Xanthoceras sorbifolium Bunge: A Review on Botany, Phytochemistry, Pharmacology, and Applications

Abstract

Xanthoceras sorbifolium Bunge (Sapindaceae) is a native Chinese plant with promising applications as a biofuel feedstock and a source of novel drugs. Historical records and documents from different periods have mentioned the use of X. sorbifolium and its botanical constituents in treating diseases, highlighting its central role in Chinese and Mongolian traditional medicinal therapies. Phytochemical research has focused on the husks, leaves, trunks, and branches of this herb. A total of 278 chemical compounds have been isolated and divided into 8 categories: triterpenoids, flavonoids, phenylpropanoids, steroids, phenols, fatty acids, alkaloids, and quinones. Modern pharmacological studies on X. sorbifolium have demonstrated positive effects on learning and memory, as well as anti-inflammatory, anti-tumor, and anti-oxidative properties. This review provides a comprehensive analysis of the available research on X. sorbifolium, focusing on the relationship between chemical constituents, traditional uses, and pharmacological effects. We also assess the potential for therapeutic and other applications of this plant in support of further research and development of X. sorbifolium.

Introduction

Xanthoceras sorbifolium, belonging to the family Sapindaceae and genus Xanthoceras, is a monotypic species widely distributed throughout China. The plant, commonly called the yellow horn or golden horn (Xu and Yu, 2010), is a valuable woody oil crop used to extract edible and medicinal ingredients, produce biofuels, and for greening of deserts. In China, X. sorbifolium was first recorded in the Chinese Materia Medica “Jiu Huang Ben Cao” (1406 AD) under the name “Wen Guan Hua.” It is used to treat arterial sclerosis, hyperlipidemia, hypertension, chronic hepatitis, and rheumatism (Wang, 1998; Li et al., 2007a). More importantly, each part of X. sorbifolium has a certain medicinal and health value and is used to prevent and treat diseases. The extract prepared from its husks has anti-inflammatory and anti-cancer properties; it also inhibits human immunodeficiency virus (HIV) protease and improves learning and memory, among other pharmacological effects (Zhang et al., 2016). The flower and calyx contain baicalin, which has antipyretic, sleep-inducing, anti-spasmodic, and anti-tumor effects. Their seeds can be used to prevent and cure arterial sclerosis (Wan et al., 2013). In Inner Mongolia, the trunks and branches were used to treat arthritis, as discussed in the Chinese Pharmacopeia in 1977 (Commission NP, 1977). Xanthoceraside is a triterpenoid saponin extracted from the husks of X. sorbifolium. It has many biological activities, such as improving learning and memory, and has anti-cancer and anti-inflammatory properties. Xanthoceraside may become a candidate for the prevention and treatment of Alzheimer’s disease (AD) (Yang C. Y. et al., 2016).

In addition to its medicinal value, X. sorbifolium has unique applications in the food and chemical industries, and in environmental protection (Wan et al., 2013). The seeds of X. sorbifolium are rich in unsaturated fatty acids and are used to prepare cooking oil. The kernels can be incorporated into seasoned dairy products or processed protein drinks. The leaves can also be used as tea (its protein content is higher than that of black tea), and the caffeine content is similar to that of flower tea (Wang, 1998). Xanthoceras sorbifolium can also be used in cosmetics and to make biodiesel. The husks of X. sorbifolium (which are considered by-products) can be used to produce chemical materials, such as activated carbon, furfural, xylitol, and alcohol (Yi et al., 2011). Furthermore, this herb is an excellent windbreak and a pioneer sand fixation species that is resistant to drought, wind, and sand. They are also easy to cultivate. Extensive X. sorbifolium plantations have been established in northern China to combat desertification. Other properties of this plant include cold tolerance, soil resistance, and high seed oil content. Therefore, it has become the preferred oil and eco-economic tree species for greening, returning farmland to forest, providing shelter against wind, and preventing sand erosion in mountainous areas (Bai et al., 2010). Xanthoceras sorbifolium has broad development prospects, especially in the fields of food, medicine, energy, and ecology. It is regarded as one of the most promising tree species for sustainable development in the 21st century.

In recent years, phytochemistry research has isolated 278 components from different sections of X. sorbifolium, including triterpenoids, flavonoids, phenylpropanoids, steroids, phenols, fatty acids, alkaloids, quinones, and others (Cheng et al., 2001; Wan et al., 2013; Yang C. Y. et al., 2016). These abundant bioactive components have a wide range of pharmacological activities (Yang L. et al., 2020; Zhang et al., 2020; Hao et al., 2021), including improved learning ability and memory (Ji et al., 2014; Rong et al., 2019), anti-inflammatory (Qi et al., 2013), anti-tumor (Wang et al., 2016a), antioxidant (Zhang et al., 2015; Yang CY. et al., 2016), anti-HIV (Li et al., 2007b), and vascular relaxation effects (Ma et al., 2000), as well as inhibition of pancreatic lipase activity (Geng et al., 2014). Increasing evidence regarding the medicinal value and excellent bioenergy value of X. sorbifolium highlights the need to evaluate its practical applications.

This review systematically summarizes the botanical and morphological characteristics, pharmacological effects, recorded medicinal history, and ethnic medicine applications of this herb. Through an extensive analysis of all relevant articles and books, we present the remarkable achievements and shortcomings of existing research, as well as some possible perspectives and trends for future studies on X. sorbifolium. This comprehensive review aims to provide a reference for future research, development, and utilization of X. sorbifolium.

Methodology and Literature Search Strategy

The extensive literature search involved articles, papers, and books from different sources, such as Embase-Elsevier, PubMed, Science Direct, SciFinder Scholar, Google Scholar, Baidu Scholar, CNKI, and Web of Science. The search strategy was based on combining different keywords, such as X. sorbifolium, traditional uses, phytochemistry, pharmacology, and review. The literature search results included publications from 1960 to 2021 to ensure a systematic analysis of data on X. sorbifolium. Literature screening involved initially reading the keywords, title, and abstract of retrieved literature to identify the article’s relevance to this research. Potentially relevant literature was then downloaded, and the full text was assessed. Any relevant literature was included in the analysis. Any literature that did not conform to the theme was excluded. The chemical structural formula used in this manuscript was created using ChemDraw 18.0 (PerkinElmer, United States).

Botany and Characteristics

Xanthoceras sorbifolium grows to 2–5 m in height with stout branchlets that are brownish red in color and glabrous with tile-liked bud scales arranged on the top and side buds. The leaf peduncle is 15–30 cm in length. There are 4–8 pairs of leaflets, membranous or papery, lanceolate or subovate. The lateral veins are slender and slightly raised on both sides. The inflorescence grows before or simultaneously with the leaves. The flowers are monoecious and the inflorescence is terminal. The axillary of the male inflorescences is 12–20 cm in length and erect with a short total pedicel and a residual bud scale at the base. The pedicel is 1.2–2 cm in length. The bracts are 0.5–1 cm long. The sepals are 6–7 mm long with gray hairs on both sides. The petals are white, but the base is purplish-red or yellow. The fruit consists of a capsule that is 5–6 cm in diameter with three seed compartments that are 1–1.5 cm in diameter. The number of seeds per compartment can vary from one to six. The seeds are black and shiny (Editorial Board of Flora of China, 1985; Xu and Yu, 2010). The different parts of X. sorbifolium are listed in Figure 1.

FIGURE 1

Xanthoceras sorbifolium grows in temperate and warm temperate zones, where the altitude ranges from 300 to 2000 m and the horizontal range is 28°34′–47°20′ E and 73°20′–120°25′ N. The species is mainly distributed in 18 provinces of China, including Inner Mongolia, Shaanxi, Shanxi, Hebei, and Henan. According to a resource survey, Chifeng in Inner Mongolia has the most concentrated populations and currently possesses the largest mangrove forest in China. The species is long-lived (up to 1,000 years), and it can grow in soil in pH ranges from 7 to 8.5. It can tolerate drought, low temperature, and soils that constitute clay, sand, or loam, including those that are alkaline, and of low fertility. It also grows well in deserted mountains, barren gullies, sandy lands, and steep hillsides (Mou et al., 2008; Xie et al., 2010).

Phytochemistry

Among the 278 compounds that have been isolated and identified from X. sorbifolium, triterpenes and flavonoids have been regarded as characteristic and main bioactive substances due to their variety, content, and pharmacological activities (Yang C. Y. et al., 2016). The structures and relevant references for these compounds are listed in Figures 2–10 and Table 1.

FIGURE 2

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FIGURE 9

FIGURE 10

Triterpenoids

Triterpenoids represent a large part of the chemical constituents in the X. sorbifolium, with 124 triterpenoid compounds having been identified from the husks, carpophores, leaves, and seeds (compounds 1–124, Figure 2). Yu et al. (2012a) extracted the seed oil residue of X. sorbifolium. The compounds were separated by D-101 macroporous resin, silica gel column chromatography, Sephadex LH-20, octadecylsilyl (ODS) column, and purified by prep-HPLC chromatography. Seven new oleanane-type triterpenoid saponins, sorbifoliaside A-J (35–44), were identified by MS, ¹H-NMR, ¹³C-NMR, ¹H-¹H COSY, HSQC, HMBC, NOESY, and TOCSY methods (Yu et al., 2012a; Yu et al., 2012b). Wang et al. (2016b) extracted X. sorbifolium with ethanol, analyzed the compounds by Sephadex LH-20, ODS, UV, MS, and NMR, and identified triterpenoids: 3-O-β-D-glucopyranosyl-28-O-[α-L-rhamnopyranosyl (1→2)]-β-D-glucopyranosyl-16-deoxybarringtogenol C (63), 3-O-[β-D-glucopyranosyl (1→6)]-[(3-O-angeloyl)-β-D-glucopyranosyl (1→2)]-β-D-glucopyranosyl-28-O-[β-D-glucopyranosyl (1→6)]-[α-L-rhamanopyranosyl (1→2)]-β-D-glucopyranosyl-16-deoxybarringtogenol C (64),3-O-[β-D-glucopyranosyl (1 →6)]-(3-O-angeloyl)-β-D-glucopyranosyl-28-O-[α-L-rhamanopyranosyl (1→2)]-β-D-glucopyranosyl-16-deoxybarringtogenol C (65) (Wang et al., 2016b). Chen et al. (2020a) extracted 70% ethanol from the husk of X. sorbifolium; separated and identified a series of compounds by D-101 macroporous resin, silica gel column, ODS column, and HPLC chromatography; and isolated compounds 108–123 for the first time (Chen et al., 2020a; Chen et al., 2020b). The chemical structures of triterpenoids are provided in Figure 2.

Flavonoids

Flavonoids are a group of naturally occurring compounds that contain a benzopyran heterocycle linked to a benzene ring (Testai, 2015). Currently, 48 flavonoids (125–172) have been obtained from the trunks and branches, leaves, husks, and flowers of X. sorbifolium. Among these compounds, quercetin and myricetin are the main aglycons. Zhang and Bao (2000) used polyamide and silica gel column chromatography to isolate the chemical constituents of lignum xanthocerais. Two flavonoids, 2α, 3β-dihydroquercetin (158), epicatechin (163), were identified by UV, MS, ¹H-NMR, ¹³C-NMR, and 2D-NMR (Zhang and Bao, 2000). Wu (2017) separated and purified the acetone extract of lignum xanthocerais by ODS, Sephadex LH-20, and preparative high-performance liquid chromatography (HPLC). After that, eight flavonoids, namely myricitrin (134), rutin (140), 3, 3′, 4′, 5, 7-pentahydroxyflavanone (156), dihydromyricetin (159), catechin (161), gallocatechin (162), epigallocatechin (165), procyanidin A-2 (169), were identified by Thin layer chromatography (TLC), ¹H-NMR, ¹³C-NMR, and MS (Wu, 2017). The chemical structures of flavonoids are provided in Figure 3.

Phenylpropanoids

Phenylpropanoids are natural compounds with benzene rings. Phenylpropanoids generally contain a phenol structure and are a phenolic substance. Fourteen simple phenylpropanoids have been extracted from X. sorbifolium, with their main components being coumarins (compounds 173–181, 185–186) and lignans (compounds 182–184). Zhu et al. (2018) isolated and purified the chemical composition of seed oil residue of X. sorbifolium by silicone, macroporous, Sephadex LH-20, and ODS column chromatography. Four phenylpropanoid compounds, namely fraxin (173), fraxetin-7-O-β-D-[6’-(3″-hydroxyl-3‴- methylglutaryl)] glucopyranoside (177), scopoletin (178), and esculetin (180) were identified by spectral and chemical methods (Zhu et al., 2018). The chemical structures of the phenylpropanoids are provided in Figure 4.

Steroids

Steroids are present in almost all plants and exhibit significant biological activity. Phytosterol is a steroid derivative of the C₁₇ side chain with 8–10 carbon atoms in the side chain. At present, 17 steroids (compounds 187–203) have been reported from the wood, husks, carpophores, seed oil residue, and kernel oil of X. sorbifolium. Yan et al. (1984) used TLC, impregnated silica gel G with 18% silver nitrate, and separated kernel oil of X. sorbifolium with petroleum ether (7:3, V/V) as the developing agent. The steroid compounds β-sitosterol acetate (200), campesterol (201), campesterol acetate (202), and cholesterol (203) were identified by TLC, MS, FT-IR, and GC-MS (Yan et al., 1984). Cheng et al. (2001) separated the husk of X. sorbifolium by column chromatography and spectroscopy to obtain two steroids (3β,5α,20R,24S)-stigmasta-7,trans-22-dien-3-ol (189) and (3β,5α,20R,24S)-stigmasta-7-en-3-ol (190) (Cheng et al., 2001). The chemical structures of the steroids are provided in Figure 5.

Phenols

Through this review, 17 phenolics (compounds 204–220) were found in X. sorbifolium. Wan et al. (2015) studied the chemical constituents of the husk of X. sorbifolium. They were isolated and purified by TLC, Sephadex LH-20 column, ODS column, and preparative HPLC. Two phenolic compounds, hydroquinone (216) and 4-hydroxybenzylcyanide (217) were identified based on physicochemical properties and spectral data (Wan et al., 2015). Wu (2017) separated and purified the acetone extract of lignum xanthocerais by ODS, Sephadex LH-20, and preparative HPLC. After that, two phenolic compounds, protocatechuic acid (209) and isochlorogenic acid B (210), were identified by TLC, ¹H-NMR, ¹³C-NMR, and MS (Wu, 2017). The chemical structures of the phenolic compounds are provided in Figure 6.

Fatty Acids

The fatty acid components are concentrated in the kernels and husks of X. sorbifolium. At present, 29 kinds of fatty acids (compounds 221–249) have been identified. Cheng et al. (2002) used GC-MS to separate and identify seven fatty acid compounds from the husk of X. sorbifolium, which were hexanoic acid (239), heptanoic acid (240), nonanoic acid (241), decanoic acid (242), 10-methylundecanoic acid (243), 12-methyltetradecanoic acid (244) and heptadecanoic acid (245) (Cheng et al., 2002). The chemical structures of fatty acids are provided in Figure 7.

Alkaloids

Nine alkaloids (compounds 250–258) were obtained from the methanol extract of the seed and husks. Among these compounds, Yu et al. (2018) identified the chemical constituents of lignum xanthocerais by 1D- and 2D-NMR, and ESI-MS and obtained three alkaloid compounds, indole-3-carboxaldehyde (251), allantoin (252), indole-3-acetylaspartic acid (253) (Yu et al., 2018). The chemical structures of alkaloids are provided in Figure 8.

Quinones

Four quinones (compounds 259–262) were also found in the fruits and wood of X. sorbifolium. Dong et al. (2008) used silica gel column, preparative TLC, and pharmadex LH-20 column chromatography to isolate compounds from the fruits of X. sorbifolium and identified their structure by a spectral method. As a result, four quinone compounds were isolated: 2,5-dimethoxy-p-benzoquinone (259), physicone (260), chrysophanol (261), and emodin (262) (Dong et al., 2008). The chemical structures of quinones are provided in Figure 9.

Others

In addition to the constituents mentioned previously, an additional sixteen compounds (263–278) were identified. Moreover, some nutritional elements were also found to be abundant in the herb. More than ten amino acids were found in the seeds of X. sorbifolium. It is worth noting that the predominant amino acids present are glutamic plus glutamine, aspartic plus asparagine, and arginine. These amino acids account for up to 43% of the total amino acids present in the species (Fan et al., 2009; Mónica et al., 2017). The chemical structures of other compounds are provided in Figure 10.

Pharmacological Activities

The pharmacological properties of X. sorbifolium have attracted a great deal of attention in recent years. The main pharmacological activities of X. sorbifolium include improving learning and memory impairments, anti-inflammatory, anti-tumor, and anti-oxidation. In particular, the triterpene saponin xanthoceraside, a characteristic compound of X. sorbifolium, shows excellent learning and memory improvement, anti-inflammatory, and anti-tumor activities. Table 2 lists some in vitro and in vivo pharmacological models and related dosage information to clarify the pharmacological activities of X. sorbifolium.

Improving Learning and Memory Impairments

Improving learning and memory impairments is mainly demonstrated through the regression of Alzheimer’s disease (AD). AD is a neurodegenerative disease that exhibits relentless progression in cognition impairment and memory dysfunction. Its formation and development are closely associated with the neurotoxicity of extracellular amyloid-beta (Aβ) deposits (Li et al., 2020). The specific mechanisms include the induction of apoptosis (Qu et al., 2000), activation of glial cells to induce inflammatory cascades (Li et al., 1998), triggering of oxidative stress (Huang et al., 1999), increase in intracellular Ca²⁺, and reduction of cell membrane fluidity (Tian et al., 2001). Among these, Aβ-associated oxidative stress and related antioxidant defense system deficits are fundamental mechanisms in AD etiopathogenesis (Ma and Klann, 2012).

Previous studies indicate that barrigenol-type triterpenoids exhibit remarkable protective effects against spatial memory impairments. As such, they have the potential to be used in AD therapy and other neurodegenerative diseases. For instance, Qi et al. (2017) used an intracerebroventricular injection of amyloid 1–42 (Aβ1-42) to establish a mouse model to test the effect of xanthoceraside on Aβ-induced cognitive dysfunction and the influence of the TLR2/NF-κB and MAPK pathway. The results showed that xanthoceraside at doses of 0.08 and 0.32 mg kg⁻¹ significantly improved learning and memory impairments in mice and significantly inhibited Aβ1-42-induced overexpression of GFAP and CD11b. The results suggested that xanthoceraside inhibited the TLR2 pathway and downregulated MAPK and NF-κB activity, which may be associated with improved learning and memory impairment (Qi et al., 2017). Li et al. (2020) isolated 8 kinds of barrigenol-type triterpenoids, all of which firstly detected the oxidative stress effect of hydrogen peroxide on human SH-SY5Y cells. Then Y-maze, Morris water maze, new object recognition, and passive avoidance tests were used to evaluate the improvement effect of the selected compounds on ICV Aβ1-42 mice. The compounds, (3-O-[β-D-glucopyranosyl (1→6)] (3′-O-angeloyl)-β-D-glucopyranosyl and 28-O-[β-D-glucopyranosyl (1→6)]-[α-L-rhamnopyranosyl (1→2)]-β-D-glucopyranosyl 16-deoxybarring-togenol C (0.32 mg kg⁻¹) showed significant improvements in enhancing memory disorders, object recognition defects, learning and memory impairments, and spatial memory disorders induced by Aβ_1-42 (410 pmol in 3 μL) in intracerebroventricular (ICV)-injected mice (Li et al., 2020).

Ji et al. (2017) reported that total triterpenoid saponins from X. sorbifolium husks significantly improves learning and memory impairments. Specifically, it significantly increased spontaneous alternation in the Y maze test and prolonged swimming duration in the fourth quadrant of the Morris water maze probe test at a dosage of 8.4 mg kg⁻¹. This substance also improved escape latency and passive avoidance test results in a dose-dependent manner. The primary mechanism might be associated with its protective effects against oxidative stress damage, cholinergic system deficiency, and synaptic damage (Ji et al., 2017). A study conducted using a rat AD model with ICV injection of Aβ_25–35 revealed that rats receiving 70% aqueous ethanol extracts containing husks of X. sorbifolium (5 and 10 mg kg⁻¹) demonstrated an upregulation of brain-derived neurotrophic factor (BDNF) expression, which protects the dendritic spine and achieves cognition-improving effects. The primary mechanism was a decrease in the dendritic spine density via activation of the BDNF/TrkB signaling pathway and inhibition of the RhoA/ROCK2 signaling pathway (Li Y. et al., 2016). In mice models impaired by scopolamine and sodium nitrite, ethanol extracts from the pericarp of X. sorbifolium (89.80, 44.90 mg kg⁻¹, i g), bunkanka saponins (1.51, 0.76 mg⋅kg⁻¹, i g), and ST-n-2 (a saponin, 0.32, 0.16 mg⋅kg⁻¹, i g) were found to notably improve memory acquisition after impairment induced by scopolamine and memory consolidation impairment induced by sodium nitrite. The mechanism may involve central cholinergic and glutamatergic nervous system functions and protection against damage caused by reactive oxygen species (ROS) in brain tissue.

In summary, the ability of X. sorbifolium to improve learning and memory impairment has been thoroughly studied, and the related active compounds and mechanisms have been revealed. Several studies reported on the signaling pathways that regulate and improve learning and memory impairment, indicating that this is an important pharmacological activity of X. sorbifolium. However, this pharmacological activity has not been widely applied in clinical research. Therefore, future research should focus on the practical application of this pharmacological activity to achieve a wide range of clinical applications and maximize the pharmacological value of this plant.

Anti-Inflammatory Activity

Anti-inflammatories are the second-largest class of drugs after antibacterial agents; thus, the anti-inflammatory effects of the active ingredients of Chinese herbal medicines have become a hot research topic (Li and Zhu, 2012; Rajendiran et al., 2018). The anti-inflammatory effect of X. sorbifolium has also been extensively studied, including the anti-inflammatory mechanism behind its traditional uses for rheumatism and scabies.

Current research has found that the extracts and compounds from X. sorbifolium mainly affect neuroinflammation, vascular inflammation, and rheumatoid arthritis. The flavonoids and phenylpropanoids isolated from the leaves of X. sorbifolium decreased nitric oxide (NO) production in the lipopolysaccharide-induced BV2 microglial cells. Among them, the inhibitory effect of 4-O-β-D-glucopyranosyl-trans-p-coumaric acid (IC₅₀ = 9.08 ± 1.23 μM) on NO was significantly stronger than that of the positive control minocycline (IC₅₀ = 37.04 ± 2.09 μM) (Li N. et al., 2016). Another report also indicated that a 70% ethanol extract of X. sorbifolium husk is rich in effective anti-neuro-inflammatory active ingredients. Among them, the two triterpenoids (IC₅₀ values of 5.01 ± 0.22 and 3.05 ± 1.21 μM) and the two alkaloids (IC₅₀ values of 9.61 ± 0.21 and 4.72 ± 0.52 μM) were significantly stronger than the positive drug minocycline (IC₅₀ = 30.31 ± 3.01 μM) (Chen et al., 2020a). The ethanol extract from X. sorbifolium seeds (1–50 μg mL⁻¹) has significant implications for the prevention of vascular complications, which is linked to inhibition of the NF-κB/reactive oxygen species (ROS) pathway and activation of the Nrf-2/HO-1 pathway (Jung Joo et al., 2018). Xanthoceraside (extracted from the husk of X. sorbifolium) significantly inhibits the release of NO, IL-1β, and TNF-α in a concentration (0.01 and 0.1 µM)-dependent manner (Qi et al., 2013). In addition, gavage with n-butanol extract (2,000 mg kg⁻¹; from X. sorbifolium wood) has shown a significant inhibitory effect on ear swelling induced by xylene (25 μL·ear⁻¹) in Chinese Kunming (KM) mice, indicating that n-butanol extracts in X. sorbifolium wood can inhibit the early exudation and edema caused by inflammation (Kuang et al., 2001). Similarly, 7 days of gavage with the n-butanol extracts of X. sorbifolium wood (1.5 g kg⁻¹) significantly inhibited the swellings in inflamed feet, non-inflamed feet, and forelimbs of Wistar male rats induced by the intradermal injection of Freund’s complete adjuvant (0.1 ml) in the plantar region of the foot. These results indicated that n-butanol extracts from lignum xanthocerais had an inhibitory effect on primary and secondary joint swelling in rats with adjuvant arthritis and improved the systemic symptoms of adjuvant arthritis in rats (Kuang and Liu, 2002).

At present, most reports only used the crude extract to verify the anti-inflammatory activity of X. sorbifolium. Although it has been verified in vivo and in vitro, there are still great shortcomings in the research of X. sorbifolium. Therefore, more extensive pharmacological studies should be carried out to clarify the mechanism underlying the anti-inflammatory effect of X. sorbifolium and determine its active compounds to provide reliable data to support the development and utilization of X. sorbifolium.

Anti-Tumor Activity

In general, the anti-tumor activities of natural products are often evaluated by their ability to inhibit the proliferation of tumor cells and induce immune cells to secrete cytokines that act on tumor cells (Keawsard et al., 2012). The functional constituents of natural plant resources as anti-cancer agents have become increasingly popular, with many focusing on barrigenol triterpenes.

In one study, xanthoceraside (10 μM) significantly inhibited the proliferation of human melanoma A375. S2 cells through the mitochondrial pathway in a concentration- and time-dependent manner without impairing the viability of normal cells and increased the percentage of cells in the sub-G₁ phase (Jiao et al., 2014). Moreover, Wang et al. (2016b) adopted the CCK-8 method to test the n-BuOH layer of a 70% X. sorbifolium husk extract and 10 barrigenol-like triterpenoids against cancer cells of the human hepatoma cell line (HepG2), human colorectal cancer cell line (HCT-116), and human glioma cell line (U87-MG). The results showed that the n-BuOH layer of a 70% X. sorbifolium husk extract exhibited many anti-tumor activities against HepG2, HCT-116, and U87-MG cell lines, with IC₅₀ values of 15.3, 6.7, and 16.3 μg mL⁻¹, respectively (Wang et al., 2016b). Furthermore, Chan (2007) isolated xanthoceraside from an 80% ethanol extract of X. sorbifolium husk, and determined its effect on the growth of various human cancer cell lines, including OVCAR3 (ovary), HTB-9 (bladder), U2OS (bone), DU145 (prostate), K562 (leukocyte), HepG2 (liver), MCF-7 (breast), T98G (brain), HCT116 (colon), H460 (lung), SK-Mel-5 (skin), and HeLa-S3 (cervix) cell lines, using the MTT assay with IC₅₀ values of 14.5 ± 1, 48.3 ± 3, 46.7 ± 8, 41.7 ± 8, 44.3 ± 6, 57 ± 11, 65 ± 0, 77.5 ± 11, 103.3 ± 3, 112.5 ± 4, 115 ± 7, and 130 ± 14 μg mL⁻¹, respectively.

Xanthoceras sorbifolium has an inhibitory effect on a variety of cancer cells. However, CCK-8 and MTT methods can only verify its inhibitory effect but fail to reveal the exact molecular mechanism. Therefore, further in vivo experiments are needed to determine the effective chemical constituents and signal pathways and clarify the anti-cancer mechanism of X. sorbifolium.

Antioxidant Activity

Oxidative stress plays a crucial role in the pathogenesis of various chronic diseases, such as diabetes, cardiovascular diseases, and neurodegenerative diseases. ROS are often associated with oxidative stress. Scavenging or inhibiting ROS generation can delay or prevent oxidative cellular oxidizable substrates from achieving anti-oxidation (Uttara et al., 2009; Small et al., 2012; Zhao et al., 2018). In recent years, deeper investigations of X. sorbifolium have highlighted its antioxidant activity.

Zhang et al. (2015) reported that the compounds epicatechin, catechin, myricetin, and dihydromyricetin, which exist in lignum xanthocerais, showed remarkable protective effects against peroxyl radical-induced DNA strand scission (when the concentration was 10 μmol L⁻¹, the protective rates were 92.10, 94.66, 75.44, and 89.95%, respectively). Furthermore, some researchers have reported that saponins from the X. sorbifolium nutshell have a higher scavenging effect than vitamin C in vitro. The hydroxyl radical-scavenging effects of saponins were 15.5–68.7% at a concentration of 0.18–2.52 mg mL⁻¹ (Zhang and Zhou, 2013a). The antioxidant activity of crude extracts in ethanol extraction fractions of 10, 30, 50, 70, and 95% showed scavenging effects on DPPH with a dose-dependent relationship. The 70% ethanol extract had the most substantial effect (the DPPH scavenging rate reached 70.82% at a mass concentration of 0.2 mg mL⁻¹) (Zhang et al., 2017). These results also support the traditional use of treating metabolic syndromes, such as diabetes and hypertension.

As various studies have revealed the antioxidant activities of X. sorbifolium, this plant should be further explored for potential novel antioxidants. However, verification methods such as DPPH analysis may overestimate the antioxidant content. Moreover, these determination methods cannot characterize all the analytical properties of the extract (Amorati and Valgimigli, 2015). Therefore, these methods are not yet sufficient for elucidating the antioxidant mechanism of X. sorbifolium, and further research is required to investigate the kinetics of this mechanism.

Other Pharmacological Activities

Xanthoceras sorbifolium has other pharmacological activities, including anti-HIV, and plays protective roles in cardiovascular and cerebrovascular diseases (Ma et al., 2000; Li et al., 2007b; Jin et al., 2010; Zhang et al., 2013; Geng et al., 2014). Furthermore, it also inhibits the activities of pancreatic lipase and tyrosinase.

For example, 3-oxotirucalla-7, 24-dien-21-oic acid, oleanolic acid, and epigallocatechin-(4β→8,2β→O-7)-epicatechin isolated from the methanol extract from lignum xanthocerais are inhibitors of HIV-1 protease with IC₅₀ values of 20, 10, and 70 μg mL⁻¹, respectively (Ma et al., 2000). Li et al. (2007b) reported that the coumarin compound (cleomiscosin B) extracted from the seed coat possessed strong anti-HIV-1 activity in vitro. It also had a strong inhibitory effect on HIV-1 IIIB-induced C8166 cell formation in the syncytia with an EC₅₀ value of 8.61–12.76 μg mL⁻¹ and a selectivity index of greater than 15.67–23.23 (Li et al., 2007b). Xu et al. (2014) found that xanthoceraside can significantly improve cerebral artery ischemia-reperfusion injury in rats. Its mechanism may promote synaptic remodeling and/or reduce synaptic structural and functional damage (Xu et al., 2014). Geng et al. (2014) found that xanthoceraside significantly inhibits pancreatic lipase activity, and the maximum inhibitory rate can reach 87.5%. Therefore, as a weight-loss factor, xanthoceraside has broad prospects as both healthy food and medicine (Geng et al., 2014). Moreover, flavonoids and saponins extracted from the husk of X. sorbifolium have been shown to exhibit inhibitory effects on tyrosinase. For example, the inhibition rate was 45% at a flavonoid concentration of 0.48 mg mL⁻¹ and showed non-linear changes (Zhang et al., 2013). Zhang et al. (2013) showed that the saponin extract inhibited tyrosinase and was non-competitive at a concentration of 0.36 mg mL⁻¹, where the inhibition rate reached 64.6% (Zhang et al., 2013). Therefore, extracting flavonoids and saponins from the husk of X. sorbifolium as whitening components is in line with the current development trend of exploiting natural compounds as beauty components and improves the economic value of agricultural byproducts.

In general, there are many studies on the pharmacological activities of triterpenoids in X. sorbifolium. It is worth noting that xanthoceraside has many biological activities, and it may become a candidate compound for the prevention and treatment of AD and related diseases (Chi et al., 2010). The effective parts or active components with anti-AD effects can be isolated from X. sorbifolium, which can be used to prepare functional foods or drugs to improve learning and memory and have the potential to become leading anti-AD drugs through further research and development. However, screening for bioactivity and evaluation of most other categories of compounds remains at the crude extract level. To date, only a few reports have investigated the chemical constituents, bioactivity, pharmacodynamic, and mechanisms of action of extracts from X. sorbifolium, which remain elusive.

Structure-Activity Relationships

In the process of summarizing the chemical composition and pharmacology of oleanane-type triterpenes in X. sorbifolium, the general structural properties of the extracts along with their biological activities have been investigated. Compounds with the same structural skeletons, but different types or positions of substituents have more significant impacts on cytotoxic activities. The triterpenoids with structural skeletons of R1-barrigenol triterpenes were the active ingredients for anti-AD. Similarly, the barringtogenol C triterpenes and 16-deoxy barringtogenol C triterpenes were the active ingredients for anti-tumor activities. The triterpenes with no hydroxyl substitution at C₁₅ and C₁₆ showed no activity. Conversely, a hydroxyl substitution at C₁₅ and C₁₆ or C₂₈ by a glycoside group displayed anti-tumor activity in vitro. However, if the hydroxyl substitution occurred at C₂₄ or glycosylation at C₃ and C₂₁, the anti-tumor activity increased. In addition, angeloyl groups at C₂₁ and C₂₂ also play a role in inhibiting cell activity (Li 2006a; Wang et al., 2016b).

Regarding the relationship between the anti-AD activity and the structure of the ingredients, the most vigorous activity occurs in the compound R1-barrigenol. This activity disappears when its C₃ is linked with a sugar group or when C₂₄ is substituted with a hydroxyl group. Conversely, if ring A or E is substituted by a hydroxyl group, acetoxy group, or sugar chains, the activity of the compound decreases or disappears because of the different steric hindrance of C₂₁/C₂₂. For example, in compounds 22-di-O-angeloyl-24-hydroxy-R₁-barrigenol and 21-O-angeloyl-24-hydroxy R1-barrigenol, if the angelic acyls substitute with either C₂₁ or C₂₂, the activity decreases. Therefore, when the activity occurs at C₂₂, the activity decreases, and when the activity at C₂₁ occurs, the activity vanishes. At both C₂₁ and C₂₂, the compound exhibits weak activity. Conversely, the substitution of α-hydroxyl at C₁₅ or C₁₆ can enhance activity (Li, 2006a). A study on the anti-tumor effects showed that saponins with the sugar chains at C₃ and C₂₁ exhibited significant cytotoxicity. When an acetoxy group and C₂₈ substituted C₂₂ with a hydroxyl group, the activity was enhanced. However, the activity decreased after exchanging the positions in the two substituent groups. Furthermore, the activity does not seem to be affected by C₂₄ substitution (Chan, 2007). The structure of barrigenol-like triterpenoids greatly influences their activity. Thus, owing to its unique biological activity, X. sorbifolium has significant and far-reaching importance in the development of new natural anti-tumor and anti-AD drugs (Yu et al., 2012a).

Applications

Xanthoceras sorbifolium is a multipurpose plant. All sections of the plant are edible, medicinal, economical, and of ecological value. The trunks and branches, fruits, leaves, and other parts contain natural products with rich structures, including a wide range of biological activities and pharmacological effects. Other sections are utilized as food in China, such as fruit, tea, and cooking oil. Xanthoceras sorbifolium has ornamental value and is useful for carbon storage, soil remediation, and water conservation. The plant can also be used as industrial raw materials.

Traditional Applications

As a traditional medicinal herb in China, X. sorbifolium has been used widely in traditional Chinese and Mongolian medicines. Various plant parts are used for medicine, including trunks and branches, leaves, fruits, seeds, and flowers. The different parts have different medicinal values. The trunks and branches, lignum xanthocerais, are also called “xi la sen deng” in traditional Mongolian medicine (Pharmacopoeia Committee of the Ministry of Health of the People’s Republic of China, 1998). The therapeutic significance of lignum xanthocerais has been well acknowledged in the ancient Mongolian classics such as “Jing Zhu Ben Cao” (Qing Dynasty, AD 1848), “Meng Yao Zheng Dian” (Qing Dynasty, AD 19th), and “Chinese Materia Medica.” (Demar, 1986) In the 1977 edition of the “Chinese Pharmacopeia,” the folk remedies for the treatment of rheumatism with X. sorbifolium leaves were first recorded (Commission NP. 1977). It has been reported that it is sweet-flavored cool-natured, and suitable to treat scurvy, rheumatism, rheumatoid arthritis, enuresis in children, rheumatic heart disease, swollen glands, overheating, and swelling, and also offers pain relief (Chinese Materia Medica Editorial Committee, 2004; Wang et al., 2011). In addition, fruits are used to treat rheumatism, gout, and enuresis in children as a folklore medicine in Inner Mongolia. It has been developed into a product named “Pediatric Urinary Suspension” by pharmaceutical companies (Zhao et al., 2008). According to the new Tibetan medicine formula, lignum xanthocerais is used in Liuweiximi pills in Tibet, China. It has the effects of tonifying the kidney, “expelling wind and dampness,” relieving pain, and treating kidney and low back pain as well as frequent urination caused by kidney cold (Institute of Tibetan medicine, 1975). X. sorbifolium is also widely used in Northeast China. For example, its seeds are used to treat nocturia in children (Xie, 1996). Its fruit is mainly used for rheumatoid arthritis (Ministry of Health of Shenyang Army Logistics Department, 1970); its wood can dispel wind, remove dampness, detumescence, and relieve pain (National Administration of Traditional Chinese Medicine, 1999).

In summary, X. sorbifolium has a wide range of traditional uses, and most of its recorded traditional applications are concentrated in northern China. Effectively combining traditional applications of X. sorbifolium with modern clinical applications will be a notable future research direction.

Clinical Applications

Xanthoceras sorbifolium is rich in 278 compounds, providing a reasonable basis for medicinal use. The triterpenes isolated from the husk are promising candidates for medicines to prevent or cure human cancer, AD, enuresis, urinary incontinence, dementia, and modulate cerebral functions (Ge and Wu, 1997; Liu et al., 2007a; Liu et al., 2007b; Chi et al., 2009; Lu et al., 2012; Li and Sun, 2019). The leaves are rich in saponin, flavonoids, protein, and trace elements, with a high inhibitory effect on various human tumor cells (such as breast cancer, prostate cancer, gastric cancer, liver cancer, cervical cancer, and leukemia). The leaves can improve the functions of the central nervous system, cholinergic nerve system and fight the damage caused by free radicals, assisting the treatment of urine incontinence and an overactive bladder (Si, 1996). After degreasing, the kernels of X. sorbifolium can be made into efficient drugs to treat pediatric enuresis. The data from 100 initial clinical results show that its efficacy rate is as high as 93%. In addition, lignum xanthocerais is often combined with other medicines in clinical preparations to treat skin diseases and rheumatism. The traditional and modern prescriptions of lignum xanthocerais are listed in Table 3.

Except for the anti-inflammatory activity, which has been widely used in clinical applications, most of the other pharmacological activities have only been studied theoretically; thus, they lack extensive practical research. Therefore, applying the pharmacological activity of X. sorbifolium to clinical practice should be the focus of future X. sorbifolium research.

Edible Applications

The food value of X. sorbifolium is mainly derived from its seeds, kernels, and leaves. Edible oil can be extracted from the seeds and the oil ratio is 30.4% in the seeds and 55–66% in the kernel (Yan, 2007). The oil is a cooking oil with a high smoke point, a yellowish color and delicious flavor and may help in preventing cardiovascular and cerebrovascular diseases. In the seed oil, the unsaturated fat has been isolated, accounting for 94.0%, including linoleic acid (36.9%) and oleic acid (57.16%). (Yan, 2007; Zeng et al., 2013). The tender kernels have a unique fruit flavor that can be eaten raw or processed into canned food for giving to infants during weaning.

Additionally, kernels can also be processed into a nutritious fruit juice and a high-quality protein drink. Moreover, the seeds are delicious when fried (Li et al., 2003). The leaves of X. sorbifolium can be processed for tea and lower blood lipids, blood pressure, and protect the cardiovascular and cerebrovascular vessels. In tea, the protein content is as high as 19.8–23.0%, which is higher than black tea, and the caffeine content is similar to scented tea (Hua, 2004). The flower is a hardy honey plant with a long flowering period, enabling a large amount of honey to be produced from the flowers. The husk remaining after oil extraction can be made into high-protein beverages (Li et al., 2003).

Other Applications

In addition to its edible and medicinal uses, X. sorbifolium has a high economic and ecological value. The plant is a potential bio-energy feedstock plant and has been identified as a major woody energy species for biodiesel production. Producers receive special support from the Chinese government for its development. The whole plant can be used as an eco-friendly tree species for soil and water conservation and land reclamation in mining areas (Bai et al., 2010). The husk contains 12.2% furfural, which is the best raw material for furfural extraction. Husks and seed coats can be used as a source of activated carbon, xylitol, alcohol, and other chemical raw materials. The trunks and branches can be exploited as top-grade furniture and farm tools because of the hard texture, strong corrosion resistance, and dark maroon color with a beautiful vein pattern (Xu and Yu, 2010). The plant has a long flowering period with bright colored flowers making it highly ornamental. As an ornamental tree, it is suitable for planting in gardens, parks, and scenic areas (Wan et al., 2010). The flowers are also edible, and the pollen and oil can be used to make advanced beauty skincare products (Zhang et al., 2012).

Conclusion and Discussion

In conclusion, X. sorbifolium, a native plant with economic and medicinal value in China, is rich in resources and is widespread throughout northern China. Here, X. sorbifolium was reviewed with regard to botany, phytochemistry, pharmacological activity, structure-activity relationship, and applications. Concerning the phytochemistry of X. sorbifolium, a total of 278 compounds have been discovered: 124 terpenoids, 48 flavonoids, 14 phenylpropanoids, 17 steroids, 17 phenols, 29 fatty acids, 9 alkaloids, 4 quinones, and 16 other compounds. Modern pharmacology has gradually verified the traditional efficacy of X. sorbifolium and explored its role in treating AD, rheumatism, vasculitis, scabies, and other diseases. The pharmacological effects have mostly focused on improving learning and memory impairment, as well as on anti-inflammatory and antioxidant effects. Nevertheless, there are still some research barriers that need to be overcome. Despite numerous studies on the chemical constituents of X. sorbifolium, research into the corresponding pharmacological activities predominantly involves terpenoids and saponins, especially the landmark compound xanthoceraside, which shows good pharmacological activity related to improving learning and memory impairment, anti-inflammation, and anti-tumor properties. However, research into other types of compounds is very limited. Moreover, it is difficult to link the phytochemistry and pharmacological effects of X. sorbifolium; therefore, this should mark the main direction of future X. sorbifolium research. Furthermore, in the process of studying the structure-activity relationships of X. sorbifolium, it was discovered that the biological activities of compounds with the same structural skeleton but different substituent positions have significant differences, especially in their anti-tumor and anti-AD properties. More research into the structure-activity relationships of X. sorbifolium will be highly significant for the development and utilization of these compounds. In addition, no studies have yet reported any differences in the main production areas or seasons for the same plant component.

Despite the substantial practical value of X. sorbifolium, current research is not comprehensive. It requires further analysis of five main aspects to fully understand all the characteristics of X. sorbifolium. First, 278 compounds were isolated from X. sorbifolium, most of which were terpenoids. However, a lot of unknown compounds are yet to be found. The bioactivity-oriented separation strategy can be used to study potential phytochemicals and explore target compounds. However, the difficulty of phytochemical separation and the low content of compounds limit drug development. In general, using abundant phytochemicals to develop potential compounds can lay a foundation for developing new drugs. Some active derivatives should be considered to enrich the medicinal value of X. sorbifolium. Second, there is currently no standard quality control method or index for assessing the components of X. sorbifolium. Therefore, considerable research should be devoted to creating a standard quality assessment approach to ensure the quality of X. sorbifolium. Specifically, it is necessary to determine X. sorbifolium contents or produce standardized fingerprints to index the components of this species. Third, research on the biological activity of the compounds remains limited, with the majority of selected biological activity research employing only the crude extract. Therefore, more studies are required to assess the pharmacodynamic material and pharmacological mechanisms to obtain relevant compounds responsible for the pharmacological effects and unveil the potential mechanisms involved. In addition, research on the antioxidant activity of X. sorbifolium is mostly based on chemical methods such as DPPH experiments, which are not particularly thorough, making it difficult to reveal the antioxidant mechanism of X. sorbifolium. We believe that X. sorbifolium can become an excellent antioxidant; however, sufficient in vivo and in vitro studies are required to support this development. Fourth, additional pharmacokinetic, metabolomic, and clinical studies are required to elucidate all chemical constituents entering the body and their processes within the body. Such research would aim to build a bridge between the chemical constituents and the systemic clinical effects, which is crucial for fully understanding the target components, pharmacological effects, and potential applications of this plant. Fifth, at present, there is little comprehensive utilization of X. sorbifolium resources, especially the research and utilization of tea-making technology, drinking methods, and health products based on the leaves, which still have a great potential for development and value-added utilization. Furthermore, the oil production from X. sorbifolium generates large volumes of waste, including husks, oil residue, seed meals, and seed coats. Research has shown that the residues are rich in various compounds. There is an urgent need to create new technological systems to develop and utilize these waste products to add value and create societal benefits.

In summary, this review provides a comprehensive and critical analysis of the phytochemistry, pharmacology, and traditional and modern applications of X. sorbifolium. We also discuss the limitations of existing literature and propose solutions for further research and development. Finally, we summarize and analyze the importance of X. sorbifolium for medicinal applications.

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