Genus Tetrastigma: A review of its folk uses, phytochemistry and pharmacology.

The genus Tetrastigma belongs to the Vitaceae family and contains over 100 species. This paper reviewed folk uses, chemical constituents, pharmacological activities, and clinical applications of the medicinal plants in the genus Tetrastigma. In addition, the paper also discussed the current problems for the further studies. Up to now, more than 240 compounds were reported from the genus Tetrastigma, covering 74 flavonoids, 14 terpenoids, 19 steroids, 21 phenylpropanoids, 14 alkaloids and others constituents. Among them, flavonoids are the major and the characteristic chemical constituents in this genus. Modern pharmacological studies and clinical practice showed that the extracts and chemical constituents of Tetrastigma species possessed wide pharmacological activities including antitumor, antioxidative, hepatoprotective, antiviral, anti-inflammatory, and analgesic activities. The information summarized in this paper provides valuable clues for new drug discovery and an incentive to expand the research of genus Tetrastigma.

Introduction

Tetrastigma (Vitaceae) contains over 100 species widely spreading in Asia and Oceania. Among them, 45 species are distributed in China, mainly in Guangdong, Yunnan and Zhejiang Provinces and Guangxi autonomous region, in China (Zhang et al., 2019). Some Tetrastigma species have a long history as ethnomedicines for the treatment of many diseases, such as menstrual disorders, rheumatic pain, bruises, gastralgia and other diseases in southwest China. These medicinal plants with remarkable curative effects were deeply loved by local people, especially Tetrastigma hemsleyanum Diels et Gilg, which was awarded as one of the new “eight famous TCMs” in Zhejiang Province (Ji et al., 2021). The medicinal plants in this genus attracted increasing attention due to their structural diversity and remarkable pharmacological activities. Besides, many studies showed that the crude extracts and the monomeric compounds from Tetrastigma species exhibited diverse biological activities, such as antitumor, antioxidative, hepatoprotective, antiviral, anti-inflammatory, and analgesic activities (Fig. 1). The chemical and pharmacological research on this genus is limited, except the species T. hemsleyanum. In order to provide theoretical reference for further research and to comprehensively understand the medicinal applications on this genus, this paper systematically reviewed folk uses, chemical constituents, pharmacological activities and clinical applications of Tetrastigma species based on available databases including SciFinder, Pubmed, Google Scholar, CNKI and others over the past 20 years.

Fig. 1

Chemical components, pharmacological activities of medicinal parts from Tetrastigma.

Folk uses

In China, many Tetrastigma species are traditionally and ethnically used as folk medicine to treat various diseases for a long time. Some species have a long medicinal history, such as T. hemsleyanum, known as “Sanyeqing” or “Jingxiandiaohulu” (Cheng & Fu, 2016), T. hypoglaucum Planch, known as “Wuzhuajinlong” (Liu, 2000), and T. obtectum (Wall.) Planch, known as “Yanwujia” (Shi, 2012) in Chinese. T. hemsleyanum was firstly recorded in Ben Cao Gang Mu (Compendium of Materia Medica) (Ming Dynasty, CE 1590) and also recorded in multiple ancient books of traditional Chinese medicine (TCM), including Zhi Wu Ming Shi Tu Kao (Chih-wu ming-shih t'u kao) (Qing Dynasty, Wu, 2014), Jiangxi Herbal Medicine and Common Folk Herbal Medicine in Zhejiang (Ji et al., 2021). These ancient works described that its root tuber or whole plant could be used as medicine and it was slightly bitter in flavor and neutral in nature. It had the effect of strengthening liver, and its functions were mainly for clearing heat and detoxification, dispelling wind and phlegm, promoting blood circulation and relieving pain. T. hypoglaucum was recorded in The Dictionary of Chinese Herbal Medicine. Its root or whole plant could be used as medicine and it was bitter, neutral in nature. Tetrastigma planicaule (Hook.) Gagnep was recorded in Handbook of Chinese Herbal Medicine in Guangzhou Army. It was one of 108 classic medicines in Yao ethnomedicine (Shao, 2011). The whole plant was used as medicine and it was pungent, astringent in flavor and warm in nature. Its main function was to dispel wind and dehumidify, relax tendons and activate collaterals. T. obtectum was recorded in Si Chuan Zhong Yao Zhi (a dictionary of Chinese medicine). Its root or whole plant could be used as medicine and it was warm in nature, pungent in taste, and non-toxic. The functions were mainly for dispelling wind, dehumidification and detoxification. Out of the 100 species of Tetrastigma identified, only five species were reported in folk medicines as medicinal plants. Moreover, T. hemsleyanum was the one that was most widely used and studied. The folk names, geographical distribution, medicinal parts and folk uses of the genus Tetrastigma are listed in Table 1.

Table 1

Sources, distribution and folk uses of Tetrastigma medicinal plants.

Species	Folk names	Distribution	Medicinal parts	Folk uses
Tetrastigma hemsleyanum Diels et Gilg	Sanyeqing (Cai et al., 2014) (Chinese)	The areas south of Yangtze River, mainly distributed in Zhejiang, Jiangxi, Jiangsu, Fujian, Hunan, Hubei, Guangdong, Guangxi, Yunnan of China and other areas (Qian et al., 2015).	Root tuber or whole plant	Children with febrile convulsion, viral meningitis, asthma, pneumonia, nephritis, hepatitis, rheumatism arthralgia, menstrual disorders and other diseases; external use for poisonous snake bite, amygdalitis, ulcerative carbuncle, phlegmon, traumatic injury and so on (Wang et al., 2015); Yao ethnomedicine: urinary tract stones, gallstones, renal calculi, gastralgia and other diseases.
Tetrastigrna hypoglaucum Planch	Wuzhuajinlong (Liu, 2000) (Chinese)	Sichuan, Yunnan and other provinces (Liu, 2000) of China.	Root or whole plant	Fracture and tendon injury, traumatic injury, rheumatic swelling and pain and other diseases (Liu, 2000).
Tetrastigma obtectum (Wall.) Planch	Zouyoucao (Song and Wan, 2003). (Chinese)	Yunnan, Gansu, Hunan, Fujian, Taiwan, Guangxi, Sichuan, Guizhou Provinces of China (Shi, 2012).		Tujia ethnomedicine: rheumatic pain, traumatic injury, osteomyelitis, menstrual disorders, lumbar muscle strain, snake bite and other diseases (Shi, 2012).
Tetrastigma planicaule (Hook.) Gagnep	Biandanteng (Chen, 2017). (Chinese)	Fujian, Guangdong, Guangxi, Guizhou, Yunnan, southeastern Tibet of China (Shao et al., 2010).	Whole plant	Zhuang ethnomedicine, Yao ethnomedicine and other nationalities; common use for rheumatic bone pain, lumbar muscle strain, traumatic injury, hemiplegia (Shao, 2011).
Tetrastigma erubescens Planch	–	Viet nam, Kampuchea and Guangxi, Hainan, Yunnan, Guangdong and other areas in China.	–	Inflammation, fever, gastralgia, hypertension and other diseases (Dao et al. 2014).

Chemical constituents

So far, a total of 248 compounds were isolated from five Tetrastigma species (T. hemsleyanum, T. hypoglaucum, T.obtectum, T. planicaule, and T. erubescens), including flavonoids and their glycosides (1–74), saccharides (75–91), terpenoids (92–105), steroids (106–124), phenylpropanoids (125–145), alkaloids (146–159) and other compounds. Flavonoids and their glycosides are the major constituents in the genus Tetrastigma and also exhibit significant antitumor activity, which are the research hotspots now. The information about chemical names, sources, and references of all compounds is summarized in Table 2.

Table 2

Names and sources of compounds isolated from genus Tetrastigma.

No.	Chemical names	Source plants	Distribution in plant	References
Flavonoids
1	Apigenin	T. hemsleyanum	Whole plant	Lin et al. (2015)
2	Apigenin-6-C-α-L-rhmnnopyranosyl-(1-4)-α-L-arabinopymnoside	T. hemsleyanum	Aerial part	Liu et al. (2002)
3	Apigenin-8-C-α-L-rhamnopyranosyl-(1-4)-α-L-arabinopymnoside	T. hemsleyanum	Aerial part	Liu et al. (2002)
4	Apigenin-6,8-di-C-β-D-glucopyranoside	T. hemsleyanum	Aerial part	Liu (2000)
5	Apigenin-8-C-α-L-rhamnopyranosyl-(1-2)-β-D-glucopyranoside	T. hemsleyanum	Whole plants	Lin et al. (2015)
6	Apigenin-8-C-[6-deoxy-2-O-(α-L-rhamnopyranosyl)-xylo-hexopyranos-3-uloside]	T. obtectum	Stem and leaf	Shi (2012)
7	Apigenin-8-C-[α-L-rhamnopyranosyl(1 → 2)]-rhamnopyranoside]	T. obtectum	Stem and leaf	Shi (2012)
8	Apigenin-8-C-[α-L-rhamnopyranosyl(1 → 2)-xyloside]	T. obtectum	Stem and leaf	Shi (2012)
9	Apigenin-7-O-β-D-glucopyranoside	T. obtectum	Stem and leaf	Shi (2012)
10	Apigenin-6-C-α-L-arabinopyranoside	T. obtectum	Stem and leaf	Shi (2012)
11	Apigenin-6-C-α-L-arabinose-8-C-β-D-glucose	T. hemsleyanum	Aerial part	Sun (2018a)
12	Apigenin-7-rhamnoside	T. hemsleyanum	Root tuber and leaf	Sun (2018a)
13	Apigenin-8-C-xylosyl-6-C-glucoside	T. hemsleyanum	Aerial part	Sun (2018a)
14	Biochanin A	T. hemsleyanum	Root tuber	Sun (2018a)
15	Daidzein	T. hemsleyanum	Root tuber	Sun (2018a)
16	Isoorientin	T. hemsleyanum	Aerial part	Sun (2018a)
17	Isoorientin-2″-O-rhamnoside	T. hemsleyanum	Aerial part	Sun (2018a)
18	Isoorientin-4″-O-xyloside	T. hemsleyanum	Aerial part	Sun (2018a)
19	Isovitexin	T. hemsleyanum	Aerial part	Sun (2018a)
20	Isovitexin-2″-O-rhamnoside	T. hemsleyanum	Aerial part	Sun (2018a)
21	Isovitexin-2″-O-xyloside	T. hemsleyanum	Aerial part	Sun (2018a)
22	Isoamylbenzoicacid-4-O-xylosyl glucoside	T. hemsleyanum	Root tuber	Wang et al. (2018)
23	Luteolin	T. hemsleyanum	Aerial part	Sun (2018a)
24	Luteolin-6,8-di-C-hexoside	T. hemsleyanum	Aerial part	Sun (2018a)
25	Luteolin-7-O-β-D-glucopyranoside	T. obtectum	Stem and leaf	Shi (2012)
26	Orientin	T. hemsleyanum	Aerial part	Sun (2018a)
27	Orientin-2″-O-rhamnoside	T. hemsleyanum	Aerial part	Sun (2018a)
28	Vitexin	T. hemsleyanum	Aerial part	Sun et al. (2018)
29	Vitexin-2″-O-rhamnoside	T. hemsleyanumT. obtectum	Aerial part	Sun (2018a)
30	Vitexin-2″-O-arabinoside	T. hemsleyanum	Aerial part	Sun (2018a)
31	Vitexin-2″-O-glucoside	T. hemsleyanum	Aerial part	Sun (2018a)
32	Vitexin-α-L-rhamnoside	T. obtectum	Stem and leaf	Shi (2012)
33	Nobiletin	T. erubescens	Stem	Dao et al. (2014)
34	Tangeretin	T. erubescens	Stem	Dao et al. (2014)
35	6-Demethoxytangeretin	T. erubescens	Stem	Dao et al. (2014)
36	6-Demethoxynobiletin	T. erubescens	Stem	Dao et al. (2014)
37	cis-Apigenin-6-vinyl-7″-rhamnoside	T. obtectum	Stem and leaf	Shi (2012)
38	cis-Apigenin-8-vinyl-7″-rhamnoside	T. obtectum	Stem and leaf	Shi (2012)
39	Astragalin	T. hemsleyanum	Leaf	Sun (2018a)
40	Dingdingting-3-O-glucoside	T. hemsleyanum	Tuber	Zeng et al. (2017)
41	Isoquercitrin	T. hemsleyanum	Root tuber	Guo (2013)
42	Isorhamnetin	T. hemsleyanum	Root tuber	Zeng et al. (2017)
43	Isorhamnetin-3-rutinoside	T. hemsleyanum	Root tuber	Sun (2018a)
44	Isorhamnetin-7-O-rhamnose-3-O-glucoside	T. hemsleyanum	Root tuber	Zeng et al. (2017)
45	Kaempferol	T. hemsleyanum	Root tuber	Chen (2014)
46	Kaempferol-3-O-neohesperiodoside	T. hemsleyanum	Root tuber	Guo (2013)
47	Kaempferol-7-O-β-L-rhamnopyranosyl-3-O-β-D-glucopyranoside	T. hemsleyanum	Aerial part	Liu (2000)
48	Kaempferol-7-O-α-L-rhamnopyranoside	T. hemsleyanum	Leaf	Sun (2018a)
49	Kaempferide	T. hemsleyanum	Root tuber; aerial part	Sun (2018a)
50	Kaempferol-3-O-rutoside	T. hemsleyanum	Root tuber	Zeng et al. (2017)
51	Kaempferol-3-O-rhamnoside	T. hemsleyanum	Aerial part; root tuber	Sun et al. (2018)
52	Kaempferol-3-robinoside-7-rhamnoside	T. hemsleyanum	Root tuber	Sun (2018a)
53	Kaempferol-3-sambubioside	T. hemsleyanum	Root tuber; aerial part	Sun, 2018a, Sun et al., 2018
54	Kaempferitrin	T. hemsleyanum	Whole plant	Lin et al. (2015)
55	Quercetin	T. hemsleyanum	Root tuber	Chen (2014)
56	Quercitrin	T. hemsleyanum	Aerial part; root tuber	Sun et al., 2018, Zeng et al., 2017
57	Quercetin-3-O-galactoside	T. hemsleyanum	Root tuber	Sun (2018a)
58	Quercetin-3-O-xylosylglucoside	T. hemsleyanum	Root tuber	Zeng et al. (2017)
59	Quercetin-3-O-xylosylglucoside-7-O-rhamnoside	T. hemsleyanum	Root tuber	Zeng et al. (2017)
60	Quercetin-3-O-rutinoside	T. hemsleyanum	Aerial part	Sun (2018a)
61	Rhamnocitrin	T. hemsleyanum	Root	Sun (2018a)
62	Rutin	T. hemsleyanum	Leaf	Sun (2018a)
63	Epicatechin-3-O-gallate	T. erubescens	Stem	Dao et al. (2014)
64	Catechin glucopyranoside isomer	T. hemsleyanum	Root	Sun (2018a)
65	(+)-Catechin	T. erubescens; T. hemsleyanum; T. hypogtaucum	Stem; aerial part	Dao et al., 2014, Zeng, 2013, Liu, 2000
66	Epigallocatechin	T. hemsleyanum	Tuber	Sun (2018a)
67	7-Galloylcatechin	T. hypoglaucum	Aerial part	Liu (2000)
68	Phloridzin	T. erubescens; T. hemsleyanum	Stem; root tuber	Dao et al., 2014, Guo, 2013
69	Eriodictyol	T. hemsleyanum	Aerial part	Sun (2018a)
70	Aromadendrin	T. hemsleyanum	Root tuber	Guo (2013)
71	Procyanidin dimmer	T. hemsleyanum	Root tuber	Sun (2018a)
72	Procyanidin trimer	T. hemsleyanum	Aerial part	Sun et al., 2018, Zeng et al., 2017
73	Procyanidins B1	T. hemsleyanum	Aerial part; root tuber	Sun et al., 2018, Xu et al., 2014
74	Procyanidins B2	T. hemsleyanum	Aerial part; root tuber	Sun et al., 2018, Xu et al., 2014
Saccharides
75	Arabinose	T. hemsleyanum	Root and leaf	Rao et al. (2016)
76	Fucose	T. hemsleyanum	Root and leaf	Rao et al. (2016)
77	Galactose	T. hemsleyanum	Root and Leaf	Rao et al. (2016)
78	Glucose	T. hemsleyanumT. planicaule	Rattan	Xu et al., 2014, Chen, 2017
79	Mannose	T. hemsleyanum	Root and leaf	Rao et al. (2016)
80	Rhamonse	T. hemsleyanum	Root and leaf	Rao et al. (2016)
81	D-Fructose	T. hemsleyanum	Leaf	Guo (2013)
82	Mannitol	T. hemsleyanum; T. planicaule	Aerial part, rattan	Liu, 2000, Chen, 2017
83	RTP-1	T. hemsleyanum	Root	Guo (2018)
84	RTP-2	T. hemsleyanum	Root	Guo (2018)
85	RTP-3-1	T. hemsleyanum	Root	Guo (2018)
86	TTP	T. hemsleyanum	Tuber	Chu et al. (2020)
87	THDP-3	T. hemsleyanum	Leaf	Ru et al. (2019b)
88	TDGP-3	T. hemsleyanum	Leaf	Ru et al. (2019a)
89	THP	T. hemsleyanum	Root
90	THP	T. hemsleyanum	Leaf	Ru et al. (2018)
91	SYQP	T. hemsleyanum	Aerial part	Zhu et al. (2020)
Terpenoids
92 Taraxerone		T. hemsleyanum; T. planicaule	Aerial part; rattan	Liu, 2000, Chen, 2017
93	Taraxerol	T. hemsleyanum	Aerial part	Liu (2000)
94	Oleanolic acid	T. Hemsleyanum；T. planicaule	Root tuber ；Rattan	Ding et al., 2015, Li, 2020
95	3-β-(Stearyolxy) olean-12-ene	T. planicaule	Stem	Chen (2017)
96	Erythrodiol	T. planicaule	Rattan	Shao et al. (2010)
97	α-Amyrin	T. hemsleyanum	Aerial part	Liu (2000)
98	Ganoderic acid H	T. hemsleyanum	Root tuber	Sun (2018a)
99	Ioliolide	T. erubescens	Stem	Dao et al. (2014)
100	(+)-Dehydrovomifoliol	T. erubescens	Stem	Dao et al. (2014)
101	Pteroside Z	T. hemsleyanum	Aerial part	Sun (2018a)
102	Camphor	T. hemsleyanum	Tuber	Huo et al. (2008)
103	(4R,5R)-4-Hydroxy-2-methyl-5-propan-2-ylcyclohex-2-en-1-one	T. hemsleyanum	Tuber	Xu et al. (2017)
104	(4S,5R)-4-Hydroxy-2-methyl-5-propan-2-ylcyclohex-2-en-1-one	T. hemsleyanum	Tuber	Xu et al. (2017)
105	(4R,5R)-4-Hydroxy-5-isopropyl-2-methylcyclohex-2-enone	T. hemsleyanum	Tuber	Xu et al. (2017)
Steroids
106	β-Sitosterol	T. hemsleyanum; T. planicaule; T. hypoglaucum	Root tuber and aerial part; rattan; aerial part	Guo, 2013, Liu, 2000, Chen, 2017

Flavonoids

Flavonoids are major and characteristic chemical components of the genus Tetrastigma. Thus far, more than 70 flavonoids were isolated in this genus and most of them are flavonoid carbon glycoside compounds. According to the conformation, they could be divided into four types: flavones (1–38), flavonols (39–62), flavanones (69), and flavan-3-ols (65–66 and 70–74). The aglycones of these flavonoids are mainly kaempferol (45), apigenin (1), orientin (26), vitexin (28), isorhamnetin (42) and quercetin (55). Most sugar moieties of flavonoid glycosides are glucose, rhamnose and xylose, which are typically connected to C-3, C-6, C-7 or C-8. What's more, there are oxygen-containing substituents at the C-7, such as OH, OMe or glycosyl in most of the flavonoid carbon glycosides. The names and sources of these compounds are shown in Table 2, and the structures are shown in Fig. 2.

Fig. 2

Chemical structures of flavonoids isolated from genus Tetrastigma.

Flavones

Up to now, 38 flavones and their glycosides (1–38) were reported from the genus Tetrastigma. The features of these compounds are that there are usually hydroxyl groups at the C-5 and C-7, and their aglycones mainly are apigenin (1), orientin (26), vitexin (28), and isorhamnetin (42). Furthermore, this series of compounds are mainly flavone carbon glycosides with glycosyl moieties connected at C-6 or C-8. Apigenin-6-C-α-L-rhmnnopyranosyl-(1-4)-α-L-arabinopymnoside (2) and apigenin-8-C-α-L-rhmnnopyranosyl-(1-4)-α-L-arabinopymnoside (3) were new natural products from T. hemsleyanum. Five new flavones (6–8 and 37–38) were isolated from stems and leaves of T. obtectum.

Flavonols

The phytochemical studies led to isolation and identification of 24 flavonols and their glycosides (39–62) from this genus. These series of compounds were mainly found in T. hemsleyanum, and they are mono-O-glycosides and di-O-glycosides, and the glycosyls are connected to C-3 or C-7. And their aglycones mainly were kaempferol (45) and quercetin (55). There are oxygen-containing substituents at the C-3' and C-4' of these flavonoid oxygen glycosides, such as OH and OMe.

Flavanones, dihydrochalcone and flavan-3-ols

Apart from flavonoids and flavonols, there are ten compounds of other types, including one dihydrochalcone (68), two flavanone (63 and 69), and eight flavan-3-ols (65–67 and 70–74). Compounds 71–74 isolated from T. hemsleyanum are flavan-3-ol derivatives tannins.

Polysaccharides and monosaccharides

Polysaccharides and monosaccharides are also important constituents in Tetrastigma species. Previous studies indicated that polysaccharides had hypoglycemic and immunoregulatory activity. So far, eight monosaccharides (75–82) and nine polysaccharides (83–91) were reported in T. hemsleyanum, only two monosaccharides (78 and 82) were reported in T. planicaule, and no saccharide was reported in other medicinal plants. The polysaccharide RTP-1 (83) and RTP-2 (84) were isolated successively from roots of T. hemsleyanum. Moreover, further study showed that the high purity polysaccharide RTP-3-1 (Guo, 2018) (85) with a molecular weight of 1244.2 kDa mainly consists of four kinds of monosaccharide: arabinose, galacturonic acid, galactose, and fructose and they account for 8.39%, 7.18%, 20.70%, and 63.70%, respectively. TTP-1 (86) (Chu et al., 2019) was a purified polysaccharide extracted from tuber of T. hemsleyanum with the average molecular weight of 478.33 kDa that was composed of 38.91% mannose, 14.87% glucuronic acid, 1.31% galacturonic acid, 42.81% galactose, and 2.1% arabinose. A novel polysaccharide named TDGP-3 (Ru et al., 2019a) (88) was extracted from leaves of T. hemsleyanum with a molecular weight of 3.31 × 105 Da, which was composed of 1,4-Glcp, 1,4-Glap and 1,3,6-Manp linkage in the main chain. Meanwhile, a novel polysaccharide THDP-3 (Ru et al., 2019b) (87) was found in cane leaves of T. hemsleyanum with a molecular weight of 77.98 kDa that consists of rhamnose, arabinose, mannose, glucose, galactose and their ratio is 1.0:1.3:2.5:2.3:3.1 with main backbones of → 4)-α-D-GalAp-(1→,→4)-β-D-Galp-(1 → and → 4)-α-D-Glcp-(1→, and main branches of β-D-Manp-(1→, →3,6-β-D-Manp-1 → and α-D-Araf-(1→. A water-soluble polysaccharide named THP (Ru et al., 2018) (89) with a molecular weight of 93307 Da is composed of rhamnose, arabinose, mannose, glucose, galactose in the molar ratio of 0.07:0.14:0.38:0.21:0.31. SYQP (Zhu et al., 2020) (91) was a purified polysaccharide extracted from the aerial part of T. hemsleyanum with an average molecular weight of 66.2 kDa that consists of galacturonic acid, glucose, mannose, arabinose, galactose, and rhamnose with a molar ratio of 11.3:7.1:2.5:1.0:0.9:0.5. The names and sources of these compounds are shown in Table 2, and the structures are shown in Fig. 3.

Fig. 3

Chemical structures of monosaccharides isolated from genus Tetrastigma.

Terpenoids

So far, there are 14 terpenoids isolated from Tetrastigma species, including seven triterpenoids (92–98) and seven others (99–105). Triterpenoids isolated from Tetrastigma species can be divided into three types for their different skeletons: oleanane-type (92–96), lanostane-type (98) and ursane-type (97). Among them, 92–94, 97 and 98 were isolated from aerial parts of T. hemsleyanum. Compounds 92, 95 and 96 were obtained from the stem of T. planicaule. Other terpenoids were monoterpenes and sesquiterpenes. One sesquiterpene (101) and four monoterpenes (102–105) were isolated from T. hemsleyanum. In particular, there were two norisoprenoids (99–100) that were found in the stem of T. erubescens. The names and sources of these compounds are shown in Table 2, and the structures are shown in Fig. 4.

Fig. 4

Chemical structures of terpenoids isolated from genus Tetrastigma.

Steroids

Steroids are another type of bioactive constituent in Tetrastigma species. Steroids are secondary metabolites formed by cyclopentano-perhydrophenthrene with four ring systems (6/6/6/5) in their basic skeleton. To date, 19 steroids were identified in the genus Tetrastigma and they were sterols and mainly found in T. planicaule and T. hemsleyanum. The names and sources of these compounds are shown in Table 2, and the structures are shown in Fig. 5.

Fig. 5

Chemical structures of steroids isolated from genus Tetrastigma.

Phenylpropanoids

At present, phytochemical studies led to the isolation and identification of 21 phenylpropanoids from the Tetrastigma species. According to the structure characteristics, they can be divided into two types: coumarins (125–144), and lignans (145). Two coumarins (125–126) and one lignan (145) were obtained from the stem of T. erubescens. Two coumarins (126–127) were isolated from the stems of T. planicaule. In fact, almost all phenylpropanoids were found in T. hemsleyanum, and 130–139 were isomers and derivatives of chlorogenic acid (137). The names and sources of these compounds are shown in Table 2, and the structures are shown in Fig. 6.

Fig. 6

Chemical structures of phenylpropanoids isolated from genus Tetrastigma.

Alkaloids

Alkaloids are also important active ingredients in this genus and they are mainly indole alkaloids. At present, 14 alkaloids were reported from this genus, including nine indole alkaloids (146–154) and five other alkaloids (155–159). Indole alkaloids: tetrastigmindole A (153) and tetrastigmindole B (154) (Shi, 2012) were new secondary metabolites isolated from T. obtectum. Seven indole alkaloids (146–151 and 153), an amide (156), a maleimide (155) and a carboline (157) were isolated from the aerial parts of T. hemsleyanum, and they were alkaloids isolated from the genus Tetrastigma firstly. Furthermore, structure–activity relationship (SAR) studies showed that the lactam moiety may be an important structural element for their anti-inflammatory activity. Only one alkaloid, coelarthenol (158) (Chen, 2017), was isolated from T. planicaule. The names and sources of these compounds are shown in Table 2, and the structures are shown in Fig. 7.

Fig. 7

Chemical structures of alkaloids isolated from genus Tetrastigma.

Other compounds

Aliphatics, phenolic acids and other compounds also presented abundantly in this genus, 160–194 are long chain fatty acids and 196–223 are phenolic acids. 196–199 were derivatives of resveratrol (196), 224–226 were anthraquinones, while 227–235 were other compounds. The names and sources of these compounds are shown in Table 2, and the structures of representative compounds are shown in Fig. 8.

Fig. 8

Chemical structures of other compounds isolated from genus Tetrastigma.

Pharmacological activities

The extracts and compounds of Tetrastigma species showed various biological activities including antitumor, antipyretic and analgesic, antiviral, hepatoprotective and antidiabetic properties. These bioactivities are summarized below.

Antitumor activity

Antitumor activity of plant extracts

Antitumor activity of the ethyl acetate extract of T. hemsleyanum was investigated by establishing colorectal cancer with HT29 cells model in mice. The extract could inhibit the growth of subcutaneous transplanted tumor of colon cancer HT29. The possible mechanism was related to up-regulation of the expression of Caspase-3 protein and induction of the apoptosis of subcutaneous transplanted tumor of colon cancer HT29 cells (Lin et al., 2016). The water extract of T. hemsleyanum was explored for their antitumor activity by CCK8 (Cell Counting Kit-8) assay and flow cytometry (FCM) in vitro. The result showed the water extract of T. hemsleyanum not only promoted the proliferation of NK (Natural Killer cell), but also enhanced the cytotoxic activity of NK cells against gastric cancer cell lines BGC-823. The possible mechanism may be that the water extract of T. hemsleyanum could increase expressions of perforin (PFP), Granzyme (GraB) and CD107a (Yuan et al., 2016). The water extract and diethyl ether extract of T. hemsleyanum displayed definite antitumor activity in vitro, and their IC50 were 99.7 µg/mL and 127.8 µg/mL, respectively. (Chen, 2014). The water, ethanol and ethyl acetate extracts of T. hemsleyanum displayed inhibitory effects on the growth of breast cancer cells MCF-7 in vitro (p < 0.05). All extracts could promote the apoptosis of MCF-7 cells and their apoptotic rates were (15.60 ± 4.03)%, (17.32 ± 3.87)% and (29.45 ± 6.19)%, respectively (Qiu et al., 2018). Polysaccharides from aerial part of T. hemsleyanum showed significant antitumor activity in inhibiting tumor growth and distal lung metastasis explored by establishing breast cancer with 4T1 cells model in mice. The result showed the tumor inhibition rates of low, middle and high dose polysaccharides were 25.09%, 28.79% and 34.21%, respectively (Guo et al., 2019). Cytotoxicity of RTP (polysaccharides extracted from roots of T. hemsleyanum) was tested by MTT assay. It was found that RTP could induce human gastric cancer cell apoptosis in dose-dependent manner, the apoptotic rates at the concentration of 0.625 mg/mL, 1.25 mg/mL and 2.5 mg/mL were 24.97%, 58.35% and 81.46%, respectively (Guo, 2018). The antitumor activity of flavonoid extracts of T. hemsleyanum were investigated by establishing Lewis lung carcinoma model in mice. The result showed the flavonoid extracts could decrease prostaglandin 2 (PGE2) and cyclooxygenase-2 (COX-2) in a dose-dependent manner. The possible mechanism may be related to regulation of the expression of PGE2 and COX-2 (Zhang and Feng, 2019). Antitumor activity of flavonoid extract of T. hemsleyanum was researched by microRNA sequencing (miRNA-seq) and bioinformatics technology. The result showed that the flavonoid extract of T. hemsleyanum could inhibit the proliferation and invasion of lung cancer cell line A549, and induce its apoptosis (Wei et al., 2018). The flavonoid extract of T. hemsleyanum had a significant inhibitory effect on the proliferation of non-small cell lung cancer A549 cells in a dose-dependent manner. The mechanism may be related to the regulation of ubiquitin–proteasome pathway (Zhong et al., 2017). The ethyl acetate extract of T. hemsleyanum showed antitumor activity by inhibiting the subcutaneous transplanted tumor of HepG-2 without dose-dependent. The mechanism may be related to the increase of the levels of serum TNF-α and IFN-γ (Wang et al., 2014). The ethyl acetate extracts of T. hemsleyanum could induce apoptosis of human liver cancer HCCC-9810 cells with a dose-dependent and time-dependent inhibitory (Wang & Peng, 2015) and its IC50 of treatment for 24 h, 48 h and 72 h were 275.3 mg/L, 183.3 mg/L and 75.8 mg/L, respectively. The possible mechanism was based on activation of the mitochondrial apoptotic pathway. Through MTT method, it was found the petroleum ether and n-butanol extracts of T. planicaule showed significant antitumor activity by inhibiting the growth of liver cancer HepG-2 cells (Chen, 2017). The flavonoid extract of T. hemsleyanum showed antitumor effect, and the possible mechanism was related to the down-regulation of MDSCs (myeloid-derived suppressor cells), COX-2 and PGE2 (Hu et al., 2021). The flavonoid extract of T. hemsleyanum showed antitumor activity in inhibiting proliferation and promoting apoptosis of bladder cancer cells through STAT3 signaling pathway (Wu, 2021). The flavonoid extract of T. hemsleyanum showed antitumor activity in reducing the proportion of Treg cells in Lewis lung cancer mice, improving the cellular immune function, and inducing the apoptosis of transplanted tumor tissues (Lin et al., 2021).

The polysaccharides from roots of T. hemsleyanum were explored for their antitumor activity by MTT methods. The result showed the polysaccharides could inhibit the proliferation, migration and invasion of hepatocellular carcinoma HepG2 cells and induce apoptosis. The mechanism may be related to the down-regulation of miR-151 expression (Wang et al., 2020). The flavonoid extract of T. hemsleyanum showed antitumor activity in inhibiting the proliferation and invasion of breast cancer cells MCF-7. The possible mechanism may be related to blockage of the cell cycle in G0/G1 phase and regulation of the expression of proteins related to Wnt/β-catenin signaling pathway (Du et al., 2020). The ethanol extract of T. hemsleyanum had inhibitory effect on the proliferation of Hela cells. At the concentration of 8 mg/mL, the inhibition rates were 38.4% and 47.2% after incubation for 24 h and 48 h, respectively (Huang et al., 2020). The polysaccharides from the roots of T. hemsleyanum could inhibit the proliferation, migration and invasion of liver cancer cells, and induce cell apoptosis by down-regulating the expression of miR-151 (Wang, 2020). The flavonoid extract of T. hemsleyanum had an inhibitory effect on the proliferation of breast cancer cells MCF-7, MDA-MB-468, 4T1 and T47D by inhibiting the expression of p-p42/44, blocking the MAPK signaling pathway, and activating the apoptosis-related protein Caspase-3. (Qiu et al., 2019).

Antitumor activity of monomeric compounds

Apigenin (1) from T. hemsleyanum exhibited significant antitumor activity and its IC50 values for HepG2 (human hepatocarcinoma), HCT-8 (human colon) and A549 (human lung adenocarcinoma epithelial) cells were (73.16 ± 0.96), (45.04 ± 1.25) and (48.66 ± 1.56) μg/mL, respectively (Lin et al., 2015). β-Sitosterol (106) and oleanolic acid (94) from T. hemsleyanum showed strong cytotoxic activity against Hela 229 (human cervical cancer cells) with IC50 of 40.78 and 25.69 μg/mL, respectively. Furthermore, oleanolic acid had strong cytotoxic activity to A375 with an IC50 of 69.87 μg/mL (Ding et al., 2015). Resveratrol (196) and kaempferol (45) displayed significant antitumor activities, and their IC50 were 92.4 and 294.2 μg/mL (Chen, 2014), respectively. Tetrastigmindole A (153) and tetrastigmindole B (154) from T. obtectum showed positive effects on antitumor metastasis in MDA-MB-231 cell lines (human breast cancer cell lines) at a concentration of 20 μg/mL. The value of inhibition ratio on MDA-MB-23 cells were 70.3% and 59.2%, respectively (Shi, 2012, Zhao et al., 2020). Astragalin (39), isoquercitrin (41), kaempferol-3-rutinoside (50), rutin (62) and catechin (65) from T. hemsleyanum exhibited potential antitumor activity against HepG2 with IC50 of (592.12 ± 3.31) μg/mL, (403.26 ± 1.26) μg/mL, (389.71 ± 4.23) μg/mL, (312.23 ± 1.17) μg/mL and (218.31 ± 2.38) μg/mL, respectively (Sun et al., 2015). p-Hydroxybenzoic acid (206) from T. hemsleyanum exhibited obvious inhibitory effects on MDA-MB-435S cell lines with IC50 value of (92.39 ± 1.68) μg/mL (Lin et al., 2016). Procyanidins B1 (73) and catechin (65) were antitumor angiogenesis active ingredient of T. hemsleyanum, which could reduce the activity of vascular endothelial growth factor (VEGF) to inhibit cell migration, invasion and tubular formation ability, and repress the expression of MAPK/ERK, PI3K/AKT pathway to inhibit tumor angiogenesis (Sun, 2018b).

Antioxidant activity

Tetrasigmol A (217), catechin (63), epicatechin-3-O-gallate (65), phlorizin (68), 3-O-galloybergenin (129), resveratrol (196), (E)-2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside(199), (+)-lyoniresinol (145) isolated from the stems of T. erubescens showed more potent antioxidant activities, with IC50 values in the range of 1.8–60.4 µmol/L. Catechin (65), epicatechin-3-O-gallate (63) and 3-O-galloyberrgenin (129) exhibited much higher activity than the positive control trolox (IC50 = 7.0 µmol/L) with IC50 of 5.4, 2.2 and 1.8 µmol/L (Dao et al., 2014), respectively. In vitro models explicitly disclosed that the polysaccharides (THP) obtained from roots of T. hemsleyanum could protect RAW264.7 cells against H2O2‑induced cytotoxicity by decreasing intracellular ROS levels, reducing catalase (CAT) and superoxide dismutase (SOD) activities, increasing lactate dehydrogenase (LDH) activity and enhancing malondialdehyde (MDA) level (Huang et al., 2021). Fe3+ reduction/antioxidant ability of the different extracts (total extract, petroleum layer, ethyl acetate layer, n-butanol layer, water layer) from T. planicaule was weaker than vitamin C (VC), but higher than tea polyphenols except water layer, and OH· scavenging activity of ethyl acetate layer (IC50 = 0.028 g/L) was higher than VC (IC50 = 0.044 g/L) and tea polyphenols (IC50 = 0.032 g/L) (Pan et al., 2013). T. planicaule exhibited a good antioxidant capacity, which may be attributed to the total flavonoid content (Pan et al., 2012). The extracts of the root tuber and aerial part from T. hemsleyanum had certain scavenging ability to 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals. When the DPPH scavenging rate of root tuber and aerial part reaches 50%, the required effective concentrations are 0.1902 and 0.1395 mg/L, respectively (Zhang et al., 2021). The soluble polysaccharide extracted by water from T. hemsleyanum showed antioxidant activity. The total antioxidant activity unit was 88.96 U·mL/L. The scavenging rates of DPPH, hydroxyl and superoxide anion radical were 36.8%, 65.1% and 36.8%, respectively (Yin et al., 2020).

Anti-inflammatory and analgesic activity

Hydroxy-3,4-dihydro-1-oxo-β-carboline (151), hippophamide (152) and S-(-)-trolline (155) from the aerial parts of T. hemsleyanum showed potent inhibitory activity against lipopolysaccharide (LPS)-stimulated NO production in RAW264.7 cells with IC50 of 31.9, 25.2 and 6.3 µmol/L, respectively. Among them, S-(-)-trolline (155) showed anti-inflammatory activity by inhibiting the activation of NF-κB (nuclear factor κB) and ERK-MAPK (extracellular signal-regulated protein kinase)-MAPK (mitogen-activated protein kinase) signaling pathway in RAW264.7 cells stimulated by LPS in a dose-dependent manner (Wang et al., 2018). Furthermore, structure–activity relationship (SAR) studies showed the lactam moiety may be an important structural element for their anti-inflammatory activity. Polysaccharide extracted from T. hemsleyanum can significantly inhibit the death of RAW264.7 cells induced by LPS, and the contents of TNF-α and IL-6 in RAW264.7 cells were significantly decreased compared with the model group in a dose-dependent manner (Huang, 2017). The extract of T. planicaule had an inhibitory effect on the degradation of IκB-α induced by TNF-α, and it was found that the extract could also inhibit the transport of NF-κB to the nucleus (Zhao et al., 1999). In the experiment of xylene ear swelling model and the acetic acid writhing in mice, T. hypoglaucum extract showed a significant inhibitory effect on ear swelling and writhing in mice (Li et al., 2018). The water extract of T. hemsleyanum showed a good anti-inflammatory effect in COPD copied by being smoked and LPS in rat model. Compared with the model group, the contents of TNF-α and IL-1β and the total number of leukocytes and neutrophils in experimental groups were significantly decreased in a dose-dependent manner (Jiang et al., 2018). The flavonoid extract of T. hemsleyanum significantly reduced the number of leukocyte and neutrophils infiltration in bronchoalveolar lavage fluid (BALF) (p < 0.01), inhibited secretion of IL-1β, IL-6, IL-12p40, TNF-α and sTNF-R1 (p < 0.01), improved the pathological damage of lung tissue, and significantly attenuated the phosphorylation of p38MAPK, NF-κB and the DNA binding activity of NF-κB in lung tissue (p < 0.01) (Liu et al., 2015). Kaempferol-3-O-rutinoside (50), isoquercitrin (41), rutin (62) in roots and vitexin (28) and orientin (26) in leaves from T. hemsleyanum showed anti-inflammatory activity by interacting with Keap1 protein and activating Nrf2（Xing et al., 2020). TTP-1 (86) from T. hemsleyanum could suppress inflammation by attenuating inflammation via COX-2, iNOS, MAPKs pathways. Meanwhile, TTP could ameliorate oxidative damage through Nrf2-Keap1, Sirt1-FoxO1 pathways in RAW264.7 cells in vitro (Chu et al., 2020). Kaempferol rutinoside (50), isoquercitrin (41), rutin (62), vitexin (28) and orientin (26) from T. hemsleyanum could reduce the protein levels of pro-inflammatory cytokines, such as IL-6 and IL-1β. Furthermore, vitexin (28) had the strongest antiinflammatory which mechanism was related to directly binds with Keap1 to block Keap1-Nrf2 interaction to activate Nrf2, and thereby inhibiting gene and protein expression of pro-inflammatory cytokines (Xing, 2020).

Hepatoprotective activity

Li et al. (2018) used ANIT (α-isothiocyanatoacetate) to replicate the acute jaundice hepatitis model that caused liver damage in mice and found that the alcohol extract of T. hemsleyanum had a protective effect on liver damage. The mechanism of action was likely through reducing the production of inflammatory factors, promoting the metabolism of total bilirubin, and reducing the degree of lipid peroxidation. The alcohol extract of T. planicaule had a remarkable protective effect against liver injury by resisting the increase of serum aspartate transaminase (AST) (p < 0.01) and alanine transaminase (ALT) (p < 0.01) in mice with acute liver injury caused by CCl4, down-regulating the content of malondialdehyde (MDA) (p < 0.01) in liver homogenate, enhancing the activity of superoxide dismutase (SOD) (p < 0.01), and significantly improving the pathological changes of liver tissue (Bin et al., 2016).

Antidiabetic activity

A novel polysaccharide THDP-3 (87) purified from cane leaves of T. hemsleyanum exhibited significant hypoglycemic activity in alloxan-induced diabetic mice. THDP-3 can promote glycogen synthesis and inhibit gluconeogenesis to reduce blood glucose, which was related to the key hepatic glycogen metabolism related enzymes including glucokinase (GK), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and AMP-activated protein kinase (AMPK) (Ru et al., 2019). THP, a water-soluble polysaccharide from T. hemsleyanum showed significantly hypoglycemic activities on alloxan-induced mice. The result of histopathological staining compared with glibenclamide in alloxan-induced mice indicate that it could restore the structure of pancreas, and had low side effects on the liver or kidney. Thus, this study provided a mechanistic basis that THP (89) could be used as a potential natural candidate for diabetes with little side effect (Ru et al., 2018). Tetrastigmindole A (153), cis-apigenin-6-vinyl-7″-rhamnoside (37) and apigenin-8-C-[6-deoxy-2-O-(α-L-rhamnopyranosyl)-xylo-hexopyranos-3-uloside (6) from T. obtectum showed potential anti-diabetic effects by enhancing the GLUT4 translocation and promoting absorption of glucose (Shi, 2012).

Antiviral bioactivity

The antiviral bioactivity of rutin (62), kaempferol (45), astragalin (39), quercitrin (56), quercetin (55), kaempferol-3-O-rutinoside (50), procyanidin dimmer (71) and epicatechin (65) from the dried rhizome parts of T. hemsleyanum was explored by correlation analysis statistical method. The result indicated that those compounds were positively related to antiviral activity (Ding et al., 2019). The n-butanol and ethyl acetate extracts of T. hemsleyanum exhibited antiviral bioactivity against RSV (respiratory syncytial virus) with therapeutic index (T1) values of 128 and 64, respectively. They were obviously superior to ribavirin (T1 = 6.25) (Wang et al., 2019). The extracts of T. hemsleyanum (petroleum ether, ethyl acetate, dichloromethane and n-butanol extracts) had inhibitory effects on hepatitis B virus (HBV) by decreasing the secretion of HbsAg and HbeAg (Yang & Wu, 2009). T. hemsleyanum leaves extract (THLE) exhibited protective effects against acrylamide-induced toxicity in HepG2 cells and Caenorhabditis elegans by in vivo and in vitro models and 5-caffeoylquinic acid was the key active component. DAF-16/FOXO gene was involved in the protective effect via regulating the expression levels of downstream antioxidant genes (Chu et al., 2020). The alcohol extract from root tuber of T. hemsleyanum could improve the survival rate of mice infected with influenza A H1N1 virus by reducing the damage of exgenous viruses to cell, enhancing spleen T cell proliferation and NK cell killing activity, improving the cellular immune function of mice. Its mechanism of action may be related to the up-regulation of the concentration of pro-inflammatory factor IFN-γ and IL-2 in serum and lung tissue, downregulating the concentration of inflammatory factor INF-α in serum or inhibiting the up-regulation of the concentration of inflammatory factor TNF-α in lung tissue (Liu, 2019).

Other activities

The flavonoids of T. hemsleyanum indicated remarkable inhibitory on viability and proliferation of leukemia NB-4 cells using CCk8 assay and BrdU test, the IC50 at 48 h was 2.26 g/L. Furthermore, it could induce apoptosis of leukemia NB-4 cells through the p38 MAPK signal pathway and the pathway of apoptotic proteins (Wu et al., 2019). T. hypoglaucum had a protective effect on myocardial ischemia reperfusion injury. It could reduce myocardial cells injury, and alleviate oxidative stress and inflammatory reaction (Wang et al., 2017). The extract of T. hemsleyanum could promote the proliferation and function changes of NK cells in patients with chronic hepatitis B, and up-regulate the NK cell surface expression of PFP, GrB, CD107a and IFN-γ (Wang et al., 2018). T. hypoglaucum extract displayed a strong bacteriostasis effect testing with the bacteriostasis of TCM. Its MICs (minimal inhibitory concentrations) against 55 strains of MRSE (methicillin-resistant Staphylococcus epidermidis) and 43 strains of MSSE (methicillin-resistant and sensitive S. epidermidis) were 1185 µg/mL and 286 µg/mL (p < 0.05), respectively (Wang et al., 2016). The monomeric compounds are summarized in Table 3, and the extracts are summarized in Table 4.

Table 3

Compound sources and pharmacological effects.

Compound names	Plant sources	Activities	Models/Methods	Results	References
Apigenin 1	T. hemsleyanum	Antitumor activity	HepG2, HCT-8 and A549 tumor cells	IC50 values of (73.16 ± 0.96), (45.04 ± 1.25) and (48.66 ± 1.56) μg/mL, respectively	Lin et al. (2015)
Astragalin 39	T. hemsleyanum	Antitumor activity	HePG2	IC50 values of (592 ± 3.31) μg/mL	Sun et al. (2015)
Catechin 65	T. hemsleyanum	Antitumor activity	HePG2	IC50 values of (218.31 ± 2.38) μg/mL	Sun et al. (2015)
Isoquercitrin 41	T. hemsleyanum	Antitumor activity	NBT-II cells	Blocking the migration of NBT-II cells and inhibiting HGF/SF-mediated cell motility and invasion in vitro, inhibiting metastasis of HGF autocrine NBT-II cells in vivo	Xia et al. (2018)
Kaempferol 45	T. hemsleyanum	Antitumor activity	MDA-MB-435 s cell investigated by MTT	IC50 values of 294.3 μg/mL	Chen (2014)
Kaempferol-3-rutinoside 50	T. hemsleyanum	Antitumor activity	HePG2	IC50 values of (389.71 ± 4.23) μg/mL	Sun et al. (2015)
Oleanolic acid 94	T. hemsleyanum	Antitumor activity	Hela229 cell and A375 cell	Cytotoxic activities against Hela229 and A375 cell with IC50 values of 25.69 μg/mL and 69.87 μg/mL	Ding et al. (2015)
Rutin 62	T. hemsleyanum	Antitumor activity	HePG2	IC50 values of (312.23 ± 1.17) μg/mL	Sun et al. (2015)
Resveratrol 196	T. hemsleyanum	Antitumor activity	MDA-MB-435 s cell investigated by MTT	IC50 values of 92.4 μg/mL	Chen (2014)
RTP-3-1 86	T. hemsleyanum	Antitumor activity	SGC-7901 cell	Inducing apoptosis of SGC-7901 cell in a dose-dependent manner	Guo (2018)
β-Sitosterol 106	T. hemsleyanum	Antitumor activity	Hela229 cell	Cytotoxic activities against Hela229 with IC50 values of 40.78 μg/mL	Ding et al. (2015)
p-Hydroxybenzoic acid 206	T. hemsleyanum	Antitumor activity	MDA-MB-435 cell	IC50 values of (92.39 ± 1.68) μg/mL	Lin et al. (2016)
Astragalin 39	T. hemsleyanum	Antiviral activity	Correlation analysis statistical method with SPSS software between LC-MS chemometrics and bioactivity of infuenza virus inhibition	Antiviral activity with the correlation coefficient of 0.711	Ding et al. (2019)
Epicatechin 63	T. hemsleyanum	Antiviral activity	Correlation analysis statistical method with SPSS software between LC-MS chemometrics and bioactivity of infuenza virus inhibition	Antiviral activity with the correlation coefficient of 0.641	Ding et al. (2019)
Kaempferol 45	T. hemsleyanum	Antiviral activity	Correlation analysis statistical method with SPSS software between LC-MS chemometrics and bioactivity of infuenza virus inhibition	Antiviral activity with the correlation coefficient of 0.580	Ding et al. (2019)
Kaempferol-3-O-rutinoside 50	T.hemsleyanum	Antiviral activity	Correlation analysis statistical method with SPSS software between LC-MS chemometrics and bioactivity of infuenza virus inhibition	Antiviral activity with the correlation coefficient of 0.514	Ding et al. (2019)
Procyanidin dimmer 71	T.hemsleyanum	Antiviral activity	Correlation analysis statistical method with SPSS software between LC-MS chemometrics and bioactivity of infuenza virus inhibition	Antiviral activity with the correlation coefficient of 0.503	Ding et al. (2019)
Quercitrin 56	T. hemsleyanum	Antiviral activity	Correlation analysis statistical method with SPSS software between LC-MS chemometrics and bioactivity of infuenza virus inhibition	Antiviral activity with the correlation coefficient of 0.617	Ding et al. (2019)
Quercetin 55	T. hemsleyanum	Antiviral activity	Correlation analysis statistical method with SPSS software between LC-MS chemometrics and bioactivity of infuenza virus inhibition	Antiviral activity with the correlation coefficient of 0.614	Ding et al. (2019)
Rutin 62	T. hemsleyanum	Antiviral activity	Correlation analysis statistical method with SPSS sofware between LC-MS chemometrics and bioactivity of infuenza virus inhibition	Antiviral activity with the correlation coefficient of 0.547	Ding et al. (2019)
Apigenin-6-C-α-L-rhmnnopyranosyl-(1-4)-α-L-Arabinopymnoside 89	T. hemsleyanum	Enhancing Immune activity	Lymphocyte proliferation assay investigated by MTT and hemolysis plaque formation assay	Enhancing the ConA -induced T cell proliferation response and increasing the production of antibody forming cells in mice	Liu (2000)
Apigenin-6,8-di-C-β-D-glucopyranoside 4	T. hemsleyanum	Enhancing immune activity	Lymphocyte proliferation assay investigated by MTT and hemolysis plaque formation assay	Enhancing the ConA-induced T cell proliferation response and increasing the production of antibody forming cells in mice	Liu (2000)
Catechin 65	T. hypoglaucum	Enhancing immune activity	Lymphocyte proliferation assay investigated by MTT and hemolysis plaque formation assay	Enhancing the ConA-induced T cell proliferation response and increasing the production of antibody forming cells in mice	Liu (2000)
6-Hydroxy-3,4-dihydro-1-oxo-β-carboline 151	T. hemsleyanum	Anti-inflammatory activity	Measuring NO production in LPS-induced RAW264.7 macrophages	IC50 values of 31.9 μmol/L	Wang et al. (2018)
Hippophamide 152	T. hemsleyanum	Anti-inflammatory activity	Measuring NO production in LPS-induced RAW264.7 macrophages	IC50 values of 25.2 μmol/L	Wang et al. (2018)
S-(-)-Trolline 155	T. hemsleyanum	Anti-inflammatory activity	Measuring NO production in LPS-induced RAW264.7 macrophages	IC50 values of 6.3 μmol/L	Wang et al. (2018)
Apigenin-8-C-[6-deoxy-2-O-(α-L-rhamnopyranosyl) -xylo-hexopyranos-3-uloside] 6	T. obtectum	Anti-diabetic activity	The experiment of GLUT4 translocation in skeletal muscle L6 cells	Enhancing the GLUT4 translocation and promoting the absorption of glucose	Shi (2012)
cis-Apigenin-6-vinyl-7″-Rhamnoside 37	T. obtectum	Anti-diabetic activity	The experimem of GLUT4 translocation in skeletal muscle L6 cells	Enhancing the GLUT4 translocation and promoting the absorption of glucose	Shi (2012)
Tetrastigmindole A 153	T. obtectum	Anti-diabetic activity	The experimem of GLUT4 translocation in skeletal muscle L6 cells	Enhancing the GLUT4 translocation and promoting the absorption of glucose	Shi (2012)
Tetrastigmindole A 153	T. obtectum	Antitumor activity	MD-MBA-231cell lines in vitro	Inhibition rates at a concentration of 20 μg/mL, 1 μg/mL, 0.05 μg/mL were 70.3%, 34.4% and 28.2%, respectively	Shi (2012)
Tetrastigmindole B 154	T. obtectum	Antitumor activity	MD-MBA-231cell lines investigated by transwell chemotaxis method	Inhibition rates at a concentration of 20 μg/mL, 1 μg/mL, 0.05 μg/mL were 59.2%, 40.8% and 11.1%, respectively	Shi (2012)
3β-Hydroxystigmast-5-en-7-one 114	T. planicaule	Antitumor activity	CNE cells investigated by MTT	Cytotoxic activities against CNE cell with IC50 of 44.2 μg/mL	Shao (2011)
7α-Hydroxysitosterol 110	T. planicaule	Antitumor activity	CNE cells investigated by MTT	Cytotoxic activities against CNE cell with IC50 of 65.63 μg/mL	Shao (2011)
Protocatechuic acid 205	T. planicaule	Antitumor activity	CNE cells investigated by MTT	Cytotoxic activities against CNE cell with IC50 of 76.75 μg/mL	Shao (2011)
SYQP 91	T. hemsleyanum	Antipyretic and antitumor activities	Brewer's yeast induced hyperthermia test and H22 tumor bearing mice	Reducing the hyperthermia temperature of the mice induced by Brew's yeast and decreasing PGE2, markedly suppressing the inhibiting the growth of H22 tumor in mice with inhibitory rate of 39.9%	Zhu et al. (2020)
TDGP-3 88	T. hemsleyanum	Antioxidant and antihyperlipidemic activities	HFD-induced hyperlipidemia mice	Repressing the weight gain induced by HFD, obviously reversing the increased TC, TG, and LDL-C level and the decreased HDL-C level in mice with HFD. increasing the levels of SOD, CAT and GSH-Px (p < 0.01) and obviously decreasing the accumulation of MDA (p < 0.01)	Ru et al. (2019 a)
THDP-3 87	T. hemsleyanum	Hypoglycemic activity	Alloxan-induced diabetic mice	Significantly reducing blood glucose levels in alloxan-induced diabetic mice (p < 0.01) and decreasing content of hepatic glycogen (p < 0.01)	Ru et al., 2019b, Ru et al., 2018
THP 98	T. hemsleyanum	Hypoglycemic effects	Alloxan-induced diabetic mice	Decreasing the blood glucose, TC, TG, LDL-C levels and increasing the body weight, HDL-C and insulin levels of mice, enhancing the activities of antioxidant enzyme system in mice	Ru et al. (2018)
Catechin 63	T. erubescens	Antioxidant activity	DPPH assay and lipid peroxidation inhibition assays in vitro	IC50 of 5.4 μmol/L and 379.2 μmol/L, respectively	Dao et al. (2014)
Epicatechin-3-O-gallate 65	T. erubescens	Antioxidant activity	DPPH assay and lipid peroxidation inhibition assays in vitro	IC50 of 2.2 μ mol/L and 52.1 μmol/L, respectively	Dao et al. (2014)
(E)-Resveratrol 196	T. erubescens	Antioxidant activity	DPPH assay and lipid peroxidation inhibition assays in vitro	IC50 of 31.3 μ mol/L and 607.5 μmol/L, respectively	Dao et al. (2014)
(E) 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside 199	T. erubescens	Antioxidant activity	DPPH assay and lipid peroxidation inhibition assays in vitro	IC50 of 31.1 μmol/L and 157.3 μmol/L, respectively	Dao et al. (2014)
(+)-Lyoniresinol 145	T. erubescens	Antioxidant activity	DPPH assay in vitro	IC50 of 8.8 μmol/L	Dao et al. (2014)
Phlorizin 68	T. erubescens	Antioxidant activity	DPPH assay and lipid peroxidation inhibition assays in vitro	IC50 of 60.4 μmol/L and 364.7 μmol/L, respectively	Dao et al. (2014)
Tetrastigmol A 217	T. erubescens	Antioxidant activity	DPPH assay and lipid peroxidation inhibition assays in vitro	IC50 of 9.5 μmol/L and 87.8 μmol/L, respectively	Dao et al. (2014)
3-O-Galloybergenin129	T. erubescens	Antioxidant activity	DPPH assay and lipid peroxidation inhibition assays in vitro	IC50 of 1.8 μmol/L and 60.9 μmol/L, respectively	Dao et al. (2014)

Note: CAT, catalase from micrococcus lysodeikticus; DPPH, the stable free radical; EMT, epithelial mesenchymal transition; GLUT4, glucose transporters 4; GSH-Px, gluthathione peroxidase; HFD, high-fat diet; HGF/SF, hepatocyte growth factor/scatter factor; HDL-C, low levels of high density lipoprotein; LPS, lipopolysaccharide; LDL-C, low density lipoprotein; MDA, Malondialdehyde; Met, is involved in the development and progression of many human cancers; NO, nitric oxide; PGE2, prostaglandin E2; SOD, superoxide Dismutase; TC, total cholesterol; TG, triglycerides.

Table 4

Sources of plant parts and pharmacological effects.

Extracts	Activities	Models/Methods	Results	References
Ethylacetate extracts of T. hemsleyanum	Antitumor activity	Nude mice bearing colorectal cancer with HT29 cells	Inhibiting the growth of HT29 cells subcutaneously transplanted tumor and its inhibitory rate of low, medium and high dose treatment groups were 8.13%, 21.75%, 37.8%, respectively	Lin et al., 2016, Lin et al., 2016
Ethylacetate extracts of T. hemsleyanum	Antitumor activity	Mice inoculated with HepG-2 cell	Inhibiting athymic mouse transplantation tumor and its inhibitory rate of low, medium and high dose treatment groups were 38. 66%, 23.53% and 31.09%, respectively	Wang et al. (2014)
Ethylacetate extracts of T. hemsleyanum	Antitumor activity	HCCC-9810 cells	IC50 of ETH treatment for 24 h, 48 h and 72 h were 275.3 mg/L, 183.3 mg/L and 75.8 mg/L, respectively	Wang et al. (2015)
Ethylacetate extracts of T. hemsleyanum	Anti-HBV activity	HepG2.2.15 cells	Significantly restraining the secretion of HBsAg and HbeAg from HepG2.2.15 cells	Yang et al. (2009)
Ethylacetate fraction of extracts from T. hemsleyanum	The immune-regulatory	ICR mice	Increasing the mouse spleen lymphocyte transformation induced by ConA, the left-hind voix pedis thickness and the number of PFCs, increasing the ink clearance ability, increasing the phagocytosis index of mononuclear-macrophages and production of IFN-γ, promoting the production of IFN-α	Xu et al. (2008)
Water, ethanol and ethyl acetate extracts of T. hemsleyanum	Antitumor activity	MCF-7 cells in vitro	Inhibiting MCF-7 cells in a dose-dependent manner (p < 0.05) and promoting the apoptosis of MCF-7 cells (p < 0.05)	Qiu et al. (2018)
Water extract from tuber of T. hemsleyanum	Antitumor activity	BGC-823 cells and NK cells in vitro	Promoting the proliferation of NK cells and enhancing the cytotoxic activity of NK cells to BGC-823 cells with the maximum (67.75 ± 2.58) %	Yuan et al. (2016)
Water extract from tuber of T. hemsleyanum	Antitumor activity	MDA-MB-435 cells investigated by MTT in vitro	IC50 values of 127.8 μg/mL	Chen (2014)
Water extract of T. hemsleyanum	Anti-inflammatory activity	COPD copied by being smoked and LPS in rat	The contents of TNF-α and IL-1β, the total number of white blood cells and neutrophils were significantly decreased	Jiang et al. (2018)
Water extract of whole plant of T. hypogtaucum	Anti-inflammatory activity	The myocardial ischemia reperfusion injury in rats.	Reducing myocardial cells injury, alleviating oxidative stress and inflammatory reaction	Wang et al. (2017)
Water extract of T. hemsleyanum	Anti-inflammatory activity	COPD copied by being smoked and LPS in rat	MMP-9 and TIMP-1 content decreased significantly (p < 0.05)	Jiang et al. (2016)
Water extract of T. hypoglaucum	Antibacterial activity	Methicillin-resistant Staphylococcus epidermidis and methicillin-resistant and sensitive S. epidermidis	Stronger bacteriostasis effect with the MIC of 1185 µg/mL and 286 µg/mL, respectively	Wang et al. (2016)
Ethanol extract of T. obtectum	Anti-inflammatory and analgesic activity	The xylene ear swelling model and the acetic acid writhing experiment in mouse	Inhibitory effect on ear swelling caused by xylene and writhing caused by acetic acid in mice	Li et al. (2018 a)
Ethanol extract of T. hemsleyanum	Hepatoprotective activity	ANIT-induced liver injury in mice	The levels of TBIL and TNF-α were significantly decreased (p < 0.05), the levels of ALT, AST, TBA, TBIL and TNF-α in serum were decreased, and the MDA content were significantly decreased	Li et al. (2018b)
Ethanol extract of T. planicaule	Hepatoprotective activity	CCl4-induced acute liver injury in mice	Significantly resisting the increase of ALT and AST, downregulating MDA content of liver homogenate, and improving SOD activity	Bin et al. (2016)
Ethanol extract T. hemsleyanum	Antiviral activity	HepG2 cells	The protective effect against ACR-induced toxicity in HepG2 cells and attenuating ACR-induced toxicity in HepG2 cell via regulating Akt/mTOR/FOXO1/MAPK signaling pathway	Chu et al. (2020)
Petroleum ether, n-butanol fraction of T. planicaule	Antitumor activity	HepG-2 cells investigated by MTT	Obvious antitumor activity against the growth of HepG-2 cells	Chen (2017)
Petroleum ether fraction, ethylacetate fraction, n-butanol fraction and waterfraction from T. planicaule	Antioxidant activity	FRAP assay, OH· scavenging assay, and ABTS + ·scavenging assay	Ferric reducing antioxidant of them were weaker than VC, but higher than tea polyphenol except water fraction	Pan et al. (2013)
Methanol extract of the aerial parts of T. hemsleyanum	Anti-inflammatory activity	RAW264.7 cells	Considerable inhibitory effect on LPS-stimulated NO production in RAW264.7 macrophages (IC50: 22.69 ± 0.75 µmol/L)	Wang et al. (2018a)
n-Butanol extract and ethyl acetate extract of the ethanol extract of T. hemsleyanum	Antiviral activity	MA104 cell	The TI of n-butanol and ethyl acetate extraction were 128 and 64, respectively	Wang et al. (2019)
Polysaccharides from the aerial parts of T. hemsleyanum	Antitumor activity	Mice inoculated with 4 T1 cell	Effectively inhibiting tumor growth and distal lung metastasis	Guo et al. (2019)
Flavonoid fraction extracted from T. hemsleyanum	Antitumor activity	Spleen mononuclear cells of mice with lung cancer	PGE2 and COX-2 were significantly reduced (p < 0.01)	Zhang et al. (2019b)
Flavonoid fraction extracted from T. hemsleyanum	Antitumor activity	A549 cells investigated by miRNA-seq and bioinformatics technology	Intracellular endocytosis pathway was significantly enriched	Wei et al. (2018)
Flavonoid fraction extracted from T. hemsleyanum	Antitumor activity	A549 cells investigated by MTT, enzyme proteasome assay, Real-time PCR and Western blot in vitro	Inhibiting the proliferation of lung cancer A549 cells in a dose-dependent manner (p < 0.05), reducing the activity of proteasome and DUB, up-regulating the protein expression of ub-prs and down-regulating the protein expression of USP14, UCHL5, POH1	Zhong et al. (2017)
Flavonoid fraction extracted from T. hemsleyanum	Antitumor activity	LPS induced ALI of aged C57BL/6J mice	Significantly reducing leukocyte, especially neutrophil infiltration in BALF, inhibiting IL-1β, IL-6, IL-12p40, TNF-α and s TNF-R1 secretion (p < 0.01), improving pathohistological change of lung tissues, significantly attenuating the phosphorylation of p38 MAPK, NF-κB and the activity of NF-κB (p < 0.01)	Liu et al. (2015)
Flavonoid fraction extracted from T. hemsleyanum	Antitumor activity	NB-4 cells investigated by CCK-8 assay, BrdU test and Flow cytometry	1. Inhibiting the viability and proliferation of NB-4 cells in a time- and dose-dependent manner, and the IC50 at 48 h was 2.26 g/L2. Inducing apoptosis of the NB-4 cells, down-regulating the expression of anti-apoptotic protein Bcl-2, and up-regulating the expression of pro-apoptotic proteins Bax, caspase-3 and Cyt-C in a dose-dependent manner (p < 0.05), decreasing the expression of ERK5 and increasing the expression of p38	Wu et al. (2019)
Flavonoid fraction extracted from T. hemsleyanum	Antitumor activity	C57BL/6 mice inoculatedwith LLC cells	Significantly inhibiting tumor growth and suppressing regulatory T-cell development	Feng et al. (2014)
Flavonoid fraction extracted from T. planicaule	Antioxidant activity	FRAP assay, salicylic acid assay and ABTS assay	The activity of reducing Fe3+ antioxidant and scavenging ABTS + ·was higher than tea polyphenol, but scavenging OH· was lower than VC and tea polyphenol	Pan et al. (2012)

Note: ACR, acrylamide; ANIT, α-isothiocyanatoacetate; ALI, acute lung injury; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BALF, bronchoalveolar lavage fluid; COPD, chronic obstructive pulmonary disease; COX-2, cyclooxygenase-2; DUB, deubiquitinating enzyme; ERK5, extracellular signal-regulated kinase 5; HBeAg, hepatitis Be antigen; HBeAg, hepatitis Be antigen; IL-1β, interleukin-1β; IL-1β, interleukin-1β; IL-6, interleukin- 6, IL-12p40, interleukin-12p40; IFN-γ, serum interferon-gamma; IFN-α, serum tumor necrosis factor-alpha; LPS, lipopolysaccharide; PGE2, prostaglandin 2; MDA, malondialdehyde; MAPK, mitogen-activated protein kinase; MMP-9, matrix met alloproteinases-9; NF-κB, nuclear factor kappa-B; TIMP-1, matrix met alloproteinases inhibitor-1; PFCs, plague forming cells; SOD, superoxide dismutase; TBIL, total bilirubin; TNF-α, tumor necrosis factor-α, TNF-R1, tumor necrosis factor receptor 1,TBA, total bile acid; USP14, ubiquitin-specific proteases 14; UCHL5, recombinant ubiquitin carboxyl terminal hydrolase L5; VC, Vitamin C.

Progress in clinical applications

Treatment of malignant tumor-related diseases

In the clinical application, Sanyeqing (T. hemsleyanum) was mainly used for treatment of malignant tumor. The tiple-negative breast cancer (TNBC) patient took Sanyeqing Sanjie Kang'ai Formula (containing herbal medicine Sanyeqing), and the result showed the treatment group's pathological complete response (pCR rate) was 30.43% and 31.25% (Lv et al., 2014). Wei (2007) used praeparatum-Jinqi Pian (Taking herbal medicine Sanyeqing as the main ingredient with Astragal Radix and ginsenoside) to treat 120 cases of patients with malignant tumor. The results indicated 52 patients were recovered and the overall efficiency was 78.33%. In addition, praeparatum Jinqi Pian (Taking herbal medicine Sanyeqing as the main ingredient with Astragal Radix and ginsenoside) was suitable for long-term health food for cancer patients and people with low immunity. Jiang and Gong (2005) used Zhonggan Oral Liquid (containing Sanyeqing) to treat 112 cases of patients with primary carcinoma of liver. The result showed treatment group's survival rate was 43.1%. Shi (Xu et al., 2015) created a prescription named Zhengyuan Yiliu Fang (containing Sanyeqing) to treat malignant lymphoma, which obtains great efficacy in clinical studies.

Treatment of other diseases

Li (2001) developed an innovative Chinese medicine (using Sanyeqing and other materials) for the treatment of chronic hepatitis B pneumonia. Many studies showed this medicine had the functions of inhibiting hepatitis B virus, regulating body's immunity. Xu (2006) established a prescription named Sanyeqing Shigao Tang (taking Sanyeqing as the main ingredient with raw gypsum) to treat 72 cases of exogenous fever in children.The result indicated 22 patients were recovered with the total efficiency of 94.4%. Ji (2020) found that Sanyeqing had a good effect on the treatment of redness, swelling, inflammation, ulceration and other symptoms after mosquito bited. Zhou (2013) used Hugan Toudu decoction containing 20 g of Sanyeqing to treat 228 cases of chronic hepatitis B. The result showed that the total efficiency of the Hugan Toudu decoction group was higher than the Chinese patent medicine group and modern medicines group (p ＜0.01). In some areas of China, Sanyeqing was also used for the treatment of common gynecological diseases such as hemorrhage, leucorrhea, measles complicated with pneumonia, anal fissure, chronic bronchitis, etc, and had good therapeutic effect on high fever and low fever cough in clinical (Liu & Wei, 2018). Ge (2012) established an oral liquid with dozens of herbal medicines such as Biandanteng (T. planicaule), combined with the Zhuang ethnomedicine Taiji-acupuncture and moxibustion to treat 113 cases of patient with chronic lumbar muscle strain. The result indicated 76 cases were cured and the total efficiency was 92.03%. Lu (2001) formulated a prescription named Qigui Qianjinba Tang with over ten herbal medicines including Biandanteng to treat 80 cases of patient with arthralgia syndrome. The treatment results showed 14 patients (17.5%) were cured and the total efficiency was 90%. Zhang et al. (2016) developed an external uses of Chinese medicine prescription (taking herbal medicine T. planicaule as the main ingredient) for treatment of rheumatism. This prescription displayed a high clinical improvement effect on rheumatism related diseases such as rheumatoid arthritis. Chen (Chen, 2000) used the juice from the rattan of T. planicaule to treat 37 cases of bovine with traumatic keratitis. The result indicated that 33 cases were cured, and the total efficiency 89.2%. This result also showed T. planicaule could improve micro blood circulation, dissipate inflammation and blood stasis, remove nebula for improving eyesight. Two cases of patient with coronavirus disease 2019 (COVID-19) were treated with some prescriptions (containing Sanyeqing and other Chinese medicines) for therapy of integrating traditional Chinese medicine and Western medicine. The clinical studies showed one case of was cured and another one was remarkably relieved with outing of critical condition (He et al., 2020). Yu (Sun et al., 2021) treated one case of children with recurrent suppurative tonsillitis with some prescriptions (containing Sanyeqing and other Chinese medicines). The result indicated the children was cured after four times treatment with little recurrence within half a year. Sanyeqing had the functions of clearing away heat and detoxification, promoting blood circulation, dispersing masses, reducing inflammation and pain, dispelling wind and phlegm, regulating qi and strengthening spleen, etc. Based on clinical experience, it was believed to have played a key role in the treatment of children with recurrent suppurative tonsillitis.

Conclusion and outlook

The Tetrastigma species had many interesting chemical constituents and obvious pharmacological activities. Therefore, Tetrastigma species could be considered a potential candidate of nutritional supplement and new drug discovery. This review summarized 248 secondary metabolites of species in genus Tetrastigma including flavonoids, saccharides, terpenoids, steroids, phenylpropanoids and alkaloids, described the recent advance in pharmacological activities of the extracts and the metabolites from Tetrastigma species, and summarized the folk uses and up-to date clinical treatments of Tetrastigma species. Plants of Tetrastigma species were most commonly used in the treatment of tumor-related diseases and had definite curative effect, and the extracts and compounds of Tetrastigma species exhibited obvious antitumor activity. It provided preliminary evidence of the relationship between modern pharmacological studies and folk uses of anti-tumor. The underlying mechanism may be related to inhibiting tumor cell proliferation, inducing cell apoptosis, inhibiting tumor cell migration and invasion, inhibiting tumor cell angiogenesis, reversing tumor cell multidrug resistance, regulating the body's own immunity and so on. Furthermore, the folk uses of these species are the treatment of pneumonia, nephritis, hepatitis, rheumatism, arthralgia, traumatic, injury, inflammation, fever, snakebites, etc. Pharmacological properties such as antiviral, anti-inflammatory and analgesic activities have supported the traditional uses of Tetrastigma species. It was noteworthy that the anti-diabetic effect was a new biological activity discovered in recent years.

However, there are still yet some problems in the further development of Tetrastigma species. Firstly, to date most studies focused mainly on the T. hemsleyanum, while the phytochemical and biological activities and clinical researches of the other species were not comprehensively investigated. In order to expand and develop new medicinal sources, more studies should be done on other species. What's more, the resources of T. hemsleyanum are limited, which greatly restrict their utilization and development. Therefore, a well-developed cultivation technique will be needed to establish. Secondly, existing pharmacological and biological activity researches were insufficient to clarify the relationship between traditional functions and clinical applications and the mechanism of action. As such, it is necessary to deepen the research on the pharmacological mechanism and analyses of the structure–activity relationships of secondary metabolites of Tetrastigma species in the future. Finally, the quality control of Tetrastigma species is poorly investigated. Thus, the well-developed analytical methods are needed to ensure their consistency, safety and efficacy. This article could be a useful tool in assisting researchers to discoveri new drug candidates for further research and provides an incentive to expand the research of genus Tetrastigma.

Editor Note

Wei Wang is Editorial Board Members of Chinese Herbal Medicines. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board Member and their research groups.

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.