Systematic Review of Chemical Constituents in the Genus Lycium (Solanaceae)

The Lycium genus is widely used as a traditional Chinese medicine and functional food. Many of the chemical constituents of the genus Lycium were reported previously. In this review, in addition to the polysaccharides, we have enumerated 355 chemical constituents and nutrients, including 22 glycerogalactolipids, 29 phenylpropanoids, 10 coumarins, 13 lignans, 32 flavonoids, 37 amides, 72 alkaloids, four anthraquinones, 32 organic acids, 39 terpenoids, 57 sterols, steroids, and their derivatives, five peptides and three other constituents. This comprehensive study could lay the foundation for further research on the Lycium genus.


Introduction
Lycium is one of the genera in the Solanaceae family, comprising 80 species, seven of which are found in China [1]. These species are all deciduous shrubbery, possessing a highly similar morphology and structure. The Lycium genus has been an important source of medicines and nutrient supplements for thousands of years in Southeast Asia, especially in China. Two species in particular, Lycium barbarum and Lycium chinense, have been widely used as traditional Chinese medicinal herbs for centuries and L. barbarum is currently widely cultivated in China.
Goji berries (Chinese name Gouqizi), which are derived from the fruits of Lycium Linn, have been used as traditional herbs for a long time in China for their benefits of replenishing vital essence to improve eyesight, nourish the liver and kidneys. Lycii cortex is a "heat cleansing" drug that is derived from the root bark of L. chinense and L. barbarum [2]. Goji berries and Cortex Lycii have demonstrated good therapeutic effects in some chronic diseases such as hectic fever, night sweats, cough, hemoptysis, and diabetes. Recently, medical research has indicated that these fruits and root bark have many pharmacological functions, such as antiglaucoma, immunoregulatory, antitumor, antioxidant, antiaging, neuroprotective, and blood sugar level reducing activities [3][4][5][6][7][8][9][10].
Traditionally, the berry and root bark available have been used as medicinal sources, as well as important components in some traditional Chinese patent medicines. They are not only famous medical herbs, but are also functional foods widely consumed in health-preserving cuisines, i.e., soups, congee, herbal tea, etc. People also eat the fresh leaves as vegetables. In particular, goji berries have become increasingly popular for improving overall well-being and as an anti-aging remedy. There are many goji derived-products on health food market, such as dried fruits, juice, goji wine and goji Two valuable medicinal herbs, namely L. barbarum and L. chinense, have received remarkable attention due to their effective clinical therapy, especially in the anti-aging category. In addition, there are increasing numbers of publications about several other Lycium plants, i.e., Lycium ruthenicum [15,16]. Many researchers have focused great attention on the Lycium genus in recent years, and many chemical components from this genus have been isolated. Therefore, a comprehensive and systematic review on the chemical constituents of the Lycium genus is much needed.
Most of the published reviews not only covered chemical composition, but also summarized the pharmacology, clinical studies, safety, toxicology and adverse actions of L. barbarum or L. chinense [17][18][19]. The aim of this review was to focus on chemical constituents in different parts of plants from different species in Lycium genus, especially small molecular compounds with updated research reports. This paper comprehensively summarizes the reports of constituents from the genus Lycium. Up to 2016, at least 355 constituents were reported from different species in the Lycium genus and different parts (fruits, root bark, leaves, seeds, and flowers) of the plant. This review describes the advances in the phytochemistry of the genus Lycium from 1975 to 2016, based on the 142 cited references. The reported constituents can be classified as glycerogalactolipids, phenylpropanoids, coumarins, lignans, flavonoids, amides, alkaloids, anthraquinones, organic acids, terpenoids, sterols, steroids, peptides, and other constituents. The aim of this review is to illustrate the recent advances in the characterization of the Lycium genus. The results, based on these phytochemical studies, could lay a solid foundation for better understanding of pharmacological activities of Lycium and quality assessment.

Constituents
Until now, other than polysaccharides, more than 355 compounds have been isolated and identified from the Lycium genus. The small molecules can be assigned to various classes of glycerogalactolipids, phenylpropanoids, coumarins, lignans, flavonoids, amides, alkaloids, anthraquinones, organic acids, terpenoids, sterols, steroids and their derivatives, and peptides. Beyond that, other groups of compounds have also been reported. The proportion of different compounds of the Lycium genus is show in Figure 1. Their structures are shown below, and their names and corresponding plant sources are included in this paper.

Glycerogalactolipids 1-22
At present, 17 compounds of this type, a series of glycerogalactolipids 1-17, listed in Table 2, have been isolated and identified. Compounds 1-15 have been isolated and identified from the fruits of L. barbarum [52], whereas 16 and 17 were isolated from the fruits of L. chinense [53]. Compounds 18-22, illustrated in Figure 2, were isolated from the root bark of L. chinense [54,55]. At present, 17 compounds of this type, a series of glycerogalactolipids 1-17, listed in Table 2, have been isolated and identified. Compounds 1-15 have been isolated and identified from the fruits of L. barbarum [52], whereas 16 and 17 were isolated from the fruits of L. chinense [53]. Compounds 18-22, illustrated in Figure 2, were isolated from the root bark of L. chinense [54,55]. At present, 17 compounds of this type, a series of glycerogalactolipids 1-17, listed in Table 2, have been isolated and identified. Compounds 1-15 have been isolated and identified from the fruits of L. barbarum [52], whereas 16 and 17 were isolated from the fruits of L. chinense [53]. Compounds 18-22, illustrated in Figure 2, were isolated from the root bark of L. chinense [54,55].

Tropane Alkaloids
As we know, the genus Lycium has been used as both a medicine and a food for a long time in Asia, particularly in China. However, the safety of Lycium has been questioned for some time, especially after the detection of the three tropane alkaloids atropine (204), hyoscyamine (205), and scopolamine (206) [101]. Atropine and hyoscyamine were identified from the fruits of L. barbarum gathered in India, while scopolamine was identified from L. halimifolium at concentrations higher than the toxic dose. However, another scholar, seeking to verify these reports, demonstrated that the atropine content of L. barbarum from different sources was just 3.0 ppb-far below the poisoning dose [102]. It was demonstrated that none of the toxic compounds were detected in fruits, leaves, stems and roots of three L. barbarum varieties ('No. 1', 'New Big' and 'Amber Sweet Goji') by densitometric

Tropane Alkaloids
As we know, the genus Lycium has been used as both a medicine and a food for a long time in Asia, particularly in China. However, the safety of Lycium has been questioned for some time, especially after the detection of the three tropane alkaloids atropine (204), hyoscyamine (205), and scopolamine (206) [101]. Atropine and hyoscyamine were identified from the fruits of L. barbarum gathered in India, while scopolamine was identified from L. halimifolium at concentrations higher than the toxic dose. However, another scholar, seeking to verify these reports, demonstrated that the atropine content of L. barbarum from different sources was just 3.0 ppb-far below the poisoning dose [102]. It was demonstrated that none of the toxic compounds were detected in fruits, leaves, stems and roots of three L. barbarum varieties ('No. 1', 'New Big' and 'Amber Sweet Goji') by densitometric TLC analysis [103]. Through field investigation and model specimen inspections, the above three tropane alkaloids were determined to be from Lycium europaeum rather than the L. barbarum. Thus, the genus Lycium is likely non-toxic, and consumers can rest assured that its use is safe [104].

Tropane Alkaloids
As we know, the genus Lycium has been used as both a medicine and a food for a long time in Asia, particularly in China. However, the safety of Lycium has been questioned for some time, especially after the detection of the three tropane alkaloids atropine (204), hyoscyamine (205), and scopolamine (206) [101]. Atropine and hyoscyamine were identified from the fruits of L. barbarum gathered in India, while scopolamine was identified from L. halimifolium at concentrations higher than the toxic dose. However, another scholar, seeking to verify these reports, demonstrated that the atropine content of L. barbarum from different sources was just 3.0 ppb-far below the poisoning dose [102]. It was demonstrated that none of the toxic compounds were detected in fruits, leaves, stems and roots of three L. barbarum varieties ('No. 1', 'New Big' and 'Amber Sweet Goji') by densitometric TLC analysis [103]. Through field investigation and model specimen inspections, the above three tropane alkaloids were determined to be from Lycium europaeum rather than the L. barbarum. Thus, the genus Lycium is likely non-toxic, and consumers can rest assured that its use is safe [104].
non-toxic, and consumers can rest assured that its use is safe [104].

Sterols, Steroids, and Their Derivatives 291-347
Fifty-seven sterols, steroids, and their derivatives 291-347, listed in Figure 22, have been identified from the genus Lycium, mainly from the seeds and the fruits. Compounds 293 and 343 were identified

Discussion
Lycium species are of valuable medicinal, nutritional and functional significance, and have been studied in terms of their chemical compounds. Phytochemical investigations on eight different species, have resulted in the isolation of at least 355 constituents up to July of 2016. Research on chemical compounds has concentrated mainly on L. barbarum and L. chinense. Therefore, future phytochemistry research should be focused on the other species in Lycium genus. In addition, diverse plant parts (i.e., the flowers, leaves, seeds) have also been testified to contain new constituents, most of which possess the novel chemical structures. Polysaccharides play a particularly significant role in

Discussion
Lycium species are of valuable medicinal, nutritional and functional significance, and have been studied in terms of their chemical compounds. Phytochemical investigations on eight different species, have resulted in the isolation of at least 355 constituents up to July of 2016. Research on chemical compounds has concentrated mainly on L. barbarum and L. chinense. Therefore, future phytochemistry research should be focused on the other species in Lycium genus. In addition, diverse plant parts (i.e., the flowers, leaves, seeds) have also been testified to contain new constituents, most of which possess the novel chemical structures. Polysaccharides play a particularly significant role in

Discussion
Lycium species are of valuable medicinal, nutritional and functional significance, and have been studied in terms of their chemical compounds. Phytochemical investigations on eight different species, have resulted in the isolation of at least 355 constituents up to July of 2016. Research on chemical compounds has concentrated mainly on L. barbarum and L. chinense. Therefore, future phytochemistry research should be focused on the other species in Lycium genus. In addition, diverse plant parts (i.e., the flowers, leaves, seeds) have also been testified to contain new constituents, most of which possess the novel chemical structures. Polysaccharides play a particularly significant role in exerting pharmacological actions. A specific class of polysaccharides, abbreviated as LBP, is used as biomarker in the 2015 Chinese Pharmacopoeia as a measure by which wolfberry is qualified. At present, LBP in products or in pharmacological studies usually are polysaccharide mixtures with heterogeneity and polydispersity. On the other hand, development of new separation, detection techniques will greatly benefit the phytochemical isolation and structural elucidation of LBP. There is a growing recognition that not only the LBP, but also the plant secondary metabolites may have the potential active ingredients, while most of the research on goji berry was LBP rather than small molecule substances, so more intensive studies of goji berry are required to shed some light on these compounds.