Traditional uses, phytochemistry, pharmacology and toxicology of Codonopsis: A review

Author’s Accepted Manuscript Traditional uses, phytochemistry, pharmacology and toxicology of Codonopsis: A review Shi-Man Gao, Jiu-Shi Liu, Min Wang, Ting-Ting Cao, Yao-Dong Qi, Ben-Gang Zhang, Xiao-Bo Sun, Hai-Tao Liu, Pei-Gen Xiao www.elsevier.com/locate/jep

PII: DOI: Reference:

S0378-8741(17)32399-1 https://doi.org/10.1016/j.jep.2018.02.039 JEP11250

To appear in: Journal of Ethnopharmacology Received date: 28 June 2017 Revised date: 23 February 2018 Accepted date: 24 February 2018 Cite this article as: Shi-Man Gao, Jiu-Shi Liu, Min Wang, Ting-Ting Cao, YaoDong Qi, Ben-Gang Zhang, Xiao-Bo Sun, Hai-Tao Liu and Pei-Gen Xiao, Traditional uses, phytochemistry, pharmacology and toxicology of Codonopsis: A review, Journal of Ethnopharmacology, https://doi.org/10.1016/j.jep.2018.02.039 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Traditional uses, phytochemistry, pharmacology and toxicology of Codonopsis: A review Shi-Man Gao, Jiu-Shi Liu, Min Wang, Ting-Ting Cao, Yao-Dong Qi, Ben-Gang Zhang, Xiao-Bo Sun, Hai-Tao Liu*, Pei-Gen Xiao* Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine (Peking Union Medical College), Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China

E-mail addresses: [email protected] (S.-M. Gao), [email protected] (J.-S. Liu), [email protected] (M. Wang), [email protected] (T.-T. Cao), [email protected] (Y.-D. Qi),

[email protected]

(B.-G.

Zhang),

[email protected]

(X.-B.

Sun),

[email protected] (H.-T. Liu), [email protected] (P.-G. Xiao)

* Corresponding author H.-T. Liu Address: No.151, Malianwa North Road, Haidian District, Beijing, P.R. China E-mail: [email protected] Tel: +86-10-57833018 Fax: +86-10-57833018 P.-G. Xiao Address: No.151, Malianwa North Road, Haidian District, Beijing, P.R. China E-mail: [email protected] Tel: +86-10-57833166 Fax: +86-10-57833166

Abstract: Ethnopharmacological relevance: Species of the genus Codonopsis are perennial herbs mainly distributed throughout East, Southeast and Central Asia. As recorded, they have been used as traditional Chinese medicines since the Qing Dynasty, where they were claimed for strengthening the spleen and tonifying the lung, as well as nourishing blood and engendering liquid. Some species are also used as food materials in southern China and Southeast Asia, such as tea, wine, soup, plaster, and porridge. Aim of the review: The review aims to assess the ethnopharmacological uses, explicit the material basis and pharmacological action, promote the safety of medical use, and suggest the future research potentials of Codonopsis. 1

Materials and methods: Information on the studies of Codonopsis was collected from scientific journals, books, and reports via library and electronic data search (PubMed, Elsevier, Scopus, Google Scholar, Springer, Science Direct, Wiley, Researchgate, ACS, EMBASE, Web of Science and CNKI). Meanwhile, it is also obtained from published works of material medica, folk records, ethnopharmacological literatures, PhD and Masters Dissertation. Plant taxonomy is confirmed to the database “The Plant List” (www.theplantlist.org). Results: Codonopsis has been used for medicinal purposes all around the world. Some species are also used as food materials in southern China and Southeast Asia. The chemical constituents of Codonopsis mainly are polyacetylenes, polyenes, flavonoids, lignans, alkaloids, coumarins, terpenoids, steroids, organic acids, saccharides, and so on. Extract of Codonopsis exhibit extensive pharmacological activities, including immune function regulation, hematopoiesis improvement, cardiovascular protection, neuroprotection, gastrointestinal function regulation, endocrine function regulation, cytotoxic and antibacterial effects, anti-aging and anti-oxidation, etc.. Almost no obvious toxicity or side effect are observed and recorded for Codonopsis. Conclusions: The traditional uses, phytochemistry, pharmacology and toxicology of Codonopsis are reviewed in this paper. Species of the genus have long been used as traditional medicines and food materials, they were reported with a large number of chemical constituents with different structures, extensive pharmacological activities in immune system, blood system, digestive system, etc. and almost no toxicity. More profound studies on less popular species, pharmacodynamic material basis and pharmacological mechanism, and quality assurance are suggested to be carried out to fulfil the research on the long-term clinical use and new drug research of Codonopsis.

Key words: Codonopsis; traditional uses; phytochemistry; pharmacology; toxicology Content 1. Introduction ................................................................................................................ 1 2. Traditional uses .......................................................................................................... 2 3. Phytochemistry .......................................................................................................... 4 3.1. Polyacetylenes, polyenes and their glycosides ................................................ 4 3.2. Flavonoids and their glycosides ...................................................................... 4 3.3. Lignans and their glycosides ........................................................................... 4 3.4. Coumarins ........................................................................................................ 5 3.5. Alkaloids and their glycosides and nitrogen compounds ................................ 5 2

3.6. Terpenoids and their glycosides ...................................................................... 5 3.7. Steroids and their glycosides ........................................................................... 5 3.8. Organic acids and their glycosides .................................................................. 5 3.9. Saccharides ...................................................................................................... 5 3.10. Other compounds ........................................................................................... 5 4. Pharmacology ............................................................................................................ 6 4.1. Immune function regulation ............................................................................ 6 4.2. Hematopoiesis improvement ........................................................................... 7 4.3. Cardiovascular protection ................................................................................ 7 4.4. Neuroprotection ............................................................................................... 8 4.5. Gastrointestinal function regulation ................................................................ 9 4.6. Endocrine function regulation ....................................................................... 10 4.7. Cytotoxic and antibacterial effects ................................................................ 11 4.8. Anti-aging and anti-oxidation ........................................................................ 12 4.9. Others ............................................................................................................. 12 5. Toxicology ............................................................................................................... 13 6. Conclusion ............................................................................................................... 13 Author contributions .................................................................................................... 14 Conflict of interest........................................................................................................ 14 Acknowledgements ...................................................................................................... 15 References .................................................................................................................... 15

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1. Introduction Species of the genus Codonopsis Wall. (Campanulaceae) are perennial herbs mainly distributed throughout East, Southeast and Central Asia. There are 46 species in this genus, with around 39 species are distributed in China (Hong, 2015). Some species have an important medicinal and economic value with a long history. Radix Codonopsis, the dried root of Codonopsis pilosula (Franch.) Nannf. (C. pilosula), Codonopsis pilosula var. modesta (Nannf.) L.D.Shen (C. pilosula var. modesta) or Codonopsis pilosula subsp. tangshen (Oliv.) D.Y.Hong (C. pilosula subsp. tangshen),. is definitely recorded as traditional Chinese medicines dating back to Qing Dynasty in Ben Cao Cong Xin (Yang and Li, 2007), with indications for strengthening the spleen and tonifying the lung, as well as nourishing blood and engendering liquid (China pharmacopoeia committee, 2015). It can help to treat hematopoietic dysfunction after chemotherapy or radiotherapy (Guo, 2015), coronary heart disease (Qu et al., 1990), hypotension, gastric ulcer (Guo, 2015) and chronic atrophic gastritis (Jiao, 2005). It is also used to improve learning and memory abilities and delay senility (Feng et al., 1995; Huang and Cui, 2006), etc.. And more than 110 TCM preparations that contain Radix Codonopsis are included in the Chinese pharmacopoeia (2015 edition). Apart from the three original plants of Radix Codonopsis, around 17 species of Codonopsis are used as popular medicines (Cao, 2012; Chinese medicine company, 1994; Hong, 1983; State administration of traditional Chinese medicine “Zhong Hua Ben Cao” editorial committee, 1999; Xie, 2008). They are successively recorded in the materia medica books of different times and districts, such as Zhong Hua Ben Cao, De Hong Yao Lu, Jing Zhu Ben Cao, Wei Wu Er Yao Zhi, etc.. And they are reported to be useful to treat qi deficiency of the spleen and the lung, lack of appetence and fatigue, deficiency of qi and blood, etc.. Information of popular medicines from Codonopsis is listed in Table 1. Now, some species of the genus are also important food materials which are widely used in southern China and Southeast Asia such as tea, wine, soup, plaster, porridge, etc.. Moreover, Radix Codonopsis has been included in the list of available health

foods

by

the

Ministry

of

Health

of

China

since

2002

(http://www.nhfpc.gov.cn/sps/s3593/200810/bc239ea3d226449b86379f645dfd881d.s html). Nearly 200 health foods that contain Radix Codonopsis have been approved by China Food and Drug Administration. Consequently, the consumption of Radix 1

Codonopsis is high, with about 40000 t per year in China. Radix Codonopsis is cultivated with large areas in Shanxi, Gansu, Shaanxi, Hubei, and Sichuan Provinces to meet the market’s huge demand. Therefore, quality control in the production process of Radix Codonopsis is becoming more and more important from seedling breeding, field management, collection and processing to preservation and transportation, etc.. In addition, sulfur fumigation of Radix Codonopsis should be controlled strictly in the course of primary processing and preservation, and some new approaches, for example, cold storage (Dong et al., 2008), sand storage (Yang, 2001), dehydration (Li, 1988), antagonistic method (Zhao, 2001), air conditioned curing (Jin et al, 2002) can be adopted in the preservation process. This present review aims to provide a current state of knowledge of the traditional uses, phytochemistry, pharmacology and toxicology of Codonopsis in order to assess the ethnopharmacological uses, explicit the material basis and pharmacological action, and promote the safety of medical application, in order to highlight the gaps for subsequent research. 2. Traditional uses Members of the genus Codonopsis have been used as traditional medicines with a long history around the world. Some species are used as food materials in southern China and Southeast Asia such as tea, wine, soup, plaster, porridge, etc.. Radix Codonopsis has been recorded in Chinese pharmacopoeia since 1963 edition until now. It has important medicinal value and can be used together with other traditional Chinese medicines in many prescriptions to treat various diseases. Among them, Si-jun-zi Decoction can be used for the treatment of deficiency of qi in middle-jiao, weakness of the spleen and the stomach, poor appetite and loose stools, weakness and fatigue, etc.. Bu-zhong-yi-qi Decoction can be used to treat deficiency of the spleen and qi sinking, chronic diarrhea and rectocele, droop of the stomach and the uterus, etc.. Bu-fei Decoction can be used to reinforce the lung and replenish qi. Sheng-mai Powder can be used for the treatment of thirst due to insufficiency of body fluid and qi, etc.. In some prescriptions, Radix Codonopsis can be used to replace Radix et Rhizoma Ginseng for the treatment of weak spleen and lung, dual depletion of qi and blood, body tiredness, chronic diarrhea and rectocele, and iron-deficiency or alimentary anemia. But the dosage should be increased in the clinical practice because of its relatively weak efficacy. In some emergency prescriptions, it is inappropriate to 2

use Radix Codonopsis instead of Radix et Rhizoma Ginseng (Guo, 2015). The medicinal uses of Radix Codonopsis have been recorded in numerous county annals in China (Longxi County Annal Compilation Committee, 1990; Min County Annal Compilation Committee, 1995; Wen County Annal Compilation Committee, 1997). In addition, Radix Codonopsis has also been used as traditional medicine in other countries for a long period. In South Korea, the root of C. pilosula is included in the Korean Herbal Pharmacopoeia as the accepted species of Radix Codonopsis, and it has been used to treat dyspepsia, relieve fatigue and improve respiratory system. In the Japanese Pharmacopoeia, the root of C. pilosula and C. pilosula subsp. tangshen are accepted as species of Radix Codonopsis, and they are widely used as traditional medicines, as well as the raw materials of many OTC drugs (Wakana et al., 2013; Wakana et al., 2011). In Vietnam, Radix Codonopsis is also a commonly used traditional medicine, and its usage is similar to that in China (Thuy et al., 2003). The market of Radix Codonopsis as food materials is wide. Radix Codonopsis is one of the 16 qi-tonifying Chinese medicines in Chinese Medicated Diet Dictionary (Wang, 1992) and is one of the top 10 raw materials of qi-tonifying or bloodreplenishing Chinese medicines used for food therapy in Zhong Yi Shi Liao Fang Quan Lu (Xiang, 1997). Radix Codonopsis is also recorded to be used as food materials of soup in some chorographies of southern China. Yuan-rou-zhu-xin soup comprising of Radix Codonopsis is used to nourish the heart and calm the nerves, and benefite qi and nourish blood (Guangzhou Huangpu District Chorography Compilation Committee, 1999). Ni-qiu soup cooked with Radix Codonopsis can be used to treat pediatric night sweating and cold sores (Guangdong Chorography Compilation Committee, 2002). Radix Codonopsis is also widely used as many other kinds of food. Radix Codonopsis tea used with Flos Chrysanthemi can benefite qi and nourish blood, because Radix Codonopsis can relieve the cold nature of Flos Chrysanthemi (Zhang, 2012). Radix Codonopsis wine can relieve body fatigue and improve hypoxia tolerance (Liu, 2015). Radix Codonopsis plaster can be used for the adjuvant therapy of chronic obstructive pulmonary disease, lung cancer, bronchiectasis and tuberculosis (Zhao et al., 1996). Radix Codonopsis porridge is appropriate for the treatment of qi deficiency of the spleen and the stomach, body tiredness, poor appetite and loose stools, dyspnea and tachypnea, and deficiency of qi and blood after illness, etc. (Wei, 2000). Besides, Radix Codonopsis is used for 3

cooking hot pot at home or in restaurants in southeast Asia, and it is generally added into Bak-Kut-Teh and health soup package in Singapore and Malaysia (Ding and Zhu, 2014; Guo, X., 2015; Zhang, X., 2012). Another popular medicine is the dried root of C. lanceolata. It has been used as a popular medicine in Korea, Japan, and China for a long time (Deng et al., 2006; Lee et al., 2007). Qing-fei Decoction which contains C. lanceolata is applied in the treatment of bronchitis (Fan and Li, 1996). C. lanceolata is also used as a wild vegetable in Yanbian area in China, Japan, North Korea, South Korea and the USA, and it is listed as one of the wild vegetables in “Chinese Food Composition” (2002 edition). Salted vegetable made by C. lanceolata is a famous wild vegetable with perfect color, aroma and taste. In Korea, C. lanceolata is eaten raw or cooked, roasted, dried, sliced, pan-fried and used in salads, cold soups, pan-fied as dried or fried vegetables (Lim, 2015). The demand for C. lanceolata is increasing by years in Southeast Asia and South Korea, thus its export has good prospect (Niu et al., 2013; Zhang et al., 2005). The medicinal uses of other species of the genus Codonopsis are listed in Table 1. 3. Phytochemistry Up to now, a lot of research on chemical constituents of Codonopsis has been reported. Polyacetylene, polyenes and their glycosides, flavonoids and their glycosides, lignans and their glycosides, coumarins, alkaloids and their glycosides and nitrogen compounds, terpenoids and their glycosides, steroids and their glycosides, organic acids and their glycosides, saccharides, volatile oils, amino acids, microelements, etc. have been isolated from Codonopsis. 3.1. Polyacetylenes, polyenes and their glycosides Polyacetylenes, polyenes and their glycosides are widely distributed in most genera of Campanulaceae, among which Codonopsis is the most representative. Polyacetylenes, polyenes and their glycosides isolated from medicinal plants of Codonopsis are listed in Fig.1. and Table 2. 3.2. Flavonoids and their glycosides Flavonoids and their glycosides isolated from medicinal plants of Codonopsis are relatively few, as listed in Fig.2. and Table 3. 3.3. Lignans and their glycosides

4

Lignans and their glycosides are special compounds that are isolated from Codonopsis. Their structures are listed in Fig.3. and Table 4. 3.4. Coumarins So far, only 2 coumarins including angelicin (1) and psoralen (2) are isolated from C. pilosula (Zhu et al., 2001), as listed in Fig.4.. 3.5. Alkaloids and their glycosides and nitrogen compounds There are pyrrolidine alkaloids, indole alkaloids, quinoline alkaloids and their glycosides, etc. and some nitrogen compounds isolated from medicinal plants of Codonopsis, as listed in Fig.5. and Table 5. 3.6. Terpenoids and their glycosides Terpenoids and their glycosides in the medicinal plants of Codonopsis mainly include triterpenes, sesquiterpene lactones, etc. as listed in Fig.6. and Table 6. 3.7. Steroids and their glycosides Steroids and their glycosides isolated from medicinal plants of Codonopsis mainly include sterols, steroidal glycosides, sterones, etc. as listed in Fig.7. and Table 7. 3.8. Organic acids and their glycosides Organic acids and their glycosides in medicinal plants of Codonopsis mainly consist of fatty acids, aromatic acids, etc. as listed in Fig.8. and Table 8. 3.9. Saccharides Monosaccharides, oligosaccharides and polysaccharides have been reported from the medicinal plants of Codonopsis. Monosaccharides include fructose, glucose, mannose, etc., oligosaccharides include sucrose, synanthrin, etc., and polysaccharides consist of monosaccharides and their derivatives (Zhou et al., 2004; Cao, 2012). Among them, polysaccharides are the main ingredients of carbohydrates in Codonopsis,

and

most

of

them

are

heteropolysaccharides.

Water-soluble

polysaccharides are made up of various ratios of fructose, mannose, xylose and galactose. Acidic polysaccharides mainly contain galacturonic acid and glucuronic acid. Neutral polysaccharides contain different ratios of arabinose, glucose, galactose and rhamnose, etc. (Wang et al., 1984, Wu et al., 2005, Sun and Liu, 2008, Wu, 2009, Wang et al., 2011, Li et al., 2012, Yang et al., 2013). 3.10. Other compounds

5

Volatile oils in the medicinal plants of Codonopsis mainly contain fatty acids, alkanes hydrogen, some acids, alcohols, fatty acid esters, alkanes, alkenes and nitrogen compounds, etc. (Xie et al., 2000a, 2000b). Amino acids in the medicinal plants of Codonopsis mainly include threonine, lysine, methionine, phenylalanine, leucine, isoleucine, valine, tryptophan, aspartic acid, histidine, arginine, glycine, cystine, tyrosine, serine, glutamic acid, proline and alanine. Among them, the first 8 kinds are essential amino acids (He et al., 1987). There are more than 10 kinds of microelements in Codonopsis, such as Ca, Cu, Ge, Zn, Mg, Mn, Fe, K, P, Na, Ni, Cd, Mo, Co, Se, etc.. The contents of Zn and Fe are relatively higher (Sun, 2007). In addition, there are some other compounds in medicinal plants of Codonopsis as listed in Fig.9. and Table 9. 4. Pharmacology Traditionally, Codonopsis is used for strengthening the spleen and tonifying the lung, promoting circulation and removing stasis, nourishing blood and relieving thirst, regulating the intestine and the stomach. Therefore, the effect on immune, hematopoietic, cardiovascular, gastrointestinal and endocrine functions should be studied. Moreover, neuroprotective, cytotoxic and antibacterial, anti-aging and antioxidation effects are also carried out in modern pharmacological research. The traditional uses as well as biomedical data have been illustrated to clarify the relevance between the traditional uses and modern pharmacological research. 4.1. Immune function regulation Codonopsis has the function of regulating immunologic balance and is often used for enhancing immune function. Mordern research show that different extracts of Codonopsis display strengthening effect on immune system. Radix Codonopsis aqueous extract could heighten the phagocytic activity of macrophage apparently at the concentration of 500~3000 μg/mL, thus could enhance the immune function (Jia et al., 2000). C. pilosula polysaccharide (40, 100, 250 mg/kg) could inhibit or partial inhibit the excessive expression of regulatory Tregs via TLR4 signaling on Tregs and trigger a shift of TH2 to TH1 with activation of CD4+ Tregs in sepsis induced by cecal ligation and puncture in mice (Zheng et al., 2014). Radix Codonopsis saponin (8 mg/100mL, i.p.) could aggravate the rejection reaction in renal transplant through impacting IL-2 and ICAM-1 expression and enhancing

6

electrophoresis band brightness after 8 d of exposure in rats, thus should be used with caution after ischemia reperfusion injury in renal transplant (Zhang et al., 2012). Total methanol extracts of fresh leaves (l-TME) and roots (r-TME) of C. lanceolata could inhibit the production of proinflammatory mediators significantly without changing mRNA level. The IL-3 and IL-6 expression were lessened markedly, while the phospho-IκB level was not influenced by the TMEs. And l-TME could promote the anti-inflammatory activity through regulating macrophage mediated immune response (Lee et al., 2007). C. lanceolata polysaccharide (0.1, 0.5 g/kg, i.g.) could significantly increase the thymus index and promote the transformation of spleen lymphocytes of diabetic rats (alloxan, i.p.) after 3 weeks so that their cellular immune function could be improved (Zhang et al., 2012). C. clematidea polysaccharide could enhance the immune function of mice through promoting the increase of spleen index and elevating the serum TNF-α level so that the activity of macrophage phagocytosis could be strengthened (Gong, 2007). 4.2. Hematopoiesis improvement Based on the efficacy of nourishing blood, the research on hematopoietic function regulation of Codonopsis have been conducted. Several studies show that the extracts of Codonopsis can regulate the growth and development of blood cells. In addition, they can enhance the hematopoietic function and inhibit platelet aggregation. Radix Codonopsis aqueous extract (10 %, p.o.) could promote the growth of blood cells including HB, RBC and WBC levels after 20 d in mice (Zhang et al., 2001). Radix Codonopsis polysaccharide (130, 260, 520 mg/kg, i.g.) could significantly elevate the peripheral blood Hb after 9 d, promote the endogenous splenic nodules after 12 d, but had little influence on the bone marrow cell DNA synthesis in mice dealt with APH (20 mg/mL, i.h.). Therefore, Radix Codonopsis polysaccharide could promote the compensatory hematopoietic function of spleen (Zhang et al., 2003). Ethanol extract of C. lanceolata (0.5 g/kg, 1 g/kg, i.g.) could reduce the plasma hemolysis LPA and PA levels and inhibit the platelet aggregation significantly 14 d later in cerebral thromboembolism rats, which was positive to prevent cerebral infarction (Lv et al., 2010). 4.3. Cardiovascular protection

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Codonopsis has the efficacy of promoting circulation and removing stasis, and based on that, many research on its action in cardiovascular system have been carried out. The results show that chemical constituents of Codonopsis have good protective effect on heart failure and myocardial ischemia/reperfusion injury. Moreover, they also have antihypertensive effects. Radix Codonopsis extract (i.g.) enhanced the ±dP/dtmax of chronic heart failure rats after myocardial infarction significantly after 9 weeks. Thus, it was beneficial to improve the symptom and delay the onset of chronic heart failure (Li et al., 2010). Radix Codonopsis aqueous solution had protective effect on lipid peroxidation damage caused by myocardial ischemia/reperfusion injury via recovering the LVSP and ±dp /dtmax, lowering the LVEDP, inhibiting the increase of MDA, LDH and CK, and strengthening the activities of SOD, GSH-Px, Na+,K+-ATPase and Ca2+-ATPase in rabbits (Zhong, 2012). Decoction of C. lanceolata could obviously reduce the blood pressure and eliminate the hypertensive effect of epinephrine through intravenous injection (0.5~1.0 g/kg) or intragastric administration (5.0 g/kg). When the dose increased, the inhibitory effect also increased (Hang et al., 1963; Jin, 1993). 4.4. Neuroprotective effect Codonopsis has a certain effect on central nervous system. Different parts of extracts from Codonopsis exhibit the activities of protecting neurocyte and improving learning and memory abilities, as well as extending cyclohexanol pentobarbital sleeping time. Radix Codonopsis alcohol injection (0.003 mL/time, twice/d, i.p.) and Vit C injection (0.005 mL/time, twice/d, i.p.) could maintain the learning and memory ability, and elevate the SOD and GSH-PX of multiple tissues and enhance the expression of antioxidant enzyme significantly after 7 d in Alzheimer’s disease rats (haloperidol, 0.001 mg/g, twice/d, i.p.) (Huang, 2006). Radix Codonopsis polysaccharide (200, 300 mg/kg, 10 mL/kg/d, i.g.) could enhance the learning and memory abilities of lead (0.2 %) poisoning mice through improving brain lipid peroxidation and scavenging free radical 42 d later (Zhang et al., 2013). Radix Codonopsis saponin extract had central inhibitory effect and could extend the cyclohexanol pentobarbital sleeping time significantly (Huang and Liu., 1984). Radix Codonopsis saponin L1 had an inhibitory effect on astrocyte injury caused by 8

hypoxia/hypoglycemia and reoxygenation (Zhang et al., 2006). Radix Codonopsis saponin LRT-1 (1.8 mg/kg/time/d, IOCV) and Xueshuantong Injection (24 mg/kg/time/d, IOCV) could alleviate the learning and memory disorder induced by cerebral ischemia-reperfusion injury through shortening the escape latency significantly after 5 d in rats (Wu, 2005). C. pilosula total alkaloids could promote the differentiation of neurite PC12 cells evoked by nerve growth factor by strengthening the upstream phase of MAPK-dependent signaling pathway (Liu et al., 2003). Fermented C. lanceolata extract (500 mg/kg, p.o.) could cut down the escape latency time that was enhenced by scopolamine on day 4 significantly and exhibited longer step-through latency time in mice. In addition, it showed a relative protection ratio of 59.62 % at 500 g/mL on glutamate-induced neurocytotoxicity in HT22 cells (Weon et al., 2013). Lancemaside A in the rhizome of C. lanceolata and its metabolite echinocystic acid could suppress acetylcholinesterase activity effectively in a dosedependent manner with IC50 values of 13.6 μM and 12.2 μM, respectively. They could reverse scopolamine-induced memory and learning damage markedly, and enhance the expression of BDNF and p-CREB in mice (Jung et al., 2012). 4.5. Gastrointestinal function regulation Codonopsis is used as effective traditional medicine for regulating the spleen and the stomach. Modern research indicate that extracts or compounds from Codonopsis have protective effects on stomach and intestine. Radix Codonopsis water decoction (40 %, 50 %) could increase blood flow and oxygen consumption obviously compared to normal saline after 4 min in small intestine of dogs in vivo. While, Radix Codonopsis water decoction (20 %, 30 %) could also increase oxygen consumption of intestinal mucosal compared with KRPB after 20 min in vitro (Li and Tan, 1999). Radix Codonopsis water decoction (10, 20, 40 g/kg, p.o.) could improve the serum gastrin concentration of Heidenhain puch significantly within 150 min in dogs. So it was beneficial to the treatment of atrophic gastritis and peptic ulcer (Chen et al., 2002). Radix Codonopsis water decoction (0.8 g/kg/d, i.g.) could elevate the somatostatin concentration in stomach antrum and duodenal mucosal obviously after 1 month in Japanese white rabbits (Chen et al., 1998). Radix Codonopsis water decoction (100 %, i.g.) could advance GAS and MTL contents and lower TNF concentration siginificantly 24 h later in ċdegree scalded guinea pigs, thus was beneficial to the adjustment of gastrointestinal dysfunction 9

(Wang et al., 2005). C. pilosula extract (CPE, 5, 10 g/kg, i.g.) and Ranitidine (0.0675 g/kg, i.g.) had effect on gastric ulcer caused by stress, acetic acid and sodium hydroxide in rats. CPE could reduce the gastric acid pepsin secretion with the possible mechanism of inhibiting gastrointestinal movement and propulsion (Wang et al., 1997). Radix Codonopsis saponin extract could offset the adverse influence on intestinal tract through withstanding 5-HT, histamine and BaCl2, and was used to strengthen spleen and stomach in clinic (Jiao, 2005). Radix Codonopsis flavonoid extract could promote cellular migration, reverse DFMO or 4-AP induced cellular migration inhibition, and increase spermidine content in IEC-6 cells within 24 h. The function might be associated with polyamine controlled signaling pathway (Li et al., 2014). C. clematidea (15, 30 g/kg, i.g.) and C. pilosula (15, 30 g/kg, i.g.) water decoction could inhibit intestinal peristalsis significantly on day 7 in vivo, and suppress the self-regulation constriction in vitro with IC50 values of 0.2889 g/mL and 0.1138 g/mL, respectively (Xiong et al., 2000). Lobetyolin (1.5 mg/kg, i.g.) and bismuth potassium citrate (100 mg/kg, i.g.) could reduce the ulcer index and gastrin content obviously, increase the prostaglandins content significantly, and elevate the epidermal growth factor to some extent, thus prevent ethanol (1 mL, i.g.) induced gastric mucosa damage in rats (Song et al., 2008). 4.6. Endocrine function regulation Codonopsis has the effect of regulating endocrine function. The regulating effect on blood sugar and blood lipid are found in extracts of Codonopsis. Radix Codonopsis polysaccharide (300, 200, 100 mg/kg, i.g.) could significantly lower the blood glucose and serum insulin levels, improve the serum SOD activity, and reduce the MDA generation in diabetic mice (ALX, 200 mg/kg, i.p.). It could also ameliorate insulin resistance in mice (HC-SS, 70 mg/kg, i.h.) significantly after i.p. insulin (Fu et al., 2008). Total saponin of Radix Codonopsis (30, 100, 300 mg/kg, i.g.) and gypenosides (100 mg/kg) had the effect of blood lipid regulation by declining the TC, TG, LDL-C levels and raising the NO, HDL-C levels and HDL-C/TC ratio after 15 d in hyperlipidemia rats i.g. high fat emulsion (Nie et al., 2002). Radix Codonopsis saponins could increase plasma corticosterone levels via i.v. in mice, it was

10

speculated that the position of action was above the pituitary or hypophysis (Liu and Zhou, 1983). Fermented milk supplement with C. lanceolata roots had impact on the blood lipid profiles in postmenopausal rats (Chang and Cheong, 2007). 4.7. Cytotoxic and antibacterial effects Mordern research find that Codonopsis has good cytotoxic and antibacterial effects. Different parts of extracts from Codonopsis show inhibitory action on several tumors and bacteria in different degree. Radix Codonopsis polysaccharide CPP1b (0, 50, 100, 200, 400 μg/mL) could significantly suppress the proliferation of human lung adenocarcinoma cell A549 after 48 h and could become an antitumor or adjuvant antitumor drug potentially (Yang et al., 2013). Radix Codonopsis saponin could inhibit P388, EC and Hep by 42.17 %, 58.6 % and 57.10 %, respectively, while Radix Codonopsis liposoluble composition could inhibit P388 and Hep by 16.23 % and 15.43 %, respectively. The liposoluble composition

could

also

suppress

staphylococcus

aureus,

escherichia

coli,

pseudomonas aeruginosa and leptospira violently (Wang et al., 1999; Wang and Di, 1999). Radix Codonopsis ethanol extract had an inhibitory effect on 11 kinds of bacteria namely epidermis staphylococcus, alpha and beta hemolytic streptococcus, etc.. Its minimal inhibitory concentration toward staphylococcus aureus was 0.14 g/mL while that toward the other 10 kinds of bacteria was 0.28 g/mL (Duan et al., 2012). N-butanol fraction of C. lanceolata (BF) could markedly inhibit the growth of human colon cancer cell HT-29 through inducing capture and apoptosis in G0/G1 phase in a dose and time dependent manner. The expression of caspase-3, p53, and Bax/Bcl-2 ratio was intensified and expression of survivin was decreased, and ROS generation was coupled with JNK activation (Wang et al., 2011). Codonoposide 1c isolated from C. lanceolata could induce HL-60 cell apoptosis of human acute promyelocytic leukemia including DNA fragmentation, DNA ladder formation and annexin-V targeted PS residue externalization (Lee et al., 2005). C. clematidea polysaccharide (CCP, 100 mg/kg/d, i.g.) alone could lengthen the life span with the rate of 17.7 %, while that with cyclophosphamide (Cy, 30 mg/kg/d, i.g.) could prolong the life span with the rate of 68.8 % after 7 d in S180 sarcoma

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mice, which indicated that CCP combined with Cy had medicinal value for treating tumors (Gong et al., 2007). 4.8. Anti-aging and anti-oxidation In the field of anti-aging, traditional Chinease medicine has the characteristic of multi-link, multi-level and multi-target action. Codonopsis has the activity of antiaging and anti-oxidation with multiple action mechanisms. Many studies show that different extracts of Codonopsis have the relevant activities. Radix Codonopsis aqueous extract (5, 10, 15 g/kg, i.g.) could resist D-galactose (50 g/L, 0.025 mL/g/d, i.h.) induced aging through lowering the serum ALT and ALP levels after 42 d in mice, the mechanism might be associated with the target regulating effect of miRNA (Wang et al., 2016). Radix Codonopsis total saponin (100, 200, 400 mg/kg, 0.2 mL/d, i.g.) could enhance the antioxidant capacity by reducing the MDA content and elevating the SOD and GSH-Px activities apparently after 2 weeks in 15Gy60Coγ ray radiated mice (Sun et al., 2010). C. lanceolata ethanol extract (CLEA, 100~400 μg/mL) showed ABTS radical scavenging activity by 27.7~70.3 % and exhibited the highest DPPH radical scavenging activity (81.6 % at 400 μg/mL), it also showed strongest ORACROO ѿ activity and antioxidant action in vitro. Influence of CLEA on antioxidant gene expression under oxidative stress condition fed a high fat diet in mice was also evaluated and 31 antioxidant genes were expressed (Kim et al., 2010). C. lanceolata aqueous extract (20 % and 80 %, 2 mL/100g/d, i.g.) could heighten the SOD activity and lower the MDA generation after 30 d in rats (Piao et al., 1998). C. clematidea total flavonoid (0.25, 0.50, 1.00 mg/kg, i.g.) had obvious physiological effects of anti-oxidative and anti-fatigue after treatment for 25 d in mice (Wang et al., 2012). 4.9. Others In addition, Radix Codonopsis also has the effects of anti-fatigue and anti-stress (Fang and Jiao, 2002; Tong et al., 2003; Wang et al., 2012; Wang et al., 2007; Wang et al., 2005), anti-radiation (Liu et al., 1981), anti-inflammation (Chu et al., 2016; Jin et al., 2009), analgesic action (Liu and Zhou, 1983), strengthening uterine contractions (Ma and Wu, 2009), strengthening the function of reticuloendothelial system (Wang et al., 2005), etc.. C. lanceolata also has the effects of antiinflammation (Joh and Kim, 2010), relieving cough, anti-microbial (“National 12

Assembly of Chinese Herbal Medicine” drafting group, 1975), liver protection (Kim et al., 2009.), skin whitening (Kim et al., 2013), antiobesity effect (Choi et al., 2013), etc.. 5. Toxicology The toxicological research on various extracts of Codonopsis have been carried out. Almost no obvious toxicity and side effect are observed and recorded. For Radix Codonopsis, the toxicity of various extracts was evaluated. The acute toxicity test indicated that Radix Codonopsis polysaccharide (20 g/kg, 3 times/d, i.g.) with normal feed for 7 days turned out no abnormal change and all mice survived (Feng and Gao, 2012). The long-term toxicity assessment showed that Radix Codonopsis polysaccharide oral liquid (2 g crude drug/mL, 1 mL/100 g, once/d, i.g.) exhibited no obvious toxicity compared to isopyknic physiological saline after 4 weeks of exposure followed by 2 weeks of recovery phase in rats (Hou et al., 2016). The subchronic toxicity test turned out that after giving Radix Codonopsis aqueous extract (0.18, 1.80, 3.60, 7.20 g/kg, once/d, i.g.) and drinking water for 13 weeks in mice, 1.80 g/kg and 0.18 g/kg were the minimal effect dose and maxial noneffective dose, respectively. The teratogenic test revealved that at the range of 0.18~9.00 g/kg, Radix Codonopsis aqueous extract showed no teratogenic effect compared to drinking water and 2-amino-1,3,4-thiadiazole (30 mg/kg) (Liu et al., 1997). The LD50 of Radix Codonopsis water decoction was 44.5 g/kg i.g. and 29.2 g/kg i.p., respectively. And the LD50 of Radix Codonopsis n-butanol extract was 7.6 g/kg i.p. and 1.7 g/kg i.v., respectively (Liu et al., 1985). For C. lanceolata, the toxicity of its aqueous extract was studied. Aqueous extract of C. lanceolata (1250, 2500, 5000 mg/kg) didn’t cause acute or subchronic toxicity in a 4-week repeated-dose oral toxicity test in rats and its LD50 was more than 5000 mg/kg p.o. (Lee et al., 2015). 6. Conclusion In order to evaluate the ethnopharmacological uses, expatiate the material basis and pharmacological action, accelerate the safety of medical application, and explore future opportunities for the research of Codonopsis, this review summarized the traditional uses, phytochemistry, pharmacology, and toxicology of Codonopsis with systematic summary of traditional literature and modern research. It can be concluded that species of this genus have been used as traditional medicines and food materials 13

around the world over years, they possess chemical constituents with different structural types, exhibit extensive pharmacological activities in immune system, blood system, cardiovascular system, central nervous system, digestive system, etc. with almost no obvious toxicity and side effect. Therefore, Codonopsis can be used as a promising ethnopharmacological plant source. It is still notable that there exist some gap in our cognition for the application of Codonopsis. First of all, the less popular species of Codonopsis remain to be fully exploited and studied. Currently, little research on the chemical constituents and pharmacological effects is carried out except for C. pilosula, C. lanceolata, C. clematidea, etc., which restrict their development and utilization. Secondly, welldesigned studies on the pharmacodynamic material basis and pharmacological mechanism should be developed, and comprehensive investigations should be conducted for further studies to obtain relevant compounds responsible for the pharmacological effects and the potential mechanisms. Besides, a thorough toxicological study of the bioactive extracts and isolated compounds from Codonopsis is urgently needed. Lastly, a feasible and reliable approach to develop the quality assurance of Codonopsis is still needed urgently. Apart from traditional quality assurance methods, phytochemical analysis and metabonomics technology that developed in recent years can also be used to establish a feasible quality standard of Codonopsis. This review emphasizes on the importance of Codonopsis and provides guidance for the future development of the medicinal and food materials. Moreover, the study also provides comprehensive references for the new drug lead research of Codonopsis. Author contributions Hai-Tao Liu and Pei-Gen Xiao contributed in designing the review and checking the data collection process. Ben-Gang Zhang contributed in assessing the ethnopharmacological purpose of the genus. Yao-Dong Qi contributed in guiding the traditional uses and taxonomy parts. Xiao-Bo Sun contributed in correcting the pharmacology part. Min Wang contributed in checking the toxicology part. Jiu-Shi Liu contributed in collecting data and revising the phytochemistry part. Ting-Ting Cao contributed in preparating table and polishing the language and grammer. ShiMan Gao contributed in writing, editing and revising the manuscript. Conflict of interest 14

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a

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26

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31

Fig.1. Chemical structures of polyacetylenes, polyenes and their glycosides isolated from medicinal plants of Codonopsis. Fig.2. Chemical structures of flavonoids and their glycosides isolated from medicinal plants of Codonopsis. Fig.3. Chemical structures of lignans and their glycosides isolated from medicinal plants of Codonopsis. Fig.4. Chemcial structures of coumarins isolated from medicinal plants of Codonopsis. Fig.5. Chemical structures of alkaloids and their glycosides and nitrogen compounds isolated from medicinal plants of Codonopsis. Fig.6. Chemical structures of terpenoids and their glycosides isolated from medicinal plants of Codonopsis. Fig.7. Chemical structures of steroids and their glycosides isolated from medicinal plants of Codonopsis. Fig.8. Chemical structures of organic acids and their glycosides isolated from medicinal plants of Codonopsis. Fig.9. Chemical structures of other compounds isolated from medicinal plants of Codonopsis.

32

33

34

35

36

37

Graphical abstract

38

Table 9 Other compounds isolated from medicinal plants of Codonopsis.

1

Table 8 Organic acids and their glycosides isolated from medicinal plants of Codonopsis.

Table 7 Steroids and their glycosides isolated from medicinal plants of Codonopsis.

Table 6 Terpenoids and their glycosides isolated from medicinal plants of Codonopsis.

Table 5 Alkaloids and their glycosides and nitrogen compounds isolated from medicinal plants of Codonopsis.

Table 4 Lignans and their glycosides isolated from medicinal plants of Codonopsis.

Table 3 Flavonoids and their glycosides isolated from medicinal plants of Codonopsis.

Table 2 Polyacetylene, polyenes and their glycosides isolated from medicinal plants of Codonopsis.

Table 1 Information of folk medicines from Codonopsis.

Xidang

Tiaodang

Codonopsis pilosula (Franch.) Nannf. (Campanulaceae)

Codonopsis pilosula var. modesta (Nannf.) L.D.Shen (Campanulaceae)

Codonopsis pilosula subsp. tangshen (Oliv.) D.Y.Hong (Campanulaceae)

Codonopsis pilosula var. volubilis (Nannf.) L.D.Shen (Campanulaceae)

Codonopsis foetens subsp. nervosa (Chipp) D.Y.Hong (Campanulaceae)

1

2

3

4

5

Codonopsis macrantha Nannf.; Codonopsis nervosa (Chipp) Nannf.; Codonopsis nervosa var. macrantha (Nannf.) L.D.Shen; Codonopsis nervosa subsp. macrantha (Nannf.) D.Y.Hong & L.M.Ma; Codonopsis ovata var. nervosa Chipp

Yedangshen

Yunshen

Ludang

Campanumoea pilosula Franch.; Codonopsis glaberrima Nannf.; Codonopsis microtubulosa Z.T.Wang & G.J.Xu; Codonopsis modesta Nannf.; Codonopsis pilosula var. glaberrima (Nannf.) P.C.Tsoong; Codonopsis pilosula var. modesta (Nannf.) L.D.Shen; Codonopsis pilosula subsp. pilosula; Codonopsis pilosula var. pilosula; Codonopsis pilosula var. volubilis (Nannf.) L.D.Shen; Codonopsis silvestris Kom.; Codonopsis volubilis Nannf.

Codonopsis tangshen Oliv.

Local names

Synonyms

Species

No.

Information of folk medicines from Codonopsis.

Table 1

2

Sichuan, Yunnan, Xizang

Shanxi, Sichuan

Hubei, Hunan, Sichuan, Guizhou

Gansu, Shaanxi, Qinghai, Sichuan

Shanxi, Gansu, Sichuan, Shaanxi

Distribution

Invigorate the spleen and the stomach and replenish qi, engender liquid and quench thirst

Invigorate the spleen and the stomach and replenish qi, engender liquid and quench thirst

Strengthen the spleen and tonify the lung, nourish blood and engender liquid

Strengthen the spleen and tonify the lung, nourish blood and engender liquid

Strengthen the spleen and tonify the lung, nourish blood and engender liquid

Efficacy

Spleen deficiency, reduced appetite, loose stool, limb weakness, heart palpitation, short breath, thirst, spontaneous sweat, rectocele, uterine prolapse, etc.

Weakness of the spleen and the stomach, deficiency of qi and blood, fatigue, etc.

Qi deficiency of the spleen and the lung, reduced appetite and fatigue, asthenic dyspnea and cough, deficiency of qi and blood, sallow complexion, heart palpitations and breath shortness, body fluid deficiency and thirst, internal heat diabetes, etc. Qi deficiency of the spleen and the lung, reduced appetite and fatigue, asthenic dyspnea and cough, deficiency of qi and blood, sallow complexion, heart palpitations and breath shortness, body fluid deficiency and thirst, internal heat diabetes, etc.

Qi deficiency of the spleen and the lung, reduced appetite and fatigue, asthenic dyspnea and cough, deficiency of qi and blood, sallow complexion, heart palpitations and breath shortness, body fluid deficiency and thirst, internal heat diabetes, etc.

Indication

e

d

c

b

a

Code

Zidang

Shetoudang



Zhilidangshen



Codonopsis clematidea var. obtuse (Chipp) Kitam.; Codonopsis obtusa (Chipp) Nannf.; Codonopsis ovata var. cuspidata Chipp; Codonopsis ovata var. obtusa Chipp; Codonopsis ovata var. ramosissima Hook.f. & Thomson; Glosocomia clematidea (Schrenk) Fisch., C.A.Mey. & Avé-Lall.; Glosocomia clematidea (Schrenk ex Fisch. & C.A. Mey.) Fisch. ex Regel; Wahlenbergia clematidea Schrenk

Codonopsis subglobosa W.W.Sm. (Campanulaceae)

Codonopsis canescens Nannf. (Campanulaceae)

Codonopsis cardiophylla Diels ex Kom. (Campanulaceae)

Codonopsis clematidea (Schrenk) C.B.Clarke (Campanulaceae)

8

9

10

11

12

Baidang

Codonopsis accrescenticalyx Codonopsis pilosa Chipp

Codonopsis tubulosa Kom. (Campanulaceae)

7

H.Lév.;

Codonopsis handeliana Nannf.; Codonopsis pilosula var. handeliana (Nannf.) L.D.Shen

Codonopsis pilosula subsp. handeliana (Nannf.) D.Y.Hong & L.M.Ma (Campanulaceae)

6

Zangdangshen

Codonopsis thalictrifolia var. mollis (Chipp) L.D.Shen (Campanulaceae)

3

Xinjiang, Xizang

Shanxi, Shaanxi, Hubei

Sichuan, Qinghai, Xizang

Sichuan, Yunnan

Guizhou, Yunnan

Sichuan, Yunnan

Xizang

Functional uterine bleeding, weakness and fatigue, gastroptosis, rheumatic heart disease, etc.

Weakness after illness, spontaneous sweating, night sweating, etc.

Invigorate the spleen and the stomach and replenish qi, engender liquid and quench thirst

Strengthen the spleen and the stomach, replenish qi and blood, engender liquid and quench thirst

Weakness of the spleen and the stomach, poor appetite and loose stools, limb weakness, lung deficiency, dyspnea and cough, breath shortness and spontaneous sweating, deficiency of qi and blood

Weakness of the spleen and the stomach, breath shortness and palpitations, poor appetite and loose stools, asthenic dyspnea and cough, internal heat diabetes, etc.

Traumatic bleeding and pain

Eczema , grasserie, rheumatic arthritis, beriberi, hysteria, etc

Invigorate the spleen and the stomach and replenish qi, engender liquid and quench thirst

Invigorate the spleen and the stomach and replenish qi, strengthen the spleen and tonify the lung Invigorate the spleen and the stomach and replenish qi, engender liquid and quench thirst

Invigorate the spleen and the stomach and replenish qi, engender liquid and quench thirst

Diminish inflammation and swelling, dispel wind, eliminate dampness, engender liquid and quench thirst

l

k

j

i

h

g

f

Codonopsis subscaposa Kom. (Campanulaceae)

Codonopsis viridiflora Maxim. (Campanulaceae)

18

19

20

Tudangshen

4

Gaoshandangshen

Codonopsis foetens subsp. foetens

Codonopsis foetens Hook.f. & Thomson (Campanulaceae)

17

Codonopsis bicolor Nannf.

Yedangshen

Campanumoea violifolia H.Lév.; Melothria violifolia H.Lév.

Codonopsis micrantha Chipp (Campanulaceae)

16



Codonopsis benthamii Hook.f. & Thomson (Campanulaceae)

15

Shanxi, Ningxia, Gansu, Qinghai, Sichuan

Sichuan, Yunnan

Gansu, Qinghai, Sichuan, Xizang

Sichuan, Yunnan

Sichuan, Yunnan, Xizang

Northeast, northern, eastern and the central south of China

Codonopsis lanceolata (Siebold & Zucc.) Benth. & Hook.f. ex Trautv. (Campanulaceae)

14

Lunyedangshen, Yangnaishen, Shanhailuo, Siyeshen, Baimangrou, Shanhuluobo

Hubei, Sichuan

Codonopsis henryi Oliv. (Campanulaceae)

Campanumoea japonica Siebold ex Merr.; Campanumoea lanceolata Siebold & Zucc.; Codonopsis bodinieri H.Lév.; Codonopsis lanceolata var. amurae T.Koyama; Codonopsis lanceolata var. emaculata Honda; Codonopsis lanceolata f. emaculata (Honda) H.Hara; Codonopsis ussuriensis f. viridiflora J.Ohara; Codonopsis yesoensis Nakai; Glosocomia hortensis Rupr.; Glosocomia lanceolata (Siebold & Zucc.) Rupr.; Glosocomia lanceolata (Siebold & Zucc.) Maxim. Codonopsis macrocalyx Diels; Codonopsis macrocalyx var. coerulescens Hand.-Mazz.; Codonopsis macrocalyx var. parviloba J.Anthony

Gansu, Sichuan

Codonopsis deltoidea Chipp (Campanulaceae)

13

Rheumatic arthritis, neuralgia, mental numbness, carbuncle, leprosy, beriberi, hysteria, etc.

Strengthen the spleen and the stomach, replenish qi and blood, engender liquid and quench thirst Invigorate the spleen and the stomach and replenish qi, engender liquid and quench thirst Diminish inflammation and swelling, nourish yin and invigorate yang Invigorate the spleen and the stomach and replenish qi, engender liquid and quench thirst Invigorate the spleen and the stomach and replenish qi, engender liquid and quench thirst

The spleen and stomach weakness, dual depleteon of qi and blood, body tiredness and fatigue, reduced appetite, thirst, diarrhoea, etc.

The lung inflammatory diseases, lung cancer, milk lacking, poisonous snake biting, diabetes and to confront the side effects of antituberculosis drugs

Malaria

Invigorate the spleen and the stomach and replenish qi, engender liquid and quench thirst

Boost qi and nourish yin, moisten the lung and engender liquid, diminish swelling and expel pus, detoxicate and cure furuncles

The spleen deficiency, reduced appetite, loose stool, limb weakness, heart palpitation, short breath, thirst, spontaneous sweat, rectocele, uterine prolapse, etc.

Invigorate the spleen and the stomach and replenish qi, engender liquid and quench thirst

t

s

r

q

p

o

n

m

5

Annotation: Code means the species of Codonopsis in the same line. “a~t” means the relevant 20 species of Codonopsis.

Compounds

lobetyolin

lobetyolinin

lobetyol

9-(tetrahydropyran-2-yl)-non-trans-2,8-diene-4,6-diyn-1-ol

Pilosulyne A

Pilosulyne B

Pilosulyne C

Pilosulyne E

Pilosulyne D

Pilosulyne F

Pilosulyne G

9-(tetrahydropyran-2-yl)-non-trans-8-ene-4,6-yn-l-ol

Codonopilodiynoside A

Codonopilodiynoside B

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

6

R1=H, R2=β-D-glucopyranosyl-(1''→

R1=H, R2=β-D-glucopyranosyl

Ƹ

4

4,5-dihydro

a

a

c

a

a

a

a

R=Glc-Glc, Ƹ12 Glc

a

a

a

a, c, o

a

a, l, o

a, c, l, o, h, f

Plant sources

R=H, 12,13-dihydro

H

Glc-Glc

Glc

Substituent groups

Polyacetylenes, polyenes and their glycosides isolated from medicinal plants of Codonopsis.

Table 2

Jiang et al. (2015)

Jiang et al. (2015)

Sun et al. (2016)

Chao, et al. (2015)

Chao, et al. (2015)

Chao, et al. (2015)

Chao, et al. (2015)

Chao, et al. (2015)

Chao, et al. (2015)

Chao, et al. (2015)

Cao (2012)

Nörr and Wagner (1994)

Ma et al. (2014);

Ishida et al. (2008)

Cao (2012)

Sun et al. (2007)

Ren (2010);

Jing et al. (2013);

Cao (2012);

References

Codonopilodiynoside D

Codonopilodiynoside E

Codonopilodiynoside F

Codonopilodiynoside G

tetradeca-4E,8E,12E-triene-10-yne-1,6,7-triol

Cordifolioidyne B

Tangshenyne A

Tangshenyne B

16

17

18

19

20

21

22

23

a a a

β-D-glucopyranosyl-(1''→2')-β-D-glucopyranosyl β-D-glucopyranosyl-(1''→2')-β-D-glucopyranosyl β-D-glucopyranosyl-(1''→2')-β-D-glucopyranosyl Glc

a

β-D-glucopyranosyl

c

c

a, b, c

a

a

R1=R2=β-D-glucopyranosyl

7

Annotation: The letters in “Plant sources” mean the relevant species of Codonopsis as can be seen in Table 1. The same in Table 3~9.

Codonopilodiynoside C

15

2')-β-D-glucopyranosyl

Sun et al. (2016)

Sun et al. (2016)

He et al. (2014)

Lin et al. (2013)

Jiang et al. (2015)

Jiang et al. (2015)

Jiang et al. (2015)

Jiang et al. (2015)

Jiang et al. (2015)

Compounds

luteolin

apigenin

tricin

chrysoeriol

quercetin

kaempferol

wogonin

quercetin

5-hydroxy-4’,6,7-trimethoxy flavone

5-hydroxy-4’,7-dimethoxy flavone

apigenin-7-O-β-D-glucopyranoside

No.

1

2

3

4

5

6

7

8

9

10

11

Flavonoids and their glycosides isolated from medicinal plants of Codonopsis.

Table 3

8

R1=Glc, R2=R3=R4=H

R=H

R=OH

R4=OCH3

R1=R2=R3=H,

R3=R4=OCH3

R1=R2=H,

R1=R2=R3=R4=H

R1=R2=R3=H, R4=OH

Substituent groups

l, r

r

r

r

r

l, r

r

r

r

l, o, r

c, l, r, f

Plant sources

Aga et al. (2012);

Zhang et al. (2005)

Zhang et al. (2005)

Fan (2011)

Fan (2011)

Ishida et al. (2008)

Fan (2011);

Peng (2010)

Aga et al. (2012)

Aga et al. (2012)

Zhou et al. (2012)

Ishida et al. (2008);

Aga et al. (2012);

Jing et al. (2013)

Ishida et al. (2008);

Fan et al. (2011);

Fan (2011);

References

luteolin-7-rutinoside

luteolin-7-galactoside

tectoridin

cynaroside

14

15

16

17

21

20

19

5,7,3’,5’-tetrahydroxy-flavone-7-O-β-D-glucopyranoside

glucopyranoside

luteolin-7-O-[(6’’’-caffeoyl)-β-D-glucopyranosyl-(1→6)]-β-D-

luteolin-7-O-D-gentibioside

glucopyranoside]

luteolin-7-O-β-D-glucopyranosyl-(1→6)-[(6’’’-O-caffeoyl)-β-D-

luteolin-5-O-β-D-glucopyranoside

13

18

luteolin-7-O-β-D-glucopyranoside

12

9

Glc

R2=R4=OH, R3=H

R1=β-D-Glc-(1ė6)-β-D-Glc,

R4=OH

R1=Glc, R2=OCH3, R3=H,

R1=Gal, R2=R3=H, R4=OH

R4=OH

R1=Glc-Rha, R2=R3=H,

R3=OH

R1=R4=H, R2=β-D-Glc,

R1=Glc, R2=R3=H, R4=OH

r

r

r, f

r

l

o

l

l

l, o, r

o, r, f

Fan et al. (2011)

Zhou et al. (2012)

Jing et al. (2013)

Aga et al. (2012);

Aga et al. (2012)

Zhu and Wei (1994)

medicine (1982)

traditional Chinese

Jilin institute of

Cao (2012)

Cao (2012)

Peng (2010)

Ishida et al. (2008);

Fan (2011);

Whang et al. (1994)

Jing et al. (2013);

Aga et al. (2012);

Cao (2012)

22

neokurarinol

10

a

Ma et al. (2014)

o c, o

c, o

c, o a a

R1=R2=β-D-Glc, R3=CH3 β-D-Glc β-D-Glc β-D-Glc

tangshenoside I-methyl ester

tangshenoside Ċ

tangshenoside ċ

tangshenoside Č

tangshenoside č

tangshenoside Ď

tangshenoside VIII

codonoside A

3

4

5

6

7

8

9

Glc

Glc

11

c, o

a, o

a, c, o

2

R1=R2=β-D-Glc, R3=H

tangshenoside I

Plant sources

1

Substituent groups

Compounds

No.

Lignans and their glycosides isolated from medicinal plants of Codonopsis.

Table 4

Tsai and Lin (2008)

Jon et al. (2004);

Aladyina et al. (1985);

Aladina et al. (1988);

Aladina et al. (1989);

Sun and Liu (2008)

Ren et al. (2013)

Guan (2015)

Zhang et al. (2015)

Sun (2007)

Ren et al. (2013);

Sun (2007)

Ren et al. (2013);

Sun (2007)

Fan (2011);

Ren et al. (2013)

Sun (2007)

Fan (2011);

References

codonoside B

codonopiloneolignanin A

syringin

3’,4’,5,9,9’-pentahydroxy-5,4,7'-epoxylignan

ethylsyringin

syringgaresinol

Lariciresinol

methyl syrigin

lanceolune A

lanceolune B

lanceolune C

10

11

12

13

14

15

16

17

18

19

20

CH3

H

Glc

CH2CH3

β-D-Glc

Glc

12

o

o

o

o

l

o

r

a

a, c, f, o, r

a

c, o

Hossen et al. (2016)

Hossen et al. (2016)

Hossen et al. (2016)

Liang et al. (2007)

Ishida et al. (2008)

Mei et al. (2010)

Aga et al. (2012)

Qing et al. (2016)

Sun (2007)

Liang et al. (2007);

Jing et al. (2013);

Cao (2012);

Aga et al. (2012);

Jiang et al. (2016)

Tsai and Lin (2008)

Jon et al. (2004);

Aladyina et al. (1985);

Aladina et al. (1989);

Aladina et al. (1988);

Compounds

codotubulosine A

codotubulosine B

codonopyrrolidium A

codonopsine

(+)codonopsine

codonopsinine

codonopsinol

choline

perlolyrine

1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid

adenosine

hypoxanthine

nicotine

5-hydroxy-2-hydroxymethylpyridine

Codonopsinol C

Codonopiloside A

Codonopsinol A

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

13

R1=OCH3, R2=OH, R3=H

R1=OCH3, R2=H, R3=glucopyranosyl

R1=OH, R2=R3=H

R1=α-OCH3, R2=α-OH, R3=OCH3

R1=β-CH3, R2=β-OH, R3=H

R1=α-CH3, R2=α-OH, R3=OCH3

R1=α-CH3, R2=α-OH, R3=OCH3

R1=substituent group 1, R2=H

R1=R2=COCH3, R3=β-CH3

R1=R2=H, R3=β-CH3

Substituent groups

Alkaloids and their glycosides and nitrogen compounds isolated from medicinal plants of Codonopsis.

Table 5

a

a

a

a

a

a

a

a, o

a, o

a, d

l

l

l

a, l

a

a, b, c, h, i, l, o

a, b, c, h, i, l, o

Plant sources

Wakana et al. (2013)

Wakana et al. (2013)

Wakana et al. (2013)

Chen (2007)

Zhou et al. (2004)

He (2004)

Tsai and Lin (2008)

Yoo et al. (2002)

Chang et al. (1986)

Cao (2012);

Zhu and Wei (1994)

Jiang et al. (1992);

Ishida et al. (2008)

Ishida et al. (2008)

Ishida et al. (2008)

Chen (2007); Fan (2011)

Wakana et al. (2010)

Li et al. (2009)

Cao (2012)

References

Codonopsinol B

uracil

radicamine A

6-methoxy-4-formyl quinoline

6-methoxyquinoline-4-carbaldehyde

N-9-formylharman

1-carbomethylcarboline

norharman

Codonopsinol 1

Codonopsine 2

radicamine A

5-hydroxy-2-pyridinemethanol

Radicamine A

codonocerebroside A

n-butyl allophanate

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

Glc

CH3

OH

R1=R2=H

14

R1=H, R2=COOCH3

R1=CHO, R2=CH3

R1=OCH3, R2=R3=H

a, d

o

a

a, d

l

l

l

o

o

o

p

p

l

a

a

Zhu and Wei (1994)

Wang et al. (1982);

Wang et al. (1988);

Hossen et al. (2016)

Ma et al. (2014)

Zhu and Wei (1994)

Wang et al. (1988);

Ishida et al. (2008)

Ishida et al. (2008)

Ishida et al. (2008)

Chang et al. (1986)

Chang et al. (1986)

Chang et al. (1986)

Wu (2009)

Wakana et al. (2013)

Ishida et al. (2008)

Qing et al. (2016)

Wakana et al. (2013)

COCH3

=O

taraxerone

taraxeryl acetate

taraxery acetate

β-amyrin acetate

Codonopilate A

Codonopilate B

Codonopilate C

24-methytenecycloartanyllinolate

4

5

6

7

8

9

10

11

substituent group 5

substituent group 4

substituent group 3

substituent group 2

OCOCH3

15

a

a

a

a

a, f

a, c

a, c, d, p, l

a, c, o

taraxerol

3

a, c, i, j

=O

OH

Atraetylenolide ċ

2

a

a, c, d, p, o

H

Atraetylenolide Ċ

1

Plant sources

OH

Substituent groups

Compounds

No.

Terpenoids and their glycosides isolated from medicinal plants of Codonopsis.

Table 6

Wakana et al. (2010)

Wakana et al. (2010)

Wakana et al. (2010)

Wakana et al. (2010)

Zhou (2014)

Jing et al. (2013);

Zhou (2004)

Zhu and Wei (1994)

Wu (2009);

Ishida et al. (2008);

Cao (2012);

Mao et al. (2000)

Zhu and Wei (1994)

Wu (2009);

Mao et al. (2000);

Cao (2012);

Hao et al. (2002)

Feng et al. (2012);

Zhu et al. (2001)

References

24-methylenecycloartan-3-ol

friedelan-3-one

1-friedelan-3-one

24-methylenecycloartanol

friedelin

oleanolic acid

echinocystic acid

bis(2-ethylhexyl) phthalate

5-methoxymethyl-2-furaldehyde

5-hydroxyl-2-furaldehyde

8β-hydroxyasterolid

5-hydroxymethyl-2-furaldehyde

oleanolic acid

12

13

14

15

16

17

18

19

20

21

22

23

24

a

R1= =O, R2=R3=CH3

R1=R2=R3=R4=H 16

R1=OH, R2=R3=H, R4=β-OH

R1=R2=R3=R4=H

a

R1= =O, R2=R3=H

d, o

a, d

a

a

a, d

a, d

a, d, o

a, d, o

a, c, d, o

a

a

H

Liang et al. (2007)

Zhu and Wei (1994)

Li et al. (2009);

Chen (2007);

Liu et al. (1989)

Zhang (2006)

Zhu and Wei (1994)

Zhang (2006);

Zhu and Wei (1994)

Zhang (2006);

Zhu and Wei (1994)

Yang et al. (1975);

Chen (2007);

Zhu and Wei (1994)

Yang et al. (1975);

Chen (2007);

Ichikawa et al. (2009)

Cao (2012);

Zhou (2004)

Wakana et al. (2010)

Wakana et al. (2010)

Wakana et al. (2010)

acid-3-β-D-

Lancemasides A

Lancemasides B

Lancemasides C

Lancemasides D

Lancemasides E

Lancemasides F

Lancemasides G

Foetidissimoside A

aster saponin Hb

foetidissimoside A

25

26

27

28

29

30

31

32

33

34

35

17

R1=β-OH, R2=R3=H, R4=α-OH

R1=O-GlcA, R2=Rha(1-2)-Ara, R3=H, R4=α-OH

R4=α-OH

R1=O-GlcA, R2=Xyl(1-4)-Rha(1-2)-Ara, R3=H,

R4=α-OH

R1=O-GlcA, R2=Xyl(1-3)-Xyl(1-4)-Rha(1-2)-Ara, R3=H,

R4=α-OH

R2=Xyl(1-3)-Xyl(1-4)-Rha(1-2)-[(1-3)-Glc]-Ara, R3=H,

R1=O-Glc(1-3)-GlcA,

R2=Xyl(1-3)-Xyl(1-4)-Rha(1-2)-Ara, R3=H, R4=α-OH

R1=O-Glc(1-3)-GlcA,

R4=α-OH

R1=O-GlcA, R2=Rha(1-2)-[(1-3)-Glc]-Ara, R3=H,

R3=H, R4=α-OH

R1=O-GlcA, R2=Xyl(1-4)-Rha(1-2)-[(1-3)-Glc]-Ara,

R4=α-OH

R2=Xyl(1-3)-Xyl(1-4)-[(1-3)-Glc]-Rha(1-2)-Ara, R3=H,

R1=O-GlcA,

R4=α-OH

R1=O-GlcA, R2=Xyl(1-3)-Xyl(1-4)-Rha(1-2)-Ara, R3=H,

R1=O-GlcA, R2=R3=H, R4=OH

l

o

o

o

o

o

o

o

o

o

o

Ishida et al. (2008)

Dubois et al. (1988);

Ichikawa et al. (2009)

Shirota et al. (2008)

Ichikawa et al. (2009);

Kawahara and Nakane (2008)

Kawahara and Nakane (2008)

Kawahara and Nakane (2008)

Kawahara and Nakane (2008)

Kawahara and Nakane (2008)

Kawahara and Nakane (2008)

Ichikawa et al. (2008)

Liang et al. (2007)

codonolasideĉ

codonolasideĊ

codonolasideċ

codonolasideČ

codonolasideč

38

39

40

41

42

atraetylenolide

albigenic acid

cycloartenol

Echinoeystie Acid

rabiprasin

lupeol

44

45

46

47

48

49

glucuronopyranoside

echinocystic acid-3-O-(6'-O-methyl)-β-D-

codonolaside

37

43

codonoposide

36

18

β-D-xylopyranosyl-(1-3)-β-D-glueuronopyranosyl

R1=O-GlcA, R2=H, R3=H, R4=OH

R2=Xyl(1-4)-Rha(1-2)-Ara, R3=H, R4=OH

R1=O-Glc(1-3)(6-O-butyl)-Xyl,

R4=OH

R1=O-Glc(1-3)-Xyl, R2=Xyl(1-4)-Rha(1-2)-Ara, R3=H,

R2=Xyl(1-4)-Rha(1-2)[Glc(1-4)]-Ara, R3=H, R4=OH

R1=O-Xyl(1-3)-GlcA,

R1=OH, R2=Xyl(1-4)-Rha(1-2)-Ara, R3=H, R4=OH

R2=Xyl(1-4)-Rha(1-2)-Ara, R3=H, R4=OH

R1=O-Xyl(1-3)(6-O-methyl)-GlcA,

R4=OH

R1=O-Xyl(1-3)-GlcA, R2=Xyl(1-4)-Rha(1-2)-Ara, R3=H,

(1-2)-α-L-arabinopyranosyl, R3=H, R4=OH

R2=β-D-xylopyranosyl(1-3)-α-L-ramnopyranosyl

R1=O-β-D-xylopyranosyl(1-3)-β-D-glucuronopyranosyl,

r

l

o

o

o

p

o

o

o

o

o

o

o

o

Peng (2010)

Ishida et al. (2008)

Lee et al. (2005)

Yuan and Liang (2006)

Wu et al. (2005)

Wu (2009)

Hossen et al. (2016)

Zhang et al. (2009)

Yuan and Liang (2006)

Xu et al. (2008)

Xu et al. (2008)

Xu et al. (2008)

Xu et al. (2008)

Lee et al. (2002)

hopane-6α,22-diol

3β-acetoxyoleanan-12-one

rubiprasin B

50

51

52

19

l

l

r

Ishida et al. (2008)

Zhu et al. (2001)

Peng (2010)

a

R1= =O, R2=β-H, R3=R4=CH3 R1=OH, R2=α-H, R3=R4=H

R1=O-β-D-Glu, R2=α-H, R3=R4=H R1=α-H, R2=R3=H R1=OH, R2=H R1=O-β-D-Glu, R2=H R1= =O, R2=β-CH3

α-spinasta-7,22-diene-3-one

Ƹ7-stigmasterol

Ƹ7-stigmasteryl glucoside

Ƹ7-stigmasta-7-ene-3-one

Ƹ5,22-stigmasterol

Ƹ5,22-stigmasteryl-β-D-glucoside

stigmasta-5,22-diene-3-one

stigmast-7-en-3-one

3

4

5

6

7

8

9

10

20

a, c, o

R1=O-β-D-Glu, R2=α-H, R3=R4=CH3

α-spinatsrol-β-D-glucoside

2

a

a, d

a

a, d

a, d, o

a, c

a, c

a, c, f, o

R1=OH, R2=α-H, R3=R4=CH3

α-spinasterol

1

Plant sources

Substituent groups

Compounds

No.

Steroids and their glycosides isolated from medicinal plants of Codonopsis.

Table 7

Wakana et al. (2010)

Wang et al. (1986)

Wang et al. (1986)

Mao et al. (2000);

Zhu and Wei (1994)

Chen et al. (1985);

Wang et al. (1986)

Zhu and Wei (1994)

Cao (2012);

Zhu and Wei (1994)

Yue et al. (1992);

Mao et al. (2000);

Wang, J.Z. and Wang, F.P. (1996)

Cao (2012)

Mao et al. (2000)

Jing et al. (2013);

Cao (2012);

References

β-sitosterol

β-daucosterol

sitosterol

14

15

16

21

a, o

Ƹ5,25-stigmasterol

13

β-D-Glu

c

α-spinasteron

12

r

a, r

a

a

stigmast-7,22-dien-3-ol

11

Peng (2010)

Zhang et al. (2015)

Qi et al. (2011);

Aga et al. (2012);

Qi et al. (2011)

Yang (2013)

Mao et al. (2000);

Wang, J.Z. and Wang, F.P. (1996)

Wakana et al. (2010)

Compounds lauric acid 9,10,13-trihydroxy-(E)-11-octadecenoic acid 2,4-nonadlenic acid 5,6,9-trihydroxy-octadec-7-enoic acid 9,12,13-trihydroxy-10,15-octadecadienoic acid 9,12,13-trihydroxy-10-octadecenoic acid 9,10-dyhydroxy-12-octadecenoic acid 9-hydroxy-10,12-octadecadienoic acid stearic acid coronaric acid succinic acid maleic acid codopiloic acid fumalic acid nicotinic acid

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

Organic acids and their glycosides isolated from medicinal plants of Codonopsis.

Table 8

22

a

a, o

c

o

a, r

a

a

a

a

a

a

c

a

c

a

Plant sources

Cao (2012)

Meng et al. (2003)

Kang (2009);

L and H (1979)

Mao et al. (2000)

Chen (2007)

Aga et al. (2012);

Ma et al. (2014)

Sun et al. (2015)

Zhang et al. (2015)

Zhang et al. (2015)

Zhang et al. (2015)

Zhang et al. (2015)

Tsai and Lin (2008)

Zhou et al. (2004)

Wang, J.Z. and Wang, F.P. (1996)

Zhou et al. (2004)

References

a

shikimic acid chlorogenic acid neochlorogenic acid 3-O-Caffeoylquinic acid 8-O-4' diferulic acid p-coumaric acid glucoside syringic acid vanillic acid 4-(β-D-glucopyranosyl)-benzoic acid 4-hydroxy benzoic acid

19

20

21

22

23

24

25

26

27

28

23

o

(Z)-2-(b-glucopyranosyloxy)-3-phenylpropenoic acid

18

a

r

a, o

a

r, f

r

r

o

c

a

2-furancarboxylic acid

17

a, r, f

caffeic acid

16

Lin et al. (2013)

Aga et al. (2012)

Kang (2009)

Cao (2012);

Xing et al. (2001)

Wu et al. (2011)

Kang (2009)

Fan et al. (2011)

Jing et al. (2013)

Aga et al. (2012)

Aga et al. (2012)

Mao et al. (2000)

Tsai and Lin (2008)

Chen (2007)

Jing et al. (2013)

Han et al. (1990);

a, d

geniposide

n-butyl-β-D-fructofuranoside

n-butyl-α-D-fructofuranoside

ethyl-α-D-fructofuranoside

7

8

9

10

24

a, c, d

hexyl-β-D-fructofuranoside

6 Glc

a, c

n-hexyl-β-D-glucopyranoside

5

a, c

a

a

a

ethyl-β-D-glucopyranoside

4

c

β-D-Glc6-β-D-Glc

hexyl-β-gentiobioside

3

a

β-D-Glc2-β-D-Glc

hexenyl-β-sophoroside

2

c, l

β-D-Glc6-α-L-Ara(p)

(E)-2-hexenyl-α-L-arabinopyranosyl-(1→6)-β-D-glucopyranoside

1

Plant sources

Substituent groups

Compounds

No.

Other compounds isolated from medicinal plants of Codonopsis.

Table 9

Materia Medica”

medicine “Chinese

traditional chinese

State administration of

Zhu and Wei (1994)

Chen et al. (1995);

Zhu and Wei (1994)

Qing et al. (2016);

Sun (2007)

Sun (2007)

Sun (2007)

Ma et al. (2014);

Wang et al. (1988)

Sun (2007)

Zhu and Wei (1994)

Sun (2007)

Ishida et al. (2008);

References

a a

a, d a

(E)-2-hexenyl-β-sophoroside

ethyl-α-D-glucopyranoside

(E)-2-hexenyl-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside

(E)-2-hexenyl-α-L-arabinopyranosyl-(1→2)-β-D-glucopyranoside

hexyl-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside

hexyl-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside

Eucommioside II

stigmasetyl-β-D-glucoside

(Z)-3-hexenyl-β-D-glucopyranoside

(6R,9S)-3-oxo-α-ionol-β-D-glucopyranoside

sweroside

syringaldehyde

o-(o-methoxyphenoxy)phenol

6-methylgingediol

16

17

18

19

20

21

22

23

24

25

26

27

28

29

r

β-D-gluc

25

l

β-D-Glc

a

c

a

a

a

a

a

a

β-D-Glc

β-D-gluc

a

ethyl-β-D-fructofuranoside

15

a

hexyl-α-D-fructofuranoside

14

a

β-D-Glc

(E)-2-hexenyl-β-D-glucopyranoside

13

a

β-D-Glc2-β-D-Glc

(E)-2-hexenyl-β-D-sophoroside

12

a

β-D-Glc2-β-D-Glc

(Z)-3-hexenyl-β-D-sophoroside

11

Zhang et al. (2015)

Zhou et al. (2004)

Zhu and Wei (1994)

Cao (2012);

Peng (2010)

Ishida et al. (2008)

Zhu and Wei (1994)

Zhang et al. (2015)

Zhang et al. (2015)

Wu et al. (2011)

Wu et al. (2011)

Xu et al. (2012)

Xu et al. (2012)

Wang et al. (1988)

Zhu and Wei (1994)

Zhu and Wei (1994)

Zhang (2006)

Zhu and Wei (1994)

Zhang et al. (2015)

Zhang et al. (2015)

(1999)

editorial committee

l r, o

tianshi acid

bis-(2-ethylhexyl)-phthalate

2-furan sodium salt

emodin

methylpalmatate

3(S)-mevalonolacton

1,3-linolein-2-olein

dibutyl terephthalate

1,6-hexanediol-3,4-bis(4-hydroxy-3-methoxyphenyl)

p-hydroxy benzaldehyde

vanillin

3-O-Caffeoylquinic acid methyl ester

3-O-Caffeoylquinic acid butyl ester

33

34

35

36

37

38

39

40

41

42

43

44

45

r

n-CH2CH2CH2CH3

26

r

o

f

r, f

c

a

a, r

a

a

a

a

CH3

β-D-gluc

woodorien

32

a

2-furancarboxylate

31

a

genipin gentiobioside

30

Fan et al. (2011)

Fan et al. (2011)

Kang (2009)

Kang (2009)

Fan et al. (2011);

Ishida et al. (2008)

Jing et al. (2013)

et al. (2013)

Fan et al. (2011); Jing

Mizutani et al. (1988)

Sha and Lu (1989)

Ma et al. (2014)

Fan (2011);

Wang et al. (1988)

Wang et al. (1988)

Ma et al. (2014)

Ma et al. (2014)

Mizutani et al. (1988)

Ma et al. (2014)