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. 2021 May 20;29(8):781–798. doi: 10.1016/j.jsps.2021.05.003

A systematic review on traditional medicine Toddalia asiatica (L.) Lam.: Chemistry and medicinal potential

Zhi Zeng 1, Rui Tian 1,1, Jia Feng 1, Nian-an Yang 1, Lin Yuan 1,⁎
PMCID: PMC8360773  PMID: 34408540

Abstract

Toddalia asiatica (L.) Lam., belonging to Toddalia genus of Rutaceae family, is a folk medicine in China used for hundreds of years. The whole plant can be used as medicine, especially the root that used to be applied in the folk. In recent decades, with the in-depth research from domestic and foreign researchers, it has gradually been discovered that the chemical components in T. asiatica are mainly coumarins and alkaloids. Its pharmacological effects are manifested in anti-inflammatory and analgesic, hemostatic coagulation, anti-tumor, treatment of cardiovascular diseases, etc. It has a wide range of clinical applications and significant effects on rheumatism, pain, wound bleeding, and bruises. Due to its important research value, in this article, the chemical compositions and pharmacological effects of T. asiatica are comprehensively expounded in recent years in order to provide a reference for the related research and application of this medicinal material, which were carried out through a bibliometric search using the Science Citation Index- Expanded (SCIE) database, web of science, Google scholar and Chinese National Knowledge Infrastructure (CNKI) and all that.

Keywords: Toddalia asiatica, Folk medicine, Chemical composition, Pharmacological effect

1. Introduction

Toddalia asiatica Lam., a plant of the genus Toddalia of the family Rutaceae, earliestly recorded in “Plant name and real picture ”, is a woody vine, and also the only plant in the genus (Xia and Liu, 2007). There are many aliases for T. asiatica, such as Jian xue fei, San bai bang, Fei long zhuang xue, Da jiu jia and so forth (Shi et al., 2011). The plant generally grows in secondary forests of roadsides, mountain forests, thickets and small trees, mainly distributed in tropical Africa and southeastern Asia, especially in the south of Wuling Mountainous areas in China (Tsai et al., 1998, Watanabe et al., 2014, Zhang et al., 2017). The old stem is brown with longitudinally lobed and protruding yellow-gray lenticels owning a thick cork layer, however, the young shoots have small round lenticels. In addition, there are many downward curved sharp thorns on the stem branches and leaf axes. The leaflets have no near stalk, while dense transparent oil spots can be seen in the light. After kneading, the aroma is similar to that of citrus leaves. The male inflorescences are panicles and umbellate but the female inflorescences are thyrses, which can blossom all the year round (Xia and Liu, 2007). Its fruit is scarlet or orange-red, 8–10 mm in diameter or slightly larger, with multiple longitudinal shallow grooves which becomes more pronounced after being dehydrated. Seeds are about 5–6 mm long on the brownish black seed coat with tiny pits (Xia and Liu, 2007).

T. asiatica has played a very important role in traditional medicine, and the whole plant can be used as medicine, especially its root often used in the folk (Yang et al., 2013, Li et al., 2018). The studies of chemical composition showed that the main chemical components were alkaloids and coumarins in T. asiatica (Wang et al., 2009, Hu et al., 2014, Sukieum et al., 2018, Lin and Chen, 2020). Otherwise, there were also some triterpenes (Huang et al., 2005), flavonoids (Shi et al., 2014), phenolic acids (Phatchana and Yenjai, 2014), lignans (Tsai et al., 1998) and what not. Modern pharmacological studies have suggested that T. asiatica shows anti-inflammatory and analgesic (Hao et al., 2004, Yang et al., 2013, Lu et al., 2015), antioxidant (Tian et al., 2011, Stephen Irudayaraj et al., 2012, Chen and Long, 2013, Tian et al., 2013), antibacterial (Ding et al., 2007, Hu et al., 2014), cardiovascular protection (Ren et al., 1993, He and Ren, 1998, Ren and He, 1998, He and Ren, 1999), anti-tumor (Iwasaki et al., 2006, Iwasaki et al., 2010, Li et al., 2018) and other pharmacological effects. According to our literature researches, this paper would review the studies on the chemical constituents and pharmacological effects of T. asiatica systematically in the following sections.

In this study, we employed the database such as Science Citation Index- Expanded (SCIE) database, web of science, Google scholar and Chinese National Knowledge Infrastructure (CNKI) et al., searching for researches that have been reported by scholars both at home and abroad during 1976–2020, in which ‘T. asiatica’ including ‘San bai bang’ and ‘Fei long zhuang xue’ was used as the main key words. Otherwise, folk medicine, chemical composition and pharmacological effect were also used for assisting us in looking for more valuable information in all directions, the aim of which is to make the review more detailed and systematic to help researchers for their studies. The detail research procedure was shown in Fig. 1.

Fig. 1.

Fig. 1

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Flow diagram of study selection.

2. Chemical composition

So far, a total of more than 165 compounds have been reported from T. asiatica, including 69 coumarins, 69 alkaloids, 8 terpenoids, 5 flavonoids, and 14 other compositions such as lipids, alcohols, phenolic acids, lignans, steroids and fatty acids. Among them, the most characteristic compounds for T. asiatica are coumarins and alkaloids.

2.1. Coumarins and its glycosides

T. asiatica is rich in coumarins, including some simple coumarins, furanocoumarins, pyrancoumarins, and dicoumarin, summarized in Table 1. The structure of each corresponding chemical component were shown in Fig. 2. Coumarins are one of the important active ingredients in T. asiatica.

Table 1.

Coumarins reported from T. asiatica.

Num. Compound name Molecular formula Molecular weight Reference
1 Toddasin C32C32O5 544.210 (Sharma et al., 1980)
2 Dihydrotoddasin C32H32O8 544.601 (Sharma et al., 1980)
3 5,7-Dimethoxy-6-(3′-chloro-2′-hydroxy-3′-methylbutyl) coumarin C16H19ClO5 326.777 (Sharma et al., 1981a, Sharma et al., 1981b)
4 Toddaculin C16H18O4 274.317 (Ishii et al., 1983)
5 Toddalenone C15H14O5 274.273 (Ishii et al., 1983)
6 8-(3,3-Dimethylallyl)-6,7-dimethoxycoumarin C16H20O4 276.328 (Ishii et al., 1983)
7 6-Formyllimettin C12H10O5 234.205 (Ishii et al., 1983)
8 Toddacoumalone C31H31NO6 513.590 (Ishii et al., 1991a, Ishii et al., 1991b)
9 Toddanone C16H18O5 290.316 (Chen et al., 1993)
10 Toddanol C16H18O5 290.316 (Chen et al., 1993)
11 Toddalolactone methyl ether C17H22O6 322.358 (Chen et al., 1993)
12 Toddasiatin C30H26O8 514.532 (Tsai et al., 1997)
13 (+)-Toddanol C16H18O5 290.316 (Tsai et al., 1998)
14 5,7,8-Trimethoxycoumarin C12H12O5 236.224 (Tsai et al., 1998)
15 6-Methoxyseselin C15H14O4 258.274 (Tsai et al., 1998)
16 Toddalolactone C16H20O6 308.331 (Tsai et al., 1998)
17 Ulopterol C15H18O5 278.305 (Tsai et al., 1998)
18 Toddanin C15H16O5 276.289 (Tsai et al., 1998)
19 Phellopterin C17H16O5 300.311 (Tsai et al., 1998, Zhang et al., 2017)
20 5,7-Dimethoxy-(8-(3′-hydroxy-3′-methyl-1′-butenyl)-coumarin C16H18O5 290.30 (Oketch-Rabah et al., 2000)
21 8-(Geranyloxy)-5,7-dimethyloxycoumarin C21H26O5 358.434 (Wang et al., 2009)
22 7-Geranyloxy-5-methoxycoumarin C20H26O 330.418 (Wang et al., 2009)
23 Norbraylin C14H12O4 244.247 (Shi et al., 2013)
24 Suberosin C15H16O3 244.286 (Nyahanga et al., 2013)
25 Toddalenol C16H18O5 290.31 (Nyahanga et al., 2013)
26 Isopimpinellin C13H10O5 246.219 (Liu et al., 2014)
27 Coumarrayin C16H18O4 274.317 (Lin et al., 2014)
28 5-Methoxyseselin C15H14O4 258.274 (Lin et al., 2014)
29 cis-Dehydrocoumurrayin C16H16O4 272.301 (Lin et al., 2014)
30 Gleinadiene C16H16O4 272.301 (Lin et al., 2014)
31 Toddacoumaquinone C23H18O7 406.392 (Lin et al., 2014)
32 Toddalin B C32H38O10 582.648 (Lin et al., 2014)
33 3′’’ -O-Demethyltoddalin A C32H36O14 644.629 (Lin et al., 2014)
34 Toddalin A C33H38O14 658.656 (Lin et al., 2014)
35 Toddalin C C32H40O12 616.662 (Lin et al., 2014)
36 Toddalin D C32H38O11 598.647 (Lin et al., 2014)
37 ent-Toddalolactone C16H20O6 308.331 (Lin et al., 2014)
38 (−)-Toddalolactone 3′-O-β-D-glucopyranoside C22H30O11 470.474 (Lin et al., 2014)
39 5-Methoxy-8-hydroxy psoralen C12H8O5 232.193 (Phatchana and Yenjai, 2014)
40 5-Methoxy-8-geranyloxypsoralen C22H24O5 368.430 (Phatchana and Yenjai, 2014)
41 8-Hydroxy-5,7-dimethoxycoumari C11H10O5 222.197 (Phatchana and Yenjai, 2014)
42 Artanin C16H18O5 290.316 (Phatchana and Yenjai, 2014)
43 Toddalosin C32H34O9 562.617 (Phatchana and Yenjai, 2014)
44 8-(3′,7′-dimethyl-7′-hydroxy-2′E,5′E-octadienyl)oxy-5,7-dimethoxycoumarin C21H26O6 374.434 (Phatchana and Yenjai, 2014)
45 8-(3′,7′-dimethyl-7′-hydroxy-2′E,5′Z-octadienyl)oxy-5,7-dimethoxycoumarin C21H26O6 374.434 (Phatchana and Yenjai, 2014)
46 6-(3-Methyl-1,3-butadienyl)-5,7-dimethoxycoumarin C16H16O4 272.301 (Phatchana and Yenjai, 2014)
47 Omphalocarpin C17H22O6 332.350 (Tong et al., 2014)
48 Aculeatin C16H18O5 290.316 (Watanabe et al., 2014)
49 Toddayanin C16H18O5 290.316 (Hirunwong et al., 2016)
50 7-Methoxy-2H-1-benzopyran-2-one C10H10O3 170.185 (Hirunwong et al., 2016)
51 5,7-Dimethoxy-2H-1-benzopyran-2-one C13H16O4 236.264 (Hirunwong et al., 2016)
52 7-Geranyloxy-coumarin C10H10O3 170.185 (Hirunwong et al., 2016)
53 Luvangetin C15H14O4 258.269 (Tang et al., 2016)
54 (+)-Spirotriscoumarin A C47H46O12 802.306 (Tang et al., 2016)
55 (−)-Spirotriscoumarin A C47H46O12 802.306 (Tang et al., 2016)
56 (−)-Spirotriscoumarin B C47H46O12 802.307 (Tang et al., 2016)
57 (+)-Spirotriscoumarin B C47H46O12 802.307 (Tang et al., 2016)
58 (+)-Toddalin E C16H16O6 304.086 (Li et al., 2017)
59 (−)-Toddalin E C16H16O6 304.086 (Li et al., 2017)
60 (+)-Toddalin F C16H18O7 311.11 (Li et al., 2017)
61 (−)-Toddalin F C16H18O7 311.11 (Li et al., 2017)
62 (±)-Toddalin G C16H16O6 304.085 (Li et al., 2017)
63 Toddalin H C17H20O5 304.13 (Li et al., 2017)
64 7-Geranyloxy-5-hydroxycoumarin C19H22O4 314.144 (Li et al., 2017)
65 2′O-((Z,Z)-Octadeca-9,12-dienoyl)-ent-toddalolactone C34H50O7 570.36 (Li et al., 2017)
66 Pimpinellin C13H10O5 246.219 (Zhang et al., 2017)
67 2′R-acetoxytoddanol C18H20O6 332.14 (Sukieum et al., 2018)
68 (−)-Toddalolactone 2′-O-β-D-glucopyranoside C22H30O11 470.47 (Li et al., 2020)
69 (+)-Toddalolactone 3′-O-β-D-glucopyranoside C22H30O11 470.47 (Li et al., 2020)
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Fig. 2.

Fig. 2

Fig. 2

Fig. 2

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Structure and corresponding chemical name of coumarins and its derivants from Toddalia asiatica.

Japanese scholar Ishii et al., (Ishii et al., 1991a, Ishii et al., 1991b) isolated 12 known simple coumarins from methanol extracts of T. asiatica root collected from Taiwan, China, which are toddaculin, coumurrayin, toddalenol, 6-(2-hydroxy-3-methoxy-3-methylbutyl)-5, 7-dimethoxycoumarin, toddalolactone, 5,7,8-trimethoxycoumarin, 5-methoxysuberenon, 8-(3,3-Dimethylallyl)-6, 7-dimethoxycoumarin, 8-formyllimettin), 6-(3-chloro-2-hydroxy-3-methylbutyl)7-dimethoxycoumarin, 6-formyllimettin, toddalenone. Oketch-Rabah et al., (Oketch-Rabah et al., 2000) isolated a new coumarin compound (5,7-dimethoxy-(8-(3′-hydroxy-3′-methyl-1′-butenyl)-coumarin) from the ethyl acetate extract of T. asiatica root using a separation method guided by biological activity. Wang et al., (Wang et al., 2009) isolated two simple coumarin compounds from the 95% ethanol extract of T. asiatica grown in Yunnan province, China, which are 8-geranyloxy-5,7-dimethoxycoumarin and 7-geranyloxy-5-methoxycoumarin. Qiu et al., (Qiu et al., 2012) using microwave-assisted extraction isolated three furanocoumarins that were pimpinellin, isopimpinellin, and phellopterin, from T. asiatica root purchased from the Chinese herbal wholesale market in Hebei province, China. Phatchana and Chavi (Phatchana and Yenjai, 2014) identified three new coumarins that were 8-(3′,7′-dimethyl-7′-hydroxy-2′E,5′E-octadienyl)oxy-5,7-dimethoxycoumarin, 8-(3′,7′-dimethyl-7′-hydroxy-2′E,5′Z-octadienyl)oxy-5,7-dimethoxycoumarin, and 6-(3-Methyl-1,3-butadienyl)-5,7-dimethoxycoumarin, and 13 known compounds. Tsai et al., (Tsai et al., 1998) isolated 30 compounds from the wood of Formosan T. asiatica, including a new coumarin identified as toddanin. By bioassay-guided fractionation of the ethanol extract of T. asiatica roots, Lin et al., (Lin et al., 2014) isolated 21 coumarins, including seven new prenylated coumarins, that were toddalin A, 3‴-O-demethyltoddalin A, toddalin B, toddalin C, toddalin D, ent-toddalolactone, and (−)-toddalolactone 3′-O-β-D-glucopyranoside. Ishii et al., (Ishii et al., 1983) isolated a new coumarin toddalenone, and ten known coumarins that were toddalolactone, isopimpinellin, coumarrayin, toddanone, toddaculin, toddanol, 5,7,8-trimethoxycoumarin, toddasin, 5,7-Dimethoxy-6-(3′-chloro-2′-hydroxy-3′-methylbutyl) coumarin, and 8-(3,3-Dimethylallyl)-6,7-dimethoxycoumarin. Nyahanga et al., (Nyahanga et al., 2013) obtained 8 compounds including 6 coumarins characterized as aculeatin, toddaculin, isopimpinellin, suberosin, toddalenol, and toddalolactone from chromatographic fractionation of n-hexane, ethyl acetate and methanol extracts of T. asiatica root bark. Moreover, two coumarin glycosides, (−)-toddalolactone 2′-O-β-D-glucopyranoside and (+) –toddalolactone-3′-O-β-D-glucopyranoside, were firstly separated using two-dimensional HPLC (Li et al., 2020). There were also some other coumarins reported in the literature, quoted in Table 1, and would not be described in detail.

2.2. Alkaloids

Alkaloids, second only to coumarins, are another mainly kind components in T. asiatica, such as quinoline alkaloids, phenanthroline alkaloids, and other alkaloids (summarized in Table 2 and Fig. 3). In recent years, with the continuous researches reported at home and abroad, scholars have found that alkaloids in T. asiatica played an important role in anti-inflammatory, analgesic, and anti-tumor effects (Hao et al., 2004, Hu et al., 2014). A rapid method using ultrafiltration liquid chromatography combined with stepwise flow rate counter-current chromatography was developed to screen and purify alkaloid that could be used as neuraminidase inhibitors (Cao et al., 2019). Quinoline alkaloids in the plant are primarily N-methylflindersine, toddacoumalone, skimmianine, integriquinolone, dictamnine, hannine, and oxyterihannine, etc. (Tsai et al., 1997, Tsai et al., 1998). Benzophenanthridine alkaloids in the plant are principally oxychelerythrine, des-N-methylchelerythrine, oxyavicine, oxyavicine, avicine, chelerythrine, chelerythrine-φ-cyanide, dihydroavicine, dihydrochelerythrine, 8-acetonyldihydrochelerythrin, 8-methoxydihydrochelerythrine, dihydronitidine, nitidine, oxynitidine, 8-hydroxydihydrochelerythrine, toddalidimerine and 6-methylnitidine etc. (Sharma et al., 1981a, Sharma et al., 1981b, Ishii et al., 1991a, Ishii et al., 1991b, Tsai et al., 1997, Tsai et al., 1998). The other ones are chiefly γ-fagarine, toddaquinoline, arnottianaide, methyltoddaliamide, isocoreximine, protopine, toddaliamide, N,N'-dicyclohexylurea, N, N'-dicyclohexyloxamide, methyltoddaliamide, toddaliamide, flindersine, etc. (Tsai et al., 1997, Tsai et al., 1998, Duraipandiyan and Ignacimuthu, 2009). In addition, three known alkaloids, 8-acetonyldihydronitidine, 8-acetonyldihydroavicine and decarine, were firstly discovered from the genus Toddalia and 8-acetonyldihydronitidine has showed strong inhibitory effect against phosphodiesterase-4 with an IC50 value of 5.14 µM (Lin and Chen, 2020).

Table 2.

Alkaloids reported from T. asiatica.

Num. Compound name Molecular formula Molecular weight Reference
1 Robustine C12H9NO3 215.06 (Deshmukh et al., 1976)
2 8-Acetonyldihydrochelerythrine C24H23NO5 405.44 (Sharma et al., 1981a, Sharma et al., 1981b)
3 Toddalidimerine C44H38N2O9 738.79 (Sharma et al., 1981a, Sharma et al., 1981b)
4 8-Methoxydihydrochelerythrine C22H21NO5 379.41 (Sharma et al., 1982)
5 2,3-Dimethoxy-6-(5-(N-methylformamido)naphtho[2,3-d][1,3]dioxol-6-yl)phenyl acetate C23H21NO7 423.42 (Sharma et al., 1982)
6 8-Acetoxydihydrochelerythrine C23H21NO6 407.42 (Sharma et al., 1982)
7 Chelerythrine-φ-cyanide C22H18N2O4 374.39 (Ishii et al., 1983)
8 Chelerythrine C21H18NO4 348.38 (Ishii et al., 1983)
9 4-Methoxy-1-methylquinolin-2-one C11H11NO2 189.21 (Ishii et al., 1983)
10 Oxychelerythrine C21H17NO5 363.37 (Ishii et al., 1983)
11 Integriquinolone C11H13NO3 207.27 (Ishii et al., 1983)
12 N-methylflindersine C15H15NO2 241.11 (Ishii et al., 1983)
13 Oxyavicine C20H13NO5 347.32 (Ishii et al., 1991a, Ishii et al., 1991b)
14 Avicine C20H14NO4Cl 367.79 (Chen et al., 1993)
15 Toddaquinoline C14H9NO3 239.23 (Chen et al., 1993)
16 Dicyclohexylurea C13H24N2O 224.35 (Tsai et al., 1997)
17 Norchelerythrine C20H15NO 333.34 (Tsai et al., 1997)
18 N,N’ -dicyclohexyloxamide C14H24N2O2 252.36 (Tsai et al., 1997)
19 Toddaliamide C22H33NO6 407.51 (Tsai et al., 1997)
20 Methyltoddaliamide C23H35NO6 421.53 (Tsai et al., 1997)
21 Toddayanis C36H43NO5 569.74 (Tsai et al., 1997)
22 Cyclohexylamine C6H13N 99.18 (Tsai et al., 1998)
23 Haplopine C13H11NO4 245.24 (Tsai et al., 1998)
24 Isocoreximine C19H21NO4 327.38 (Tsai et al., 1998)
25 8-Hydroxy-9-methoxy-5-methyl-2,3-methylenedioxybenzo[c]phenanthridin-6(5H)-one C20H15NO5 349.34 (Tsai et al., 1998)
26 N-[6-(6-hydroxy-benzo[1,3]dioxol-5-y l)-naphtho[2,3-d][1,3]dioxol-5-yl]-N-methyl-formamide C20H15NO6 365.34 (Tsai et al., 1998)
27 Nitidine CHCLl3 adduct C22H18Cl3NO4 466.75 (Tsai et al., 1998)
28 Oxyterihannine C20H15NO5 349.34 (Tsai et al., 1998)
29 Chelerythrine chloride C21H18ClNO4 383.83 (Jain et al., 2006)
30 Nitidine chloride C21H18NO4Cl 383.83 (Jain et al., 2006)
31 3-(2,3-Dihydroxy-3-methylbutyl)-4,7-dimethoxy-1-methyl-1H-quinolin-2-one C17H23NO5 321.37 (Jain et al., 2006)
32 N-methyl-4-hydroxy-7-methoxy-3-(2,3-epoxy-3-methylbutyl)-1H-quinolin-2-one C16H19NO4 289.33 (Jain et al., 2006)
33 Flindersine C14H13NO2 227.26 (Duraipandiyan and Ignacimuthu, 2009)
34 Demethylnitidine C20H16NO4 334.35 (Iwasaki et al., 2010)
35 Dihydroavicine C20H15NO4 333.34 (Shi et al., 2011)
36 Skimmianine C14H13NO4 259.26 (Shi et al., 2013)
37 γ-Fagarine C13H11NO3 229.24 (Shi et al., 2013)
38 Dihydrochelerythrine C21H19NO4 349.38 (Shi et al., 2013)
39 Dihydronitidine C21H19NO4 349.39 (Nyahanga et al., 2013)
40 Zanthocadinanine A C37H45NO5 583.76 (Liu et al., 2014)
41 Protopine C20H19NO5 353.37 (Liu et al., 2014)
42 Oxynitidine C21H17NO5 363.37 (Hu et al., 2014)
43 Arnottianamide C21H19NO6 381.39 (Hu et al., 2014)
44 5-Methoxydictamnine C13H11NO3 229.23 (Hu et al., 2014)
45 8-Methoxychelerythrine C22H20NO5 378.40 (Hu et al., 2014)
46 Methoxynitidine C22H20NO5 378.40 (Hu et al., 2014)
47 11-Demethylrhoifolin B C20H15NO5 349.34 (Hu et al., 2014)
48 Rhoifoline B C21H17NO5 363.36 (Hu et al., 2014)
49 8-Methoxynorchelerythrine C21H17NO5 363.36 (Hu et al., 2014)
50 8,9,10,12-tetramethoxynorchelerythrine C22H19NO6 393.39 (Hu et al., 2014)
51 8-Acetylnorchelerythrine C22H17NO5 375.37 (Hu et al., 2014)
52 1-Demethyl dicentrinone C18H13NO5 323.30 (Hu et al., 2014)
53 Dicentrinone C18H11NO5 321.28 (Hu et al., 2014)
54 (2,3,10,11)-dimethylenedioxytetrahydroprotob-erberine C19H17NO4 323.34 (Hu et al., 2014)
55 11-hydroxy-10-methoxy-(2,3)-methylenedioxytetrahydroprotoberberine C20H19NO5 353.13 (Hu et al., 2014)
56 4-Hydroxy-N-methylproline C6H11NO3 145.16 (Shi et al., 2014)
57 Dictamnine C12H9NO2 199.21 (Shi et al., 2014)
58 8-hydroxy-dihydrochelerythrine C21H19NO5 365.38 (Shi et al., 2014)
59 Nitidine C21H18NO4 348.38 (Rashid et al., 2014)
60 Magnoflorine C20H24NO4 342.41 (Rashid et al., 2014)
61 Pioglitazone C19H20N2O3S 356.45 (Watanabe et al., 2014)
62 N-cis-feruloyltyramide C18H19NO4 313.35 (Hu et al., 2015)
63 (7E)-N-(4′ -hydroxyphenethyl)-3,4,5-trihydroxycinnamamide C17H17NO5 315.33 (Hu et al., 2015)
64 (7Z)-N-(4′ -hydroxyphenethyl)-3-methoxy-4,5-dihydroxycinnamamide C18H19NO5 329.35 (Hu et al., 2015)
65 (7Z)-N-(4′ -methoxyphenethyl)-3-methoxy-4-hydroxycinnamamide C19H21NO4 327.38 (Hu et al., 2015)
66 8S-10-O-demethylbocconoline C21H19NO5 365.38 (Sukieum et al., 2018)
67 8-Acetonyldihydronitidine C24H23NO5 405.45 (Lin and Chen, 2020)
68 8-Acetonyldihydroavicine C23H19NO5 389.41 (Lin and Chen, 2020)
69 Decarine C19H13NO4 319.32 (Lin and Chen, 2020)
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Fig. 3.

Fig. 3

Fig. 3

Fig. 3

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Structure and corresponding chemical name of alkaloids from T. asiatica.

2.3. Terpenoids

Except alkaloids and coumarins in T. asiatica, terpenoids, an important source of bioactive ingredients of natural medicines, are another important natural monomeric component in this medicinal material, summarized in Table 3 and Fig. 4. Huang et al (Huang et al., 2005) collected six triterpenoids that were 2α,3α,19α-trihydroxy-11-oxo-urs-12-en-28-oic acid, 2α,3α-dihydroxy-19-oxo-18,19-seco-urs-11,13(18)-diene-28-oic acid, 2α,3β,19α-trihydroxy-olean-11, 13(18)-dien-28-oic acid, 2α,3α,1lα,19α-tetrahydroxy-urs-12-en-28-oic acid, euscaphic acid, and arjunic acid from the ethanol extract of T. asiatica stem from Baiji Township, Nanning City, Guangxi Zhuang Autonomous Region, China. Moreover, another triterpene compound, β-amyrin (Ishii et al., 1983), was isolated from T. asiatica. Recently, a new sesquiterpene, (3S,4aR, 5S,8R)-8-Hydroxy-3-((R)-2-(hydroxymethyl) oxiran-2-yl) −4a,5-dimethyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one, was firstly separated from T. asiatica (Lin and Chen, 2020).

Table 3.

Terpenoids reported from T. asiatica.

Num. Compound name Molecular formula Molecular weight Reference
1 β-Amyrin C30H50O 426.72 (Ishii et al., 1983)
2 2α,3α,19α-Trihydroxy-11-oxo-urs-12-en-28-oic acid C30H46O6 502.68 (Huang et al., 2005)
3 2α,3α-Dihydroxy-19-oxo-18,19-seco-urs-11, 13(18)-diene-28-oicacid C30H46O5 486.68 (Huang et al., 2005)
4 2α, 3β,19α-Trihydroxy-olean-11, 13(18)-dien-28-oic acid C30H46O5 486.68 (Huang et al., 2005)
5 2α,3α,1lα,19α-Tetrahydroxy-urs-12-en-28-oic acid C30H48O6 504.70 (Huang et al., 2005)
6 Euscaphic acid C30H48O5 488.70 (Huang et al., 2005)
7 Arjunic acid C30H48O5 488.70 (Huang et al., 2005)
8 (3S,4aR, 5S,8R)-8-Hydroxy-3-((R)-2-(hydroxymethyl) oxiran-2-yl) −4a,5-dimethyl-4,4a,5,6,7,8- hexahydronaphthalen-2(3H)-one C15H22O4 266.34 (Lin and Chen, 2020)
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Fig. 4.

Fig. 4

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Structure and corresponding chemical name of terpenoids from T. asiatica.

2.4. Flavonoids

Flavonoids are an important member in natural products. It also existed in T. asiatica, including hesperidin, hesperetin, neohesperidin, diosmin and hesperetin-7-O-β-D-glucopyranoside, seen in Table 4 and Fig. 5. (Chen et al., 2013, Shi et al., 2014).

Table 4.

Flavonoids reported from T. asiatica.

Num Compound name Molecular formula Molecular weight Reference
1 Hesperetin C16H14O6 302.28 (Chen et al., 2013)
2 Hesperidin C28H34O15 610.57 (Shi et al., 2014)
3 Neohesperidin C28H34O15 610.57 (Shi et al., 2014)
4 Diosmin C28H32O15 608.54 (Shi et al., 2014)
5 Hesperetin-7-O-β-D-glucopyranoside C22H24O11 464.42 (Shi et al., 2014)
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Fig. 5.

Fig. 5

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Structure and corresponding chemical name of flavonoids from T. asiatica.

2.5. Other compounds

Except the above-mentioned major components, T. asiatica also contains phenolic compounds such as chlorogenic acid, benzoic acid, and nelumol A; Lignin compounds: dl-lyoniresinol, and dl-syringaresinol; Quinones: 2,6-dimethoxy-p-benzoquinone; Steroids: β-sitosterol, daucosterol and stigmasterol; Fatty acids: octadecanoic acid, oleic acid, linoleic acid, and hexacosanoic acid. These compounds were summarized in Table 5 and Fig. 6.

Table 5.

Other compounds reported in T. asiatica.

Num. Compound name Molecular formula Molecular weight Reference
1 dl-Lyoniresinol C22H28O8 420.45 (Tsai et al., 1998)
2 dl-Syringaresinol C22H26O8 418.44 (Tsai et al., 1998)
3 2,6-Dimethoxy-p-benzoquinone C8H8O4 168.15 (Tsai et al., 1998)
4 Benzoic acid C7H6O2 122.12 (Jain et al., 2006)
5 Stigmasterol C29H48O 412.70 (Jain et al., 2006)
6 β-Sitosterol C29H50O 414.71 (Shi et al., 2012)
7 Citronellol C10H20O 156.26 (Chen et al., 2013)
8 Chlorogenic acid C16H18O9 354.31 (Liu et al., 2014)
9 Daucosterol C35H60O6 576.90 (Shi et al., 2014)
10 Eugenol C10H12O2 164.20 (Shi et al., 2014)
11 Nelumol A C21H30O4 346.46 (Phatchana and Yenjai, 2014)
12 4-O-geranylconiferyl alde-hyde C19H26O3 302.41 (Phatchana and Yenjai, 2014)
13 1,2-seco-Dihydromethylumbelliferonem methyl ester C11H14O4 210.23 (Phatchana and Yenjai, 2014)
14 Methyl(E)-3,4-bis(4-hydroxyphenyl)-4-oxobut-2-enoate C17H14O5 298.08 (Li et al., 2017)
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Fig. 6.

Fig. 6

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Structure and corresponding chemical name of other compounds from T. asiatica.

3. Pharmacological effects of T. asiatica

At present, researches on the pharmacological activities of T. asiatica show that extracts and chemical components of T. asiatica have some biological activities including anti-inflammatory and analgesic, hemostatic coagulation, antibacterial, anti-oxidant and anti-tumor effects and so forth. To the best of our knowledge, pharmacological effects were mainly focused on the extracts of alcohol, water and methanol and so on. Just few monomeric compounds on their pharmacological effects were reported summarized in Fig. 7. The following will elaborate on these activities in turn.

Fig. 7.

Fig. 7

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Relationship between chemical compounds from T. asiatica and their pharmacological effects.

3.1. Anti-inflammatory analgesic effect

Researches (Lu et al., 2015, Zhang et al., 2019) found that the alcohol, water and n-butanol extracts of T. asiatica root had analgesic effects and the former had better analgesic effects than the two latter. Its mechanism may be related to increasing the content of serum β-endor endorphin (β-EP), decreasing the content of prostaglandin E2 (PGE2) and nitric oxide (NO), up-regulating the expression of β-EP receptor and down-regulating the expression of PGE2 receptor. Yang et al., (Yang et al., 2013) found that feeding arthritis mice with type II bovine collagen injected with ethanol and ethyl acetate extracts of T. asiatica could relieve swelling of paws and joints. Histopathological examination showed that the extracts could protect the knee joint from the erosion and deformation of bone and cartilage, significantly decrease the concentration of tumor necrosis factor-α (TNF- α), interleukin-1-1 β (IL-1 β) and interleukin-6 (IL-6), and increase the concentration of interleukin-10 (IL-10), compared with the control group, which showed similar results according with the consequence obtained by Tian et al., (Tian et al., 2018). The anti-inflammation mechanism of T. asiatica extract maybe involve the balance between Th17 and Treg in the rat model with wind-chill and dampness adjuvant arthritis (Wang et al., 2016, Liu et al., 2018a, Liu et al., 2018b).

Tong et al., (Tong et al., 2014) used RAW264.7 as the test cell to study the anti-inflammatory activity of coumarin omphalocarpin. The consequences suggested that omphalocarpin could reduce the release of NO induced by lipopolysaccharide and the secretion of TNF- α and IL-6 inflammatory factors, strongly inhibit the expression and activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and inhibit the transfer of NF- κ B to the nucleus. Kumagai et al., (Kumagai et al., 2018) also found that aculeatin and toddaculin isolated from T. asiatica could also play important roles in anti-inflammation in LPS-stimulated RAW264 macrophages via different mechanisms, which further demonstrated that extracts from T. asiatica own significant anti-inflammatory effect.

Hao et al., (Hao et al., 2004) found that the total alkaloids from the root bark of T. asiatica can significantly inhibit xylene-induced ear swelling and agar-induced foot swelling in mice, and significantly inhibit the migration of hemameba in abdominal cavity induced by sodium carboxymethyl cellulose and the writhing reaction induced by acetic acid in mice, which showed no damage to the liver when given for a long time. Wang et al., (Wang et al., 2007) found that the water extract from the rhizome of T. asiatica had anti-inflammatory and analgesic effects, and could also reduce the number of writhing induced by glacial acetic acid in mice and prolong the latent period of licking hind feet in mice through hot plate test. It could significantly inhibit the foot swelling induced by carrageenan and the ear swelling induced by xylene in mice. Liu et al., (Liu et al., 2007) investigated the analgesic and anti-inflammatory effects of alcohol extract and water extract of T. asiatica. The results showed that both alcohol extract and water extract had certain analgesic and anti-inflammatory effects, but the analgesic and anti-inflammatory effect of alcohol extract was stronger than that of water extract. Balasubramaniam et al., (Balasubramaniam et al., 2012) found that 50% ethanol extract from T. asiatica had good analgesic and anti-inflammatory effects through carrageenan-induced foot swelling and cotton ball-induced granuloma in rats. Kariuki et al., (Kariuki et al., 2013) using formalin-induced pain test and carrageenan-induced foot swelling test investigated the analgesic and anti-inflammatory effects of methane/methanol (1:1) extract from T. asiatica. The results showed that the methane/methanol (1:1) extract from T. asiatica had good analgesic and anti-inflammatory effects under 100 mg/kg. Hu et al., (Hu et al., 2000) found that the ethanol extract from T. asiatica could reduce the writhing times of mice induced by acetic acid and alleviate the foot swelling induced by agar, both of which were dose-dependent. Besides, investigation performed by Qin et al., (Qin et al., 2020) found that 60% ethanol extract from T. asiatica could inhibit macrophage migration through high throughput screening. Those consequences showed that compounds from T. asiatica had played an important role in anti-inflammatory effect.

3.2. Bacteriostatic effect

Ding et al., (Ding et al., 2007) selected four different polar solvents (distilled water, anhydrous ethanol, ethyl acetate, petroleum ether) and two different extraction methods (cold soaking method and heating reflux method) to extract the root of T. asiatica. It was found that anhydrous ethanol and ethyl acetate extracts could significantly inhibit the growth of Bacillus subtilis, Shigella dysentery and Saccharomyces cerevisiae. At the same time, the alkaloids isolated from the ethanol extract of T. asiatica root by Hu et al., (Hu et al., 2014) can inhibit the growth of bacteria and fungi. Narod et al., (Narod et al., 2004) found that aqueous extracts of T. asiatica stems and leaves could inhibit the proliferation of Pseudomonas aeruginosa and Staphylococcus aureus; the extract of methanol/chloroform (1:1) from stem can inhibit the proliferation of P. aeruginosa, S. aureus and Aspergillus; the extract of n-hexane from leaves can inhibit the growth of P. aeruginosa, S. aureus, Aspergillus and Candida albicans. Continuous extraction was used by Duraipandiyan et al (Duraipandiyan and Ignacimuthu, 2009) to extract the leaves and root of T. asiatica, and found that ethyl acetate extract had the best antibacterial activity. Moreover, flindersine was further isolated from the ethyl acetate layer extract, and demonstrated to inhibit the growth of S. aureus, Bacillus subtilis, S. epidermidis, Enterococcus faecalis, P. aeruginosa, Acinetobacter baumannii, Trichophyton rubrum, T. dermatophytes and C. albicans. Karunau Raj et al., (Karunai Raj et al., 2012) also found a coumarin compound (Ulopterol), from the ethyl acetate extract of the leaves of T. asiatica, which could inhibit the growth of S. epidermidis, Enterobacter aerogenes, Klebsiella pneumoniae, Escherichia coli, A. flavus, C. Cruise, Botrytis cinerea etc.. Indirect immunofluorescence was used to observe the effects of different herbs on the adhesion of C. albicans to oral mucosal epithelial cells in vitro. It was found that T. asiatica had the dual effects of anti- C. albicans and anti- C. albicans adhesion (Hou and Wang, 1990). Microbroth dilution method (Xu et al., 2012) was used to investigate the inhibitory effect of ethanol extract of T. asiatica in vitro, the consequences of which showed that the minimum inhibitory concentration of ethanol extract against C. albicans was 7.5 mg/mL, while the minimum bactericidal concentration was 15.0 mg/mL. With the increase of drug concentration, the expression of virulence factors SNF2 and PDE2 decreased obviously, which inferred that the antibacterial effect is mainly due to inhibiting the formation of pathogenic mycelium and destroying the integrity of bacterial cell wall. It has also been confirmed that the metabolites of T. asiatica had broad-spectrum bacteriostatic activity (Guo et al., 2014). Furthermore, He et al., (He et al., 2018) investigated the antibacterial mechanism of chelerythrine isolated from T. asiatica root and discovered that chelerythrine could play a role in antibacterial activity via destroying the bacterial cell wall and membrance, and inhibiting protein biosynthesis.

3.3. Antioxidant activity

Tian et al., (Tian et al., 2011) using Fenton and 1,1-Diphenyl-2-picrylhydrazine (DPPH) method, found that polysaccharides from the root of T. asiatica could scavenge hydroxyl radical and DPPH free radical, and the scavenging ability of the two free radicals was positively correlated in the concentration range of 0.2–0.4 g/L and 5 × (10−3–10−1) g/L, respectively. The scavenging rate of hydroxyl radical was 73.7% when the concentration of 0.4 g/L was 0.5 g/L, and the scavenging rate of DPPH free radical was 79.5%. With vitamin C (VC) and tea polyphenols as positive controls, the ability of scavenging hydroxyl free radicals of polysaccharides from T. asiatica was studied by flow injection chemiluminescence method. The scavenging ability of 0.1–500 mg/L to hydroxyl radical was related to the concentration, and the IC50 values were 5.69, 2.19 and 0.745 mg/L, respectively. The free radical scavenging rate was as high as 94% when the concentration of polysaccharides was up to 500 mg/L, and the photostability was stronger than that of VC and tea polyphenols (Tian et al., 2011). Chen et al., (Chen and Long, 2013) investigated the antioxidant activity of the extract from T. asiatica stem by Fenton method, DPPH method and Fe2+- cysteine reaction and found that the n-butanol extraction exhibits strong hydroxyl radical scavenging ability; Ethyl acetate extract has the strongest ability of scavenging DPPH; 70% ethanol extract and n-butanol extract showed strong anti-lipid peroxidation activity, which indicated that the extracts of different polar solvents had certain antioxidant activity. Balasubramaniam et al., (Balasubramaniam et al., 2012) found that 50% ethanol extract of T. asiatica stem can scavenge hydroxyl radical, diphenylpicryl hydrazide radical and nitric oxide radical, and also has the ability of chelating divalent iron ion, which indicates that 50% ethanol extract of T. asiatica stem has antioxidant activity in vitro. Stephen Irudayaraj et al., (Stephen Irudayaraj et al., 2012) found that the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) were low in diabetic rats, while the activities of the three enzymes returned to the normal range in intragastric administration of ethyl acetate extract from T. asiatica leaves of diabetic rats, indicating that the ethyl acetate extract has antioxidant activity.

3.4. Cardiovascular protective effect

Ren et al., (Ren et al., 1993) performed a systematic study on the cardiovascular protective effect of T. asiatica and found that Long Jing 1 (L01, extract from T. asiatica) could reduce the blood pressure of anesthetized rats and relax the contractile smooth muscle induced by KCl in vitro, and its mechanism might be related to inhibition of calcium influx. Iso-anise coumarin (isopimpinelline) found in ethanol extract could antagonize the contraction of rat aortic ring induced by KCl (Guo et al., 1998). In addition, Fei Long 1 (F01), aqueous extract from T. asiatica, has protective effects on coronary artery contraction induced by pituitrin, myocardial overexcitation caused by isoproterenol, and acute myocardial ischemia caused by coronary artery occlusion and ligation (He and Ren, 1998, Ren and He, 1998, He and Ren, 1999). F01 can significantly reduce the work and oxygen consumption of acute ischemic myocardium in New Zealand rabbits without ligation of the left anterior descending branch of pleural coronary artery, regulate the balance of oxygen supply and demand, and improve the function of pumping blood, so as to protect the ischemic myocardium (He et al., 2000). Through the study of cardiac function and hemodynamics in normal domestic cats, it is proved that F01 can inhibit the heart and dilate peripheral blood vessels, and reduce cardiac afterload as well as myocardial work and oxygen consumption, which may be another anti-myocardial ischemia mechanism (Ren et al., 2000). Rats were fed with high fat diet and injected isoprenaline hydrochloride (Iso) once a day for consecutive three days at the end of the 4-weeks treatment and the results suggested that T. asiatica extract could significantly improve the Iso-induced electrocardiogram changes in rats, reduce the heart, liver and fat indexes, the level of total cholesterol (TC), triglyceride (TG), low density (LDL), TNF-α, interferon-γ (INF-γ) and IL-6, increase the contents of high density lipoprotein (HDL) and IL-10, and improve the pathological damages of myocardium, which may regulate the balance of anti-inflammatory and proinflammatory cytokines in protecting rat model from cardiovascular diseases (Liu et al., 2018a, Liu et al., 2018b).

3.5. Antimalarial activity

Orwa et al., (Orwa et al., 2013) carried out antimalarial experiments on extracts from different parts of the T. asiatica, using chloroquine-sensitive D6 and chloroquine-resistant Plasmodium falciparum strain W2 incorporated 50% radioisotope to determine the inhibitory concentration of antimalarial parasite IC50 in vitro. Through the experiment of mice infected with P. berghei, quinine hydrochloride used as positive control, it was found that the ethyl acetate extract from T. asiatica fruit showed high activity against chloroquine-resistant P. falciparum strain with IC50 1.87 ug/mL, followed by the water extract of root bark with IC50 2.43 µg/mL. The inhibitory activity of ethyl acetate extract (500 mg/kg) and root bark water extract (250 mg/kg) of fruit against P. berghei in vivo were 81.34% and 56.8%, respectively. The root bark extracts of T. asiatica and the isopimpinellin, geraniol and D-limonene separated from T. asiatica (Liu et al., 2013) were found to have antimalarial and insecticidal effect.

3.6. Inhibitory effect on the proliferation of human cancer cells

Iwasaki et al., (Iwasaki et al., 2006, Iwasaki et al., 2010) found that two alkaloids, nitidine and dihydronitidine, which were isolated from T. asiatica could inhibit the proliferation of mouse and human lung adenocarcinoma cells in vitro. Results have shown that nitidine can effectively inhibit the growth of mouse and human lung adenomas in subcutaneous xenograft models without any significant side effects; dihydronitidine is highly specific cytotoxic to human lung adenocarcinoma (A549) cells. It can up-regulate apoptosis-related genes and regulate cell cycle gene expression, that is, inhibiting cell proliferation. Furthermore, researchers isolated 18 compounds from T. asiatica, named todayanin, toddayanis, artanin, coumurrayin, toddaculin, toddanol, toddalolactone, isopimpinellin, phellopterin, 5-methoxy-8-geranyloxypsoralen, 8-methoxydihydrochelerythrine, methoxynorchelerythrine, skimmiamine, norchelerythrine, chelerythrine, oplopanone, nelumol and p-isopentenoxybenzenepropanoic acid. Among them, todayanis is toxic to human epidermal carcinoma KB cells, breast cancer cell line MCF-7 cells, and human small cell lung cancer (NCI-H187) cell lines, with IC50 of 32.2, 5.8, and 17.6 μg/mL, respectively. Artanin is toxic to all three cancer cells, with IC50 ranging from 7.4 to 31.0 μg/mL. Moreover, 8-methoxydioxychelerythrine is the most toxic to NCI-H187 cells with IC50 of 0.8 μg/mL. In addition, toddaculin and skimmiamine can inhibit MCF-7 cell proliferation with IC50 of 23.4 and 8.7 μg/mL, separately, which have been suggested that the two compounds are the most likely anticancer lead compounds (Murakami et al., 2000, Hirunwong et al., 2016). Vázquez et al., (Vazquez et al., 2012) isolated six isoprene-substituted coumarins from T. asiatica, among which toddaculin had the strongest cytotoxicity and anti-proliferative activity against U-937 cells. Further research found that toddaculin had dual effects, which could induce apoptosis of U-937 cells at a drug concentration of 250 μmol/L, and promote cell differentiation at a concentration of 50 μmol/L.

3.7. Inhibiting the pathogenesis of Alzheimer’s disease (AD)

Alzheimer’s disease (AD) is the most common cause of dementia and a chronic and progressive neurodegenerative disorder following with memory impairment, gradual loss of attention, emotions, mental capacity and the learning ability and what not. Takomthong et al., (Takomthong et al., 2020) investigated that seven out of nine coumarins isolated from T. asiatica were identified as the multifunctional agents which could inhibit the pathogenesis of AD, especially the phellopterin that showed significant protective effect of neuronal cell damage induced by H2O2 and Aβ1-42 toxicity. With the intensification of aging in the whole world, the number of AD patients is increasing, which aggravates the burden of families and social medical treatment, specially there are no specific medicine used in clinic. Therefore, traditional Chinese herb is another effective breach that could provide a new treatment for AD patients, which has also attracted extensive attention of scholars engaged in medical researches.

3.8. Other pharmacological effects

T. asiatica has also played an important role in other pharmacological effects other than the above six pharmacological effects. Using mouse tail amputation and capillary glass tube method, the bleeding time, bleeding volume and clotting time were used to investigate the hemostatic activity of different polar parts of blood root bark (Zhao et al., 2016). The average bleeding time, bleeding volume and clotting time of ethyl acetate in cold extract were (59.67 ± 12.31) s, (4.42 ± 1.67) mg and (79.67 ± 5.57) s, respectively. It was also found that the hemostatic activity of ethyl acetate in cold immersion was better than the other polar extracts. Ethanol extract can significantly shorten the mice’s bleeding and clotting time, and the hemostatic time is similar to that of Panax notoginseng powder which has better hemostatic effect at present. Further studies found that the hemostatic effect of T. asiatica may be related to the increase of fibrinogen content (p < 0.05), the promotion of endogenous coagulation pathway and the change of platelet morphology (Liu et al., 2016). To observe the bleeding and coagulation activity of different polar parts of T. asiatica in mice, methanol part has the best coagulation effect, which can improve the coagulation function of the body and enhance the hemostatic effect (Shi et al., 2010). Research carried out by Tsai et al., (Tsai et al., 1998) showed that seven compounds had anti-platelet aggregation effect in vitro after biological activity guided the separation of chemical constituents from T. asiatica. Watanabe et al., (Watanabe et al., 2014) found that extracted from T. asiatica could increase the differentiation and lipolysis of adipocytes at the same time, and be used in the treatment of dyslipidemia and diabetes. They then found that the toddaculin in T. asiatica acted on osteoclasts RAW264 and osteoblasts MC3T3-E1 in vitro via inhibition of osteoclast differentiation by activating NF- κ B, ERK1/2 and p38MAPK signal transduction pathways (Watanabe et al., 2015). Otherwise, T. asiatica. also has the effects of antiviral (Tan et al., 1991, Mao et al., 2002, Li et al., 2005), antispasmodic (Lakshmi et al., 2002), diuretic (Liu et al., 2007), anti-HIV (Rashid et al., 2014) and larvicidal (Borah et al., 2010).

4. Conclusion and future perspectives

T. asiatica is a traditional Chinese herbal medicine in China, which is a characteristic ethnic medicine in southwest China, Wuling Mountainous areas, such as Guizhou, Yunnan, Guangxi and Enshi, Hubei province and others. Its unique geographical advantages and abundant medicinal resources have laid a solid foundation for its sustainable development and utilization. However, there has been a lack of theoretical guidance for the study of modern medicine. It is of great significance for the development of new drugs with reliable efficacy to carry out the systematic pharmaceutical research on T. asiatica. So far, large-scale clinical application of T. asiatica is still relatively rare, mainly in anti-inflammation and analgesia, hemostasis and coagulation. Moreover, pharmacological research is still in the basic research stage. With the rapid development of modern medical science and technology, the active material basis, pharmacological effects and mechanisms of T. asiatica would be explored more deeply. A small number of unknown active natural compounds, novel pharmacology and pharmacological mechanisms will also be found. Otherwise, there are few reports on the safety of T. asiatica, which needs to be further strengthened and improved in the future, so as to provide a scientific basis for the development and rational application of the medicinal resources.

Based on the bioactivities and pharmacokinetics, coumarins and alkaloids are the main compounds in T. asiatica as there are 138 compositions isolated from the plant. On one hand, these compounds provide framework for biosynthesis; on the other hand, they play an important role in pharmacological activities in vitro, which lay a foundation for clinic application, although there is still a long way to go. As shown in Fig. 7, pharmacological mechanisms of monoclonal compounds are still defective and more work could be done in future. In addition, the resource of T. asiatica is abundant, but the officinal part of this plant is root and stem, which would lead to decrease the number of the wild T. asiatica. Therefore, more works need to be done to fill gaps in protection of the medicine resource.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Acknowledgements

We are thankful to the Hubei Natural Science Foundation (2019CFB630) and National Natural Science Foundation of China (NSFC 81860757).

We thank academic staff members in Lin Yuan’s group at Hubei Provincial Key Laboratory of Occurrence and Intervention of Rhumatic Disease, Hubei Minzu University. Thanks for Qiulong Zhang who is studying for his PhD at Sun Yat-sen University.

Footnotes

Peer review under responsibility of King Saud University.

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