Wednesday, 22 November 2017

Traditional uses, botany, phytochemistry, pharmacology and toxicology of Panax notoginseng (Burk.) F.H. Chen: A review

Journal of Ethnopharmacology Volume 188, 21 July 2016, Pages 234-258 Review Author links open overlay panelTingWangRixinGuoGuohongZhouXidanZhouZhenzhenKouFengSuiChunLiLiyingTangZhujuWang Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, No. 16, Nanxiaojie, Dongzhimennei Ave., Beijing 100700, China Received 18 August 2015, Revised 2 May 2016, Accepted 2 May 2016, Available online 3 May 2016. crossmark-logo Get rights and content Abstract Ethnopharmacological relevance Panax notoginseng (Burk.) F.H. Chen is a widely used traditional Chinese medicine known as Sanqi or Tianqi in China. This plant, which is distributed primarily in the southwest of China, has wide-ranging pharmacological effects and can be used to treat cardiovascular diseases, pain, inflammation and trauma as well as internal and external bleeding due to injury. Aims of the review This paper provides up-to-date information on investigations of this plant, including its botany, ethnopharmacology, phytochemistry, pharmacology and toxicology. The possible uses and perspectives for future investigation of this plant are also discussed. Materials and methods The relevant information on Panax notoginseng (Burk.) F.H. Chen was collected from numerous resources, including classic books about Chinese herbal medicine, and scientific databases, including Pubmed, SciFinder, ACS, Ebsco, Elsevier, Taylor, Wiley and CNKI. Results More than 200 chemical compounds have been isolated from Panax notoginseng (Burk.) F.H. Chen, including saponins, flavonoids and cyclopeptides. The plant has pharmacological effects on the cardiovascular system, immune system as well as anti-inflammatory, anti-atherosclerotic, haemostatic and anti-tumour activities, etc. Conclusions Panax notoginseng is a valuable traditional Chinese medical herb with multiple pharmacological effects. This review summarizes the botany, ethnopharmacology, phytochemistry, pharmacology and toxicology of P. notoginseng, and presents the constituents and their corresponding chemical structures found in P. notoginseng comprehensively for the first time. Future research into its phytochemistry of bio-active components should be performed by using bioactivity-guided isolation strategies. Further work on elucidation of the structure-function relationship among saponins, understanding of multi-target network pharmacology of P. notoginseng, as well as developing its new clinical usage and comprehensive utilize will enhance the therapeutic potentials of P. notoginseng. Graphical abstract fx1 Download high-res image (382KB)Download full-size image Keywords Panax notoginseng (Burk.) F.H. Chen Botany and ethnopharmacology Phytochemistry Pharmacological activities Toxicity 1. Introduction Panax notoginseng (Burk.) F.H. Chen (P. notoginseng) is a species of the genus Panax, family Araliaceae. Three species in this genus [Panax ginseng C.A. Meyer, Panax quinquefolius L. and P. notoginseng (Burk.) F.H. Chen] are highly regarded as medicinal plants in China and the USA (Wen and Zimmer, 1996). The root of P. notoginseng, known as Sanqi or Tianqi in East Asian countries, is one of the primary herbs in traditional Chinese medicine. Sanqi, which has been widely used as a tonic and haemostatic drug for more than 400 years, still has an important place in today's regional market. With the increasing study of Chinese material medica, substantial efforts have been made to research the phytochemistry and pharmacological effects of P. notoginseng, over 200 compounds have been isolated from P. notoginseng, and a variety of pharmacological effects have been found. Such promising progress of P. notoginseng is calling for a timely and comprehensive review of our current understandings. Therefore, in this article, we review recent research efforts that have been put from different aspects in researching P. notoginseng. We start with briefly introducing the botany and ethnopharmacology of P. notoginseng, and then focusing on the isolated and identified chemical compounds, as well as their corresponnding structures, which haven’t been adequately summarized and comprehensively presented in other publications. We next touch on the pharmacological activities and discuss the toxicity of P. notoginseng. Finally, we provide our viewpoints on future perspective of P. notoginseng. To the best of our knowledge, there has not been a recent review that covers all aspects of this plant, and we hope this paper will be helpful to provide a better understanding of this plant. 2. Botany P. notoginseng (Burk.) F.H. Chen [Synonyms: Aralia quinquefolia var. notoginseng Burkill, Panax pseudoginseng var. notoginseng (Burkill) G. Hoo & C.J. Tseng] (Fig. 1) is one of about twelve species in Panax genus of the Araliaceae. Fig. 1. Download high-res image (646KB)Download full-size image Fig. 1. The whole plant view (A) and medicinal part (B) of P. notoginseng. Typical botanical characteristics of P. notoginseng include growing to a height of 30–60 cm, dark green leaves branching from a stem and a cluster of red berries in the middle. The stems are upright, simple, erect and unbranched (Guo et al., 2010). The main root is conical or cylindrical and ranges in length from 1 to 6 cm. The main root is taupe or drab yellow on the surface, with several wrinkles and root marks. Generally, P. notoginseng is removed from the soil and dried before it blooms in autumn. It can be ground singly into powder that is swallowed or combined with other herbs (Committee for the Pharmacopoeia of China, 2010). The distribution of P. notoginseng is very narrow due to its sensitivity to sunlight. After a long period of evolution, it grows primarily in the Wenshan mountain area of Yunnan province. It has a narrow habitat located around N 23.5° and E 104° that ranges in altitude from 1200 to 2000 m. A large percentage of the raw materials in China is produced here (Guo et al., 2010). 3. Ethnopharmacology The root of P. notoginseng has played an indispensable role in Chinese healthcare for a long time. It is the main ingredient in Yun Nan Bai Yao (云南白药), a famous haemostatic herbal remedy that is used to stop bleeding, decrease inflammation and relieve pain (Sun et al., 2010). P. notoginseng is also one of the sources of cardiotonic pill that has been used in China, Korean and Russia for the treatment of cardiovascular diseases, such as occlusive vasculitis, coronary diseases, atherosclerosis, and cerebral infarction (Zhao et al., 2006). The initial description of this plant can be traced back to the Compendium of Material Medica (《本草纲目》), written by Shi Zhen Li. In this classic book, P. notoginseng was recorded to have the actions to stop bleeding, remove blood stasis, alleviate pain, and it could be applied to treat bleeding caused by swords or axes, as well as hemoptysis, hematemesis, epistaxis and blood dysentery. Then the subsequent book Supplements for Compendium of Material Medica (《本草纲目拾遗》), written by Xue Min Zhao, described the function of Sanqi as similar to that of Panax ginseng C. A. Meyer. The difference is that Panax ginseng C.A. Meyer is good for tonifying qi, while P. notoginseng is especially helpful for nourishing the blood. It is worthy to note that this tonic action, which is usually used in folk hasn’t been written in Compendium of Material Medica (《本草纲目》) and many material medica books, and just can be found in few books, like New Compilation of Material Medica (《本草新编》) and Chinese Medicine Dictionary (《中国医药大辞典》). In the Chinese pharmacopoeia, the properties of this herb are described as warm in nature, sweet and slightly bitter in taste. It is attributive to the liver and spleen meridians, it has the actions to dissipate blood stasis, stop bleeding, promote blood circulation and alleviate pain, so it can be applied in haemoptysis, hematemesis, rhinorrhagia, haemafecia, metrorrhagia and metrostaxis, traumatic bleeding and pain caused by traumatic injury (Committee for the Pharmacopoeia of China, 2010). Because of its defined clinical effects, some formulas (Table 1) were created by ancient doctors. Nowadays, many prescriptions (Table 1) are in clinical use, there are nearly 60 kinds of Chinese patent medicines in the Chinese pharmacopoeia, and the forms including capsules, granules, tablets, pills, dripping pills, powders, etc., capsules and tablets are the most used forms (Shi et al., 2012). Table 1. The traditional and clinical usages of Panax notoginseng (Burk.) F.H. Chen in China. Preparation name Compositions Traditional and clinical usages Origin Hua xue dan ( 化血丹 ) Ophicalcitum, notoginseng radix et rhizoma, crinis carbonisatus It has the action of removing blood stasis to stop bleeding. It can be used for hemoptysis, hematemesis, epistaxis, hemafecia and hematuria Yi xue zhong zhong can xi lu (《医学衷中参西录》) An shen zhi tong tang ( 安神止痛汤 ) Nelumbinis semen, codonopsis radix, paeoniae radix alba, rehmanniae radix, dioscoreae rhizoma, astragali radix, ziziphi spinosae semen, notoginseng radix et rhizoma, corydalis rhizoma (processed with vinegar), olibanum (processed), myrrha (processed), poria, polygalae radix, glycyrrhizae radix et rhizoma, uncariae ramulus cum uncis It can tranquilize the mind, invigorate qi and relieve pain. And it is used in the treatment of excruciating pain caused by serious injury and restlessness Lin ru gao gu shang yan fang ge jue fang jie (《林如高骨伤验方歌诀方解》) Wan fu dan ( 完肤丹 ) Notoginseng radix et rhizoma, olibanum, draconis sanguis, ginseng radix et rhizoma It has the actions of stopping bleeding and promoting granulation, so it can be used for bleeding caused by incised wounds Dong tian ao zhi (《洞天奥旨》) An beng tang ( 安崩汤 ) Ginseng radix et rhizoma, astragali radix, atractylodis macrocephalae rhizoma, notoginseng radix et rhizoma It is usually used to treat five types of fulminant vaginal discharge Yi xue ji cheng (《医学集成》) San qi shang yao pian* ( 三七伤药片 ) Notoginseng radix et rhizoma, aconiti kusnezoffii radix (steamed), drynariae rhizoma, carthami flos, paeoniae radix rubra It has the actions of relaxing tendons, promoting the circulation of blood, removing blood stasis to alleviate pain. And it is indicated for traumatic injury, bi-syndrome of wind and damp type with painful joints, acute or chronic strains and neuralgia with above symptoms Pharmacopoeia of PR China Die da huo xue san* ( 跌打活血散 ) Carthami flos, angelicae sinensis radix, draconis sanguis, notoginseng radix et rhizoma, drynariae rhizoma, dipsaci radix, olibanum (processed), myrrha (processed), catechu, rhei radix et rhizoma, borneolum syntheticum, eupolyphaga steleophaga It can relax tendons, promote blood circulation, and remove blood stasis to alleviate pain. It is used for traumatic injury with bruise and pain or lumbar sprain Pharmacopoeia of PR China Fu fang xue shuan tong jiao nang* ( 复方血栓通胶囊 ) Notoginseng radix et rhizoma, astragali radix, salviae miltiorrhizae radix et rhizoma, scrophulariae radix It has the functions to promote blood circulation to remove blood stasis, supplement qi and nourish yin. It is usually applied for retinal vein occlusion and stable angina pectoris resulting from blood stasis Pharmacopoeia of PR China Die da wan* ( 跌打丸 ) Dipsaci radix, notoginseng radix et rhizoma, paeoniae radix rubra, paeoniae radix alba, carthami flos, draconis sanguis, sappan lignum, olibanum (processed), myrrha (processed), sparganii rhizoma (processed with vinegar), glycyrrhizae radix et rhizoma It can promote blood circulation to remove blood stasis and relieve swelling to alleviate pain. It can be used to treat traumatic injury, broken tendons and fracture, bruise with swelling and pain or lumbar sprain Pharmacopoeia of PR China Fu fang dan shen di wan ( 复方丹参滴丸 ) Salviae miltiorrhizae radix et rhizoma, notoginseng radix et rhizoma, borneolum syntheticum It can promote blood circulation to remove blood stasis, regulate qi to relieve pain. It is indicated for the treatment of thoracic fullness due to qi stagnation and blood stasis or angina pectoris in coronary heart disease with the symptoms of oppression in the chest Pharmacopoeia of PR China Note: * cited from Shi et al. (2012). The radix and rhizome of P. notoginseng can be used medicinally for various kinds of internal and external bleeding, especially for the bleeding with blood stasis. For bleeding due to trauma, its powder is used externally on local area to arrest bleeding and alleviate pain. In addition, it can circulate the blood and alleviate pain and is used in the treatment of coronary heart disease with angina pectoris and ischemic cerebrovascular disease (Zuo, 2003). Also it is used for chronic hepatitis due to blood stasis (Park et al., 2005). Besides, it can be added in cook or wine due to its tonic action. The flower of P. notoginseng also has certain medicinal value and health care function, it is recorded in the book named the traditional Chinese Medicine of Yunnan (《云南中草药》) as sweet in flavor, cold in nature, and has the actions to clear away heat, calm the liver and lower the blood pressure. It can be used to treat hypertension. What's more, the flower can be added in the food industry to make scented tea. 4. Phytochemistry To the best of our knowledge, over 200 chemical constituents have been isolated from P. notoginseng. Saponins are considered as the main constituents, but there are others reported to be flavonoids, cyclopeptides, saccharides and inorganic elements. Phytochemical studies have been performed on many parts of this plant, including the root, the stem, the leaf and the flower. The isolated compounds are listed below in Table 2, and their corresponding structures are also comprehensively presented for the first time. Table 2. The chemical constituents isolated from Panax notoginseng (Burk.) F.H. Chen. No. Chemical components Part of the plant Representative references Saponins 1 Ginsenoside Ra3 Ro; Ro & Rh Qiu et al. (2014); Yu et al. (2013)* 2 Ginsenoside Rb1 Ro; HRo; Ro & Rh; Rh; L; St & L; Fr; Fp; Fb; Se Qiu et al. (2014), Liao et al. (2008)*; Wei et al. (1980); Yu et al. (2013)*; Cui et al. (2008); Li et al. (2014); Li et al. (2000); Shi et al. (2010); Wang et al. (2008); Yoshikawa et al. (2003), Zhang (2009); Yang et al. (1983) 3 Ginsenoside Rb2 Ro; Ro & Rh; Rh; L; Fb; Fp Ma et al. (1999); Yu et al. (2013)*; Zhou et al. (2007a); Huang et al. (2009); Li (2009); Wang et al. (2008) 4 Ginsenoside Rb3 Ro; St & L; L; Fb; Fr; Fp; Se Massayuki et al. (2001); Li et al. (2000); Guo et al. (2014), Liu et al. (2011b)*; Li (2009), Zuo et al. (1991); Shi et al. (2010); Wang et al. (2008); Zhou et al. (2007a), Yang et al. (1983) 5 Ginsenoside Rc St & L; L; Fb; Fp; Se Li et al. (2000); Li et al. (2014), Liu et al. (2011b)*; Li (2009), Zuo et al. (1991); Wang et al. (2008); Zhou et al. (2007a), Yang et al. (1983) 6 Ginsenoside Rd Ro; HRo; Ro & Rh; Rh; L; St & L; Fb; Fr; Fp; Se Qiu et al. (2014), Liao et al. (2008)*; Wei and Du (1992), Wei et al. (1988); Yu et al. (2013)*; Cui et al. (2008); Li et al. (2014), Li et al. (2006); Li et al. (2000); Zhou et al. (2007a), Yoshikawa et al. (2003); Xia et al. (2014), Shi et al. (2010); Wang et al. (2008); Zhou et al. (2007a), Yang et al. (1983) 7 Ginsenoside Rg3 Ro; HRo; FRo; Ro & Rh; Rh; L; St & L Liao et al. (2008)*; Wei and Du (1992), Wei et al. (1988); Li et al. (2005); Yu et al. (2013)*; Cui et al. (2008); Zhou et al. (2007b); Li et al. (2006), Liu et al. (2011b)*, Wei et al. (1986); Li et al. (2000) 8 Ginsenoside compound K L Guo et al. (2014), Jiang et al. (2004a) 9 Ginsenoside F2 Ro; Ro & Rh; Rh; L; St & L; Fb; Fp Kaunda et al. (2013); Yu et al. (2013)*; Song et al. (2007); Liu et al. (2011b)*, Li et al. (2006); Li et al. (2000); Xia et al. (2014); Wang et al. (2008) 10 Ginsenoside MC L Li et al. (2014), Chen et al. (2002) 11 Ginsenoside Rh2 L; St & L Li et al. (2014), (2006), Liu et al. (2011b)*; Li et al. (2000) 12 Malonyl-ginsenoside Rb1 Ro Wan et al. (2010) 13 Notoginsenoside D Ro & Rh; Ro; Fb Yu et al. (2013)*; Qiu et al. (2014), Yoshikawa et al. (1997); Yoshikawa et al. (2003) 14 Notoginsenoside Fa Ro; Ro & Rh; Rh; L; St & L; Fb; Fp; Se Qiu et al. (2014); Yu et al. (2013)*; Cui et al. (2008); Li et al. (2014); Li et al. (2000); Zhang and Zuo (2011), Yoshikawa et al. (2003); Wang et al. (2008); Yang et al. (1983) 15 Notoginsenoside Fc St & L; L; Fb; Fr; Fp; Se Wei and Du (1992); Li et al. (2014), Liu et al. (2011b)*, Yang et al. (1983); Zhang and Zuo (2011); Wei and Du (1992); Wang et al. (2008); Yang et al. (1983) 16 Notoginsenoside Fe L; Fb; Fp Li et al. (2014), Yang et al. (1983); Li (2009), Zhang (2009), Zuo et al. (1991); Zhou et al. (2007a), Wei and Du (1992) 17 Notoginsenoside FP2 L; Fb; Fp Guo et al. (2013); Wang et al. (2009); Wang et al. (2008) 18 Notoginsenoside O Fb Yoshikawa et al. (2003) 19 Notoginsenoside P Fb Yoshikawa et al. (2003) 20 Notoginsenoside Q Fb Li (2009), Yoshikawa et al. (2003) 21 Notoginsenoside R4 Ro; HRo; Rh; Ro & Rh Qiu et al. (2014), Matsuura et al. (1983); Wei and Du (1992), Wei et al. (1988); Yang et al. (1985); Yu et al. (2013)* 22 Notoginsenoside S Rh; Fb Cui et al. (2008), Zeng et al. (2007); Yoshikawa et al. (2003) 23 Notoginsenoside ST-4 Ro Pei et al. (2011)* 24 Notoginsenoside T Ro; Rh; Fb Wan et al. (2010), Cui et al. (2008); Zeng et al. (2007); Yoshikawa et al. (2003) 25 Gypenoside IX L; St & L; Fb; Fp; Se Li et al. (2014), Liu et al. (2011b)*; Li et al. (2000); Yoshikawa et al. (2003), Zuo et al. (1991); Wang et al. (2008); Yang et al. (1983) 26 Gypenoside XIII L; St & L; Fp Huang et al. (2009), Li et al. (2006); Li et al. (2000); Wang et al. (2008) 27 Gypenoside XVII Ro; HRo; Ro & Rh; Rh; L; St & L; Fb; Fp Kaunda et al. (2013); Wei et al. (1988); Yu et al. (2013)*; Wei and Du (1992); Huang et al. (2009), Li et al. (2006); Li et al. (2000); Li (2009); Wang et al. (2008), Wei et al. (1992) 28 Notoginsenoside L Ro Massayuki et al. (2001), Ma et al. (1999) 29 Quinquenoside R1 Ro Guo et al. (2014), Wan et al. (2010) 30 Vina-ginsenoside R7 L; Fp Li et al. (2014); Wang et al. (2008) 31 Notoginsenoside K Ro Guo et al. (2014), Ma et al. (1999) 32 Ginsenoside Rs3 Ro; L Zhang et al. (2013a); Liu et al. (2011b)* 33 Compound P6 L Guo et al. (2013) 34 Ginsenoside Ra1 L Guo et al. (2013) 35 Gypenoside XV Fp Zhou et al. (2007a), Wei et al. (1992) 36 Notoginsenoside-FZ L Li et al. (2014) 37 20(S)-protopanaxadiol Fr; L Shi et al. (2010); Li et al. (2014) 38 Chikusetsusaponin L5 Ro; Fp Wan et al. (2010); Wang et al. (2008) 39 Ginsenoside F1 Ro; Rh; L; Fp Qiu et al. (2014); Song et al. (2007), Zhou et al. (2007a); Li et al. (2014); Chen et al. (2002); Wang et al. (2008) 40 Ginsenoside Re Ro; HRo; Ro & Rh; Rh; L; St & L; Fb; Fp; Fr Qiu et al. (2014), Liao et al. (2008)*; Wei and Du (1992); Yu et al. (2013)*; Cui et al. (2008), Li et al. (2006); Li et al. (2000); Zhang and Zuo (2011), Li (2009); Wang et al. (2008), Wei and Cao (1992); Shi et al. (2010) 41 Ginsenoside Rf Ro; Rh Han et al. (2014), Liao et al. (2008)*; Cui et al. (2008) 42 Ginsenoside Rg1 Ro; HRo; Ro & Rh; Rh; L; St & L; Fb; Fp Qiu et al. (2014), Liao et al. (2008)*; Wei and Du (1992), Wei et al. (1980); Yu et al. (2013)*; Cui et al. (2008), Yang et al. (1985); Huang et al. (2009), Li et al. (2006); Li et al. (2000); Xia et al. (2014); Wang et al. (2008) 43 20(S)-Ginsenoside Rg2 Ro; Ro & Rh; Rh; Fr Qiu et al. (2014), Liao et al. (2008)*; Yu et al. (2013)*; Cui et al. (2008), Yang et al. (1985); Xia et al. (2014), Shi et al. (2010) 44 Ginsenoside Rh1 Ro; HRo; FRo; Ro & Rh; Rh; L; Fb Qiu et al. (2014), Liao et al. (2008)*; Wei and Du (1992); Li et al. (2005); Yu et al. (2013)*; Cui et al. (2008); Li et al. (2014); Xia et al. (2014) 45 20−O-glucoginsenoside Rf Ro; Rh Yoshikawa et al. (1997); Cui et al. (2008) 46 Koryoginsenoside R1 Ro; Rh Han et al. (2014), Liao et al. (2008)*; Cui et al. (2008), Zhou et al. (2007b) 47 Notoginsenoside FP1 Fp Wang et al. (2008) 48 Notoginsenoside M Ro Massayuki et al. (2001), Ma et al. (1999) 49 Notoginsenoside N Ro Han et al. (2014), Massayuki et al. (2001) 50 Notoginsenoside R1 Ro; HRo; Ro & Rh; Rh; L; St & L; Fb; Fp Qiu et al. (2014), Liao et al. (2008)*; Wei and Du (1992); Yu et al. (2013)*; Cui et al. (2008), Huang et al. (2009), Li et al. (2006); Guo et al. (2014), Li et al. (2000); Xia et al. (2014); Wang et al. (2008), Wei and Cao (1992) 51 Notoginsenoside R2 Ro; Ro & Rh; Rh; FRo Qiu et al. (2014), Liao et al. (2008)*; Yu et al. (2013)*; Cui et al. (2008); Li et al. (2005) 52 Notoginsenoside R3 Ro Matsuura et al. (1983) 53 Notoginsenoside R6 Ro Matsuura et al. (1983) 54 Notoginsenoside RW−1 Rh Guo et al. (2014), Cui et al. (2008) 55 Notoginsenoside U Ro Sun et al. (2006), Sun et al. (2005) 56 Yesanchinoside D Ro Liao et al. (2008)* Ro Han et al. (2014) 57 Pseudoginsenoside RT3 Ro Han et al. (2014), Liu et al. (2011a) 58 20(S)−6−O-[β-d-xylopyranosyl-(1→2)-β-d-xylopyranosyl]dammar-24-ene-3β,6α,12β,20-tetrol Ro Qiu et al. (2014) 59 20(S)-protopanaxtRool Ro; L Liao et al. (2008)*; Liu et al. (2011b)* 60 20(S)−20−O-[β-d-xylopyranosyl-(1→6-β-d-glucopyranosyl-(1→6)-β-d-glucopyranosyl]dammar-24-ene-3β,6α,12β,20-tetrol Ro Qiu et al. (2014) 61 6′-O-Acetyl ginsenoside Rh1 Ro; Ro & Rh Qiu et al. (2014); Yu et al. (2013)* 62 20(S)-protopanaxatRool-20−O-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside Ro Qiu et al. (2014) 63 20(S)-sanchirhinosides A1 Ro Zhang et al. (2013b) 64 20(S)-sanchirhinosides A2 Ro Zhang et al. (2013b) 65 20(S)-sanchirhinosides A3 Ro Zhang et al. (2013b) 66 20(S)-sanchirhinosides A4 Ro Zhang et al. (2013b) 67 20(S)-sanchirhinosides A5 Ro Zhang et al. (2013b) 68 20(S)-sanchirhinosides A6 Ro Zhang et al. (2013b) 69 6−O-(β-d-glucopyranosyl)−20−O-(β-d-xylopyranosyl)−3β,6α,12β,20(S)-tetrahydroxydammar-24-ene Ro Qiu et al. (2014), Liu et al. (2011a) 70 Notoginsenoside A Ro Zhou et al. (2007a), Yoshikawa et al. (1997) 71 Notoginsenoside B Ro Zhou et al. (2007a), Yoshikawa et al. (1997) 72 Notoginsenoside C Ro Zhou et al. (2007a), Yoshikawa et al. (1997) 73 Notoginsenoside E Ro; Rh Zhou et al. (2007a), Yoshikawa et al. (1997); Guo et al. (2014), Song et al. (2007) 74 Ginsenoside II Rh Song et al. (2007) 75 Floranotoginsenosides B Fl Wang et al. (2009) 76 Gypenoside LXXI Fl Wang et al. (2009) 77 Notoginsenosides SFt1 L Liu et al. (2011b)* 78 Notoginsenosides SFt2 L Liu et al. (2011b)* 79 Floranotoginsenosides A Fl Wang et al. (2009) 80 Floranotoginsenosides C Fl Wang et al. (2009) 81 Floranotoginsenosides D Fl Wang et al. (2009) 82 Gypenoside LXIX Fl Wang et al. (2009) 83 3β,12,20(S)-tRohydroxy-25-hydroperoxydammar-23-ene-3−O-[β-D–glucopyranosyl(1→2)-β-d-glucopyranosyl]−20−O-[β-d-xylopyranosyl(1→6)]-β-d-glucopyranoside Fl Wang et al. (2009) 84 Floraginsenoside O Fl Wang et al. (2009) 85 Ginsenoside V Ro Kaunda et al. (2013) 86 Notoginsenoside H Ro Guo et al. (2014), Yoshikawa et al. (1997) 87 Notoginsenoside J Ro Guo et al. (2014), Yoshikawa et al. (1997) 88 Notoginsenoside RW−2 Rh Zhou et al. (2008a), Cui et al. (2008) 89 Vinaginsenoside R15 Ro Liu et al. (2011a) 90 Notopanaxoside A Ro Zhou et al. (2007a), Komakine et al. (2006) 91 Vinaginsenoside R22 Ro Han et al. (2014) 92 Notoginsenoside R8 Ro Zhao et al. (1996) 93 Ginsenoside Rg5 Ro; Ro & Rh; L Liao et al. (2008)*; Yu et al. (2013)*; Liu et al. (2011b)* 94 Ginsenoside Rh4 Ro; Ro & Rh; Rh; Se; FRo Qiu et al. (2014), Liao et al. (2008)*; Yu et al. (2013)*; Cui et al. (2008), Zeng et al. (2007); Song et al. (2010); Li et al. (2005) 95 Ginsenoside Rk1 Ro; Ro & Rh; L Liao et al. (2008)*; Yu et al. (2013)*; Liu et al. (2011b)* 96 Ginsenoside Rk3 Ro; Ro & Rh Han et al. (2014), Liao et al. (2008)*; Yu et al. (2013)* 97 Notoginsenoside R7 Ro Zhou et al. (2007a), Zhao et al. (1993) 98 Notoginsenoside ST-1 Ro Liao et al. (2008)* 99 Notoginsenoside ST-2 Ro Liao et al. (2008)* 100 Notoginsenoside ST-3 Ro Liao et al. (2008)* 101 Notoginsenoside ST-5 Ro Liao et al. (2008)* 102 Notoginsenoside T5 Rh Cui et al. (2008), Song et al. (2007) 103 Pn-1 L Mao et al. (2012) 104 Sanchinoside B1 Ro; HRo Liao et al. (2008)*; Wei and Du (1992), Wei et al. (1985) 105 20(S)-Panaxadiol Rh; L; Fr Zhou et al. (2007a); Li et al. (2014); Shi et al. (2010) 106 3β,6α,12β-tRohydroxydammar-20(21),24-diene Ro Liao et al. (2008)* 107 Ginsenoside R10 L Liu et al. (2011b)* 108 Vinaginsenoside R4 Ro Qiu et al. (2014) 109 Ginsenoside Rk2 L Liu et al. (2011b)* 110 Ginsenoside Rs5 L Liu et al. (2011b)* 111 Ginsenoside Rh3 L Liu et al. (2011b)* 112 Ginsenoside Rs4 L Liu et al. (2011b)* 113 Pseudoginsenoside F11 Ro Wang et al. (2014a) 114 3−O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranoside-12β,25-dihydroxydammar-(E)20(22)-ene Ro Liu et al. (2011a) 115 Ginsenoside F4 Ro Zhang et al. (2013a) 116 Notoginsenoside Spt1 Ro Zhang et al. (2013a) 117 20(S)-panaxatriol Rh Zhou et al. (2007a) 118 Sanchirhinoside D Ro Kaunda et al. (2013) 119 Pseudoginsenoside Rt5 Ro Han et al. (2014) 120 3β,12β-dihydroxydammar-(E)−20(22),24-diene-6−O-β-d-xylopyranosyl-(1→2)-β-d-glucopyranoside Ro Han et al. (2014) 121 Notoginsenoside SFt3 L Liu et al. (2011b)* 122 Notoginsenoside SFt4 L Liu et al. (2011b)* 123 Notoginsenoside R10 Ro Li et al. (2001a) 124 20(R)-Ginsenoside Rg3 Ro; Rh; Ro & Rh; L; Fb; Fr Qiu et al. (2014); Cui et al. (2008), Zhou et al. (2007b); Yu et al. (2013)*; Chen et al. (2002); Zhang and Zuo (2011), Li (2009); Shi et al. (2010) 125 20(R)-Ginsenoside Rh2 Fr; L Shi et al. (2010); Li et al. (2014), Chen et al. (2002) 126 Notoginsenoside Ft1 L Liu et al. (2011b)* 127 6″-O-acetylginsenoside Rg3 Ro Liao et al. (2008)* 128 20(R)-protopanaxadiol Rh; L Zhou et al. (2008a), Cui et al. (2008); Li et al. (2014) 129 3β,6α−20(S)−6,20-bis(β-d- glucopyranosyloxy)−3-hydroxy dammar-24-en-12-one Ro Kaunda et al. (2013) 130 Notoginsenoside I Ro Guo et al. (2014), Yoshikawa et al. (1997) 131 Vinaginsenoside R3 Ro Liu et al. (2011a) 132 5,6-didehydroginsenoside Rd Ro Wan et al. (2010) 133 Notoginsenoside G Ro Guo et al. (2014), Qiu et al. (2014), Yoshikawa et al. (1997) 134 5,6-didehydroginsenoside Rb1 Ro Wan et al. (2010) 135 20(R)-protopanaxtriol Ro; L; Rh Liao et al. (2008)*; Liu et al. (2011b)*, Li et al. (2014); Cui et al. (2008), Zhou et al. (2008a) 136 20(R)- Ginsenoside Rg1 F1 Shi et al. (2010) 137 20(R)-Ginsenoside Rh1 Ro; Ro & Rh; L; Fr Qiu et al. (2014), Liao et al. (2008)*; Yu et al. (2013)*; Li et al. (2014); Shi et al. (2010) 138 Ginsenoside U Ro Han et al. (2014) 139 25-hydroxy-20(R)-ginsenoside Rh1 Ro Liao et al. (2008)* 140 Notoginsenoside R9 Ro Zhao et al. (1996) 141 Notoginsenoside-LX L Li et al. (2014) 142 Notoginsenoside-LY L Li et al. (2014) 143 Sanchirhinoside B Ro Zhang et al. (2013b) 144 6−O-β-d-glucopyranosyl-20−O-β-d-glucopyranosyl-20(S)-protopanaxadiol-3-one Ro Fu et al. (2013) 145 Lupeol Se; Fr Song et al. (2010), Zhou et al. (2008b); Wei and Du (1992) 146 Betulin F1 Wei and Du (1992) 147 16β-hydroxy lupeol Se; Fr Song et al. (2010), Zhou et al. (2008b); Wei and Du (1992) 148 Lup-20-ene-3β,16β-diol-3-ferulate Se Song et al. (2010) 149 Notoginsenoside Rw-3 Rh Guo et al. (2014); Zhou et al. (2007a) 150 Notoginsenoside Rw-4 Rh Guo et al. (2014); Zhou et al. (2007a) 151 Notoginsenoside Rw-5 Rh Guo et al. (2014); Zhou et al. (2007a) 152 Notoginsenoside RW−6 Rh Guo et al. (2014); Zhou et al. (2007a) 153 Notoginsenoside Rw-7 Rh Guo et al. (2014); Zhou et al. (2007a) Flavonoids 154 Liquiritigenin L; St & L Huang et al. (2009), Li et al. (2006); Li et al. (2000) 155 Liquiritin apioside L; St & L Huang et al. (2009), Li et al. (2006); Li et al. (2000) 156 Quercetin HRo; St & L Xia et al. (2014), Wei et al. (1980); Zheng et al. (2006) 157 Quercetin-3-O-Sophoroside L Xia et al. (2014), Wei and Wang (1987) 158 Quercetin3-O-(2″-β-d-glucopyranosyl-β-d-galactopyranoside Fb; St & L Xia et al. (2014), Zhang et al. (2009a); Zheng et al. (2006) 159 Quercetin3−O-β-d-xylopyranosyl-β-d-galactopyranoside Ro Choi et al. (2010b) 160 Kaempferol St & L; Se Zheng et al. (2006); Zhou et al. (2008b) 161 Kaempferol-7−O-α-l-rhamnoside Se & L Zheng et al. (2006) 162 Kaempferol-3-O-β-d-galactoside Se & L Zheng et al. (2006) 163 Kaempferol-3-O-α-l-rhamnoside Fb Xia et al. (2014), Huang et al. (2012) 164 Kaempferol3−O-(2″-β-d-glucopyranosyl)-β-d-galactopyranoside Fb; Se & L; Fp Xia et al. (2014), Zhang et al. (2009a); Zheng et al. (2006); Wang et al. (2008) 165 Quercetin3−O-β-d-glucopyranosyl-(1→2)-β-d-galactopyranoside Fp Wang et al. (2008) 166 Kaempferol-3−O-(2″,3″-di-E-p-coumaroyl)-α-l-rhamnoside Fb Xia et al. (2014), Huang et al. (2012) Cyclopeptides 167 Cyclo-(Leu-Thr) Ro Wang et al. (2004b), Tan et al. (2003) 168 Cyclo-(Leu-Ile) Ro Wang et al. (2004b), Tan et al. (2003) 169 Cyclo-(Leu-Val) Ro Wang et al. (2004b), Tan et al. (2003) 170 Cyclo-(Ile-Val) Ro Wang et al. (2004b), Tan et al. (2003) 171 Cyclo-(Leu-Ser) Ro Wang et al. (2004b), Tan et al. (2003) 172 Cyclo-(Leu-Tyr) Ro Wang et al. (2004b), Tan et al. (2003) 173 Cyclo-(Val-Pro) Ro Wang et al. (2004b), Tan et al. (2003) 174 Cyclo-(Ala-Pro) Ro Wang et al. (2004b), Tan et al. (2003) 175 Cyclo-(Phe-Tyr) Ro Wang et al. (2004b), Tan et al. (2003) 176 Cyclo-(Phe-Ala) Ro Wang et al. (2004b), Tan et al. (2003) 177 Cyclo-(Phe-Val) Ro Wang et al. (2004b), Tan et al. (2003) 178 Cyclo-(Leu-Ala) Ro Wang et al. (2004b), Tan et al. (2003) 179 Cyclo-(Ile-Ala) Ro Wang et al. (2004b), Tan et al. (2003) 180 Cyclo-(Val-Ala) Ro Wang et al. (2004b), Tan et al. (2003) Sterols 181 β-sitosterol HRo; Fb; Fr; Se; Rh; Fl Wei and Du (1992), Wei et al. (1980); Xia et al. (2014), Zuo et al. (1991), Xia et al. (2014), Shi et al. (2010); Song et al. (2010), Zhou et al. (2008b); Zhou et al. (2008a); Wei and Du (1992) 182 Daucosterol HRo; Ro; L; Fb; Fr; Rh; Fl; Se Xia et al. (2014), Wei et al. (1980); Komakine et al. (2006); Chen et al. (2002); Long (2013), Zuo et al. (1991); Shi et al. (2010); Zhou et al. (2008a), Guo (2013); Wei and Du (1992); Song et al. (2010), Zhou et al. (2008b) 183 Stigmasterol Fr; HRo Wei and Du (1992); Zhang et al. (2004) 184 Stigmasterol-3−O-β-d-glucopyranoside Fb Yoshikawa et al. (2003) 185 Stigmast-7-en-3β-ol-3−O-β-d-glucopyranoside Fb Yoshikawa et al. (2003) Po1yacetylenes 186 Falcarindiol Rh Zhang et al. (2004), Rao et al. (1997) 187 Panaxytriol Rh; Ro Zhang et al. (2004), Rao et al. (1997); Komakine et al. (2006), Liao et al. (2008)* 188 Panaxynol Ro; Se; Fb Komakine et al. (2006), Massayuki et al. (2001); Song et al. (2010), Zhou et al. (2008b), Yoshikawa et al. (2003) 189 Panaxydol Rh; Ro Zhou et al. (2008a); Komakine et al. (2006), Massayuki et al. (2001) 190 PQ-2 Ro Komakine et al. (2006) 191 Panaxydol chlorohydRone Ro Komakine et al. (2006) 192 (8E)−1,8-hepatadecadiene-4,6-diyene-3,10-diol Ro Komakine et al. (2006) 193 Ginsenoyne E Ro Komakine et al. (2006) 194 Notoginsenic acid β-sophoroside Ro Massayuki et al. (2001), Yoshikawa et al. (1997) 195 PQ-1 Ro Massayuki et al. (2001) Saccharides 196 sucrose Ro Wei et al. (1980) 197 PF3111 Ro Gao et al. (1996) 198 PF3112 Ro Gao et al. (1996) 199 PBGA11 Ro Gao et al. (1996) 200 PBGA12 Ro Gao et al. (1996) 201 PNPSI Ro Sheng et al. (2007) 202 PNPSIIb Ro Sheng et al. (2007) 203 Arabinogalactan polysaccharode Fl Wang et al. (2015) 204 Sanchinan A Ro Xia et al. (2014), Ohtani et al. (1987) Amino acids 205 Dencichine Ro Xie et al. (2007), Lv and Li (1988) Others 206 Benzyl-β-primeveroside Fp Wang et al. (2008) 207 (S)-tryptophan Fp Wang et al. (2008) 208 Icariside B6 Fp Wang et al. (2008) 209 3-hydroxy-4-methoxybenzoic acid Ro Komakine et al. (2006) 210 2-(1′,2′,3′,4′-Tetrahydroxybutyl)−6-(2″,3″,4″-tRohydroxybutyl)-pyrazine Xia et al. (2014) Li et al. (2001b) 211 Cinnamic acid Ro Komakine et al. (2006) 212 1β,6α-dihydroxyeudesm-4(15)ene Ro Komakine et al. (2006), Massayuki et al. (2001) 213 2-methoxy-1 h-pyrrole Ro Komakine et al. (2006) 214 5-hydroxymethyl-2-furancarboxaldehyde Ro Liao et al. (2008)* 215 Aromadendrane-7α,11α -diol Ro Komakine et al. (2006) 216 Aromadendrane-7β,11α -diol Ro Komakine et al. (2006) 217 Alloaromadendrane-7α,11α-diol Ro Komakine et al. (2006) 218 Spathulenol Ro Komakine et al. (2006) 219 Adenosine Fb; Fr Xia et al. (2014), Zhang et al. (2009a); Shi et al. (2010) 220 Guanosine hydrate Fb Xia et al. (2014); Zhang et al. (2009a) 221 (Z,Z)−9,12-octadecadienoic acid 2-hydroxy-1, 3-propanedinyl ester Ro Liao et al. (2008)* 222 Succinic acid methyl ester Ro Komakine et al. (2006) 223 Succinic acid monobuthyl ester Ro Komakine et al. (2006) 224 5-hydroxy-3-methoxydec-2-enoic acid Ro Komakine et al. (2006) 225 Aromadendrane-4β,10β-diol Rh Zhou et al. (2008a) 226 p-coumaric acid 4-hydroxyphenyl ester Ro Komakine et al. (2006) 227 Pananotin Ro Lam and Ng (2002b), (2001a) 228 Tripalmitin Se Song et al. (2010), Zhou et al. (2008b) Notes: * Compounds isolated from steam-treated P. notoginseng. Ro, Root; Rh, Rhizome; HRo, Hair Ro; L, Leaf; St, Stem; Se, Seed; Fr, Fruit; Fl, Flower; FP, Flower pedicel; Fb, Flower bud; Fro, Fermented Ro 4.1. Saponins (1-153) Saponins are the major constituents of P. notoginseng, and they are also considered as the main active compounds. More than 100 saponins have been isolated and identified, including ginsenosides, notoginsenosides and gypenosides (Fig. 2). They are mainly dammarane triterpenes with 20(S)-protopanaxadiol or 20(S)-protopanaxatriol aglycon moieties. In the 20(S)-protopanaxadiol and 20(S)-protopanaxatriol aglycon moieties, which all belong to dammarane triterpenes, both C3 and C12 of the dammarane skeleton have been replaced by hydroxyl groups. There is one angular methyl group at C8, the configuration at C13 is β-H and the configuration at C20 is S. The difference between them is that 20(S)-protopanaxadiol has a hydroxyl group at C6 that is not present in the 20(S)-protopanaxatriol. No oleanolic acid saponins were found, which is different from Panax ginseng C.A. Meyer and Panax quinquefolius L. (Bao et al., 2006). Different types of saponins are enriched in different parts of P. notoginseng. Ginsenoside Rb1 is abundant in all parts, whereas ginsenoside Rg1 is enriched in the root and the rhizome. It is worthy to note that ginsenoside Rb3, which has been reported to have a neuroprotective effect, is particularly abundant in the flower buds (Liu et al., 2014b). Usually, the five main saponins–notoginsenoside R1 (7–10%), ginsenosides Rb1 (30–36%), Rg1 (20–40%), Rd (5–8.4%) and Re (3.9–6%)—constitute up to 90% of the total P. notoginseng saponins (PNS) used in pharmacological experiments (Liu et al., 2014b). Among them, ginsenoside Rb1 (2), ginsenoside Rg1 (42) and notoginsenoside R1 (50) are chosen as the standard compounds to evaluate the quality of P. notoginseng. Fig. 2. Download high-res image (1MB)Download full-size image Fig. 2. Download high-res image (761KB)Download full-size image Fig. 2. Download high-res image (708KB)Download full-size image Fig. 2. The structures of saponins isolated from P. notoginseng. To enhance the molecular diversity of ginsenosides, which concomitantly enhances the chances to find new biologically active substances, scientific studies have been conducted to investigate the hydrolysed saponins (Wang and Zhao, 2008a, 2008b; Teng et al., 2004; Chen et al., 2006; Cao et al., 2013; Yang et al., 1986; Hu et al., 2008) and bio-transformed chemical components of P. notoginseng (Luo et al., 2013; Zhang et al., 2009b; Han et al., 2007a, 2007b; Jiang et al., 2004b). New active compounds have been isolated through these studies, representing a new direction for drug discovery in P. notoginseng. 4.2. Flavonoids (154-166) Flavonoids are of particular concern because of their well-defined pharmacological activities, which include antioxidant activity, liver-protective activity, anti-tumour activity, etc. To date, some flavonoids (Fig. 3) have been isolated from this plant, they are mainly flavonols and flavone glycosides, such as liquiritigenin (154), quercetin (156) and kaempferol-3−O-α-l-rhamnoside (163). A flavonol glycoside named quercetin 3−O-β-d-xylopyranosyl-β-d-galactopyranoside (159) was reported to have the potential to treat Alzheimer's disease (Choi et al., 2010b). Further drug discovery research on this compound is necessary. Fig. 3. Download high-res image (256KB)Download full-size image Fig. 3. The structures of flavonoids isolated from P. notoginseng.. 4.3. Cyclopeptides (167-180) Cyclopeptides are cyclic compounds formed mainly with the peptide bonds of 2–37 protein or nonprotein amino acids. They are found in plants of the Caryophyllaceae and Rhamnaceae families, and they can be divided into two classes, five sub-classes and eight types (Tan and Zhou, 2006). Only 14 cyclopeptides (Fig. 4) have recently been isolated, and they were all cyclodipeptides. Their structures were elucidated as cyclo-(Leu-Thr), cyclo-(Leu-Ile), cyclo-(Leu-Val), cyclo-(Ile-Val), cyclo-(Leu-Ser), cyclo-(Leu-Tyr), cyclo-(Val-Pro), cyclo-(Ala-Pro), cyclo-(Phe-Tyr), cyclo-(Phe-Ala), cyclo-(Phe-Val), cyclo-(Leu-Ala), cyclo-(Ile-Ala) and cyclo-(Val-Ala) based on spectral methods. Fig. 4. Download high-res image (325KB)Download full-size image Fig. 4. The structures of cyclopeptides isolated from P. notoginseng. (For interpretation of the references to color in this figure, the reader is referred to the web version of this article.) 4.4. Sterols (181-185) There are few reports regarding sterols compounds. Sterols isolated from P. notoginseng include β-sitosterol (181), daucosterol (182), stigmasterol (183), stigmasterol-3−O-β-d-glucopyranoside (184) and stigmast-7-en-3β-ol-3−O-β-d-glucopyranoside (185). Their structures are listed in Fig. 5. Fig. 5. Download high-res image (181KB)Download full-size image Fig. 5. The structures of sterols isolated from P. notoginseng. 4.5. Polyacetylenes (186-195) Polyacetylenes are usually highly unsaturated with potent activity because of two or more conjugated triple bonds (Wang and Yuan, 1990). Reports regarding polyacetylenes in P. notoginseng are rare (Fig. 6). However, panaxynol (188) and panaxydol (189) isolated from P. notoginseng have been reported to have strong antimicrobial activity against S. aureus (Lin et al., 2002). Thorough research in this area may be promising. Fig. 6. Download high-res image (209KB)Download full-size image Fig. 6. The structures of polyacetylenes isolated from P. notoginseng. 4.6. Saccharides (196-204) Saccharides in P. notoginseng include monosaccharides, oligosaccharides and polysaccharides. Polysaccharides exist in many parts of this plant, with the highest content in the main root (Liu et al., 2012). The total sugar content of the P. notoginseng root is nearly twice that of the rhizome (Liu et al., 2005). The polysaccharides content of the flower is twice that of the stem and leaf of P. notoginseng (Qu et al., 2014). Scientific studies have demonstrated that the polysaccharides in P. notoginseng have certain immunological adjuvant activity and immunostimulatory action (Gao et al., 1996). Therefore, it might be promising to cultivate the P. notoginseng flower due to its relatively high polysaccharides content. 4.7. Amino acids (205) There are more than 19 kinds of amino acids in P. notoginseng, and 7 of them are considered essential amino acids (Zhu et al., 2014). One amino acid, named dencichine (205) (Fig. 7), is special. It is a nonprotein amino acid named β-N-oxalyl-l-α,β-diaminopropionic acid that was first isolated from the seed of Lathyrus sativus (Leguminosae) (Rao et al., 1964). It has been reported that this compounds from P. notoginseng had certain haemostatic and platelet-increasing properties in vivo (Qiao et al., 2013). However, the compound dencichine, found in the Lathyrus species, is considered to be the component responsible for primary upper motor neuron degenerative diseases (Rao, 1978). Besides, dencichine exerts haemostatic effect at low doses, while it is neurotoxic at higher doses (Qiao et al., 2013). Therefore, it is important to use P. notoginseng at an appropriate dosage. Fig. 7. Download high-res image (65KB)Download full-size image Fig. 7. The structures of dencichine from P. notoginseng. 4.8. Volatile oil The volatile constituents of P. notoginseng include terpenes, alcohols, aldehydes, olefins and alkanes. Terpenes are considered as a significant component because of its relatively high percentage among these compounds (Hou, 1993; Lv et al., 2005). Up till now, forty-one compounds have been identified in the neutral fraction of the volatile constituents of P. notoginseng by gas chromatography coupled with mass spectrometry (Zhang et al., 2004). But, there is a lack of pharmacological study of the volatile constituents of P. notoginseng, which provides a new direction for further research. 4.9. Others (206-228) Apart from the chemical compounds listed above, there are also other constituents (Fig. 8) that have been isolated from P. notoginseng, including icariside B6 (208), guanosine hydrate (220), fatty acids (Liu et al., 1990), inorganic elements and mineral salts (Li et al., 1996). Some compounds were demonstrated to possess biological activities. It is noticeable that a water-soluble polyhydroxy derivative of 1, 4- diazine, namely 2-(1c, 2c, 3c, 4c-tetrahydroxybutyl)−6-(2d, 3d, 4d-trihydroxybutyl)-pyrazine (210), was shown to be toxic to liver cancer cells, with an IC50 of 0.05 mg/ml (Li et al., 2001b). A protein, pananotin, was shown the anti-fungal and cell-free translation inhibitory activities (Lam and Ng, 2002b). Fig. 8. Download high-res image (372KB)Download full-size image Fig. 8. The structures of others compounds isolated from P. notoginseng. 5. Pharmacological activities Scientific studies on P. notoginseng indicate that it has wide-reaching pharmacological activities (Table 3), including the effects on the cardiovascular system and the immune system, as well as anti-atherosclerotic activity, haemostatic activity, anti-tumour activity and so on. Meanwhile, the effects on cardiovascular system is more outstanding. Table 3. Pharmacological activities of Panax notoginseng (Burk.) F.H. Chen. Extracts/compounds Material/model Dosage and administration route Results references Effects on the cardiovascular system PNS Rat/myocardial ischemia model In vivo 30 mg/kg and 60 mg/kg; Oral ↑ Left ventricular ejection fractions, left ventricular fractional shortening Chen et al. (2011) ↓ Left ventricular dimensions at end diastole and left ventricular dimensions at end systole H9c2 cells In vitro 0.05−2.25 g/L ↓ The loss of mitochondrial membrane potential PNS Rat In vivo 50–200 mg/ kg; i. p. ↑ cAMP content, adenyl cyclase activity Zhang et al. (2003) Trilinolein Neonatal rat cardiomyocytes In vitro 1 and 10 μM ↓ Superoxide production in cardiomyocytes Yang et al., (2005) Anti-atherosclerotic activity PNS Rat/atherosclerosis models In vivo 100 mg/kg; i. p. ↑ LXRα Fan et al. (2012) ↓ AS pathological alterations THP-1 macrophages In vitro 0–100 mg/L ↑ LXRα mRNA levels, ABCA1 and ABCG1 expression ↓ NF-kB DNA binding activity, IL-6 and MCP-1 PNS Rat/atherosclerosis models In vivo 100 mg/kg; i. p. ↓ Formation of foam cell, the expression of most integrin families Yuan et al. (2011) Peritoneal macrophage In vitro 10–100 μg/ml ↓ Phosphorylation of FAK on threonine 397 and translocation of NF-kB. Ginsenoside Rd ApoE−/−mice/ fed with high cholesterol In vivo 20 mg/kg/day; i. p. ↓ Atherosclerotic plaque areas, oxidized low-density lipoprotein uptake, thapsigargin and l-oleoyl-2-acetyl-glycerol (, membrane-permeable diacylglycerol analog)-induced Ca2+ influx Li et al. (2011) RAW264.7 cells In vitro ↓ ox-LDL-induced foam cell formation, increase of thapsigargin- and OAG-induced Ca2+ influx Haemostatic and wound healing activities Different extracts of PN Rat/hemorrhagic model In vivo 40 mg; applied externally ↓ The bleeding time White et al. (2001) PN and PNS Rat/bleeding model In vivo 40 mg; applied externally ↓ The bleeding time White et al. (2000) PNS Rat/hemorrhagic shock model In vivo 200 mg/kg; i. v. ↑ superoxide dismutase level Liu et al. (2014a) ↓ MDA, MPO, endotoxin, TNF-α, and IL-6 Notoginsenoside Ft1 Rat In vivo 1.25 mg/kg; i. v. ↓ The bleeding time Gao et al. (2014) Rat blood In vitro 200 μM ↑ Platelet aggregation Antioxidant activity Different extracts from various parts of PN Rat pheochromatocytoma PC12 cell In vitro 0.1 mg/ml ↓ The amount of reactive oxygen species Choi et al. (2010a) 20(S)-sanchirhinosides A1-A6 and sanchirhinoside B L6 cell In vitro 10 μmol/L 20(S)-sanchirhinosides A4, A6 and sanchirhinoside B had protective effects against antimycin A-induced L6 cell injury Zhang et al. (2013b) 20(S)-Ginsenoside Rg2 Human umbilical cord vein endothelial cell line In vitro 50 μg/ml ↑ PA level Xin et al. (2005) Anti-inflammatory activity Water extract of PN Mouse peritoneal macrophages In vitro 0–100 μg/ml ↓ NO and prostaglandin E2 production Jin et al. (2007) Mouse paw edema In vitro 4, 10 and 20 mg/kg; i. p. ↓ Levels of prostaglandin E2 PNS Rat/air-pouch acute inflammatory model In vivo 60–240 mg/kg; i. p. ↓ Protein content, Neu-, phospholipase A2 activity, Din content Li and Chu (1999) Pseudoginsenoside-F11 Mice/injected with LPS In vivo 8 mg/kg; oral Mitigated the microglial activation and proinflammatory factors expression Wang et al. (2014b) Murine microglia cell line N9 In vitro 1–100 μM ↓ The increase of iNOS and COX-2 mRNA expression, IL-1β, IL-6 and TNF-α production, expression of TLR4 and MyD88 Hypoglycaemic and anti-hyperlipidemic activities PNS, notoginsenoside R1, ginsenosides Rb1, Rg1, Rd and Re Rat/diabetic model In vivo PNS 200 mg/kg, Rb1 60 mg/kg, Rg1 40 mg/kg, Rd 15 mg/kg, Re 14 mg/kg and R1 6 mg/kg; i. p. ↑ Glucose tolerance Yang et al. (2010) ↓ Fasting blood glucose levels, serum insulin, leptin and triglyceride levels, food intake PNS 3T3-L1 cell In vitro 10, 50 and 100 μg/ml ↑ Glucose uptake in a dose-dependent manner, GLUT4 Kim et al. (2009) PNS Mice/type 2 diabetic KK-Ay gene mice model In vivo 50 or 200 mg/kg; i. p. ↑ Glucose tolerance Chen et al. (2008) ↓ Fasting blood glucose levels, body weight incremental percentage, serum insulin resistance index and triglyceride levels n-BuOH extract of PN Rat/hyperlipidemic model In vivo 30, 60 and 100 mg/kg; i. p ↓ Serum TC, TG and LDL-C Ji and Gong. (2007) HepG2 cells In vitro 10, 50, 100, 150, 200 μM ↑ LDLR mRNA level ↓ Expression levels of CYP7A1, ApoCIII and SREBP1c genes Ginsenoside Re Ob/ob mice In vivo 7, 20 and 60 mg/kg; i. p. ↑ Glucose tolerance Xie et al. (2007) ↓ Fasting blood glucose levels Neuroprotective effect PN Mice/transient focal brain ischemia model In vivo 50 mg/kg; i. p. ↓ Infarct volume, microglial density Son et al. (2009) Glial cells and BV-2 mouse microglial cells In vitro 10 – 100 μg/ml ↓ Production of iNOS-derived NO and COX-2–derived prostaglandin E2 PNS Rat hippocampal NSCs/model of brain ischemia In vitro 17.5 μg/ml ↑ NSC proliferation and the expression of nestin/BrdU, Tuj-1, vimentin, and nestin mRNA expressions Si et al. (2011) PNS Brain of Rat/ischemia-reperfusion model In vivo 25 mg/kg; i. p. ↓ Expression of caspase-1 and caspase-3 Li et al. (2009) PTS Mice In vivo 50 and 100 mg/kg; i. p. ↑ TRX-1 expression Luo et al. (2010) PC12 cell In vitro 0.25, 0.5, and 1 mg/ml ↑ TRX-1 expression ↓ MPP+-induced neurotoxicity Notoginsenoside R1 PC12 cells/ model of AD In vitro 1–100 μM ↑ Cell viability Ma et al. (2014) ↓ Oxidative damage, stress-activated MAPK signaling pathways Immunological adjuvant activity and immunostimulatory action PNS Mice In vivo 50, 100, 200 μg ↑ Splenocyte proliferation, serum ovalbumin-specific IgG antibody titers Sun et al. (2003) Ginsenoside Rh4 Mice In vivo 10, 25, 50 μg ↑ Splenocyte proliferation, serum IgG, IgG1, and IgG2b antibody levels Yang et al. Yang et al., (2007) Notoginsenoside K Mice In vivo 10, 25, 50 μg ↑ Splenocyte proliferation, serum IgG, IgG1, and IgG2b antibody levels Qin et al. (2006) Anti-coagulation activity PN Rat In vivo 43 mg/kg/day or 86 mg/kg/day; oral ↓ fibrinogenaemia Cicero et al. (2003) Notoginsenoside Rl HUVECs In vitro 0.01–100 μg/ml ↑ tPA mRNA Zhang et al. (1994) ↓ PAI-1 activity Notoginsengnosides Rat platelets In vivo 200 microg/ml ↑ growth factor receptor-bound protein 2, thrombospondin 1, tubulin alpha 6 Yao et al. (2008) ↓ thioredoxin, Cu-Zn superoxide dismutase, DJ-1 protein, peroxiredoxin 3, thioredoxin-like protein 2, ribonuclease inhibitor, potassium channel subfamily V member 2, myosin regulatory light chain 9 and laminin receptor 1 Effects on the kidney PNS Rat/nephrotoxicity model In vivo 31.35 mg/kg; i. p. ↑ The expression of Bcl-2 Liu et al. (2014c) ↓ BUN, Scr and urinary NAG, the expression of Bax and caspase 9 Ginsenoside Rg1 Rats with unilateral ureteral obstruction In vivo 50 mg/kg; i. p. ↑ The expression of E-cadherin Xie et al. (2008) ↓ The expression of α-SMA, thrombospondin-1, TGF-β1 mRNA, phosphorylated Smad2 Ginsenoside Rg1 Rat renal tubular epithelial cells (NRK-52E) In vitro 10−40 ng/ml ↑ E-cadherin Xie et al. (2009) ↓ The expression of α-SMA, the levels of collagen I and fibronectin, P-ERK1/2 Effects on the liver Different extracts of PN, ginsenosides- Re and -Rg1 Rat/liver injury model In vivo 300 mg/kg PN, 20 mg/kg ginsenosides Re and Rg1; i. p. ↓ The serum enzymes level and blood GPT Prasain et al. (1996) Hot water extract of PN Rat/hepatotoxicity model In vivo 10, 25 and 50 mg/kg; p. o. ↓ The chronic ethanol-induced SGOT and SGPT elevation Lin et al. (2003) Mouse mouse liver homogenate In vitro 0.01, 0.1 and 1.0 mg/ml ↓ The lipid peroxidation PNS Rat/hepatic fibrosis model In vivo 130 mg/kg PNS; i. p. ↓ Levels of ALT, AST and liver index, serum TGF-β1, TNF-α and IL-6 Peng et al. (2009) ↑ The production of IL-10 Ginsenoside-Rg1 Rat/hepatic fibrosis model In vivo 15, 50, 100 mg/kg; i. c. ↓ The serum levels of alanine transaminase, aspartate transaminase and alkaline phosphatase Geng et al. (2010) Hepatic stellate cells (HSCs) In vitro 0.1, 1, 10 μM ↓ Cell proliferation, activation and formation of reactive oxygen species Anti-tumour activity PNS Mice/spontaneous tumour and experimental metastasis mode In vivo 150 mg/kg; i. p. ↓ Lung metastasis Wang et al. (2014a) 4T1 cells In vitro 50, 100, 200, 300 and 400 μg/ml ↑ Expression of Brms1, Mtss1, Timp2 and E-cadherin ↓ Expression of MMP3, MMP9 and vimentin. Ginsenoside Rd Human cervical cancer (HeLa) cells In vitro 0–240 μg/ml ↑ The expression of Bax Yang et al. (2006) ↓ The cell growth, the expression of Bcl-2 proteins, the mitochondrial transmembrane potential An arabinogalactan from flowers of PN Human microvascular endothelial cells In vitro 0.5 mg/ml, 1 mg/ml ↓ The migratory activity of endothelial cells and their abilityof tube formation on matrigel, but no effect on endothelial cells growth Wang et al. (2015) athymic nude (nu/nu) mice/ xenograft model In vivo 0.5 mg/kg and 20 mg/kg; oral ↓ Microvessel formation in the BxPC-3 pancreatic cancer cell xenograft tumour in nude mice Notes: Abbreviations: PN, P. notoginseng; PNS, P. notoginseng saponins; TNF-α, tumour necrosis factor α; IL-1β, interleukin-1β; cAMP, cyclic adenosine monophosphate; MDA, malondialdehyde; MPO, myeloperoxidase; IL-6, interleukin-6; COX-2, cyclooxygenase-2; NO, nitric oxide; MMP, matrix metalloproteinase; iNOS, inducible nitric oxide synthase; TGF-β1, transforming growth factor-β1; LXRα, liver X receptor α 5.1. Effects on the cardiovascular system 5.1.1. Protective effect on myocardial cells P. notoginseng has been proven to be effective in protecting myocardial cells. Administration of saponins of P. notoginseng (PNS) is beneficial to cardiac function at the early phase of burned rat (Zhang et al., 2003; Huang et al., 1999). P. notoginseng exhibits protective effects on myocardial cells through multiple signaling pathways. First, the extracts of P. notoginseng can decrease oxidative stress on myocardial ischemia model of rat (Han et al., 2013). Trilinolein isolated from P. notoginseng can attenuate the production of superoxide in cardiomyocytes (Yang et al., 2005). Second, PNS can protect H9c2 cells from serum, glucose and oxygen deprivation-induced apoptosis in mitochondrial-dependent pathway in vitro and increase the phosphorylation of Akt in myocardial tissues of rat ischemic heart (Chen et al., 2011), the later effect was also found when pretreatment with notoginsenoside R1 in the heart tissues of endotoxemic mice (Sun et al., 2013). Third, the extracts of P. notoginseng can repress inflammatory cascade (Han et al., 2013), and notoginsenoside R1 can preserve activation of ERα, which causes the attenuation of pro-inflammatory state in the myocardium (Sun et al., 2013). Besides, PNS can regulate several proteins which are involved in pathways including energy metabolism, lipid metabolism, muscle contraction, heat shock stress, cell survival and proliferation in a rat model of ischemia-reperfusion (Liu et al., 2014b; Yue et al., 2012). Moreover, the effects of PNS on myocardium in burned rats involved its action to increase myocardial Gsα mRNA expression and adenyl cyclase activity, cyclic adenosine monophosphate content as well as ATPase activities (Zhang et al., 2003). Despite all these possible mechanisms, a complete view of how it protect myocardial cells from ischemic lesion is still lacking (Liu et al., 2014b). And some mechanisms about the exact cellular and molecular targets need to be fully elucidated. 5.1.2. Protective effect on endothelial cells Endothelial cells cover the inner lining of blood vessels, which play a predominant role in modulating many aspects of vascular homeostasis. Dysfunction of endothelial cell structure and function may contribute to the occurrence of diseases such as thrombosis and atherosclerosis. PNS can regulate the behavior of arterial endothelial cells in several ways. The extract of P. notoginseng, ginsenoside Rb1 and Rg1 were suggested to increase endothelial-dependent vessel dilatation of rat through the activation of nitric oxide (NO) by modulating the PI3K/Akt/eNOS pathway and l-arginine transport in endothelial cells (Pan et al., 2012). PNS (i. v. 30 or 50 mg/kg) can promote the endothelial regeneration and reduce extra-cellular matrix thickening, which was related to the down-regulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 expression (Chen et al., 2004). In addition, 20(S)-Ginsenoside Rg2 and notoginsenoside Ft1 can stimulate the proliferation of human umbilical cord vein endothelial cell (Xin et al., 2006; Shen et al., 2012), and have protection effects on human umbilical cord vein endothelial cells from H2O2-induced cell apoptosis (Xin et al., 2005). 5.2. Anti-atherosclerotic activity Atherosclerosis underlies most cardiovascular disease, and causes more death and disability worldwide than any other pathology except infection (Wan et al., 2009). P. notoginseng possesses anti-atherosclerotic activity. PNS, the main constituent, has shown its therapeutic effects on atherosclerosis via several mechanisms. The first mechanism is via its anti-inflammatory action (Jia et al., 2008; Zhang et al., 2008; Fan et al., 2012; Wan et al., 2009; Dou et al., 2012). Second, PNS regulates the blood lipid profile and triglyceride levels (TG) metabolism (Jia et al., 2008; Zhang et al., 2008; Fan et al., 2012; Liu et al., 2009; Wan et al., 2009). PNS can increase TG metabolism via increasing the activity of lipoprotein lipase (Jia et al., 2008). Besides, it increases the efflux of cholesterol by enhancing transcriptional activation of the liver X receptor α (LXRα) gene promoter, which in turn up-regulating its target genes ATP-binding cassette A1 and G1 and LXRα (Fan et al., 2012; Jia et al., 2010). Integrin families are also closely related with atherosclerosis. PNS can inhibit the expression of most integrin families except Itgav and Itgb2 in atherosclerosis models of rat, FAK phosphorylation and NF-kB translocation are also suppressed (Yuan et al., 2011). Furthermore, PNS reduces the size of atherosclerotic plaques by increasing progenitor cell mobilization, which is a new mechanistic insight into the capacity of PNS to protect apoE−/− mice from atherosclerosis (Liu et al., 2013). In addition, ginsenoside Rd prevents the development of atherosclerosis via inhibiting Ca2+ influx through voltage-independent Ca2+ channels (Li et al., 2011). 5.3. Haemostatic and wound healing activity P. notoginseng is regarded as a trauma panacea, and it is usually used for the treatment of internal and external bleeding due to injury. Applying the powder, alcohol extract of P. notoginseng and PNS externally significantly shorten the bleeding time of rat (White et al., 2000, 2001). PNS exerts its haemostatic action in several ways. It was suggested to decrease inflammatory reaction, reduce oxidative stress, and inhibit endotoxin and myeloperoxidase in the recovery stage of rat with hemorrhagic shock (Liu et al., 2014a). Meanwhile, PNS and ginsenoside Rg1 promote angiogenesis through the kinase-domain region/foetal liver kinase-1 (VEGF-KDR/FIK-1) pathway and the phosphatidylinositol-3 kinase-Akt-endothelial nitric oxide synthase (PI3K-Akt-eNOS) signaling pathway (Hong et al., 2009). In addition, notoginsenoside Ft1 can enhance platelet aggregation via activating a signaling network mediated through P2Y12 receptors, interestingly, this mechanism is different from that of the currently used haemostatic drugs, such as etamsylate, amniomethylbenzoic acid, transmic acid and adrenosin (Gao et al., 2014). These findings are very helpful to place the traditional use of P. notoginseng for wound healing and traumatic injuries on a scientific footing. 5.4. Antioxidant activity Flavonoids (Hong et al., 2014) and saponins (Xin et al., 2005; Zhong et al., 2013b) from P. notoginseng were reported to have antioxidant and radical-scavenging activity. Diets supplemented with sanqi can improve hepatic antioxidant status of rat fed with a high fat diet (Xia et al., 2011). The water extract of the biennial flower was reported to have inhibitory effect on the enzymatic activity of xanthine oxidase and protective effect on neuronal PC12 cells against H2O2-induced cytotoxicity (Choi et al., 2010a). Zhao et al. (2007) found that P. notoginseng extracts had strong ferrous ion chelating activity and high scavenging activities against hydrogen peroxide, hydroxyl radicals, and weak activities against superoxide anion and 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals. However, Wu and Wang (2008) reported an arabinoglucogalactan with an strong scavenging activity against DPPH free radicals, with a 50% scavenging concentration of 11.72±0.91 μg/ml. 5.5. Anti-inflammatory activity P. notoginseng also has anti-inflammatory activity. Ethanol and n-butanol extracts of P. notoginseng can inhibit the production of pro-inflammatory cytokines and modulate important accessory molecules (Rhule et al., 2006; Chang et al., 2007). The mechanisms that P. notoginseng exerts anti-inflammatory effect may be complicated. Water extract of P. notoginseng can inhibit the function of neutrophil (Neu), as well as the overproduction of nitric oxide (NO) and prostaglandin E2 (PGE2) through decreasing the iNOS and COX-2 expression in mouse peritoneal macrophages stimulated with lipopolysaccharide (LPS) (Jin et al., 2007). Besides, PNS decreases Neu migration by inhibiting Neu activation following blocking effect on Ca2+ level in Neu (Li and Chu, 1999), and reduces arachidonic acid metabolism and dinoprostone content via inhibiting the PLA2 activity (Li and Chu, 1999). Meanwhile, methanol extract of P. notoginseng flower and PNS can suppress the expression of the inflammation-associated genes by inhibiting the NF-κB activation in LPS-stimulated mouse macrophage cells (Jung et al., 2009; Dou et al., 2012) and decrease TNF-α mRNA expression regulated by PKC-NF-kB signaling pathway in scalded mice (Wang et al., 2006). Also, PNS reduces the expression of pro-inflammatory factors by inhibiting the expression of RAGE, MAPK signaling pathways in the lesions of apoE-/- mice (Dou et al., 2012). Furthermore, PNS can inhibit NF-kB DNA-binding activity, and this effect is dependent on LXRα in LPS-stimulated THP-1 macrophages (Fan et al., 2012). Pseudoginsenoside-F11, a puried compound from P. notoginseng, was found to exert anti-neuroinflammatory effects on LPS-activated microglial cells by inhibiting TLR4-mediated TAK1-IKK-NF-kB, MAPK and Akt signaling pathways, and this neuroinflammation action was confirmed in mice in vivo (Wang et al., 2014b). 5.6. Hypoglycaemic and anti-hyperlipidemic activities PNS, as well as ginsenoside Rb1, Re can lower fasting blood glucose levels and improve glucose tolerance in KK-Ay mice and ob/ob mice (Chen et al., 2008; Yang et al., 2010; Xie et al., 2005; Xiong et al., 2010). This hypoglycemic effect of PNS in KK-Ay mice may be related to the improvement of insulin sensitivity (Yang et al., 2010). Meanwhile, PNS enhances insulin-stimulated glucose uptake and glycogen synthesis in adipocytes, as well as enhances the GLUT4 expression and translocation in 3T3-L1 cells (Kim et al., 2009). However, there remains gap in clinical studies, which should be carried out to support these findings. P. notoginseng also possesses anti-hyperlipidemic activity. Dietary supplementation with it improves lipid profiles and lowers serum total cholesterol (TC) and TG in hyperlipidemic mice (Xia et al., 2011; Joo et al., 2010). N-BuOH extract of P. notoginseng can decrease the levels of serum low-density lipoprotein cholesterol and TC by increasing the expression level of low density lipoprotein receptor. Besides, it lowers the biosynthesis of TG levels by targeting SREBP-1c gene expression and accelerates the lipolysis of lipoprotein TG by increasing the activity of lipoprotein lipase (Ji and Gong, 2007). 5.7. Neuroprotective effects P. notoginseng has certain neuroprotective effects. Total PNS, as well as ginsenosides Rg1, Rb1, notoginsenoside R1, Panax notoginsenoside, P. notoginseng plysaccharides can inhibit apoptosis through increasing Bcl-2/Bax ratio and the expressions of Trx-1, SOD-1, HSP70, reducing the expression of caspase-1, caspase-3 and apoptosis-related proteins (Fas and FasL), restoring the anti-apoptotic Akt–NF-kB signaling pathway (Jia et al., 2014; Li et al., 2009; Ning et al., 2012; Zeng et al., 2014; Ma et al., 2014 ). The anti-inflammatory function also contributes to its neuroprotective effects. The methanol extract of P. notoginseng can inhibit inflammation related events, including microglial activation and the induction of inflammatory inducible enzymes such as iNOS and COX-2 (Son et al., 2009). Panax notoginsenoside can reduce the activity of leukocytes, decrease expression of these inflammatory factors, and relieve the secondary inflammation-induced injury (Ning et al., 2012). Its anti-edema action via suppressing the expression of AQP-4 is also involved in neuroprotective effects (Ning et al., 2012). In addition, PNS can improve the metabolism of energy and preserve the structural integrity of neurons against hypoxic damage in vitro (Jiang and Qian, 1995), promote proliferation of hippocampal neural stem cell, and differentiate into new neurons and glial cells (Si et al., 2011). Notoginsenoside Rb1 is able to up-regulate the protein level of brain-derived neurotrophic factor (Wang et al., 2013). Further more, P. notoginseng has anti-neurodegenerative effect. It modulates the levels of protein and gene expressions such as ADAM9 gene and BACE1 gene involved with α and β secretase, thereby increasing α-secretase activity and reducing β-secretase activity (Huang et al., 2014). Panaxatriol saponins can induce thioredoxin-1 expression, and attenuate 1-methyl-4- phenylpyridinium ion-induced cell death of PC12 cells (Luo et al., 2010). Quercetin 3−O-β-d-xylopyranosyl-β-d-galactopyranoside from P. notoginseng can block the Aβ- induced Ca2+ mobilization (Choi et al., 2010b). Notoginsenoside Rb1 is able to down-regulate Tau protein phosphorylation in Alzheimer’s disease (Wang et al., 2013). 5.8. Immunological adjuvant activity and immunostimulatory action PNS, protopanaxadiol-type saponins (PDS), ginsenosides-Rb1, -Rd, notoginsenosides-K, -R4 isolated from P. notoginseng were shown to enhance significantly specific antibody and cellular response against ovalbumin (OVA) in mice, and increase the activation potential of both T and B cells in mice immunized with OVA (Sun et al., 2003; Yang et al., 2007; Qin et al., 2006; Sun et al., 2005). Four polysaccharides isolated from P. notoginseng were also proved to have immunostimulating activities in vitro (Gao et al., 1996). It is note worth that ginsenoside Rd induced the stronger various antibody responses of mice against OVA among ginsenosides-Rb1, -Rd, notoginsenosides-K, -R4, and further structure–activity relationship studies revealed that the length of sugar side chains at position C-20 and the linkage of glucose moiety at position C-3 of protopanaxadiol could affect the haemolytic and adjuvant activities of PDS. This structure–adjuvant activity relationship deserves further investigation because it might be useful for developing semisynthetic tetracyclic triterpenoid saponins derivatives with immunological adjuvant activity, as well as a reference to the distribution of the functional groups composing the saponins molecule (Sun et al., 2005), but adequate purified structurally consecutive saponins, antigen and animals for the induction of various other responses should be needed. 5.9. Anti-coagulation activity Apart from hemostasis, P. notoginseng still has anti-coagulation effect which involves several pathways. Fibrinolysis is an integral part of the coagulation cascades, and it can be regulated by the plasminogen activator (PA) and PA inhibitor (PAI-1) (Liu et al., 2014b). Notoginsenoside R1 can increase the expression of tissue-type PA and decrease PAI-1 activity in human umbilical vein endothelial cells (Zhang et al., 1994). This saponin also increases the fibrinolytic and proteolytic potential of human pulmonary artery and human skin microvascular endothelial cells by up-regulating the production of t-PA and u-PA (Zhang et al., 1997). Besides, it inhibits TNF-α-induced PAI-1 over-expression in human aortic smooth muscle cell by suppressing ERK and PKB signaling pathways (Zhang and Wang., 2006). Platelet activation and aggregation constitute another important pathway in blood coagulation (Liu et al., 2014b). Notoginsengnosides treatment increases the expression of three proteins and decreases the expression of nine proteins in platelets, which might contribute to its inhibitory on platelet aggregation (Yao et al., 2008). Xuesaitong capsule, a preparation made of multi-component of P. notoginseng saponins, can inhibit platelet superficial activation, adhesion and aggregation (Wang et al., 2004a). Furthermore, P. notoginseng can induce a significant reduction in the rat fibrinogenaemia (Cicero et al., 2003). 5.10. Effects on the kidney P. notoginseng was proved to have certain effects on the kidney. PNS can protect against cisplatin-induced nephrotoxicity, and reduces renal tissue apoptosis via inhibiting the mitochondrial pathway, as it down-regulates the expression of caspase 9 and Bax, and up-regulates the Bcl-2 expression (Liu and Zhou., 2000; Liu et al., 2014c). Also, it has therapeutic effects on the tubulointerstilial fibrosis in the rat model of adenine nephropathy (Zhao et al., 2008). Meanwhile, ginsenoside Rg1, a monomer isolated from P. notoginseng was found to have beneficial effect on renal. In vivo study, it inhibited renal interstitial fibrosis in rats with UUO through inhibiting tubular Epithelial-myofibroblast transition (EMT), which was achieved by suppressing the expression of TSP-1 and then suppressing the transcription and activation TGF-β1 (Xie et al., 2008). In vitro study, ginsenoside Rg1 could inhibit the process of EMT by suppressing P-ERK1/2 expression (Xie et al., 2009). However, research about the other monomer compounds in P. notoginseng on renal is still lacking, suggesting that determine whether other compounds also have benefical effect requires further research. 5.11. Effects on the liver Trials regarding the hepatoprotective effects of P. notoginseng and its potential mechanisms have been conducted due to its usage in liver disease. The methanol and water extracts of P. notoginseng were found to have protective effects on carbon tetrachloride-induced liver injury in rats (Prasain et al., 1996). Hot water extract of P. notoginseng can protect against alcoholic liver injury in vitro and vivo (Lin et al., 2003). Besides, ginsenosides Re and Rg, isolated from the methanol extract, also showed a significant hepatoprotective effect on d-galactosamine/ LPS-induced liver injury in mice (Prasain et al., 1996). The certain therapeutic effects of PNS on hepatic fibrosis is probably related to its immunoregulation action of pro-fibrotic and anti-fibrotic cytokines, as well as its antioxidant properties (Peng et al., 2009; Geng et al., 2010). In addition, PNS can attenuate the gut ischemia and reperfusion-induced hepatic micro-vascular dysfunction and sequential hepatocellular damage via its anti-inflammatory effect (Park et al., 2005). 5.12. Anti-tumour activity Recently, investigations upon the anti-tumour effect of P. notoginseng have been conducted. The extracts and its constituents have been proved to have potential anti-cancer activities on colon cancer (He et al., 2012; Wang et al., 2007a, 2007b; Wen et al., 2014 ), liver cancer (Toh et al., 2011), lung cancer ( Bi et al., 2009), lymphocytoma (Chen et al., 2013; Yoo et al., 2011), pancreatic cancer (Wang et al., 2015), breast cancer (Wang et al., 2014a). The main possible mechanism is to inhibit cell proliferation and induce cell apoptosis through down-regulating Bcl-2 expression, up-regulating Bax expression, lowering the mitochondrial transmembrane potential, and activating the caspase-3 pathway (Yang et al., 2006). Interestingly, the anti-proliferation effect of steamed P. notoginseng extract is much better (Sun et al., 2010; Toh et al., 2011). Apart from these, PNS can enhance the anti-proliferation effect of 5- FU on HCT-116 human colorectal cancer cells and has the potential to overcome the negative side effects of doxorubicin (Wang et al., 2007a; Liu et al., 2008). It is worthy to note that 20(S)−25-OCH3-PPD, a saponin isolated from the leaves of P. notoginseng, showed effective activities in several human cancer cell lines, including glioma, pancreatic cancer, lung cancer, breast cancer and prostate cancer, providing a basis for the future development of 20(S)−25-OCH3-PPD as a novel anti-cancer agent (Zhao et al., 2007). The mechanism may be related to the expression reduction of β-catenin and its transcriptional targets (Bi et al., 2009). Further in vivo and human trials are needed in order to confirm the efficacy and safety. 5.13. Other activities In addition to the pharmacological effects noted above, P. notoginseng displays other activities. A saponin fraction prepared from the root of P. notoginseng was shown to increase the motility and progression of sperm (Chen et al., 1998). The ginsenoside Rg1 was reported to have oestrogen-like activity (Chan et al., 2002). A protein exerted anti-fungal activity against Coprinus comatus, Fusarium oxysporum and Mycosphaerella arachidicola (Lam and Ng, 2001a). It still has ribonuclease (Lam and Ng, 2001b) and xylanase activity (Lam and Ng, 2002a). Additionally, PNS can stimulate bone formation (Chen et al., 2012), reverse the rats’ depression-like behavior (Xiang et al., 2011; Yao et al., 2012), postpone the appearance of fatigue and accelerate the restoration from fatigue in the plateau environment (Zhou et al., 2012). PNS combined with western medications is a better treatment option than conventional drugs alone in improving clinical symptoms of angina pectoris (Yang et al., 2014). As an alternative and complementary medicine, PNS may provide another choice for angina pectoris patients, but further large-scale high-quality trials are needed to confirm its efficacy. 6. Toxicology Studies regarding the toxicity of P. notoginseng are very few, but there are a few studies about the toxic effects of PNS due to its widespread use in clinical treatment (Tang et al., 2012). It has been reported that PNS has cytotoxic effects as well as toxic effects on the liver, kidney and other organs. In a cell-based study, PNS was added to NIH/3T3 cells, and the results showed that PNS had notable cytotoxicity, with an LD50 of approximately 0.4 mg/ml. PNS also strongly inhibited NBS-stimulated cell proliferation (Liu et al., 1999). Han et al., (2006) noted that PNS exhibited significant hepatotoxicity and nephrotoxicity in rat at a dosage of 450 mg/kg, indicating that PNS at higher doses (≥150 mg/kg) potentially possessed cardiac toxicity (Xu et al., 2009). Studies in animal models have demonstrated that dencichine has certain neurotoxic effect at an inappropriate dosage (Zhang and Yu, 2010), showing the importance of proper clinical dosage. There are also some clinical reports regarding adverse reactions to PNS. For example, Yin et al. (2014) reported four elderly patients (one male and three females) with drug eruption induced by PNS injection. These four patients had some interesting features in common, including pustules, fever and elevated circulating neutrophil counts. Zheng and Yan (1998) published a review of the allergic reactions to P. notoginseng, all of which provide a useful reference and warning for clinicians. The occurrence of adverse reaction to P. notoginseng may result from the misuse or over-dosage of P. notoginseng. Two different forms of P. notoginseng are available in the clinic: the raw and steamed forms. These two forms have different clinical indications due to their different pharmacological activities. The raw form of P. notoginseng is known for its haemostatic and cardiovascular properties; it arrests various internal or external haemorrhages, eliminates blood stasis, improves blood circulation, disperses bruises and reduces swelling and pain. However, the steamed form has been claimed to be a tonic herb, used to nourish blood and increase production of various blood cells in anaemic conditions. Because the raw and steamed forms of P. notoginseng have different pharmacological actions, it is pertinent to administer the correct form of the herb to avoid any undesirable consequences. Over-dosage of PNS can also lead to adverse reactions such as nausea, vomiting and nose bleeding. Additionally, there are also adulterations or confusions of P. notoginseng. Obviously, the misuse of these plants will cause undesirable adverse reactions. Furthermore, certain people should take P. notoginseng with caution, such as pregnant women. 7. Future perspectives and conclusions P. notoginseng has been used in Asian countries for many centuries, and people have witnessed its successful use. Significant breakthrough has been made in the past decade into the chemistry and pharmacology of P. notoginseng. However, there are still several research challenges which need to be addressed for accelerating the ongoing translational, clinical research. First, research of the flavonoids, polysaccharides and alkyne alcohols of P. notoginseng was relatively slow compared with the study of saponins, and the study of protein compounds in P. notoginseng is still in its initial stage, besides, a majority of the pharmacological studies were conducted using crude and poorly characterized extracts. Thus, it may be possible that more bio-active components should be identified by using bioactivity- guided isolation strategies. With respect to the pharmacology of P. notoginseng, one substantial issue is that many ongoing studies use total extracts or PNS rather than individual compounds, partly due to the technical difficulty in acquiring and purifying sufficient amount of the latter. However, several reports have revealed the interaction and mechanisms different among individual saponins, for example, ginsenoside Rg1 can inhibit the production of both TNF-α and interleukin-6 (IL-6), whereas the ginsenoside Rb1 only affects the production of IL-6. when the ginsenoside Rg1 was combined with the ginsenoside Rb1, the inhibitory effect of the ginsenoside Rg1 was lost (Rhule et al., 2008). Hence, a systematic comparison on the bio-activities and mechanisms among individual saponins (and total PNS) becomes crucial (Liu et al., 2014b), and the inherent relation between them should be explicited enough. Moreover, the pathways of its distribution, absorption, metabolism and excretion need to be clarified by the pharmacokinetic studies. Besides, the pharmacological effects of other compounds and possible mechanisms also ought to be explored. Another direction is the investigations on how to develop P. notoginseng's new clinical usage on the basis of its pharmacological effects and comprehensive utilize this plant. Some pharmacological effects of P. notoginseng and its mechanisms have been performed, but some pharmacological effects of P. notoginseng are intriguing and needing further study, such as anti-depressant (Xiang et al., 2011; Yao et al., 2012), anti-fatigue effect (Zhou et al., 2012) etc. The other parts of these plant, like flower and seed also has their unique advantages, for instance, P. notoginseng flower has the actions to clear away heat, calm the liver and lower the blood pressure, P. notoginseng seed contains abundant fats and proteins (Gu et al., 2009). 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