Phytochemical and pharmacological studies on Solanum lyratum: a review

Yue Zhao, Wen-Ke Gao, Xiang-Dong Wang, Li-Hua Zhang, Hai-Yang Yu and Hong-Hua Wu

Abstract Solanum lyratum is one of the temperate plants, broadly distributed in Korea, China, Japan, India, and South-East Asia and well-documented in those oriental ethnic medicine systems for curing cancers, jaundice, edema, gonorrhea,cholecystitis, phlogosis, rheumatoid arthritis, etc. This review systematically summarized the research progress on S.lyratum respecting the botany, traditional uses, phytochemistry, pharmacology, and toxicology to increase people’s in-depth understanding of this plant, by data retrieval in a series of online or off-line electronic databases as far as we can reach. Steroidal saponins and alkaloids, terpenoids, nitrogenous compounds, and flavonoid compounds are the main chemical constituents in S. lyratum. Among them, steroidal alkaloids and saponins are the major active ingredients ever found in S. lyratum, exerting activities of anti-cancer, anti-inflammation, anti-microbial, anti-allergy, and antioxidation in vivo or in vitro. As a result, S. lyratum has been frequently prescribed for the abovementioned therapeutic purposes, and there are substantial traditional and modern shreds of evidence of its use.

Keywords: Solanum lyratum Thunb., Steroidal saponins, Steroidal alkaloids, Anti-cancer, Toxicity

1 Introduction

Solanum lyratumThunb. is a herbaceous vine of the family Solanaceae, with white villous hairs on violinshaped leaves and stems, distributed throughout China,Japan, Korea, etc. [1].S. lyratumprefers a warm and humid environment and is distributed widely in valley grass, roadside and field.S. lyratumis 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. lyratumhas the functions of clearing heat and removing toxicity(“Qingre Jiedu” in Chinese), dispelling wind and eliminating dampness (“Qufeng Lishi” in Chinese). Therefore,S. lyratumhas been traditionally prescribed mainly for healing jaundice, edema, gonorrhea, cholecystitis,phlogosis, and rheumatoid arthritis [3]. Modern phytochemistry and pharmacological studies revealed thatS. lyratumconsists 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 ofSolanumplants have been published, occasionally referring few phytochemistry and pharmacological reports onS. lyratum[5–8] (Fig. 1).However, there is no specialized and systematic research review on theS. lyratumspecies, 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 ofS. lyratumto fill a gap in the research review of this plant and provides for a better exploration and application ofS. lyratum. The literature for this manuscript was obtained from reports published from 1981 to Mar 2022.

Fig. 1 Reviews of Solanum species published in last ten years

Fig. 2 Plant morphology of S. lyratum, (a) leaves, (b) flowers (c) fruits (d) the whole plant [data originated from the Plant Photo Bank of China (http://ppbc. iplant. cn/), accessed 10 April 2022]

2 Botany

S. lyratumis 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. lyratumis 0.5–1 m long, and its stems and twigs are densely covered with white villous hairs[2]. The botanical characteristics ofS. lyratumwere 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].

Fig. 3 Three types of steroidal alkaloid aglycones reported in S. lyratum

S. lyratumis commonly known as "Bai-Mao-Teng"in TCM. It should be noted that there are several adulterants ofS. lyratum, includingAristolochia mollissima,Paederia scandens(Lour.) Merr. andSolanumrrdulcamaraL., 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 ofA. mollissimainstead ofS. lyratum, has ever led to a renal failure event in patients of Hong Kong [13]. Those adulterants closely resembleS. lyratumin botanical morphology, it is very important to seek advice from a professional or pharmacist before use. The plant morphological characteristics ofS. lyratumare 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 ofS. lyratumis 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].

3 Traditional uses

In TCM,S. lyratumhas 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 ofS. lyratum[22] have been recorded to treat carbuncle, furuncle and swollen poison, etc. In the "Compendium of Materia Medica",S. lyratumis 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 ofS. lyratumin 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 fromS. 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 ofS.lyratum[32, 33].

Table 1 Traditional uses of S. lyratum

Fig. 4 Glycones of steroidal alkaloids reported in S. lyratum

4.1 Steroidal alkaloids

Steroidal alkaloids inS. lyratuminclude 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.

Steroidal alkaloid is one of the characteristic ingredients ofSolanumplants [34]. Until now, a total of fortyone steroidal alkaloids (1–41) have been identified fromS. lyratum(Table 2). It is noteworthy that there were two epimers for the most abundant spirosolane-type steroidal alkaloids inSolanumplants, one is 22-β Ntype (1–4, 6–11) [33, 35–39] and the other is 22-α Ntype (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 fromS. lyratum,exemplified by compounds 31–41 [39, 43], as shown in Fig. 5.

4.2 NMR characteristics of steroidal alkaloids

Representative NMR data of the common steroidal alkaloids and saponins fromS. lyratumwere summarized in Tables 3, 4, 5 and 6.13C NMR spectra of the spirosolanetype, spirostanol-type, and furostanol-type steroidal alkaloids or saponins, with intrinsic twenty-seven steroid skeleton, normally exhibit characteristic carbon signals for C-22 aroundδC98.0 [35], 109.0 [22], and 112.0 [40] ppm,respectively. In addition, in the high field of the1H NMR spectra of steroidal alkaloids and saponins, the resonance signals of methylene and methine protons are generally aroundδH1.1–3.0, while the four methyl groups show proton resonances atδH0.6–1.4, 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 the13C NMR spectra, spirosolane-type of steroidal alkaloids, characterizing a A/B/C/D ring system of C27steroid scaffold (Table 3 and Fig. 6), show twenty-seven carbon signals generally containing four methyl carbon signals around atδC16.0 (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, fromδC109.0 and 67.0 to 98.0 and 47.5, respectively [30, 39, 40, 46]. In the13C NMR spectra of the solanidane-type steroidal alkaloids, there were four methyl carbon signals around atδC16.0 (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 atδC69.0 (C-16), 78.0 (C-22) and 58.0 (C-26) [35, 41]. And,chemical shifts of the glycosyl anomeric carbon are atδC100.0–108.0, especially when the glycosidation taking place at OH-3 of the steroidal alkaloids [47–49].

Fig. 5 Chemical structures of steroidal alkaloids from S. lyratum

4.3 Steroids and steroidal saponins

4.3.1 Steroids

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

4.3.2 Steroidal saponins

Steroidal saponins reported inS. lyratumare 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 inS. 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.

Table 2 Steroidal alkaloids isolated from S. lyratum

Table 2 (continued)

Fig. 6 Representative six common steroidal alkaloids

Till now, a total of thirty steroidal saponins (72–101)have been identified fromS. lyratum(Table 5 and Fig. 10). Most of the isolated steroidal saponins ofS.lyratumbelong 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 fromS. lyratumup to now (94–101) [22, 23, 40, 46].

4.4 NMR characteristics of steroidal saponins

In short, in the13C 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 atδC16.0 (C-18), 19.0 (C-19), 14.0(C-21), and 17.0 (C-27) or two olefinic carbon signals atδC140.0 (C-5) and 120.0 (C-6) [47, 49] (Table 6 and Fig. 11). The carbon chemical shift of CH3-19 will downfield shifted fromδC12.0 toδC19.0 [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 aboutδC81.0, 62.0, 109.0 and 67.0, respectively [47, 49], while those in a furostanoltype steroidal saponin were at aboutδC81.0, 64.0, 112.0and 75.0, respectively [22, 48]. It is worth noting that the proton chemical shift (δH) difference (?ab=δa-δb) of the two geminal protons (Ha and Hb) of CH2-26 has been recognized for ascertaining 25Ror 25Sorientation 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).

Table 3 Representative 13C NMR data of six common steroid alkaloids

Table 3 (continued)

4.5 Terpenoids

So far, fifty-one terpenoids, including sesquiterpenoids, monoterpenoids and triterpenoids (Table 7 and Fig. 12), have been isolated fromS. lyratum. Among them, sesquiterpenoids are the most common terpenoids inS. 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 inS.lyratum.

4.6 Nitrogenous compounds

Nitrogenous compounds found inS. lyratuminclude 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].

4.7 Phenylpropanoids

4.7.1 Lignans

Till now, a total of twenty-eight lignans (179–205) have been isolated fromS. 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 fromS. lyratumin 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].

Table 4 Steroids isolated from S. lyratum

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 fromS. lyratumas shown in Table 10 and Fig. 15.

4.8 Flavonoids

Thirty-one flavonoids (228–258) have been reported fromS. 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].

4.9 Other compounds

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

Table 5 Steroidal saponins isolated from S. lyratum

5 Pharmacology

Water decoction of the whole herb ofS. lyratumwas 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 fromS. lyratumpossessed 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 ofS. lyratumhave also been assessed, as summarized in Table 13.

Table 6 Representative 13C NMR data of six common steroidal saponins (in C5H5N-d5)

Table 6 (continued)

Fig. 7 Chemical structures of steroids from S. lyratum

Fig. 8 Sapogenin scaffolds of saponins reported in S. lyratum

Fig. 9 Glycones of saponins reported in S. lyratum

5.1 Anti?cancer

5.1.1 Extracts and fractions

The heat-clearing and detoxicating property ofS. lyratumis favorable in the treatment of cancer [17, 19, 21]. It has been reported thatS. lyratumtreats 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 S180tumor-bearing mice, both ethanol and aqueous extracts ofS. lyratumcould 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 fromS. 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) ofS. lyratumshowed similar inhibitory activity on tumor growth in mice with Lewis lung carcinoma tumor, potentially acting through upregulating Fas, caspase-8, caspase-3, and p53, and downregulating FasL and B-cell lymphoma-2 (Bcl-2) in the mitochondrial pathway [27, 79].

Fig. 10 Chemical structures of steroidal saponins from S. lyratum

Fig. 11 Representative six common steroidal saponins

Fig. 12 Chemical structures of terpenoids from S. lyratum

Further studies revealed that the 70% ethanol extract ofS. 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 ofS. 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 ofS. lyratumhave shown that the compounds isolatedfromS. lyratumpossess a good cytotoxic potential for several cancer cells.

Table 7 Terpenoids isolated from S. lyratum

Table 7 (continued)

Fig. 13 Chemical structures of nitrogenous compounds from S. lyratum

In the process of cytotoxic investigation by MTT assay and flow cytometry, the characteristic ompounds 5, 8, 21 from the methanolic extract ofS. lyratumshowed significant cytotoxicities against huh-7 and HepG2 cell lines with IC50values 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 IC501.9–8.6 μg/mL against HONE-1 cells [1, 57, 58, 60, 61]. Among them, compounds 126–127 showed potent cytotoxicity activity with IC502.1 and 1.9 μg/mL, slightly weaker than the positive controls etoposide and cisplatin (IC501.6 and 1.7 μg/mL) [1, 57, 58, 60, 61]. Notably, the IC50differences 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.

Table 8 Nitrogenous compounds isolated from S. lyratum

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 IC50values of 6.39–9.11 μM, 3.19–8.86 μM and 0.39–1.16 μM, as compared with IC50values 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 IC503.5 μM, as compared to IC50values 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 ofS. 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 IC50values 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 ofS. lyratumcan be used as a supplement to modern anti-inflammatory agents.

Total alkaloid fraction from the 70% ethanol extract ofS. lyratumsignificantly 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

Fig. 14 Chemical structures of lignans from S. lyratum

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 significantβ-glucuronidase inhibitory activities with IC50values range of 6.3–9.1 μM [25],while four 4-hydroxyisoflavans 252–255 afforded antiinflammatory activities with inhibitory ratios release ofβ-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 thatS. lyratumextracts and compounds possess significant antioxidant activities.

Table 9 Lignans isolated from S. lyratum

50% Ethanol extract ofS. 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 fromS. lyratumshowed antioxidative potential with IC50of 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 ofS. lyratumpossessed the capability of scavenging DPPH free radicals with IC50values 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 ofS. lyratumextracts. For example, the water-soluble polysaccharide ofS. lyratumexerted a significant antibacterial activity againstStaphylococcus aureus,Salmonella,Pasteurella,Escherichia coli,Candida albicans,andPseudomonas 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. aureusandEnterococcus faecalis) were used to assess the antimicrobial activity of a new compound 266 fromS. 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].

Fig. 15 Chemical structures of coumarins, simple phenylpropanoids and their derivatives from S. lyratum

5.5 Other activities

The extracts ofS. lyratumshowed 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 ofS. lyratumpossessed 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 ofS. lyratumpossesses molluscicidal activities with IC50values of 30–50 mg/mL [95].

Notably, several Chinese patent prescriptions withS.lyratumas the major component herb, showed significant anticancer efficacies in reported clinic trials. For example, ’Baiyingtang’ (composed ofS. lyratum,Herba Patriniae,Houttuynia cordata,Lilium browniivar.,Aspa raguscochinchinensis(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 ofS. lyratum,Ophiocordyceps sinensis,Houttuynia cordata,Lilium browniivar.,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 ofS. lyratummay have been overlooked by researchers, while few studies have found the toxic potential ofSolanumglycoalkaloid [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 ofS. lyratumat 5000 mg/kg [31]. In future,more pharmacological evidences should be sought on the possible adverse effects and the toxicities ofS. lyratumextracts and their bioactive constituents whenused in treatments of acute, subchronic, or chronic diseases. Further, more clinical trials must be conducted to evaluate the safety and clinical efficacy ofS. lyratumin humans.

Table 10 Coumarins, simple phenylpropanoids and their derivatives isolated from S. lyratum

Fig. 16 Chemical structures of flavonoids from S. lyratum

Table 11 Flavonoids isolated from S. lyratum

7 Conclusion

This review summarized the latest advancements ofS. lyratumin 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 fromS. 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 ofS. lyratumextracts, aqueous and ethanol extracts were commonly acquired fromS. lyratum, whose main components included total alkaloids and total saponins. In modern pharmacological studies, compounds and extracts fromS. lyratumwere evaluated in vivo and in vitro, and their anticancer and cytotoxic, antiinflammatory, antioxidant, antimicrobial, anti-allergy,and hepatoprotective activities have been demonstrated. However, many aspects ofS. lyratumhave not been studied yet and some relative studies onS.lyratumshould be further explored in the following aspects in the future.

Fig. 17 Chemical structures of other compounds reported from S. lyratum

Firstly, the pharmacological activities are mostly proven from the aqueous and ethanol extracts fromS.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 IC50values of the test extracts/compounds ofS.lyratumare 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 ofS. lyratumin 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 ofS. lyratumare needed urgently and should be improved. Simultaneous qualitative and quantitative measures are recommended to be used for those major active constituents ofS. lyratum.

Table 13 Pharmacological activities of S. lyratum

Table 13 (continued)

Table 13 (continued)

Table 13 (continued)

Table 13 (continued)

Finally, in toxicological studies ofS. 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 ofS. lyratumhave 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 onS. lyratum.

In summary,S. lyratumcan 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 ofS. lyratum.

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 Committee 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.

Received: 6 August 2022 Accepted: 13 October 2022References:

1. Yao F, Song QL, Zhang L, Li GS, Dai SJ. Three new cytotoxic sesquiterpenoids fromSolanum lyratum. Phytochem Lett. 2013;6:453–6.

2. Kang B, Lee E, Hong I, Lee J, Kim H. Abolition of anaphylactic shock bySolanum lyratumThunb. Int J Immunopharmacol. 1997;19:729–34.

3. Ren J, Feng G, Wang M, Sun L. The primary study on the anti-tumor effect of total saponin ofSolanum lyratumThunb. Cancer Res Prevent Treat. 2006;33:262–4.

4. Shoji Y, Murakami N, Yamasaki M. A furostanol glucuronide fromSolanum lyratum. Phytochemistry. 1985;24:2748–50.

5. Chen FF, Zhang YW, Huang XF. Steroidal saponins and their pharmacological activities in Solanum plants. Zhongguo Zhong Yao Za Zhi.2016;41:976–88.

6. Bártová V, Bárta J, Jaro?ová M. Antifungal and antimicrobial proteins and peptides of potato (Solanum tuberosumL.) tubers and their applications. Appl Microbiol Biotechnol. 2019;103:5533–47.

7. Kaunda JS, Zhang YJ. The genus solanum: an ethnopharmacological,phytochemical and biological properties review. Nat Prod Bioprospect.2019;9:77–137.

8. Elizalde-Romero CA, Montoya-Inzunza LA, Contreras-Angulo LA,Heredia JB, Gutiérrez-Grijalva EP. Solanum fruits: phytochemicals, bioaccessibility and bioavailability, and their relationship with their healthpromoting effects. Front Nutr. 2021;8: 790582.

9. Su J. Xinxiu Bencao. Shanghai: Shanghai Scientific & Technical Publishers; 1957. p. 174.

10. Tang SW, Shang ZJ. Zhenglei Bencao. Shanghai: Shanghai Classics Publishing House; 1991. p. 176.

11. Wu P, Sun XY, Sun FY. Compendium of Materia Medica. Beijing: Scientific and technical documentation press; 1996. p. 20.

12. Du X. Study on the material basis mechanism and preclinical safety of total alkaloids fromSolanum lyratumagainst NSCLC, Doctoral thesis.China Academy of Chinese Medical Sciences. 2020.

13. Jiang XW, Wu QN. Comparison and identification ofSolanum lyratumThunb and Aristolochia mollissima Hance. J Jiangxi Univ Tradit Chin Med. 2006;18:35–6.

14. Chen XM, Chen QH.Solanum lyratumand its mixed varieties. Zhong Yao Cai. 2005;28:462–3.

15. Liu XB, Wu J. Study on pharmacognostic identification ofSolanum lyratum. J Sci Teachers’ Univ. 2021;41:72–6.

16. Knapp S. A revision of the Dulcamaroid Clade of Solanum L. (Solanaceae). PhytoKeys. 2013;22:1–432.

17. Editorial Board of Flora of China. Flora of China. Beijing: China Science Publishing; 1978. p. 86–7.

18. Ming HY, Wang E, Ma XP. Study on the ethnic medicineSolanum lyratumThunb. and patent literature analysis. Asia-Pacific Tradit Med.2017;13:59–61.

19. Xiao ZM, Wang AM, Wang XY, Shen SR. A study on the inhibitory effect ofSolanum lyratumThunb extract on Lewis lung carcinoma lines. Afr J Tradit Complement Altern Med. 2013;10:444–8.

20. Li SS, Hou ZL, Yao GD, Guo R, Wang YX, Lin B, Huang XX, Song SJ.Lignans and neolignans with isovaleroyloxy moiety from Solanum lyratum Thunb.: chiral resolution, configurational assignment and neuroprotective effects. Phytochemistry. 2020;178:112461.

21. Chen H, Du K, Sun Y, Hao Z, Zhang Y, Bai J, Wang Q, Hu H, Feng W, Solanrubiellin A. a hydroanthraquinone dimer with antibacterial and cytotoxic activity fromSolanum lyratum. Nat Prod Res.2020;34:3176–81.

22. Xu YL, Lv J, Wang WF, Liu Y, Xu YJ, Xu TH. New steroidal alkaloid and furostanol glycosides isolated fromSolanum lyratumwith cytotoxicity. Chin J Nat Med. 2018;16:499–504.

23. Shoji Y, Mitsuyuki M, Murakami N. Two new steroidal glucuronides fromSolanum lyratum, II1. Planta med. 1986;6:496–8.

24. Lee Y, Hsu FL, Nohara T. Two new soladulcidine glycosides fromSolanum lyratum. Chem Pharm Bull. 1997;45:1381–2.

25. Zhang DW, Yang Y, Yao F, Yu QY, Dai SJ. Solalyratins A and B, new antiinflammatory metabolites fromSolanum lyratum. J Nat Med-Tokyo.2012;66:362–6.

26. Li SS, Liu QB, Zhang YY, Shi SC, Guo R, Yao GD, Lin B, Huang XX,Song SJ. Oxylipin vanillyl acetals fromSolanum lyratum. Fitoterapia.2020;143: 104559.

27. Lee JH, Lee YH, Lee HJ, Lee HJ, Lee EO, Ahn KS, Shim BS, Bae H, Choi SH, Ahn KS, Baek NI, Kim DK, Kim SH. Caspase and mitogen activated protein kinase pathways are involved inSolanum lyratumherba induced apoptosis. J Ethnopharmacol. 2009;123:121–7.

28. Ikeda T, Tsumagari H, Honbu T, Nohara T. Cytotoxic activity of steroidal glycosides from Solanum plants. Biol Pharm Bull.2003;26:1198–201.

29. Yang JS, Wu CC, Kuo CL, Lan YH, Yeh CC, Yu CC, Lien JC, Hsu YM, Kuo WW, Wood WG, Tsuzuki M, Chung JG.Solanum lyratumextracts induce extrinsic and intrinsic pathways of apoptosis in WEHI-3 murine leukemia cells and inhibit allograft tumor. Evid Based Complement Alternat Med. 2012;2012: 254960.

30. Lee MH, Cheng JJ, Lin CY, Chen YJ, Lu MK. Precursor-feeding strategy for the production of solanine, solanidine and solasodine by a cell culture ofSolanum lyratum. Process Biochem. 2007;42:899–903.

31. Guo XH, Weng LJ, Yi LT, Geng D. Toxicological safety evaluation in acute and 21-day studies of ethanol extract fromSolanum lyratumThunb.Evid Based Complement Alternat Med. 2022;31:8518324.

32. Xu YL, Xu YJ, Shi HX, Liu Y, Xu TH. Lignanoids fromSolanum lyratum. J Chin Pharm Sci. 2018;27:289–94.

33. Han L, Wang JN, Sun CX, Cao XQ, Du X. Anti-angiogenic activities of glycoalkaloids isolated fromSolanum lyratumin tumor-derived vascular endothelial cells. Phytochem Lett. 2019;29:212–9.

34. Zhao DK, Zhao Y, Chen SY, Kennelly EJ. Solanum steroidal glycoalkaloids: structural diversity, biological activities, and biosynthesis. Nat Prod Rep. 2021;38:1423–44.

35. Zang YL. Study on antitumor active components ofSolanum lyratumThunb, Master’s thesis. China Academy of Chinese Medical Sciences.2008.

36. Yang YD. Studies on the chemical constitutents and bioactivities of three plants, Doctoral thesis. Huazhong University of Science and Technology. 2014.

37. Jia YR, Tian XL, Liu K, Chen C, Wang XL, Zhang CC, Sun LX. Simultaneous determination of four alkaloids inSolanum lyratumThunb by UPLC-MS/MS method. Pharmazie. 2012;67:111–5.

38. Ye WC, Wang H, Zhao SX, Che CT. Steroidal glycoside and glycoalkaloid fromSolanum lyratum. Biochem Syst Ecol. 2001;29:421–3.

39. Wu T, Du X, Wang JN, Liu LY, Yang YK. Two new glycoalkaloids fromSolanum lyratumThunb. J Chin Pharm Sci. 2021;30:518–23.

40. Yin HL. Study on the active constituents from Solanum indicum andSolanum lyratumfor ANTI-HSN1 influenza virus, Doctoral thesis. Beijing University of Technology. 2013.

41. MurakamI K, Ezima H, Takaishi Y, Takeda Y, Fujita T, Sato A, Tomimatsu T.Studies on the constituents of Solanum plants. V. The constituents ofS.lyratumThunb II. Chem Pharm Bull. 1985;33:67–73.

42. Qi W. Study on chemical constituents and pharmacokinetics of antitumor traditional Chinese medicineSolanum lyratum, master’s thesis.Shenyang Pharmaceutical University. 2009.

43. Du X, Wang JN, Sun J, Wu T, Cao XQ, Liu LY, Yang YK. Steroidal glycoalkaloids fromSolanum lyratuminhibit the pro-angiogenic activity of A549-derived exosomes. Fitoterapia. 2020;141: 104481.

44. Sun LX, Li F, Wang C, Li W, Wang M, Bi K. Isolation and identification of chemical constituents ofSolanum lyratumThunb. J Shenyang Pharm Univ. 2008;25:36–46.

45. Simonet AM, Durán AG, Pérez AJ, Macías FA. Features in the NMR spectra of the aglycones of Agave spp. saponins. HMBC method for aglycone identification (HMAI). Phytochem Anal. 2021;32:38–61.

46. MurakamI K, Saijo R, Nohara T, Tomimatsu T. Studies on the constituents of Solanum plants. L. on the constituents of the stem parts of Solanum lyratum Thunb. Yakugaku Zasshi. 1981;101:275–9.

47. Xu YL. Study on chemical constituents ofSolanum lyratumThunb and its antitumor activity, Doctoral thesis. Beijing University of Chinese Medicine. 2019.

48. Kang SY, Sung SH, Park JH, Cho JH, Kim YC. A phenolic glucoside and steroidal sapogenins ofSolanum lyratum. Yakhak Hoeji. 2000;44:534–8.

49. Hirai Y, Konishi T, Sanada S, Ida Y, Hoji J. Studies on the constituents of Aspidistra elatior Blume. I. on the steroids of the underground part.Chem Pharm Bull. 1982;30:3476–84.

50. Yang L, Feng F, Gao Y. Chemical constituents from herb ofSolanum lyratum. Zhongguo Zhong Yao Za Zhi. 2009;34:1805–8.

51. Sun LX, Fu WW, Ren J, Xu L, Bi KS, Wang MW. Cytotoxic constituents fromSolanum lyratum. Arch Pharm Res. 2006;29:135–9.

52. Yu SM, Kim HJ, Woo E, Park H. Some Sesquiterpenoids and 5α,8αepidioxysterols fromSolanum lyratum. Arch Pharm Res. 1994;17:1–4.

53. Wang Y, Kazuhir O, Roji K, Kazuo Y. Steroidal saponins from fruits of Tribulus Terrestis. Phytochemistry. 1996;42:1417–22.

54. Agrawal PK. Assigning stereodiversity of the 27-Me group of furostane-type steroidal saponins via NMR chemical shifts. Steroids.2005;70:715–24.

55. Agrawal PK. Dependence of 1H NMR chemical shifts of geminal protons of glycosyloxy methylene (H2–26) on the orientation of the 27-methyl group of furostane-type steroidal saponins. Magn Reson Chem. 2004;42:990–3.

56. Yue XD, Yao F, Zhang L, Li GS, Dai SJ. Sesquiterpenoids fromSolanum lyratum. Zhongguo Zhong Yao Za Zhi. 2014;39:453–6.

57. Nie XP, Zhang L, Yao F, Xiao K, Dai SJ. Study on sesquiterpenes fromSolanum septemlobum. Zhongguo Zhong Yao Za Zhi. 2015;40:1514–7.

58. Ren Y, Shen L, Zhang DW, Dai SJ. Two new sesquiterpenoids fromSolanum lyratumwith cytotoxic activities. Chem Pharm Bull (Tokyo).2009;57:408–10.

59. Nie XP, Yao F, Yue XD, Li GS, Dai SJ. New eudesmane-type sesquiterpenoid fromSolanum lyratumwith cytotoxic activity. Nat Prod Res.2014;28:64–5.

60. Yao F, Song QL, Zhang L, Li GS, Dai SJ. Solajiangxins A-C, three new cytotoxic sesquiterpenoids fromSolanum lyratum. Fitoterapia.2013;89:200–4.

61. Li GT, Yao F, Zhang L, Yue XD, Dai SJ. Two new cytotoxic sesquiterpenoids fromSolanum lyratum. Chinese Chem Lett. 2013;4:1030–2.

62. Li SS, Cheng ZY, Zhang YY, Guo R, Wang XB, Huang XX, Li LZ, Song SJ.Sesquiterpenoids from the herbs ofSolanum lyratumand their cytotoxicity on human hepatoma cells. Fitoterapia. 2019;139: 104411.

63. Shang SZ, Zhao W, Tang JG, Pu JX, Zhu DL, Yang L, Sun HD, Yang GY,Chen YK. 14-Noreudesmane sesquiterpenes from leaves of Nicotiana tabacum and their antiviral activity. Phytochem Lett. 2016;17:173–6.

64. Li GS, Yao F, Zhang L, Yue XD, Dai SJ. New sesquiterpenoid derivatives fromSolanum lyratumand their cytotoxicities. J Asian Nat Prod Res.2014;16:129–34.

65. Sun LX, Qi W, Yang HY, Jia YR, Tong LJ. Nitrogen-containing compounds fromSolanum lyratumThunb. Biochem Syst Ecol. 2011;39:203–4.

66. Wang XW, Zhao Y, Dong XQ, Wu XL, Yu HY, Zhang LH, Han LF, Zhang Y,Wang T, Wu HH. Amides and lignans fromSolanum lyratum. Phytochem Lett. 2021;45:25–9.

67. Yang JZ, Guo GM, Zhou LX, Ning D. Study on the chemical constituents ofSolanum lyratum. Zhongguo Zhong Yao Za Zhi. 2002;27:46–7.

68. Li RL. Extraction, isolation and structural identification of chemical constituents ofSolanum lyratumThunb, Master’s thesis. Zhengzhou University. 2006.

69. Yin HL, Li JL, Dong JX. Chemical constituents fromSolanum lyratumThunb. Military Med Sci. 2010;34:65–7.

70. Ji H, Hou LH, Yuan M. Chemical Constituents Having Antioxidant Activities ofSolanum lyratum. Chem Nat Compd+. 2014;50:179–80.

71. Zhang DW, Li GH, Yu QY, Dai SJ. Studies on flavonoids and amides from herbs ofSolanum lyratum. China J Chin Mat med. 2009;34:721–3.

72. Wang LJ. Study on chemical constituents of Chinese herbal medicine for anti-cancer and anti-malarial, Maeter’s thesis. ZhengZhou University.2004.

73. Zhang DW, Li GH, Yu QY, Dai SJ. New anti-inflammatory 4-hydroxyisoflavans fromSolanum lyratum. Chem Pharm Bull (Tokyo). 2010;58:840–2.

74. Kim SP, Nam SH, Friedman M. The tomato glycoalkaloidα-tomatine induces caspase-independent cell death in mouse colon cancer CT-26 cells and transplanted tumors in mice. J Agr Food Chem.2015;63:1142–50.

75. Han L, Wang JN, Cao XQ, Sun CX, Du X. An-te-xiao capsule inhibits tumor growth in non-small cell lung cancer by targeting angiogenesis.Biomed Pharmacother. 2018;108:941–51.

76. Xiao ZM, Wang AM, Wang XY, Shen SR. A study on the inhibitory effect ofSolanum lyratum thumbextract on lewis lung carcinoma lines. Afr J Tradit Complement Altern Med. 2014;10:444–8.

77. Guan Y, Zhao H, Yan X, Meng J, Wang WL. Study on anti-tumor effect ofSolanum lyratumThunb. extract in S180 tumor-bearing mice. Afr J Tradit Complement Altern Med. 2013;10:345–51.

78. Yang JS, Wu CC, Kuo CL, Yeh CC, Chueh FS, Hsu CK, Wang CK, Chang CY,Ip SW, Hsu YM, Kuo WW, Chung JG.Solannm lyratumextract affected immune response in normal and leukemia murine animal in vivo. Hum Exp Toxicol. 2010;29:359–67.

79. Mo XQ, Wei HY, Huang GR, Xu LY, Chen YL, Qi J, Xian W, Qin YC, Wei LD,Zhao LJ, Huang YQ, Xing W, Pu HQ, Wei PY, Li CG, Liang QC. Molecular mechanisms of apoptosis in hepatocellular carcinoma cells induced by ethanol extracts ofSolanum lyratumThumb through the mitochondrial pathway. World J Gastroentero. 2017;23:1010–7.

80. Wu T, Wang J, Du X. Effect of the effective parts of total steroidal alkaloids fromSolanum lyratumon tumor inhibition in vivo and immune regulation in vitro. Cent South Pham. 2020;18:1786–90.

81. Sun XF, Hu SL, Zhou F, Wang Y. Effect of total alkaloids fromSolanum lyratumThunb. combined with cisplatin on tumor growth in mice with Lewis lung cancer. Chin J Clin Pharmacol. 2019;35:1781–3.

82. Wei X, Li CG, Li T, Nong S, Yan WJ.Solanum lyratumThunberg alkaloid induces human lung adenoearcinoma A549 cells apoptosis by inhibiting NF-κB signaling pathway. Zhong Yao Cai. 2013;36:787–90.

83. Fekry MI, Ezzat SM, Salama MM, Alshehri OY, Al-Abd AM. Bioactive glycoalkaloides isolated fromSolanum melongenafruit peels with potential anticancer properties against hepatocellular carcinoma cells.Sci Rep-UK. 2019;9:1–11.

84. Cao W, Zhou XQ. Protective effect of notoginsenoside and tanshinone IIA on inflammation-related colorectal cancer mice and the inhibition effect on COX-2 expression. Digit Chin Med. 2021;4:54–63.

85. Lin SH, Yi Y, Yu NC. Anti-inflammatory activity of total alkaloids fromSolanum lyratum. China Pharm. 2016;19:1263–6.

86. Zhou XX. Studies on the separation of chemical constituents of Solanum lyratum Thunb. and the interaction of pharmacodynamics,Master’s thesis. Huazhong Agricultural University. 2020.

87. Taveira M, Sousa C, Valent?o P, Ferreres F, Teixeira JP, Andrade PB. Neuroprotective effect of steroidal alkaloids on glutamate-induced toxicity by preserving mitochondrial membrane potential and reducing oxidative stress. J Steroid Biochem. 2014;140:106–15.

88. Kuo WW, Huang CY, Chung JG, Yang SF, Tsai KL, Chiu TH, Lee SD, Ou HC.Crude extracts ofSolanum lyratumprotect endothelial cells against oxidized low-density lipoprotein-induced injury by direct antioxidant action. J Vasc Surg. 2009;50:849–60.

89. Chen CJ, Huang KY, Sun CL. Study on DPPH free radicals caventinct activity ofSolanum lyratumThunb fruit extractives. Food Res Dev.2006;27:45–8.

90. Yang HL, Sun ZL, Ding R, Cao G. Extraction andin vitroantibacterial test of polysaccharide fromSolanum lyratumThunb. J Tradit Chin Veterinary Med. 2005;4:24–5.

91. Yang JH, Choi CU, Kim DK, Lee KR, Zee OP. Effect ofSolanum lyratumextract on the hepatotoxicity of carbon tetrachloride in rats. Saengyak Hakhoe Chi. 1996;27:167–72.

92. Li GT. Protective effect ofSolanum lyratumThunb ethanol extract for carbon tetrachloride-induced acute liver injury. Chin Pract Med.2015;10:8–9.

93. Kim HM, Lee EJ.Solanum lyratuminhibits anaphylactic reaction and suppresses the expression of L-histidine decarboxylase mRNA. Immunopharm Immunot. 1998;20:135–46.

94. Kang B, Lee E, Hong I, Lee J, Kim H. Abolition of anaphylactic shock bySolanum lyratumThunb. Int J Immunopharmacol. 1998;19:729–34.

95. Cai SX. Studies on extraction, purification, determination and molluscicidal effect of glycosidal steroid alkaloids inSolanum lyratumThunb,Master’s thesis. Hunan Agricultural University. 2005.

96. Yin LH, Zhang J, Pan XY, Zhao FD, Liu QM. Effect of Baiyingtang on inflammatory cytokines in patients with acute radiolectitis. Jiangxi Med J. 2020;55:1781–3.

97. Liu YS, Xin XB. Efficacy of the Baiying decoction plus chemotherapy on NSCLC. Clin J Chin Med. 2018;10:27–9.

98. Han L, Zhuo Y, Sun CX, Wang JN. Inhibitory effect of lung cancer cells total alkaloids fromSolanum lyratumThunb. on the growth of transplanted Lewis in mice. Trad Chin Drug Res Clin Pharm. 2015;26:573–6.

99. Fu HW. SLT screening of anticancer active site and researching of lung cancer A549 cell proliferation inhibition mechanism, Master’s thesis.Nanchang University. 2008.

100. Tu S, Wei X, Zhao XM, Yu LH, Wan FS. The influence ofSolanum lyratumThunb extract on apoptosis and the expression of Fas/Fasl, genes in human lung cancer A549 cells. Lishizhen Med Mater Med Res.2008;19:603–5.

101. Han L, Sun CX, Wang JN. Effect of total alkaloids fromSolanum lyratumon regulating apoptosis and cell cycle of A549 cells through VEGFrelated pathway. Trad Chin Drug Res Clin Pharm. 2016;27:509–13.

102. Tu S, Wan FS, Wei X, Nong S, Zhu JF, Liu ZQ.Solanum lyratumThunberg alkaloid induces human lung adenoearcinoma A549 cells apoptosis by activating FAS-pathway. Lishizhen Med Mater Med Res. 2013;24:66–8.

103. Wang MF, Yu LH, Wan HF, Tu SS. Influence of extracts ofSolanum lyratumthunb on apoptosis and Bcl-xl/Bid expression in human lung cancer SPC-A-1 cells. J Nanchang Univ Med Sci. 2013;51:8–12.

104. Wei X, Tu S, Zhao XS, Wan FM, Yu LH. Experimental study on apoptosis induced by ethanol extracts ofSolanum lyratumThunb in human lung cancer SPC-A-1 cells. China Pharm. 2008;19:256–8.

105. Huo Y, Wang M, Wang XB, Han ZF, Dong X. Effects ofSolanum lyratumthunberg alkaloid on the expression of p38 MAPK and Caspase-3 in hepatoma Huh-7cells. Global Tradit Chin Med. 2018;11:987–90.

106. Liu SH, Shen XH, Wei XF, Mao XH, Huang T. Immunomodulatory activity of butanol extract fromSolanum lyratumin tumor-bearing mice. Immunopharm Immunot. 2010;33:100–6.

107. Wang WF, Liu Y, Wu GM, Yang T, Zhang D, Xu YJ. Screening the antitumor active components of the Solanum lyratum Thunb. extract. J Changchun Univ Tradit Chin Med. 2018;34:8883–6.

108. Liu HR, Peng XD, He HB, Wang YH, Li Y, He GX, Liu YL, Li YL, Zeng CJ.Antiproliferative activity of the total saponin ofSolanum lyratumThunb in Hela cells by inducing apoptosis. Pharmazie. 2008;63:836–42.

109. Liu SH, Mao XH, Wei XF. High-efficiency inhibitory effect of steroid saponin on HeLa cells proliferation and its mechanism. Shandong J Tradit Chin Med. 2009;28:724–6.

110. Zhang C, Li ZM, Wang JL, Jiang XT, Xia MF, Wang J, Lu SY, Li SY, Wang HM. Ethanol extracts ofSolanum lyratumThunb regulate ovarian cancer cell proliferation, apoptosis, and epithelial-to-mesenchymal transition (EMT) via the ROS-mediated p53 Pathway. J Immunol Res.2021;2021:5569354.

111. Huang HS, Wei X, Huang YQ, Wei LD. Effects ofSolanun lyratumThunb extracts on growth of HO8910 of ovarian cancer cells. J Mod Oncol.2011;19:1279–81.

112. Yan J, Luo J, He KY, Pan R, Hu Q, Peng B, Liu X. Apoptosis induced bySolanum lyratumon ovarian carcinoma cell SKOV3. Moder Tradi Chin Med Mat Med-World Sci Tech. 2008;2008:60–3.

113. Cao JY, Tan XL. The damage effect of Chinese herb medicine Baimaoteng (Solanum lyratum) on G2-PC Chromosome in CHO cells. Chin J Mod Appl Pharm. 1988;5:1–3.

114. Yang XD, Zhang J, Zhao RJ. Effect of total glycosides ofSolamum lyratumsurvivin and bax in MCF-7 human breast on expression of cancer cells. Chin J New Drags. 2011;20:1123–6.

115. Chiu CH, Chou YC, Lin JP, Kuo CL, Lu HF, Huang YP, Yu CC, Lin ML, Chung JG. Chloroform extract ofSolanum lyratuminduced G0/G1 arrest via p21/p16 and induced apoptosis via reactive oxygen species, caspases and mitochondrial pathways in human oral cancer cell lines. Am J Chinese Med. 2015;43:1453–69.

116. Lv J. Study on chemical constituents ofSolanum lyratumThunb, Master’s thesis. Changchun University of Chinese Medicine. 2009.

117. Wan FS, Wu J, Li H, Tu S, Yu LH. Study on apoptosis of human stomach SGC-7901 cells induced by extracts ofSolanum lyratum. Zhong Yao Cai.2009;32:245–9.

118. Wan CX. Study on apoptosis inducing effect ofSolanuml lyratumwater extract and its rnechanisrn on human colorectal cancer HT29 cells,Master’s thesis. Nanchang Uiversity. 2011.

119. Yue XD, Qu GW, Li BF, Xue CH, Li GS, Dai SJ. Two new C13-norisoprenoids fromSolanum lyratum. J Asian Nat Prod Res. 2012;14:486–90.

120. Shi WR, Liu Y. Effects ofSolanum lyratumThunb on multiplication in human acute promyelocytic HL-60 Cells. J Fujian Univ Tradit Chin Med.2002;12:36–9.

121. Pan B, Zhong WF, Deng ZH, Lai CY, Chu JY, Jiao GL, Liu JF, Zhou QZ. Inhibition of prostate cancer growth by solanine requires the suppression of cell cycle proteins and the activation of ROS/P38 signaling pathway.Cancer Med. 2016;5:3214–22.

122. Lin YT, Huang AC, Kuo CL, Yang JS, Lan YH, Yu CC, Huang WW, Chung JG. Induction of cell cycle arrest and apoptosis in human osteosarcoma U-2 OS cells bySolanum lyratumextracts. Nutr Cancer. 2013;65:469–79.

123. Huo Y, Wang C, Wang M, Wang XB, Han ZF, Dong X. Study on the mechanisms ofSolanum lyratumthunberg alkaloid against tert-butyl hydroperoxide-induced oxidative stress and apoptosis in human neuroma metrocyte cell line SH-SYSY cells. Chin Med. 2018;13:1738–41.

124. Fei YM, Gong CG. Experimental study of anti-inflamatory and analgesic effects of extracts ofSolanum lyratumThunb. J Pharm Pract.2009;27:111–4.

125. Li ZW, Zhou BL, Liu X, Zhang P. The progress of researching into physiological and ecological activities of glycoalkaloid in Solanaceae. Acta Agric Shanghai. 2011;27:129–34.

126. Al Sinani SSS, Eltayeb EA. The steroidal glycoalkaloids solamargine and solasonine in Solanum plants. S Afr J Bot. 2017;112:253–69.

127. Arkhypova VN, Dzyadevych SV, Soldatkin AP, El’Skaya AV, Martelet C, Jaffrezic-Renault N. Development and optimisation of biosensors based on pH-sensitive field effect transistors and cholinesterases for sensitive detection of solanaceous glycoalkaloids. Biosens Bioelectron.2003;18:1047–53.