Biological Activities and Secondary Metabolites from Sophora tonkinensis and Its Endophytic Fungi

The roots of Sophora tonkinensis Gagnep., a traditional Chinese medicine, is known as Shan Dou Gen in the Miao ethnopharmacy. A large number of previous studies have suggested the usage of S. tonkinensis in the folk treatment of lung, stomach, and throat diseases, and the roots of S. tonkinensis have been produced as Chinese patent medicines to treat related diseases. Existing phytochemical works reported more than 300 compounds from different parts and the endophytic fungi of S. tonkinensis. Some of the isolated extracts and monomer compounds from S. tonkinensis have been proved to exhibit diverse biological activities, including anti-tumor, anti-inflammatory, antibacterial, antiviral, and so on. The research progress on the phytochemistry and pharmacological activities of S. tonkinensis have been systematically summarized, which may be useful for its further research.


Introduction
Sophora tonkinensis Gagnep. belongs to the Sophora genus of the Leguminosae family, which is widely distributed in the southwest provinces of China [1,2]. As a famous folk medicine of the Miao people, the roots of S. tonkinensis were known as Shan Dou Gen or  60 17-Oxo-α-isosparteine C 15

Anti-Tumor Effect
The anti-tumor effect was one of the most reported activities of S. tonkinensis ( Table 2). The chloroform extracts of S. tonkinensis have been discovered its inhibitory effect on cell viability and clonal growth in a dose-dependent manner [87]. Meanwhile, the extracts of S. tonkinensis also have been reported the inhibit ability target the proliferation, adhesion, invasion, and metastasis of mouse melanoma cells [86]. The anticancer activities of compounds have also been reported [38]. The natural compounds from S. tonkinensis exhibited inhibitory effects against different tumor cells. The growth-inhibitory and apoptosis-inducing activities of sophoranone (120) for leukemia U937 cells were investigated [88].

Hepatoprotective
The components of S. tonkinensis were reported significant protective effects against immune induced liver injury (Table 2). Previous works suggested that the nonalkaloid constituents of S. tonkinensis obviously reduced the alanine aminotransferase (ALT), aspartate aminotransferase (AST) serum, malondialdehyde (MDA), and nitric oxide (NO), as well as increased the superoxide dismutase (SOD) and glutathione (GSH) in mice with immune-induced liver injury [13]. The water extract of S. tonkinensis alleviated hepatic inflammation, liver fibrosis, and hepatic lipids accumulation [91]. Compounds matrine (1) and oxymatrine (4) may be the main components contributing to the lipid-lowering activity of the water extract of S. tonkinensis [91]. Meanwhile, two purified polysaccharide fractions (STRP1 and STRP2) from the roots of S. tonkinensis have been reported to attenuate hepatic oxidative damage in vivo [95]. In addition, some compounds, including sophocarpine (34) from S. tonkinensis have been reported to significantly improve liver injury in mice [93].

Toxicity
The roots of S. tonkinensis were the famous toxic Miao drug (Table 2) and were named Shan Dou Gen or Guang Dou Gen [4,110]. The aqueous and alcoholic parts of S. tonkinensis caused obvious liver damage in mice, which could result in both the alteration of liver function and the organelle damage of hepatocytes [111,112]. Meanwhile, the extracts of S. tonkinensis exhibited pulmonary toxicity, which may trigger pulmonary cancer, dyspnea, and oxidative stress [113]. The obvious toxicity of sophoranone (120) to zebrafish was mainly characterized as hepatotoxicity, neurotoxicity, cardiovascular toxicity, and nephrotoxicity in the acute toxicity model [104]. Besides, the alkaloids matrine (1), oxymatrine (4), cytisine (50), and sophocarpine (34) of S. tonkinensis showed significant cardiotoxicity [114].

Other Pharmacological Activities
The extracts of S. tonkinensis have the ability to reduce blood glucose and resist microbial activities (Table 2, Figure 2). Cytochalasin E (310) and H (306) inhibit a variety of plant pathogens [71]. The flavonoid-rich extracts of S. tonkinensis administrated orally to mice significantly increased sensibility to insulin, as well as reduced fasting blood-glucose levels [33]. Moreover, matrine (1) from S. tonkinensis could improve glucose metabolism and increased insulin secretion in diabetic mice, which may be used as a potential drug for diabetes treatment [108]. Methanol extracts of S. tonkinensis exhibited antidiarrheal activities [115]. Moreover, diverse anti-microbial activities of compounds from S. tonkinensis and its endophytic fungi have been reported [26,67]. a potential drug for diabetes treatment [108]. Methanol extracts of S. tonkinensis exhibited antidiarrheal activities [115]. Moreover, diverse anti-microbial activities of compounds from S. tonkinensis and its endophytic fungi have been reported [26,67].

Conclusion and Future Prospective
In this review, we provide a detailed summary of the medicinal chemistry, pharmacological activities, and related toxicity research of S. tonkinensis. Structurally, more than 300 compounds have been isolated from S. tonkinensis and its endophytic fungi, including alkaloids, triterpenes and triterpenoid saponins, flavonoids, and so on. Some of the star molecules, including matrine (1) and oxymatrine (4), were documented to exhibit well biological activities [110]. For its pharmacological research, previous studies suggested the usage of S. tonkinensis in the folk treatment of upper respiratory tract infection diseases. It is generally believed that the alkaloid components of S. tonkinensis were the main active substances in the roots of S. tonkinensis [116]. Interestingly, the extracts of S. tonkinensis have been reported for hepatotoxicity, while the other related studies showed the opposite hepatoprotective effects. The in-depth toxicological or structure-activity relationship study may be worth for further research. Moreover, the roots of S. tonkinensis combined with other medicines form dozens of marketing Chinese patent medicine for the treatments of pharyngitis, tonsillitis, and aphthous ulcers [9][10][11]. However, it is rare for its prescription pharmacological research in the treatment of upper respiratory tract diseases, especially works on the drug combination mechanism, which may need to be further developed.

Conclusion and Future Prospective
In this review, we provide a detailed summary of the medicinal chemistry, pharmacological activities, and related toxicity research of S. tonkinensis. Structurally, more than 300 compounds have been isolated from S. tonkinensis and its endophytic fungi, including alkaloids, triterpenes and triterpenoid saponins, flavonoids, and so on. Some of the star molecules, including matrine (1) and oxymatrine (4), were documented to exhibit well biological activities [110]. For its pharmacological research, previous studies suggested the usage of S. tonkinensis in the folk treatment of upper respiratory tract infection diseases. It is generally believed that the alkaloid components of S. tonkinensis were the main active substances in the roots of S. tonkinensis [116]. Interestingly, the extracts of S. tonkinensis have been reported for hepatotoxicity, while the other related studies showed the opposite hepatoprotective effects. The in-depth toxicological or structure-activity relationship study may be worth for further research. Moreover, the roots of S. tonkinensis combined with other medicines form dozens of marketing Chinese patent medicine for the treatments of pharyngitis, tonsillitis, and aphthous ulcers [9][10][11]. However, it is rare for its prescription pharmacological research in the treatment of upper respiratory tract diseases, especially works on the drug combination mechanism, which may need to be further developed.