Phytochemical and pharmacological studies on Solanum lyratum: a review

1 Introduction

Solanum lyratum Thunb. is a herbaceous vine of the family Solanaceae, with white villous hairs on violin-shaped leaves and stems, distributed throughout China, Japan, Korea, etc. [1]. S. lyratum prefers a warm and humid environment and is distributed widely in valley grass, roadside and field. S. lyratum is commonly known as "Bai-Mao-Teng" in traditional Chinese medicine and "Back-Mo-Deung" in traditional Korean medicine [2]. In traditional Chinese medicine (TCM), S. lyratum has the functions of clearing heat and removing toxicity ("Qingre Jiedu" in Chinese), dispelling wind and eliminating dampness ("Qufeng Lishi" in Chinese). Therefore, S. lyratum has been traditionally prescribed mainly for healing jaundice, edema, gonorrhea, cholecystitis, phlogosis, and rheumatoid arthritis [3]. Modern phytochemistry and pharmacological studies revealed that S. lyratum consists of a variety of active ingredients, including steroidal saponins, steroidal alkaloids, terpenoids, lignans, and flavonoids [4]. And steroidal saponins and steroidal alkaloids have been used in the modern clinic to treat various cancers, especially lung cancer, cervical cancer, and liver cancer [3].

In the last ten years, dozens of reviews on the research progress of Solanum plants have been published, occasionally referring few phytochemistry and pharmacological reports on S. lyratum [5-8] (Fig. 1). However, there is no specialized and systematic research review on the S. lyratum species, especially on its phytochemistry and pharmacological aspects. Thus, this review intends to provide an updated and comprehensive summary on the botanical characterization, phytochemistry, and pharmacological and toxicity studies of S. lyratum to fill a gap in the research review of this plant and provides for a better exploration and application of S. lyratum. The literature for this manuscript was obtained from reports published from 1981 to Mar 2022.

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2 Botany

S. lyratum is a herbaceous vine of the family Solanaceae, well-known native in China, India, Japan, Korea, North Vietnam, and the Indochina Peninsula [1]. This plant grows in a warm and humid environment, prefers light and fertile organic soil, and is distributed on hillsides, grass, ditch, and roadside at altitudes of 100–850 m. S. lyratum is 0.5–1 m long, and its stems and twigs are densely covered with white villous hairs [2]. The botanical characteristics of S. lyratum were recorded in many classics of TCM, including "Tang Xinxiu Bencao" in the Tang Dynasty [9], "Zhenglei Bencao" in the Song Dynasty [10], and "Compendium of Materia Medica" in Ming Dynasty [11].

S. lyratum is commonly known as "Bai-Mao-Teng" in TCM. It should be noted that there are several adulterants of S. lyratum, including Aristolochia mollissima, Paederia scandens (Lour.) Merr. and Solanumrr dulcamara L., all of which are so called as "Bai-Mao-Teng" that it may easily cause an event of medication confusion [12]. For example, a misuse of A. mollissima instead of S. lyratum, has ever led to a renal failure event in patients of Hong Kong [13]. Those adulterants closely resemble S. lyratum in botanical morphology, it is very important to seek advice from a professional or pharmacist before use. The plant morphological characteristics of S. lyratum are as follows: Root is slender and cylindrical. Leaves are mostly violin-shaped, with 3.5–5.5 cm long and 2.5–4.8 cm wide, and the base is 3–5 cm deep-lobed. Lateral lobes are smaller near the base. Middle lobes are usually larger oval and tend to apex acuminate. Both sides of the leaves were covered with white shiny villous hairs, and the levels own midvein and lateral veins. Flowers are sparsely terminal inflorescence or extra-axillary inflorescence, and the pedicel is approximately 2–2.5 cm long. Corollas are blue-purple or white and corollas are about 1.1 cm in diameter. Fruits are spherical and about 8 cm in diameter, which become reddish-black when it matures. Seeds are nearly disc-shaped and about 1.5 mm in diameter. The flowering period of S. lyratum is between May and June, while the fruiting period is between August and October. Significantly, the suitable harvest time has been recommended to be between October and December (Fig. 2) [14, 17].

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3 Traditional uses

In TCM, S. lyratum has been considered as one of the "Top-grade" herbs in "Shennong Bencao Jing" (100 BC-200 AD, Han Dynasties) [18]. For centuries, it has been used for the treatments of cold and fever, malaria, jaundice, nephritis, edema, cholecystitis, rheumatoid arthritis, vaginitis, uterine erosion, and several types of cancer including lung cancer, cervical cancer, and gastric cancer [19, 21]. External applications of S. lyratum [22] have been recorded to treat carbuncle, furuncle and swollen poison, etc. In the "Compendium of Materia Medica", S. lyratum is documented [11] to have the effects of clearing heat, detoxification, and expelling rheumatism, for the treatment of rubella, erysipelas, malaria, cancer, etc. The traditional uses of S. lyratum in Korea, Japan, and the Indochina Peninsula focused mainly on the treatments of several types of cancers, warts, herpes, pyretic syndrome, diarrhea, etc., as summarized in Table 1.

4 Phytochemistry

So far, hundreds of phytochemicals have been isolated and identified from S. lyratum, including steroidal alkaloids (1–41), steroids and steroidal saponins (42–101), terpenoids (102–153), nitrogenous compounds (154–178), phenylpropanoids (179–227), flavonoids (228–258) and other compounds (259–270). Among them, steroidal alkaloids, steroidal saponins and terpenoids are so often recognized as the main active constituents of S. lyratum [32, 33].

4.1 Steroidal alkaloids

Steroidal alkaloids in S. lyratum include mostly solanidane (27 carbon atoms), spirosolane (27 carbon atoms) and solayraine (27 carbon atoms) (Fig. 3) types of nitrogenous sapogenins. The glycone moieties are most likely to be substituted at C-3 position of the nitrogenous sapogenin aglycone. D-glucose (D-Glc), D-galactose (D-Gal), D-xylose (D-Xyl), and L-rhamnose (L-Rha) are the common components of the glycones, in which one to four monosaccharides linked linearly or with one or more branched chains, as shown in Fig. 4.

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Steroidal alkaloid is one of the characteristic ingredients of Solanum plants [34]. Until now, a total of forty-one steroidal alkaloids (1–41) have been identified from S. lyratum (Table 2). It is noteworthy that there were two epimers for the most abundant spirosolane-type steroidal alkaloids in Solanum plants, one is 22-β N type (1–4, 6–11) [33, 35-39] and the other is 22-α N type (5, 13–22) [24, 35-40] in clue of the existence of an oxa-azaspirodecane system. In addition, solanidane-type steroidal alkaloids (23–30) [35, 36, 41, 42], with a unique octahydroindolizine complex cholestane skeleton, have also been found to be existed in this plant. Further, other unusual spirosolane-type glycoalkaloids with a deformed E and F rings (piperidine, pyridine or other derived F rings) have been also occasionally discovered from S. lyratum, exemplified by compounds 31–41 [39, 43], as shown in Fig. 5.

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4.2 NMR characteristics of steroidal alkaloids

Representative NMR data of the common steroidal alkaloids and saponins from S. lyratum were summarized in Tables 3, 4, 5 and 6. ¹³C NMR spectra of the spirosolane-type, spirostanol-type, and furostanol-type steroidal alkaloids or saponins, with intrinsic twenty-seven steroid skeleton, normally exhibit characteristic carbon signals for C-22 around δ_C 98.0 [35], 109.0 [22], and 112.0 [40] ppm, respectively. In addition, in the high field of the ¹H NMR spectra of steroidal alkaloids and saponins, the resonance signals of methylene and methine protons are generally around δ_H 1.1–3.0, while the four methyl groups show proton resonances at δ_H 0.6–1.4, among which there are two singlets for the methyl groups at C-18 and C-19 [44], and two doublets for those methyls at C-21 and C-27 [45].

In the ¹³C NMR spectra, spirosolane-type of steroidal alkaloids, characterizing a A/B/C/D ring system of C₂₇ steroid scaffold (Table 3 and Fig. 6), show twenty-seven carbon signals generally containing four methyl carbon signals around at δ_C 16.0 (C-18), 19.0 (C-19), 15.0 (C-21), and 19.0 (C-27). Steroidal alkaloid can be simply recognized to be a steroidal saponin with a replacement of the oxygen atom in F ring by a nitrogen atom, resulting in the high-field shifting of the carbon chemical shifts of C-22 and C-26, from δ_C 109.0 and 67.0 to 98.0 and 47.5, respectively [30, 39, 40, 46]. In the ¹³C NMR spectra of the solanidane-type steroidal alkaloids, there were four methyl carbon signals around at δ_C 16.0 (C-18), 12.0 (C-19), 19.0 (C-21), and 22.0 (C-27) [30, 38, 39, 46] besides those characteristic carbon signals around at δ_C 69.0 (C-16), 78.0 (C-22) and 58.0 (C-26) [35, 41]. And, chemical shifts of the glycosyl anomeric carbon are at δ_C 100.0–108.0, especially when the glycosidation taking place at OH-3 of the steroidal alkaloids [47-49].

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4.3 Steroids and steroidal saponins

4.3.1 Steroids

Cholestanol, containing a perhydrocyclopentenophenanthrene moiety (rings A, B, C and D) with a acyclic side-chain, has been considered as the precursor of furostanol and spirostanol (Fig. 7). At present, thirty steroids have been isolated from S. lyratum (42–71) (Table 4) [35, 36, 39, 47, 48, 50, 52].

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4.3.2 Steroidal saponins

Steroidal saponins reported in S. lyratum are well-known characterized by possessing the steroid-derived aglycones normally consisting of a hydrophobic C₂₇-skeleton of cholestane with an oxygen fused into the F ring, exemplified by the spirostanol (27 carbon atoms), furostanol (27 carbon atoms) and cholestanol (27 carbon atoms) as the most common scaffolds. Nevertheless, C₂₁- steroidal saponins have also been reported to be existed in S. lyratum (Fig. 8). As is known, the remaining hydrophilic glycone unit of a steroidal saponin has been frequently reported to be substituted at the C-3 position of the sapogenin. D-Glc, D-Gal, D-Xyl, L-Rha, and L-arabinose (L-Ara) are the common members of the glycones, in which one to five monosaccharides linked linearly or with one or more branched chains, as shown in Fig. 9.

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Till now, a total of thirty steroidal saponins (72–101) have been identified from S. lyratum (Table 5 and Fig. 10). Most of the isolated steroidal saponins of S. lyratum belong to the spirostane-type (72–87) [4, 22, 46, 47, 49], C₂₁-steroidal subclass (89–93) [40, 46, 51] and furostanol-type (94–101) [22, 23, 40, 46]. Notably, when F-ring of a spirostanol is ring-opened, a new sapogenin skeleton of a furostanol is then afforded. As far as we know, the furostanol and its derivatives are the only reported ring-opened steroidal saponins ever isolated from S. lyratum up to now (94–101) [22, 23, 40, 46].

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4.4 NMR characteristics of steroidal saponins

In short, in the ¹³C NMR spectra, spirostanol and furostanol-types of steroidal saponins, characterizing a A/B/C/D ring system of C₂₇-steroidal scaffold, show twenty-seven carbon signals generally containing four methyl carbon signals at δ_C 16.0 (C-18), 19.0 (C-19), 14.0 (C-21), and 17.0 (C-27) or two olefinic carbon signals at δ_C 140.0 (C-5) and 120.0 (C-6) [47, 49] (Table 6 and Fig. 11). The carbon chemical shift of CH₃-19 will down-field shifted from δ_C 12.0 to δ_C 19.0 [47, 49], when the two methylenes at C-5, 6 being dehydrogenated (-H₂) to form a double bond [53]. The carbon resonances of C-16, 17, 22 (spiroketal carbon) and C-26 in a spirostanol-type steroidal saponin, were at about δ_C 81.0, 62.0, 109.0 and 67.0, respectively [47, 49], while those in a furostanol-type steroidal saponin were at about δ_C 81.0, 64.0, 112.0 and 75.0, respectively [22, 48]. It is worth noting that the proton chemical shift (δ_H) difference (∆_ab = δ_a-δ_b) of the two geminal protons (Ha and Hb) of CH₂-26 has been recognized for ascertaining 25R or 25S orientation of the CH₃-27 [∆_ab ≤0.48 for 25R, ∆_ab≥ 0.57 for 25S] in the spirostanol and furostanol-types of steroidal saponins [45, 54, 55]. Similarly, the abovementioned empirical law for configuration assignment of C-25 applies equally well to spirosolane-type of steroidal alkaloids (Table 3).

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4.5 Terpenoids

So far, fifty-one terpenoids, including sesquiterpenoids, monoterpenoids and triterpenoids (Table 7 and Fig. 12), have been isolated from S. lyratum. Among them, sesquiterpenoids are the most common terpenoids in S. lyratum, including eudesmane-type sesquiterpenoids (102–119) [52, 56-64] and the related derivatives (120–128) [39, 47, 58, 60, 62], monocyclic sesquiterpenoids (129–139) [25, 47, 56, 58, 62], vetispirane-type sesquiterpenoids (140–147) [1, 56, 62, 64], and guaiane-type sesquiterpenoids (148) [47]. In addition to the abovementioned constituents, two monoterpenoids (149–150) and three pentacyclic triterpenoids (151–153) have also been found in S. lyratum.

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4.6 Nitrogenous compounds

Nitrogenous compounds found in S. lyratum include arylamides (154–167) [36, 47, 65-68], aliphatic amides (168–169) [47], and other nitrogenous compounds (170–178) (Table 8 and Fig. 13) [47, 65].

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4.7 Phenylpropanoids

4.7.1 Lignans

Till now, a total of twenty-eight lignans (179–205) have been isolated from S. lyratum (Table 9, Fig. 14), including simple lignans (184, 188) [32, 47, 68], lignanolides (185) [47], cyclolignans (179–183) [32, 47], monoepoxyligans (187), bisepoxylignans (189–193) [32, 47, 66], and norlignans (203–205) [20, 32, 47]. Lignans with one or more isovaleroyloxyl substitution, as exemplified by compounds 195–204 [20], has been frequently uncovered from S. lyratum in recent years. Notably, neolignans including compounds 186–187 [47], and 195–202, exhibited neuroprotective effects against human neuroblastoma SH-SY5Y cell injury induced by H₂O₂ [20].

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4.7.2 Coumarins, simple phenylpropanoids and their derivatives

So far, seven coumarins (206–212) and eight simple phenylpropanoids (213–220) and their derivatives (221–227) have been isolated from S. lyratum as shown in Table 10 and Fig. 15.

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4.8 Flavonoids

Thirty-one flavonoids (228–258) have been reported from S. lyratum (Table 11, Fig. 16), including flavonols (228, 230, 232–236, 246–249, 251, 256–258) [47, 54, 68, 70-72], flavanones (229, 245) [47, 72], isoflavones (237–244, 250) [47, 54, 69, 71], chalcones (231) [47], and isoflavan-4-ols (252–255) [73], usually in the form of flavonoid glycoside with C-3 or C-7 substitution of the monosaccharides (D-Glc, D-Gal, D-Xyl, L-Rha, and L-Ara) and disaccharides [Rha (1 → 6) Glc, Xyl (1 → 2) Glc, Api (1 → 2) Glc and Xyl (1 → 6) Glc].

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4.9 Other compounds

In addition to the abovementioned constituents, other compounds including anthraquinones and fatty acids have also been isolated from S. lyratum (Table 12, Fig. 17).

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5 Pharmacology

Water decoction of the whole herb of S. lyratum was commonly used to treat various diseases, and the fresh whole herb was mashed to remedy herpes and warts for external use. Modern pharmacological evaluations revealed that extracts, fractions or compounds isolated from S. lyratum possessed various therapeutic potentials. Recently, the plant has been most extensively studied for its anti-cancer pharmacological properties. Meanwhile, other pharmacological effects such as anti-inflammatory, anti-oxidant, anti-microbial, anti-allergy, and hepatoprotective activities of S. lyratum have also been assessed, as summarized in Table 13.

5.1 Anti-cancer

5.1.1 Extracts and fractions

The heat-clearing and detoxicating property of S. lyratum is favorable in the treatment of cancer [17, 19, 21]. It has been reported that S. lyratum treats various cancers by inhibiting the tumor growth [74, 75], enhancing immunity [76, 78] and inducing apoptosis via activating both extrinsic and intrinsic apoptotic pathways [27, 34, 79].

In S₁₈₀ tumor-bearing mice, both ethanol and aqueous extracts of S. lyratum could improve immune function and exhibited anti-cancer potential with certain tumor inhibitory effect by improving the activities of natural killer (NK) and cluster of differentiation 4 (CD4) cells, and elevating the contents of serum Interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α) [77, 78, 80]. Total alkaloids from S. lyratum (SLTA, 24 mL/kg) could inhibit the tumor growth in mice with Lewis lung cancer, and when combined with cisplatin, a synergistic effect had been shown to down-regulate the mRNA expression of Notch1, Notch3 and Jagged1 in Notch signaling pathway [81]. In addition, the hexane fraction of the methanol extract (50 mg/kg) of S. lyratum showed similar inhibitory activity on tumor growth in mice with Lewis lung carcinoma tumor, potentially acting through up-regulating Fas, caspase-8, caspase-3, and p53, and down-regulating FasL and B-cell lymphoma-2 (Bcl-2) in the mitochondrial pathway [27, 79].

Further studies revealed that the 70% ethanol extract of S. lyratum (SLE) could suppress tumor angiogenesis in vitro by repressing migration, invasion, and tube formation of tumor-derived vascular endothelial cells (Td-ECs). The mechanism of the anti-angiogenic effect of SLE may be related to the inhibitory activity of vascular endothelial growth factor (VEGF) via reducing the number of lipid rafts in the cell membrane [43] and interfering with the lipid rafts by agglutinating cell membrane cholesterol [75]. These changes led to the inhibition of VEGFR2 phosphorylation and activation of its downstream signaling molecules, thereby inhibiting tumor angiogenesis [43]. In addition, SLTA could induce apoptosis of lung carcinoma A549 cells by inhibiting the nuclear factor-kappa B (NF-κB) signaling pathway [82], while glycoalkaloids of S. lyratum (SLGS) significantly inhibited the activity of A549-derived exosomes with IC₅₀ = 99.59 μg/mL [43].

5.1.2 Compounds

The cytotoxic tests involved in most in vitro studies of S. lyratum have shown that the compounds isolated from S. lyratum possess a good cytotoxic potential for several cancer cells.

In the process of cytotoxic investigation by MTT assay and flow cytometry, the characteristic ompounds 5, 8, 21 from the methanolic extract of S. lyratum showed significant cytotoxicities against huh-7 and HepG2 cell lines with IC₅₀ values of 9.6 ± 0.5 and 10.8 ± 0.1 μM, 11.7 ± 0.3 and 19.4 ± 0.4 μM, and 10.3 ± 1.5 and 91.8 ± 9.4 μM, respectively. The mechanism was attributed to cell cycle arrest at S-phase [83]. while sesquiterpenoids 104, 106, 108, 109, 116, 118, 124, 126, 127, 132, 135, 142, and 143 were evaluated for their cytotoxicity activities with IC₅₀ 1.9–8.6 μg/mL against HONE-1 cells [1, 57, 58, 60, 61]. Among them, compounds 126–127 showed potent cytotoxicity activity with IC₅₀ 2.1 and 1.9 μg/mL, slightly weaker than the positive controls etoposide and cisplatin (IC₅₀ 1.6 and 1.7 μg/mL) [1, 57, 58, 60, 61]. Notably, the IC₅₀ differences of the positive controls (etoposide and cisplatin) may have been caused by the operation of the author, so the experimental cytotoxicity results need to be further verified.

Further, the cytotoxic potentials of nine steroids saponins and alkaloids (36, 72, 73, 81–83, 86) against ASGC7901 and BEL-7402 cancer cell lines were tested, and compounds 72, 73, and 83 showed attractive antiproliferative activities with respective IC₅₀ values of 6.39–9.11 μM, 3.19–8.86 μM and 0.39–1.16 μM, as compared with IC₅₀ values of 0.17–5.34 μM and 8.15–23.06 μM of positive control adriamycin and 5-fluorouracil, respectively [22]. Another, a glycoalkaloid (10) exhibited significant cytotoxicity against mouse colon cancer CT-26 cells with IC₅₀ 3.5 μM, as compared to IC₅₀ values of 1.8 μM of positive control etoposide, in clue of the inhibition on the expressions of survivin and NF-κB/p65 and the induction of the AIF nuclear translocation [74]. Besides those characteristic constituents of S. lyratum, four other compounds 267–270 have been evaluated their cytotoxicities against hepatocellular carcinoma cell lines, and 267 and 269 showed significant inhibitory activities against HepG2 cell lines with IC₅₀ values of 46.07 μM and 45.39 μM, respectively [26].

5.2 Anti-inflammatory

5.2.1 Extracts and fractions

Inflammation is closely related to cancer disease [84]. The detoxication and detumescence effect of S. lyratum can be used as a supplement to modern anti-inflammatory agents.

Total alkaloid fraction from the 70% ethanol extract of S. lyratum significantly relieved the inflammatory effect of the lipopolysaccharide-stimulated RAW264.7 macrophages for 48 h. Further evaluation revealed that this total alkaloid fraction could inhibit the release of Cyclooxygenase-2 (COX-2), and Prostaglandin E2 (PGE2) from lipopolysaccharide-stimulated RAW264.7 macrophages [85].

5.2.2 Compounds

In vitro, diosgenin-3-O-α-L-rhamnosyl-(1 → 2)-O-β-D-glucopyranosiduronic acid (75) could inhibit the lipopolysaccharide-induced expression of intercellular cell adhesion molecule-1 (ICAM-1) protein at 16 μg/mL, and exhibited anti-inflammatory activities [86]. In addition, in the anti-inflammatory experiments with polymorphonuclear leukocytes of rats (rat PMNs) with ginkgolide B as the positive control, compounds 139, 207–210 showed significant β-glucuronidase inhibitory activities with IC₅₀ values range of 6.3–9.1 μM [25], while four 4-hydroxyisoflavans 252–255 afforded anti-inflammatory activities with inhibitory ratios release of β-glucuronidase in the range of 30.3–38.6% at 10 μM [73].

5.3 Antioxidant activity

5.3.1 Extracts

Modern pharmacological studies have revealed that cancer or other diseases are primarily associated with the production and accumulation of excessive free radicals [87], which are commonly produced by the continuous contact between our body and the outside world. Thus, antioxidants can effectively relieve the harmful effects of free radicals. It has been confirmed that S. lyratum extracts and compounds possess significant antioxidant activities.

50% Ethanol extract of S. lyratum (10 μg/mL) could protect against oxidized low-density lipoprotein (Ox-LDL)-induced injury in cultured human umbilical vein endothelial cells (HUVECs) by direct antioxidative action [88]. In the DPPH radical-scavenging tests in vitro using the spectrophotometric method with vitamin C as the positive control, the ethanol and ethyl acetate extracts from S. lyratum showed antioxidative potential with IC₅₀ of 0.230 mg/mL and 1.010 mg/mL, respectively [89].

5.3.2 Compounds

Five flavones 236, 248, 249, 251, and 258 from the ethanol extracts of S. lyratum possessed the capability of scavenging DPPH free radicals with IC₅₀ values of 2.56–21.33 μg/mL [70]. It seems that the glycosidation of the flavone C-3 and C-5 is essential for the scavenging of DPPH free radicals.

5.4 Antimicrobial

5.4.1 Extracts and fractions

There were reports verified the antibacterial potential of S. lyratum extracts. For example, the water-soluble polysaccharide of S. lyratum exerted a significant antibacterial activity against Staphylococcus aureus, Salmonella, Pasteurella, Escherichia coli, Candida albicans, and Pseudomonas aeruginosa. The inhibition zone diameters were > 13 mm at a concentration of 120 mg/mL [90].

5.4.2 Compounds

Several gram-positive bacteria (S. aureus and Enterococcus faecalis) were used to assess the antimicrobial activity of a new compound 266 from S. lyratum, with minimum inhibitory concentration (MIC) values of 2.0 μM (1.08 μg/mL) and 10.0 μM (5.44 μg/mL), respectively [21].

5.5 Other activities

The extracts of S. lyratum showed a therapeutic potential on the tetrachloride-induced liver damage in rats, by decreasing significantly the activity of transaminase in rat serum [91, 92]. Further, there was an in vivo report revealed that the aqueous extract of S. lyratum possessed strong antiallergy activity [93] by inhibiting dose-dependently the histamine release from the rat peritoneal mast cells and decreasing the mRNA expression of L-histamine decarboxylase [94]. Lastly, the ethanol extract of S. lyratum possesses molluscicidal activities with IC₅₀ values of 30–50 mg/mL [95].

Notably, several Chinese patent prescriptions with S. lyratum as the major component herb, showed significant anticancer efficacies in reported clinic trials. For example, 'Baiyingtang' (composed of S. lyratum, Herba Patriniae, Houttuynia cordata, Lilium brownii var., Asparaguscochinchinensis(Lour.)Merr.) retention enema could reduce plasma transforming growth factor-β1 (TGF-β1), interleukin-6 (IL-6) levels and increase plasma IL-4 levels in patients with pelvic tumors receiving radiotherapy [96]. 'Baiying decoction' (composed of S. lyratum, Ophiocordyceps sinensis, Houttuynia cordata, Lilium brownii var., Asparaguscochinchinensis(Lour.)Merr.) treatment could ameliorate the marrow suppression and the quality of life in patients with advance non-small cell lung cancer, with high safety [97].

6 Toxicology

Up to now, the toxicity studies of the isolated compounds and extracts of S. lyratum may have been overlooked by researchers, while few studies have found the toxic potential of Solanum glycoalkaloid [125]. The toxic properties of Glycoalkaloids including solamargine (8) have been reviewed by Sinani AI S.S.S. et al. are due to (1) their ability to disrupt cell-membrane function by complexation with membrane 3β-hydroxysterols to form aggregates and damage the membrane integrity [126], (2) their anti-acetylcholinesterase activity on the central nervous system [126, 127], and (3) changes caused by them in active transport of ions through membranes, resulting in disorders in general body metabolism [126]. Additionally, in the acute toxicity experiment with rats, neither mortality nor clinical alterations were shown, except for the mild transient diarrhea with 70% ethanol extract of S. lyratum at 5000 mg/kg [31]. In future, more pharmacological evidences should be sought on the possible adverse effects and the toxicities of S. lyratum extracts and their bioactive constituents when used in treatments of acute, subchronic, or chronic diseases. Further, more clinical trials must be conducted to evaluate the safety and clinical efficacy of S. lyratum in humans.

7 Conclusion

This review summarized the latest advancements of S. lyratum in botany, traditional uses, phytochemistry, pharmacology, and toxicology. Phytochemical and pharmacological studies have validated many modern usages of this plant. A total of 270 chemical constituents have been isolated from S. lyratum, including steroidal alkaloids, steroidal saponins, terpenoids, nitrogenous compounds, phenylpropanoids, flavonoids, etc. It has been popular in traditional practices due to its potential efficacy on cancer and inflammation, and showed important biological properties in scientific investigations. In the phytochemical analysis of S. lyratum extracts, aqueous and ethanol extracts were commonly acquired from S. lyratum, whose main components included total alkaloids and total saponins. In modern pharmacological studies, compounds and extracts from S. lyratum were evaluated in vivo and in vitro, and their anticancer and cytotoxic, anti-inflammatory, antioxidant, antimicrobial, anti-allergy, and hepatoprotective activities have been demonstrated. However, many aspects of S. lyratum have not been studied yet and some relative studies on S. lyratum should be further explored in the following aspects in the future.

Firstly, the pharmacological activities are mostly proven from the aqueous and ethanol extracts from S. lyratum, while insufficient pharmacological studies have been conducted on pure compounds. In addition, some activities are lacking comparisons to standards or positive and negative controls. Other studies especially on anticancer and anti-inflammatory activities have shown that the IC₅₀ values of the test extracts/compounds of S. lyratum are above 200 μg/mL, which can be considered that such extracts/compounds are actually poorly active.

Secondly, pharmacological studies were mostly performed in cell models and animals while investigations in humans have been seldomly performed. Hence, the future investigation should be focused on the bioactivity of S. lyratum in various clinical studies with humans. In addition, the DPPH radical scavenging test and antimicrobial activities also should be guaranteed in vivo, instead of solely relying on method models in vitro.

Thirdly, global quality control standards of S. lyratum are needed urgently and should be improved. Simultaneous qualitative and quantitative measures are recommended to be used for those major active constituents of S. lyratum.

Finally, in toxicological studies of S. lyratum, no unequivocal proof of the toxicological activities in human exists. Further, relationship studies between systematic toxicity and safety evaluation are still needed to assure safety for clinical application in the future. Pharmacological effects of S. lyratum have been demonstrated by ethanol and aqueous extracts of high doses, the effectiveness of high doses extracts in treating diseases provides the possibility of finding active compounds. Therefore, it is important to study the therapeutic window (the range between the doses that produce the desired therapeutic effect and doses that produce toxicity) and the long-term in vivo toxicity for further research on S. lyratum.

In summary, S. lyratum can be considered as an important and valuable resources for human's health. Further research is needed in terms of quality control, toxicity and pharmacological mechanism to provide a theoretical basis for exploitation of the medicinal functions of S. lyratum.

Notes

Acknowledgements

The authors are grateful to the staff of researchers at the State Key Laboratory of Component-based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine. The authors acknowledge the support of the Tianjin Committee of Science and Technology of China, the National Key Research and Development Project of China, and the Important Drug Development Fund, Ministry of Science and Technology of China.

Author contributions

The manuscript was prepared by Y. Zhao. Y. Zhao, W.-K. Gao, and X.-D. Wang completed the writing of this review. The research work was supported by the projects of H.-H. Wu. All the authors reviewed the final version of the manuscript and approve it for publication. To the best of our knowledge and belief, this manuscript has not been published in whole or in part nor is it being considered for publication elsewhere. All authors have seen the manuscript and approved to submit to your journal. All authors read and approved the final manuscript.

Funding

This study was funded by a grant (No. 21ZYJDJC00080) from the Tianjin Com- mittee of Science and Technology of China, the National Key Research and Development Project of China (No. 2018YFC1707904, 2018YFC1707905, and 2018YFC1707403) and the Important Drug Development Fund, Ministry of Science and Technology of China (No. 2018ZX09735-002).

Declarations

Competing interests

The authors declare no conflict of interest.