Pengyu Wang, Jian Li, Fatma Alzahra K. Attia, Wenyi Kang, Jinfeng Wei,Zhenhua Liu,?, Changqin Li,?

a National R & D Center for Edible Fungus Processing Technology, Henan University, Kaifeng 475004, China

b School of Food Science and Engineering, Hefei University of Technology, Hefei 23009, China

c Department of Ornamental, Medicinal and Aromatic Plants, Faculty of Agriculture, Assiut University, 71515, Egypt

d Joint International Research Laboratory of Food & Medicine Resource Function, Henan Province, Kaifeng 475004, China

Keywords:Lilium Chemical constituents Pharmacological effects

ABSTRACT Genus Lilium is famous for edible and medicinal function which is related to its chemical constituents and pharmacological effects. Chemical researches showed that genus Lilium genus mainly contains steroidal saponins, polysaccharides, alkaloids and flavonoids. Pharmacological effects of Lilium include anti-tumor,hypoglycemic, antibacterial, anti-oxidation, anti-depression and anti-inflammatory. This paper summarized chemical constituents and pharmacological effects of Lilium.

1. Introduction

The plants of Lilium in the Liliaceae family are distributed in China and they are cultivated as ornamental plants throughout the world, as well as used as important edible plants and biological medicinal products. Lilium has the effects of nourishing yin to moisten the lung, clearing away heart fire and tranquilizing the mind. It is also used for yin deficiency lasted cough,hemoptysis, anxiety, insomnia, dreaminess, and spirit trance [1].The bulbs of genus Lilium plants have a quite high medicinal value, such as L. pumilum and L. lancifolium. Many studies have been conducted the chemical constituents of genus Lilium genus involving saponins, sterols, alkaloids, polysaccharides,glycerol glycerides, phenylpropanoids and flavonoids, which illustrated their pharmacological effects of anti-tumor, hypoglycemic,antibacterial, anti-inflammatory, hypolipidemic, reducing blood lipid, anti-depression, anti-fatigue and hypoxia tolerance. In this paper, we summarized recent studies concerning the phytochemistry and pharmacology of the genus Lilium, which can provide references for further research and for the application of these species (Figs. 1–5).

2. Chemical constituents

2.1. Steroidal saponins

To date, more than 32 compounds (1-32) have been obtained from 10 species of the genus Lilium (L. lancifolium, L. brownii F.E.Brown var. viridulum Baker, L. pumilum, L. longiflorum Thunb,L. brownii var. colchesteri, L. candidum, L. speciosum, L. tenuifolium,L. callosum Sieb. et Zucc) (Table1) [2–12]. Compounds 9, 12, 19, and 22 to 30 were identified as new compounds from 9 species of the genus Lilium (L. lancifolium, L. pumilum, L. brownii var. colchesteri,L. candidum, L. speciosum, L. tenuifolium, L. brownii F.E.Brown var.viridulum Baker, L. callosum) [4,5,7–11].

2.2. Sterols

Compounds 34 and 35 were isolated from L. lancifolium and L.brownii F. E. Brown var. viridulum Baker [3,12,13].

Fig. 1. Saponins isolated from the family Lilium.

Fig. 2. Sterols isolated from the family Lilium.

Fig. 3. Alkaloids isolated from the family Lilium.

Fig. 4. Flavonoids and organic acids isolated from the family Lilium.

2.3. Alkaloids

Some studies on alkaloids in Lilium were reported as early as the 1960s. Berberine was isolated from L. lancifolium by Wenyan Hu [3]. MIMAKI et al. [7] isolated and identified compounds 36 and 37 from L. brownii var. colchesteri. The steroidal alkaloids and another alkaloids of steroid glycoside, which named as (22R,25R)-spirosol-5-en-3β-ylO-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl-(1→4)βD-glucopyranoside, and(22R,25R)-spirosol-5-en-3β-ylO-α-L-rhamnopyranosyl-(1→2)-[6-O-acetyl-β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside were found from L. candidum and L. longiflorum, respectively [14,15].

2.4. Polysaccharides

Ten polysaccharides were isolated from L. lancifolium, L. davidii var. unicolor Salisb. They have different molecular weight, sugar composition, connection mode and main chain. The two polysaccharides (LP1and LP2) were composed by glucose, galactose,mannose, arabinose, and galacturonic acid. They had different molecular weight. The molecular weight of LP1was 7.94 × 104kDa,LP2was 1.815 × 104kDa [16]. A polysaccharide obtained from L.brownii named as LBPS-I, which was consisted of α-D-(1,4)-Glcp and α-D-(1,3)-Glcp with the molar ratio of 2:1 as the backbone and α-D-(1,6)-Glcp as side chains [17]. Crude LLPS was extracted by hot water assisted with ultrasonic wave from L. lancifolium, and then it was purified through chromatography column of Sephadex G-100.Finally, LLPS-1, LLPS-2 and LLPS-3 were obtained. Their average molecular weight were 350.51, 403.29 and 146.18 kDa, respectively. The backbone chains of LLPS-1 were mainly glucose and mannose in a molar ratio of about 2:1, with traces of arabinose,and a very small amount of fucose and galactose. The backbone chains of LLPS-2 were mainly glucose and mannose in a 1:1 ratio,including trace amounts of arabinose. LLPS-3’s backbone chains were mainly composed of arabinose, galacse, glucose and mannose in a molar ratio of about 2:2:2:1, contained trace amounts of galacturonic acid [18]. Another polysaccharide from L. lancifolium through further purified exhibited a homogeneous fraction and the average molecular weight were 8.52 × 103kDa. The fraction was composed of rhamnose, arabinose, glucose and galactose residues with the molar ratio of 15:17:8:20. According to infrared spectrum and NMR, it was conjectured that the fraction was consisted of→4)-α-D-GalA-(1→, →2)-α-Rhap-(1→ as the backbone and →4)-α-Rhap-(1→, →3)-α-Araf- (1→, →4)-β-Galp-(1→, 4→)-β-Glc-(1→as side chains [19].

Fig. 5. The sugar residues isolated from the family Lilium.

Table 1 Steroidal saponin of Lilium L. plants.

2.5. Others

There are also other constituents in the family Lilium, such as flavonoids (41, 42), organic acids (43,44), etc. [20–24].

3. Biological activities

3.1. Antitumor activity

The bulbs of Lilium plants including L. brownii, and L. lancifolium are used as antitumor herbs in Chinese medicine. The antitumor activities of the genus Lilium have been confirmed in HepG2, K562,SGC-7901, A549, HGC-27 and SPCA-1 cells, and in mouse models of S180, H22, B16 [15,25–31].

Polysaccharides of L. brownii could inhibit the growth of S180 and H22 tumor-bearing mice, but the inhibitory effect was not obvious [15,26]. When treated with 0.1, 0.15 g/L of the methanol extract of lily and 1.1, 1.4 g/L of the lily extract alkaloid, the proliferation of SGC-7901 (human gastric cancer cell) was inhibited and the SGC-7901 cell was blocked in the G2/M period [27]. The p-coumaric acid, gallic acid, rutin from the bulbs of L. lancifolium could inhibit the proliferation of A549, SGC-7901 and HGC-27 cells [28]. Moreover, water extraction, alcohol extraction, alkaloids extraction, and saponins extraction from L. lancifolium could inhibit the proliferation of A549 cell [30,31]. Compound 28 isolated from L. callosum showed strong anticancer cytotoxic activities against SGC7901,K562, SPCA-1 cells [11].

From these findings, it can be seen that the crude extracts and some active constituents from L. brownii, L. lancifolium, L. callosum exhibited potential antitumor effects. These in vivo and in vitro experiments suggested different underlying mechanisms summarized as follows: (i) improve immune function to kill tumor cells.(ii) inhibit the proliferation of cells and make the cells block in the G2/M period.

3.2. Anti-inflammatory activities

The root extract of L. lancifolium inhibited the numbers of macrophages and neutrophils in cigarette smoke-exposed mouse model and reduced the protein secretion levels of TNF-α, IL-6, IL-1β and MCP-1 [32]. Kwon et al. [33] demonstrated that the methanol extracts of the root of L. lancifolium had anti-inflammatory effects as it significantly inhibited the content of lipopolysaccharideinduced NO, PGE2, IL-6 and TNF-α induced by lipopolysaccharide,and inhibited the expression of iNOS and COX-2 in RAW264.7 cells to exert anti-inflammatory effect. The two phenylpropanoid acylglycerols were obtained and identified from the chloroform fraction of L. brownii significantly decreased the production of PGE2 and several other pro-inflammatory cytokines, such as IL-1, IL-6 and TNF-α. They also down-regulated the protein levels of iNOS and COX-2. Moreover, they also inhibited the nuclear translocation of NF-kB p65 subunit and suppressed MAPKs pathway. So the anti-inflammatory mechanisms were the inhibitory effect of inflammatory factors production to show the effect of antiinflammation [34]. These data suggested that Lilium plants may be potential therapeutic candidates for the treatment of inflammatory diseases. However, the possible major bioactive components, and mechanisms of these bulbs’ extracts should be defined.

3.3. Anti-oxidant activity

Polysaccharides from L. brownii (200,400 mg/kg) had obvious in vivo anti-oxidant activity in mice by decreasing the content of MDA in serum and tissues, enhancing the activity of SOD,and improving the activity of CAT in liver and serum [35]. The crude polysaccharides from L. brownii (1.0 mg/mL) exhibited the strongest scavenging capability on hydroxyl and nitrite [36].Besides, phenolic compounds extracted from bulbs of L. lancifolium showed strong anti-oxidant capacity and free radical scavenging capacity in vitro against DPPH, ABTS and hydroxyl [23]. The bulb extracts of L. lancifolium had signficant antioxidant capacity and could be a potential nature source of antioxidants.

3.4. Effect on the immune system

Hu et al. [35] proved that L. brownii polysaccharide middle and heavy dose groups (200,400 mg/kg) could improve the clearance rate of charcoal particles and the weight index of immune organs, indicated that L. brownii polysaccharide could promote the phagocytic function of reticuloendothelial system in mice and strengthen non-specific immune function. Furthermore, L. brownii polysaccharide could improve the level of serum hemolysin in mice.These results indicated that L. brownii polysaccharide had certain enhancement to the humoral immunity function of the mice.

3.5. Hypoglycemic effects

The polysaccharides from L. brownii had obvious hypoglycemic effect on hypoglycemic mice induced by alloxan [37]. Xiao et al. [38]investigated the effect of alkali washing L. brownii polysaccharide on blood glucose in type I diabetic rats induced by streptozotocin.Polysaccharide from L. brownii had a positive effect on the hypoglycemic mechanisms exertion through enhancing the activities of antioxidant enzymes, improving antioxidant function and inhibiting oxygen free radical damage to pancreatic β cells resulting in increasing insulin secretion. Furthermore, Zhu et al. [39] found that steroidal glycoside rich fraction (SGL) could increase glucose consumption in HepG2 cells and 3T3-L1 adipocytes, and enhance 3T3-L1 preadipocyte differentiation.

3.6. Antibacterial activity

The antibacterial activity of the bulbs of L. davidii, L. leucanthum,L. regale, L. brownii, L. lancifolium were related with effective substances, such as alkaloids, flavanoids and saponins [40,41]. There existed a significant dose-effect relation between the antibacterial activity and the contents of lily bulb extracts. The antibacterial activity increased proportionally along with the increasing of the contents of lily bulb extracts [41].

3.7. Antidepressant effect

The rats’ depression model by chronic psychological stimulation was used to observe the influence of L.brownii saponins on the blood COR, ACTH [42]. In the study, saponins from L. brownii could reduce the elevated COR and ACTH of depression model rats, indicated that there existed a significant dose-effect relation between the anti-depressant effect and the contents of L. brownii saponins. Wang et al. [43] studied the duration of immobility within 4 min which recorded in tail suspended experiment and forced swimming experiment. The suspended experiment and forced swimming experiment showed that compared with normal control group, the duration of immobility within 4 h in tail suspended experiment and force swimming experiment was decreased in L.brownii saponins extract medium-dose and low-dose groups. The L. brownii saponins have certain anti-depressant activity in mice.Gao et al. [44] reported that total saponins fraction possessed antidepression combined with IBS action of rat by filling stomach with different dosage and showed certain dose-effect relationship.

3.8. Anti-fatigue and anti-hypoxia

He et al. [45] observed the anti-fatigue pharmacological effect of L. lancifolium polysaccharide in mice, and found that lily polysaccharide could lengthen the mice’s swimming time and enhance the activity of SOD and reduce the content of MDA. So polysaccharide from lily could en-hance mice’s anti -fatigue capability.

4. Future perspectives and conclusion

The literatures indicate that saponins, flavonoids and polysaccharides are the main and active ingredients in the genus Lilium.Recently, more and more researchers were interested in pharmacological effects of the Lilium. The research on chemical constituents is mainly concentrated on the bulbs of Lilium, few studies on their flower. The pharmacological effects of compounds isolated from Lilium are less researched, and the mechanism is not clearly.

In view of this, in the future research and rational development of Lilium, we could start from the following points: (i) identify chemical components in Lilium by new techniques, such as UPLCQ-TOF-MS; (ii) systematic study of the pharmacological effects and mechanisms of the chemical constituents of Lilium, including the flower parts of Lilium and the mechanism should be explored further; (iii) it is significance for its in-depth research and development in food, health care products and related drugs.

Acknowledgements

This work was supported by Science and Technology Development Program of Henan Province (192102110112) and Science and Technology Project of Kaifeng (1908005).