quality ginseng leaf-stem and its preparations were safe in normal use.

Limitations of current research

(1) Most studies on the constituents of ginseng leaf-stem extract have been qualitative. Quantitative studies will be required. (2) Quality control of ginseng leaf-stem preparations has not been adequately assured. (3) Few randomized, double-blind, placebo-controlled clinical trials on ginseng leaf-stem extracts are available. Further laboratory and clinical studies are warranted for wider pharmaceutical use of ginseng leaf-stem.

Conclusion

Extracts from ginseng root and leaf-stem have similar multifaceted pharmacological activities (e.g. CNS and cardiovascular system). In terms of costs and source availability, ginseng leaf-stem has advantages over its root. Further research will facilitate a wider use of ginseng leaf-stem.

Abbreviations

AMI: acute myocardial infarction; ANP: atrial natriuretic peptide; bFGF: basic fibroblast growth factor; CHD: coronary heart disease; CK: creatine kinase; CNS: central nervous system; CHD: coronary heart disease; FFA: free fatty acid; GLSS: ginseng leaf-stem saponin; GSH-Px: Gtutathione peroxidase; GR: glucocorticoid receptor; HPLC: high performance liquid chromatography; LC/ESI-MS: liquid chromatography/electron spray ionization mass spectrometry; LD50: lethal dose to 50% of the sample; LDH: lactate dehydrogenase; LDL: low-density lipoprotein; LPO: lactoperoxidase; NE: norepinephrine; RP-HPLC: reversed phase-high performance Liquid chromatographic; SOD: superoxide dismutase; TCM: traditional Chinese medicine; UV: ultra-violet; VEGF: vascular endothelial growth factor; WGLE: wild ginseng leaf extract.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

HWW, DCP and JTX conceived the topic, collected data and drafted the manuscript. All authors read and approved the final version of the manuscript.

Acknowledgements

We thank R Flagg and DJ Spergel for their comments on the manuscript.

References

  1. Chevallier A: Encyclopedia of herbal medicine. New York: DK Publishing Inc; 2000.

  2. Xie J-T, Attele AS, Yuan C-S: Ginseng: beneficial and potential adverse effect. In A textbook of complementary and alternative therapies. Edited by Yuan C-S, Beiber E, Bauer BA. Boca Raton, London, New York, Washington, DC: CRC Press Company; 2006:71-89. OpenURL

  3. Sun XB, Matsumoto T, Yamada H: Purification of an anti-ulcer polysaccharide from the leaves of Panax ginseng.

    Planta Med 1992, 58:445-448. PubMed Abstract | Publisher Full Text OpenURL

  4. Gillis CN: Panax ginseng pharmacology: a nitric oxide link?

    Biochem Pharmacol 1997, 54(1):1-8. PubMed Abstract | Publisher Full Text OpenURL

  5. Li J, Huang M, Teoh H, Man RY: Panax quinquefolium saponins protects low density lipoproteins from oxidation.

    Life Sci 1999, 64(1):53-62. PubMed Abstract | Publisher Full Text OpenURL

  6. Keum YS, Park KK, Lee JM, Chun KS, Park JH, Lee SK, Kwon H, Surh YJ: Antioxidant and anti-tumor promoting activities of the methanol extract of heat-precessed ginseng.

    Cancer Letters 2000, 150:41-48. PubMed Abstract | Publisher Full Text OpenURL

  7. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA: Recent patterns of medication use in the ambulatory adult population of the United States.

    JAMA 2002, 287:337-344. PubMed Abstract | Publisher Full Text OpenURL

  8. Kim YK, Guo Q, Packer L: Free redical scavenging activity of red ginseng aqueous extracts.

    Toxicology 2002, 172:149-156. PubMed Abstract | Publisher Full Text OpenURL

  9. Seely D, Dugoua JJ, Perri D, Mills E, Koren G: Safety and efficacy of panax ginseng during pregnancy and lactation.

    Can J Clin Pharmacol 2008, 15(1):87-94. OpenURL

  10. Cheng TO: Panax (ginseng) is not a panacea.

    Arch Intern Med 2000, 160:3329-3330. PubMed Abstract | Publisher Full Text OpenURL

  11. Attele AS, Wu JA, Yuan CS: Ginseng pharmacology: multiple constituents and multiple actions.

    Biochem Pharmacol 1999, 58(11):1685-1693. PubMed Abstract | Publisher Full Text OpenURL

  12. Lim J-Y, Ishiguro K, Kubo I: Tyrosinase inhibitory p-coumaric acid from ginseng leaves.

    Phytother Res 1999, 13:371-375. PubMed Abstract | Publisher Full Text OpenURL

  13. Li TSC, Mazza G, Cottrell AC, Gao L: Ginsenosides in roots and leaves of American ginseng.

    J Agric Food Chem 1996, 44:717-720. Publisher Full Text OpenURL

  14. Hou JP: The chemical constituents of ginseng plants.

    Comp Med East and West 1977, 5:123-145. Publisher Full Text OpenURL

  15. Yip TT, Lau CN, But PP, Kong YC: Quantitative analysis of ginsenosides in fresh Panax ginseng.

    Am J Chin Med 1985, 13:77-88. PubMed Abstract | Publisher Full Text OpenURL

  16. Zhonghua Bencao Editors: Zhonghua Bencao (Chinese Herbal Medicine). Shanghai: Shanghai Science and Technology House; 1996.

  17. Huang KC: The Pharmacology of Chinese Herbs. Boca Raton, FL: CRC Press; 1999.

  18. Yang XW, Li LY, Tian JM, Zhang ZW, Ye JM, Gu WF: Ginsenoside-Rg6, a novel triterpenoid saponin from the stem-leaves of Panax ginseng C. A. Mey.

    Chinese Chemical Letters 2000, 11:909-912. OpenURL

  19. Dou DQC, Liang YJ, Pang LH, Shimizu FG, N Takeda T: Six new dammarane-type triterpene saponins from the leaves of Panax ginseng.

    Chem Pharm Bull 2001, 49:442-446. PubMed Abstract | Publisher Full Text OpenURL

  20. Ma XQ, Liang XM, Xu Q, Zhang XZ, Xiao HB: Identification of ginsenosides in roots of Panax ginseng by HPLC-APCI/MS.

    Phytochem Anal 2005, 16(3):181-187. PubMed Abstract | Publisher Full Text OpenURL

  21. Xie JT, Mehendale SR, Wang A, Aung HH, Wu J, Osinski J, Yuan C-S: American ginseng leaf: Ginsenoside analysis and hypoglycemic activity.

    Pharmacol Res 2004, 49:113-117. PubMed Abstract | Publisher Full Text OpenURL

  22. Li TSCWD: Seasonal fluctuations of leaf and root weight and ginsenosides contents of 2-, 3-, and 4-year-old American ginseng plants.

    HortTechnology 2002, 12:229-232. OpenURL

  23. Jackson CJC, Dini JP, Lavandier C, Faulkner H, Rupasinghe HPV, Proctor JTA: Ginsenoside content of North American ginseng (Panax quinquefolius L. Araliaceae) in relation to plant development and growing locations.

    J Ginseng Research 2003, 27:135-140. Publisher Full Text OpenURL

  24. Assinewe VA, Baum BR, Gagnon D, Arnason JT: Phytochemistry of Wild Populations of Panax quinquefolius L. (North American Ginseng).

    J Agric Food Chem 2003, 51:4549-4553. PubMed Abstract | Publisher Full Text OpenURL

  25. Wang CZ, Wu JA, McEntee E, Yuan CS: Saponins composition in american ginseng leaf and berry assayed by high-performance liquid chromatography.

    J Agric Food Chem 2006, 54(6):2261-2266. PubMed Abstract | Publisher Full Text OpenURL

  26. Li XW, Gui MY, Zheng Y, Jin YR, Zhang HQ: [Determination of 20 (S)-ginsengnoside Rh2 in the alkali-hydrolysis product of saponins from leaves of Panax qinquefolium by RP-HPLC].

    Zhongguo Zhong Yao Za Zhi 2006, 31(5):386-388. PubMed Abstract OpenURL

  27. Shi W, Wang Y, Li J, Zhang H, Ding L: Investigation of ginsenosides in different parts and ages of Panax ginseng.

    Food Chemistry 2007, 102:664-668. Publisher Full Text OpenURL

  28. Yan B, Wang G, A J, Xie L, Hao H, Liang Y, Sun J, Li X, Zheng Y: Construction of the fingerprints of ginseng stem and leaf saponin reference substances and spiked plasma sample by LC-ESI/MS and its application to analyzing the compounds absorbed into blood after oral administration of ginseng stem and leaf saponin in rat.

    Biol Pharm Bull 2007, 30(9):1657-1662. PubMed Abstract | Publisher Full Text OpenURL

  29. Wu LJ, Wang LB, Gao HY, Wu B, Song XM, Tang ZS: A new compound from the leaves of Panax ginseng.

    Fitoterapia 2007, 78(7-8):556-560. PubMed Abstract | Publisher Full Text OpenURL

  30. Saqito H, Morita M, Takagi K: Pharmacological studies of panax ginseng leaves.

    Japan J Pharmacol 1973, 23:43-56. OpenURL

  31. Wang BX, Cui JC, Liu AJ: Antidiuretic effect of ginsenosides of the stems and leaves of Panax ginseng (author's transl).

    Zhongguo Yao Li Xue Bao 1980, 1(2):126-130. PubMed Abstract OpenURL

  32. Wang BX, Cui JC, Liu AJ: The action of ginsenosides extracted from the stems and leaves of Panax ginseng in promoting animal growth.

    Yao Hsueh Hsueh Pao 1982, 17(12):899-904. PubMed Abstract OpenURL

  33. Wang A, Gao Y, Wang Y, Zhao R, Liu C: Effects of Chinese ginseng root and stem-leaf saponins on learning, memory and biogenic monoamines of brain in rats.

    Zhongguo Zhong Yao Za Zhi 1995, 20:493-495. PubMed Abstract OpenURL

  34. Ma TC, Yu QH, Chen MH: Effects of ginseng stem-laef saponins on one-way avoidance behavior in rats.

    Acta Pharmacol Sinica 1991, 12:403-406. OpenURL

  35. Deyama TN, S Najazawa Y: Constituents and pharmacological effects of Eucommia and Siberian ginseng.

    Acta Pharmacol Sin 2001, 22:1057-1070. PubMed Abstract OpenURL

  36. Song C-SR, Shi Y, Song J, Tian J-J, Guo J-Z, J Dai X, Yang J-D: Effect of qutan huoluo jiannao preparation in improving memory impairment of rats with cerebral ischemia.

    Chinese Journal of Clinical Rehabilitation 2006, 10:32-35. OpenURL

  37. Li M, Ling CQ, Huang XQ, Shen ZL: Effects of ginsenosides extracted from ginseng stem and leaves on glucocorticoid receptor in different viscera in heat-damaged rats.

    Zhong Xi Yi Jie He Xue Bao 2006, 4(2):156-159. PubMed Abstract | Publisher Full Text OpenURL

  38. Petkov VD, Cao Y, Todorov I, Lazarova M, Getova D, Stancheva S, Alova L: Behacioral effects of stem-leaves extract from Panax ginseng C. A. Meyer.

    Acta Physiol Pharmacol (Bulg) 1992, 18:41-48. PubMed Abstract OpenURL

  39. Sui DY, Yu XF, Qu SC, Lu ZZ, Wang L, Chen MQ: Protective effect of Panax quinquefolium 20s-proto-panaxdiolsaponins on acute myocardial infarction in dogs.

    Zhongguo Zhong Yao Za Zhi 2001, 26(6):416-419. PubMed Abstract OpenURL

  40. Wang CL, Shi DZ, Yin HJ: Effect of panax quinquefolius saponin on angiogenesis and expressions of VEGF and bFGF in myocardium of rats with acute myocardial infarction.

    Zhongguo Zhong Xi Yi Jie He Za Zhi 2007, 27(4):331-334. PubMed Abstract OpenURL

  41. Zhang J-M, Matsuura Y, Sueda T, Orihashi K: Beneficial effects of ginsenosides of stems and leaves on cardiac and coronary vascular functions after 12-hour rat heart preservation.

    Transplantation proceedings 1999, 31:2175-2178. PubMed Abstract | Publisher Full Text OpenURL

  42. Guan L, Yi X, Feng Q, Yang L: Effects of saponins from stems and leaves of Panax quinquefolium L. on the contraction of rabbit aortic strips.

    Zhongguo Zhong Yao Za Zhi 1996, 20:431-434. OpenURL

  43. Chen X, Yang SJ, Chen L, Ma XL, Chen YP, Wang LL, Sun CW: The effects of Panax quinquefolium saponin (PQS) and its monomer ginsenoside on heart.

    Zhongguo Zhong Yao Za Zhi 1994, 19(10):617-620. PubMed Abstract OpenURL

  44. Hu JX, Jia GX, Yan ZR: Clinical and experimental stydy of shenshao tongguan pian in treating angina pectoris of coronary heart disease.

    Zhong Xi Yi Jie He ZA Zhi 1990, 10:596-599. PubMed Abstract OpenURL

  45. Hong M: Effects of ageing and ginsenoside on atrial natriuretic peptide gene expression.

    Zhonghua Yi Xue Za Zhi 1991, 71:140-143. PubMed Abstract OpenURL

  46. Hong M, Jin Y, Mai YQ, Boersma A, Han KK, Vantyghem MC, Lefebere J: The decline of atrial natriuretic peptide (ANP) gene expression in older rats and the effects of ginsenoside on ANP gene expression.

    Comp Biochem Physiol B 1992, 101:35-39. PubMed Abstract | Publisher Full Text OpenURL

  47. Yang Y, Wu T, He K, Fu ZG: Effect of aerobic exercise and ginsenosides on lipid metabolism in diet-induced hyperlipidemia mice.

    Acta Pharmacol Sin 1999, 20:563-565. OpenURL

  48. Wen Y, Pei Y, Chen Y, Wang Z, Ma Z, Wang M, Li W: Effects of ginsenosides from stems and leaves on hyperlipemia induced by prednisone acetate in rabbits.

    Zhongguo Zhong Yao Za Zhi 1996, 21:430-431. PubMed Abstract OpenURL

  49. Shane-McWhorter L, Oderda LH: Importance of cultural issues in managing a patient with diabetes.

    Consult Pharm 2007, 22(5):431-437. PubMed Abstract OpenURL

  50. Sotaniemi EA, Haapakoski E, Rautio A: Ginseng therapy in non-insulin-dependent diabetic patients.

    Diabetes Care 1995, 18(10):1373-1375. PubMed Abstract | Publisher Full Text OpenURL

  51. Vuksan V, Sievenpiper JL, Koo VY, Francis T, Beljan-Zdravkovic U, Xu Z, Vidgen E: American ginseng (Panax quinquefolius L) reduces postprandial glycemia in nondiabetic subjects and subjects with type 2 diabetes mellitus.

    Arch Intern Med 2000, 160(7):1009-1013. PubMed Abstract | Publisher Full Text OpenURL

  52. Vuksan V, Sievenpiper JL, Xu Z, Wong EY, Jenkins AL, Beljan-Zdravkovic U, Leiter LA, Josse RG, Stavro MP: Konjac-Mannan and American ginsing: emerging alternative therapies for type 2 diabetes mellitus.

    J Am Coll Nutr 2001, 20(5 Suppl):370S-380S.

    discussion 381S-383S

    PubMed Abstract | Publisher Full Text OpenURL

  53. Chung SH, Choi CG, Park SH: Comparisons between white ginseng radix and rootlet for antidiabetic activity and mechanism in KKAy mice.

    Arch Pharm Res 2001, 24(3):214-218. PubMed Abstract | Publisher Full Text OpenURL

  54. Attele AS, Zhou YP, Xie JT, Wu JA, Zhang L, Dey L, Pugh W, Rue PA, Polonsky KS, Yuan CS: Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component.

    Diabetes 2002, 51(6):1851-1858. PubMed Abstract | Publisher Full Text OpenURL

  55. Xie JT, Aung HH, Wu JA, Attele AS, Yuan CS: Effects of American ginseng berry extract on blood glucose levels in ob/ob mice.

    Am J Chin Med 2002, 30(2-3):187-194. PubMed Abstract | Publisher Full Text OpenURL

  56. Xie JT, Zhou Y-P, Dey L, Attele A, Wu J, Gu M, Polonnsky K, Yuan C: Ginseng berry reduces blood glucose and body weight in db/db mice.

    Phytomedicine 2002, 9:254-258. PubMed Abstract | Publisher Full Text OpenURL

  57. Molokovskii DS, Davydov VV, Tiulenev VV: The action of adaptogenic plant preparations in experimental alloxan diabetes.

    Probl Endokrinol (Mosk) 1989, 35(6):82-87. PubMed Abstract OpenURL

  58. Broadhurst CL, Polansky MM, Anderson RA: Insulin-like biological activity of culinary and medicinal plant aqueous extracts in vitro.

    J Agric Food Chem 2000, 48(3):849-852. PubMed Abstract | Publisher Full Text OpenURL

  59. Davydov VV, Molokovskii DS, Limarenko A: Efficacy of ginseng drugs in experimental insulin-dependent diabetes and toxic hepatitis.

    Patol Fiziol Eksp Ter 1990, (5):49-52. PubMed Abstract OpenURL

  60. Xie JT, Wang CZ, Wang AB, Wu J, Basila D, Yuan CS: Antihyperglycemic effects of total ginsenosides from leaves and stem of Panax ginseng.

    Acta Pharmacol Sin 2005, 26(9):1104-1110. PubMed Abstract | Publisher Full Text OpenURL

  61. Xie JTWC, Ni M, Wu JA, Mehendale SR, Aung HH, Yuan CS: American ginseng berry juice intake reduces blood glucose and body weight in ob/ob mice.

    J Food Sci 2007, 72(8):S590-S594. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  62. Park HSKT, Moon DG, Kim JJ, Cheon J: Development of the novel anti-cancer immunotherapy for human prostate cancer: In vivo characterization of an immunotropic and anti-cancer activities of the new polysaccharide from the leaves of Panax ginseng C.A. Meyer.

    Eur Urol Suppl 3 2004, (2):365-366. OpenURL

  63. Widodo N, Takagi Y, Shrestha BG, Ishii T, Kaul SC, Wadhwa R: Selective killing of cancer cells by leaf extract of Ashwagandha: Components, activity and pathway analyses.

    Cancer Lett 2008, 262:37-47. Publisher Full Text OpenURL

  64. Zhang QH, Wu CF, Duan L, Yang JY: Protective effects of total saponins from stem and leaf of Panax ginseng against cyclophosphamide-induced genotoxicity and apoptosis in mouse bone marrow cells and peripheral lymphocyte cells.

    Food Chem Toxicol 2008, 46(1):293-302. PubMed Abstract | Publisher Full Text OpenURL

  65. Kitts DD, Popovich DG, Hu C: Characterizing the mechanism for ginsenoside-induced cytotoxicity in cultured leukemia (THP-1) cells.

    Can J Physiol Pharmacol 2007, 85(11):1173-1183. PubMed Abstract | Publisher Full Text OpenURL

  66. Kitts DD, Wijewickreme AN, Hu C: Antioxidant properties of a North American ginseng extract.

    Mol Cell Biochem 2000, 203:1-10. PubMed Abstract | Publisher Full Text OpenURL

  67. Dou DQ, Chen YJ, Liang LH, Pang FG, Shimizu N, Takeda T: Six new dammarane-type triterpene saponins from the leaves of Panax ginseng.

    Chem Pharm Bull (Tokyo) 2001, 49(4):442-446. PubMed Abstract | Publisher Full Text OpenURL

  68. Jung CH, Seog HM, Choi IW, Choi HD, Cho HY: Effects of wild ginseng (Panax ginseng C.A. Meyer) leaves on lipid peroxidation levels and antioxidant enzyme activities in streptozotocin diabetic rats.

    J Ethnopharmacol 2005, 98(3):245-250. PubMed Abstract | Publisher Full Text OpenURL

  69. Jung C-HS, H-M Choi I-W, Cho H-Y: Antioxidant activities of cultivated and wild Korean ginseng leaves.

    Food Chemistry 2005, 92:535-540. Publisher Full Text OpenURL

  70. Jung C-HS, H-M Choi I-W, Park M-W, Cho H-Y: Antioxidant properties of various solvent extracts from wild ginseng leaves.

    LWT 2006, 39:266-274. Publisher Full Text OpenURL

  71. Jiang Y, Zhong GG, Chen L, Ma XY: Influences of ginsenosides Rb1, Rb2, and Rb3 on electric and contractile activities of normal and damaged cultured myocardiocytes.

    Zhongguo Yao Li Xue Bao 1992, 13(5):403-406. PubMed Abstract OpenURL

  72. Wang B, Cui J, Liu A, Wu S: Studies on the anti-fatigue effect of the saponins of stems and leaves of panax ginseng (SSLG).

    J Tradit Chin Med 1983, 3:89-94. PubMed Abstract OpenURL

  73. Wang B, Cui J, Liu A: Antidiuretic effect of ginsenosides of the stems and leaves of Panax ginseng.

    Acta Pharmacol Sin 1980, 1:126-130. OpenURL

  74. Zhou L, Hao R, Jiang L: Clinical study on retarding aging effect of tongbu recipe to traditional Chinese medicine.

    Zhongguo Zhong Xi Yi Jie He Za Zhi 1999, 19:218-220. PubMed Abstract OpenURL

  75. Yi RL, Li W, Hao XZ: Inductive differentiation effect of ginsenosides on human acute nonlymphocytic leukemic cells in 58 patients.

    Zhongguo Zhong Xi Yi Jie He Za Zhi 1993, 13:722-724. PubMed Abstract OpenURL

  76. Singh B, Saxena AK, Chandan BK, Gupta DK, Bhutani KK, Anand KK: Adaptogenic activity of a novel, withanolide-free aqueous fraction from the roots of Withania somnifera Dun.

    Phytother Res 2001, 15:311-318. PubMed Abstract | Publisher Full Text OpenURL

  77. Klepser TB, Klepser ME: Unsafe and potentially safe herbal theraties.

    Am J Health Sys Pharm 1999, 56:125-138. OpenURL

  78. Xie JT, Mehandale S, Malecar S: Is ginseng free from adverse effects? In A Textbook of Complementary and Alternative Therapies. Edited by Yuan C-S, Beiber E. Boca Raton: CRC Press Company; 2002:219-224. OpenURL

  79. Coon JT, Ernst E: Panax ginseng : a systematic review of adverse effects and drug interactions.

    Drug Saf 2002, 25:323-344. PubMed Abstract | Publisher Full Text OpenURL

  80. Siegel RK: Ginseng abuse syndrome. Problems with the panacea.

    JAMA 1979, 241(15):1614-1615. PubMed Abstract | Publisher Full Text OpenURL

  81. Nocerino E, Amato M, Izzo A: The aphrodisiac and adaptogenic properties of ginseng.

    Fitoterapia 2002, 71:S1-S5. Publisher Full Text OpenURL

  82. Morgan A, Cupp MJ: Panax ginseng. In Toxicology and clinical pharmacology of herbal products. Edited by Cupp MJ. Totowa, NJ: Humana Press; 2002:141-153. OpenURL

  83. Ang-Lee MKM, J Yuan C-S: Herbal Medicines and perioperative care.

    JAMA 2001, 286:208-216. PubMed Abstract | Publisher Full Text OpenURL

  84. Saito H, Morita M, Takagi K: Pharmacological studies of Panax Ginseng leaves.

    Jpn J Pharmacol 1973, 23(1):43-56. PubMed Abstract OpenURL