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Review

A Review on the Ethnomedicinal Usage, Phytochemistry, and Pharmacological Properties of Gentianeae (Gentianaceae) in Tibetan Medicine

by
Xiaofeng Chi
1,2,
Faqi Zhang
1,2,
Qingbo Gao
1,2,
Rui Xing
1,2 and
Shilong Chen
1,2,*
1
Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China
2
Qinghai Provincial Key Laboratory of Crop Molecular Breeding, Xining 810008, China
*
Author to whom correspondence should be addressed.
Plants 2021, 10(11), 2383; https://doi.org/10.3390/plants10112383
Submission received: 8 October 2021 / Revised: 2 November 2021 / Accepted: 3 November 2021 / Published: 5 November 2021
(This article belongs to the Special Issue Ethnobotanical Uses, Biological Properties and Phytoconstituents of Endemic Plants)
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Abstract

:
Gentianaceae is a large plant family and is distributed worldwide. As the largest tribe in Gentianaceae, Gentianeae contains 939–968 species, and the Qinghai-Tibet Plateau and adjacent areas are the main centers of diversity for Gentianeae. Species from the Gentianeae are widely used in traditional Tibetan medicine. In this review, a systematic and constructive overview of the information on botany, ethnomedicinal usage, phytochemistry, and pharmacological properties of Gentianeae in Tibetan medicine is provided. The results of this study are based on a literature search, including electronic databases, books, websites, papers, and conference proceedings. Botanical studies showed that Gentianeae includes the subtribe Gentianeae and Swertiinae, and several new genera and taxa have been identified. Approximately 83 species from Gentianeae were used in Tibetan medicine, among which Gentiana and Swertia constituted the largest number of species with 42 and 24 species, respectively. The species from Gentianeae are mainly used as Bangjian (སྤང་རྒྱན།), Jieji (ཀྱི་ལྕེ།), Dida (ཏིག་ཏ།), and Ganggaqiong (གང་གྰཆུང་།) in Tibetan medicine with different clinical applications. More than 240 formulas were found containing Gentianeae species with different attending functions. Phytochemical studies showed that the main active components of Gentianeae species are iridoids, xanthones, flavonoids, and triterpenoids. The bioactivities of plants from Gentianeae include hepatic protection, upper respiratory tract protection, joint and bone protection, glucose regulation, antibacterial, antioxidant, anticancer, and antiviral effects. This review will provide a reference for future research on natural resource protection, plant-based drug development, and further clinical investigation.

1. Introduction

Tibetan medicine has a long history of being rich in active components, which embodies the precious experience of Tibetans in their long-term struggle against diseases. Moreover, Tibetan medicine is based on a unique theoretical system and strong national characteristics. The origin of Tibetan Medicine is extremely complicated. Tibetan medicine is not only a syncretism of Chinese, India, and Persia medicinal opinions but also has unique historical origins, which may stem from pre-Buddhist sources or may have Ayurvedic origins [1,2,3]. In 2006, Tibetan medicine was included in the first batch of the national intangible cultural heritage list of China.
The history of Tibetan medicine dates back to 200 BC (the reign of Nyatri Tsenpo [གཉའ་ཁྲི་བཙན་པོ།], the first governor of Tibet). The famous assertion of Tibetan medicine, “Poisonous, there is medicine” was proposed, which foreshadowed the budding of Tibetan medicine [4]. In 641 BC, the governor of Tibet, Songtsen Gampo (སྲོང་བཙན་སྒམ་པོ), married Princess Wen Cheng, princess of the Tang dynasty. Several medical books, diagnostics, herbal prescriptions, and medical instruments were brought to Tibet, which significantly promoted the development of Tibetan medicine [5]. Around the middle of the 8th century, a classic book on Tibetan medicine, “Sman-dpyad Zla-bavirgyal-po” (སྨན་དཔྱད་ཟླ་བའི་རྒྱལ་པོ།) was published, in which more than 440 types of botanical medicine, 260 types of animal-based medicine, and 80 types of medicine of mineral origin were recorded, and 30 materia medicas were unique to the Qinghai-Tibet Plateau [6]. At the end of the 8th century, Yuthok Yontan Gonpo (གཡུ་ཐོག་རྙིང་མ་ཡོན་ཏན་མགོན་པོ་) wrote “Dpl Ldn rGyud Bzhi” (༅༅།།བདུད་རྩི་སྙིང་པོཡན་ལག་བརྒྱད་པ་གསང་བམན་ངག་གི་རྒྱུད་ཅེས་བྱ་བ་བཞུགས་སོ།།), in which 1002 types of medicines were included and divided into 8 categories [7]. In 1835, the book “Shel Gong Shel Phreng” (ཤེལ་གོང་ཤེལ་ཕྲེང་།) was written by Devu Dmr Dge Bshes Bstn Vdzin Phun Dzogs (དེའུ་དམར་བསྟན་འཛིན་ཕུན་ཚོགས།), which is regarded as the greatest achievement in Tibetan medicine [8]. It lists 2294 drugs (1006 botanical drugs, 448 drugs from animal origin, and 840 drugs of mineral origin) classified into 13 categories. Most importantly, the shape, color, use, and habitat of each drug are described and many previous studies from the literature have been cited.
More than 2400 types of Tibetan medicine were included in ancient books and records and include more than 2170 botanical drugs, 210 drugs of animal origin, and 50 mineral drugs [9]. Among botanical medicines, more than half were distributed in the Qinghai-Tibet Plateau, especially a variety of alpine plants were widely used, such as “Snow Lotus”, “Himalayan poppy”, “Rhododendrons”, and “Gentians” [10,11,12]. Unique growing environments such as high altitude, long exposure to strong ultraviolet rays, cold, drought, and lack of oxygen partially contributed to the distinctive therapeutic effects of herbals. However, the cultivation of medicinal herbs was difficult in this area owing to the unique geographical conditions and climatic characteristics, and most herbal medicines were collected from the wild by excessive mining [13].
In terms of the varieties of medicines used, there is currently no professional market for Tibetan medicinal materials as the production of these materials mainly depends on the collection from wild resources. Most medicinal materials used in Tibetan medical institutions and pharmaceutical enterprises in various locations are self-equipped to collect the local, wild medicinal resources. Approximately 80% of medicinal materials consist of varieties unique to Tibetan medicine and are produced in Tibet, Qinghai, Gansu, Sichuan, and Yunnan. Different regions in Tibet use different medicinal materials, the source is closely related to the condition of local species of medicinal resources, and the significant characteristics of the “regional”, “homonym”, “synonyms”, “local learning supplies”, or substitute more phenomenon are extremely common [14]. Owing to the particularity of the traditional Tibetan cultural background and the relatively weak scientific and technological strength of Tibetan medicine, research on variety arrangement, quality standards, resource protection, and the utilization of Tibetan medicinal materials lag considerably and the quality standard of the products used in this system of medicine is far from perfect [15]. Thus, strengthening the sorting of Tibetan medicine species and establishing a standard system are important aspects to regulate their use in a clinical setting, guide pharmaceutical enterprises to synthesize qualified, safe, and effective drugs, improve the ability of drug supervision, protect, and ensure the rational use of Tibetan medicinal resources, and promote the cultural exchange of Tibetan medicine.
Gentianaceae is a large plant family with a global distribution [16]. It is primarily distributed in the temperate regions of the Northern hemisphere. There are about 103 genera and approximately 1600 species worldwide. Gentianaceae contains six tribes in which Gentianeae takes up more than half of the species in Gentianaceae. A total of 15 genera and 410 species of Gentianeae are found in China, of which 2 genera and 251 species are endemic [17]. The Qinghai-Tibet Plateau and adjacent areas are the main centers of diversity for Gentianeae [18]. Therefore, species from the Gentianeae tribe are one of the most widely used medicinal plants in traditional Tibetan medicine.
The potential of Tibetan medicine in healthcare is being recognized; thus, Gentianeae is attracting increased attention from medical professionals. A systematic review of the traditional use of this tribe and elucidating the chemical composition and pharmacological effects of Gentianeae will provide a powerful reference for the in-depth study, rational use, and effective protection of this valuable resource.

2. Data Collections

All data in this review were summarized from references, including scientific journals, book chapters, or dissertations. All the references were searched in several electronic databases, including PubMed, Web of Science, Scopus, ScienceDirect, CNKI (https://oversea.cnki.net/index/), Google Scholar (https://scholar.google.com/), and Baidu Scholar (https://xueshu.baidu.com/) with “Gentianeae (Gentianaceae) in Tibetan Medicine” as keywords without any other restrictions. Subsequently, literature closely related to botanical study chemical composition, traditional uses, and pharmacological properties were screened. In addition, the classification and geographical distribution of Gentianeae plants were searched in Plant Plus of China (https://www.plantplus.cn/cn), Global Biodiversity Information Facility (GBIF, https://www.gbif.org/) and The Plant List (http://theplantlist.org/). The last accessed date to the links mentioned above in order to acquire data was 31 May 2021.

3. Results

3.1. Botanical Studies of Gentianeae

Gentianeae has the largest number of species amounting to 939–968, which account for about 57% of Gentianaceae [16]. Gentianeae includes the subtribe Gentianeae and Swertiinae. The morphology, palynology, flower anatomy, and chromosome characteristics of Gentianeae were comprehensively summarized, and the classification history was analyzed [16,19,20]. On the basis of classical morphological classification, phylogenetic studies of Gentianeae have made a lot of progress with the development of molecular systematics, and the phylogenetic relationships among groups have become increasingly clear. Several new genera and taxa have been identified.

3.1.1. Subtribe Gentianeae

Struwe et al. divided the subtribe Gentianeae into three genera, Gentiana, Crawfurdia, and Tripterospermum based on the analysis of trnL-intron, matK, and ITS sequences combined with morphological studies [16]. Ho et al. published a new genus, Metagentiana, based on morphological characteristics [21]. Faver et al. separated the genus Sinogentiana from Metagentiana and the genus Kuepferi from Gentiana based on morphological characteristics and molecular phylogeny [22]. Thus, the current subtribe Gentianeae consists of six genera, namely, Gentiana, Metagentiana, Kuepferia, Crawfurdia, Sinogentiana, and Tripterospermum. Gentiana (350 species) is the largest genus of Gentianaceae that originated in the Qinghai-Tibet Plateau and differentiated with the rise of the plateau and with climatic changes [18]. Kuepferia (14 species) and Sinogentiana (2 species) prefer cool and dry habitats and are rather conserved niches. Despite a tendency for niche evolution, Crawfurdia (18 species) and Metagentiana (14 species) are probably restricted to a narrow distribution range owing to their poor dispersal ability [23]. In contrast, Tripterospermum (18 species) has the broadest niche and thrives under the warmest and wettest conditions [24]. A total of 279 species of the subtribe Gentianeae are distributed in China, including 231 species in Gentiana, 9 species in Metagentiana, 9 species in Kuepferia, 16 species in Crawfurdia, 2 species in Sinogentiana, and 16 species in Tripterospermum [17]. In the Qinghai-Tibetan plateau, there are about 176 species of subtribe Gentianeae, including Ca. 145 species in Gentiana, 3 species in Metagentiana, 9 species in Kuepferia, 15 species in Crawfurdia, 2 species in Sinogentiana, and 2 species in Tripterospermum.

3.1.2. Subtribe Swertiinae

Subtribe Swertiinae is a larger and more complex group than subtribe Gentianeae. According to Struwe et al., subtribe Swertiinae consists of 579–608 species in 14 genera, including Bartonia, Comastoma, Frasera, Gentianella, Gentianopsis, Halenia, Jaeschkea, Latouchea, Lomatogonium, Megacodon, Obolaria, Pterygocalyx, Swertia, and Veratrilla [16]. Ho et al. published two new genera, Lomatogoniopsis and Sinoswertia [25,26]. Therefore, there are 16 genera in the subtribe Swertiinae, of which 13 genera are native to China, including 3 endemic genera. A total of 131 species of subtribe Swertiinae are found in China, including 11 species in Comastoma, 9 species in Gentianella, 5 species in Gentianopsis, 2 species in Halenia, 2 species in Jaeschkea, 1 species in Latouchea, 3 species in Lomatogoniopsis, 17 species in Lomatogonium, 2 species in Megacodon, 1 species in Sinoswertia, 76 species in Swertia, and 2 species in Veratrilla [17]. In the Qinghai-Tibetan plateau, there are about 98 species of subtribe Swertiinae, including 9 species in Comastoma, 7 species in Gentianella, 4 species in Gentianopsis, 2 species in Halenia, 2 species in Jaeschkea, 3 species in Lomatogoniopsis, 15 species in Lomatogonium, 1 species in Megacodon, 1 species in Sinoswertia, 52 species in Swertia, and 2 species in Veratrilla. Although subtribe Swertiinae can be morphologically divided into two large groups (Rotate and Tubular), molecular phylogeny shows that several groups within subtribe Swertiinae are distinct complex groups [20]. Swertia is the main group of subtribe Swertiinae, whereas other related genera, either monophyletic or symphyletic, are derived from Swertia [27]. There are significant inconsistencies between the morphological taxonomy and molecular phylogeny among the genera of subtribe Swertiinae. The possible explanation is that morphological taxonomy cannot reflect the true evolutionary history, and the most significant reason may be the plasticity of the morphological characteristics [27,28,29].

3.2. Ethnomedicinal Usage of Gentianeae in Tibetan Medicine

Gentianeae species are important resources in traditional Chinese medicine and Tibetan medicine [5,30,31]. Approximately 133 species (including varieties) in 17 genera of Gentianeae were used in traditional Chinese medicine, among which Gentiana and Swertia constituted the largest number of species with 60 and 35 species, respectively, accounting for 71% of the species [32]. According to our investigation, approximately 83 species were used in Tibetan medicine (Table 1), including 3 species of Comastoma, 42 species of Gentiana, 3 species of Gentianopsis, 3 species of Halenia, 5 species of Lomatogonium, 1 species of Megacodon, 1 species of Sinoswertia, 24 species of Swertia and 1 species of Veratrilla (Figure 1). The history of the use of Gentianeae species in Tibetan medicine can be traced back to the 8th century in the book “The Remain of Dunhuang Tibetan Medicine” [33], “Sman-dpyad Zla-bavirgyal-po” [6], and “Dpl Ldn Rgyud Bzhi” [7], in which there are descriptions of the efficacy of Tibetan medicines, such as Bangjian (སྤང་རྒྱན།), Jieji (ཀྱི་ལྕེ།), Dida (ཏིག་ཏ།), and Ganggaqiong (གང་གྰཆུང་།), belonging to Gentianaceae. These classical works of Tibetan medicine not only record the use and usage of the medicine but cover the morphological characteristics and habitats of the plants used in traditional Tibetan medicine.

3.2.1. Bangjian (སྤང་རྒྱན།)

“Bangjian” is the general name of several medicinal plants of Gentiana and is a representative and commonly used term in Tibetan medicine. These plants are mainly used for the treatment of respiratory diseases, such as pneumonia, cough, tracheitis, and laryngitis, and fever [5,6,7,8]. According to our investigation, 15 species of Gentiana plants were used as the material medica resources of “Bangjian.” In accordance with the classification and nomenclature of Tibetan medicine, the material medica resources of “Bangjian” are classified by flower color. “Shel Gong Shel Phreng” divides “Bangjian” into three types: white (Bangjian·Gabao [སྤང་རྒྱན་དཀར་པོ།]), blue (Bangjian·Wenbao [སྤང་རྒྱན་སྔོན་པོ།]), and black (Bangjian·Nabao [སྤང་རྒྱན་ནག་པོ།]) [8]. “Bee Sngon” (བེེཌྰུརྱ་སྔོན་པོ།) divided “Bangjian” into white flower (Bangjian·Gabao), blue flower (Bangjian·Wenbao), and other colored flowers (Bangjian·Chabao [སྤང་རྒྱན་ཁྲ་པོ།]), among which the white flower was the best [34].
“Bee Sngon” documents that “Bangjian·Gabao grows on grassy slopes. The leaves are small, and the flowers are abundant. The taste is bitter and the effect is to cure the fever epidemic” [34]. “Shel Gong Shel Phreng” records that “Bangjian·Gabao grows in the alpine cold region. The leaves are like Jieji·Gabao (ཀྱི་ལྕེ་དཀར་པོ།) with no stem. Four or five white flowers are clustered with red luster” [8]. “Sgrol Ma Sngo Vbum” (བོད་སྨན་ཚད་ལྡན་འཁྲུངས་དཔེ།) states that “the leaves of Bangjian·Wenbao are like the Bangjian·Gabao. It is bitter in taste and cold-natured” [35]. “Shel Gong Shel Phreng” wrote “Bangjian·Wenbao grows on very wet marsh grassy flats with small leaves and pale blue flowers. The function is consistent with Bangjian·Gabao” [8]. “Shel Gong Shel Phreng” wrote “the flowers of Bangjian·Nabao are dark blue, very conspicuous, and slightly bolder than the Bangjian·Wenbao” [8]. “Bdud Rthi Smn Gyi Vkhrung Dpe” (བདུད་རྩི་སྨན་གྱི་འཁྲུངས་དཔེ་ལེགས་བཤད་ནོར་བུའི་ཕྲེང་མཇེ།) recorded that “the roots of Bangjian·Chabao were light yellow with fibrous roots. The leaves and stems were like Bangjian·Nabao, but without branches. The flowers are variegated and shaped like horns” [36]. “Tibetan medicine” (༄༄།།བོད་སྨན་གྱི་རྣམ་བཤད།) reports that “Bangjian·Chabao may refer to the distinct heterochromatic stripes and spots in the corolla, similar to Bangjian·Nabao, and not easily distinguishable from the Bangjian·Wenbao” [5].
The experience of the usage of “Bangjian” was summarized by Tibetan ancestors. It is extremely complicated to determine the origin of its medicinal materials because of the lack of systematic taxonomic knowledge and detailed description in the classic works of Tibetan medicine [14,37,38]. Herbological studies on the material medica resources of “Bangjian” are, therefore, necessary. After a systematic review and analysis of herbalism and phytotaxonomy in both ancient and modern literature, it is widely believed that G. szechenyii and G. algida (including G. algida var. algida and G. algida var. purdomii) are the two original plants of “Bangjian·Gabao” [39]. Nevertheless, research on the material medica resources of Bangjian·Nabao, Bangjian·Wenbao, and Bangjian·Chabao is extremely difficult as existing standards in the material medica resources are inconsistent [40,41,42]. Several plants in Gentiana, Sect. Monopodiae, Ser. Ornatae were used as the resources of “Bangjian·Nabao”, “Bangjian·Wenbao”, and “Bangjian·Chabao” (Table 1). These plants are very similar in morphology and have different flowers and colors in different regions, seasons, and habitats. It is impossible for Tibetan doctors and farmers in the field to distinguish medicinal materials based on plant taxonomy; thus, the situation of mixed use arises during production [40,41,43,44]. Although the material medica resources of “Bangjian·Nabao”, “Bangjian·Wenbao”, and “Bangjian·Chabao” are mixed, their effects are similar. These components are mainly used to treat fever and respiratory diseases, and the mixed components may not affect efficacy. It is particularly important to set more reasonable standards and thoroughly study the material medica resources of “Bangjian”.

3.2.2. Jieji (ཀྱི་ལྩེ།)

“Jieji” is a widely used Tibetan medicine. “Shel Gong Shel Phreng” documented that “Jieji” can clear fever of the viscera and gallbladder and can also cure leprosy [8]. It is widely used in the treatment of acute jaundrax hepatitis, rheumatoid arthritis, tonsillitis, leprosy, and urticaria [45]. According to our investigation, 9 species in the Gentiana Sect. Cruciata were used as the material medica resources of “Jieji.” “Shel Gong Shel Phreng” divided “Jieji” into two types: white flower (Jieji·Gabao [ཀྱི་ལྩེ།་དཀར་པོ།]) and black flower (Jieji·Nabao [ཀྱི་ལྩེ།་ནག་པོ།]) [8].
“Shel Gong Shel Phreng” recorded that “Jieji·Gabao grows in hillside meadows. Its stems are red with thick green leaves that are long and glossy. The flowers are white with many green stripes. The stems are erect with apical flowers like Bangjian” [8]. “Tibetan medicine” considers the abovementioned plant with red stems, white flowers, and green stripes as G. straminea and the plant with erect stems and apex flowers is G. tibetica or G. officinalis [5]. “Bee Sngon” states that “Jieji·Nabao growing in the mountains has morphological characteristics like Jieji·Gabao, with blue-purple flowers and thin leaves” [34]. “Shel Gong Shel Phreng” described that “Jieji·Nabao was like Jieji·Gabao, but the stem and leaves tiled on the ground. The leaves are slightly large and the flowers are white without significant luster” [8]. “Tibetan medicine” considered that the material medica resources of “Jieji·Nabao” are mainly G. dahurica and G.crassicaulis [5]. Moreover, other material medica resources of Jijie were used in actual production [46]. In the Qinghai Province, Tibetan doctors use G. hexaphylla as “Jieji·Gabao”. In Tibet, M. stylophorus was used as “Jieji·Gabao·Manba” (ཀྱི་ལྩེ།་དཀར་པོ་དམན་པ) [47]. In addition, G. waltonii, G. robusta, and G. siphonantha were also used as “Jieji” [47].

3.2.3. Dida (ཏིག་ཏ།)

“Dida” is one of the most representative medicines used in Tibetan medicine. “Shel Gong Shel Phreng” recorded that “Dida” has the effect of purging the liver and gallbladder, promoting diuresis, renewing the physique, and stanching bleeding [8]. Currently, “Dida” is widely used in the treatment of acute jaundice hepatitis, viral hepatitis, cholecystitis, urinary tract infections, blood disease, injuries, dysentery, edema, influenza, and other diseases [48].
“Sman-dpyad Zla-bavirgyal-po” divides “Dida” into three categories according to its origin: “Indian Dida” (“Jadi”, རྒྱ་ཏིག), “Nepalese Dida” (“Wadi”, བལ་ཏིག), and “Tibet Dida” (“Wodi”, བོད་ཏིག) [7]. “Shel Gong Shel Phreng” followed the above classification and further divided “Tibet Dida” into six groups: “Songdi” (སུམ་ཏིག), “Saierdi”(གསེར་ཏིག), “Edi” (དངུལ་ཏིག), “Sangdi” (ཟངས་ཏིག), “Jihedi” (ལྕགས་ཏིག), and “Gouerdi”(གུར་ཏིག) [8]. “Shel Gong Shel Phreng” recorded that “Jiadi is like a shrub and the whole plant is shiny. The stem is hollow and knobbly and the epidermis is thin and hard. The leaves are thick and dark green” [8]. It is widely believed that S. sinensis is the material medica resource of “Jiadi” [49,50]. S. sinensis is mainly distributed in India and Nepal and was recently found to be distributed in China (Dingjie and Jilong conty in Tibet) [51]. “Shel Gong Shel Phreng” documents that “In contrast to Jiadi, the color of Wadi is light and soft and the leaves are slightly yellow, whereas the other characteristics are similar” [8]. According to literature records and textual research, S. ciliate, S. racemosa, and C. pedunculatum are the material medica resources of “Wadi”, among which, the morphological characteristics of S. ciliate are more consistent with the picture of “Wadi” in Mantang (སྨན་ཐང་རྒྱལ་འགྲེལ།, Figure 2) [52]. “Tibetan medicine” considers that C. pedunculatum was used as “Wadi” in some regions; however, more evidence is needed to confirm these findings [5]. “Shel Gong Shel Phreng” documented that “Songdi grows in rock mountains, grassy slopes, under forests, and rock crevices. The stem is red and the leaves are small. The basal leaves are dense like rosettes with red and yellow flowers” [8]. The literature suggests that the material medica resources of “Songdi” are mainly from Saxifraga [5,8,47]. “Shel Gong Shel Phreng” documented that “Saierdi grows in fields and the beach. The stem and leaf are upward extensions with red or yellow flowers. The seeds are yellow and small” [8]. The material medica resources of “Saierdi” are also from Saxifraga in the literature [5,8,47]. “Shel Gong Shel Phreng” documents that the “stems and leaves of Edi are quite long and the flowers are white” [8]. Currently, the doctors in Tibet mainly use species from Parnassia as “Edi”, whereas those in Qinghai mainly use species in Cerastium as “Edi” [5,47]. However, their morphological characteristics are not consistent with the above description. The material medica resources of “Edi” remain to be further characterized. According to “Shel Gong Shel Phreng”, “Sangdi” is characterized by “tufted and red stems, clustered leaves, and slightly hairy, red and yellow flowers” [8]. This is similar to the genus Saxifraga, but according to the actual use situation in various regions, “Sangdi” is considered a variant of Swertia, which gradually formed in the long history of use under the influence of the distribution of resource species in different regions [5,47]. As recorded in “Shel Gong Shel Phreng”, the stems of “Jihedi” are like iron chopsticks; the leaves are green, the flowers are light blue or blue, and the fruits are similar to flax seeds [8]. The literature holds that the material medica resources of “Jihedi” are mainly species of Halenia and Gentiuanopsis [5,47,49,53]. Other Swertia and Lomatogonium plants recorded in Tibetan Medicine as “Jihedi” may be regional substitutes. “Shel Gong Shel Phreng” records that “Gouerdi grows in the shady area of green slopes. The leaves are thick, basal, and with beady, silver spots. The flowers are pale-yellow” [8]. These likely appear to be plants of Saxifraga or Parnassia [5]. However, some literature considers S. nigroglandulifera and Mentha haplocalyx as “Gouerdi”, which need to be further confirmed [47,54].

3.2.4. Others

Many other Gentianaceae plants are also used in Tibetan medicine. “Ganggaqiong” (གང་ག་ཆུང་།), “Shel Gong Shel Phreng” recorded that “It tastes bitter, has heat-clearing and detoxifying effects, and cures blood diseases and Chiba disease. It grows in mountains at high altitudes and the roots are similar to tendons. The plants are fluffy and messy with overlapping leaves, which are similar to eight-corner pagodas. The flowers are in white and urceolate in shape” [8]. Doctors in Tibet and Qinghai (Yushu) mainly use G. urnula as “Ganggaqiong” [5]. Furthermore, in some regions of Tibet, G. phyllocalyx was used as “Ganggaqiong·Manba” (གང་ག་ཆུང་དམན་བ།) [47]. “Shel Gong Shel Phreng” documents that “Saibao·Guzhui (སེར་པོ་རྒུ་དྲུས།) can detoxify and cure sores. It can be divided into two types and the top grade grows in the mountains. The stems are very long and the leaves are thin and smooth similar to those of Jieji·Gabao. The flowers are pale yellow” [8]. Doctors in Tibet mainly use S. multicaulis and S. kingie as “Saibao·Guzhi” [47].
In addition, G. aristata was used as a substitute for “Wengbu” (སྔོན་བུ།); G. spathulifolia was used as “Aolamu” (སྔོ་ལྟ་མོ།); G. crassuloides was used as “Ebu·youyou” (སྔོན་བུ་ཡོལ་ཡོལ།); G. rigescens was used as “Axue·Dida” (ཨ་ཉོག་ཏིག་ཏ།); S. marginata and S. bifolia were used as “Daiwa” (དེ་བ།) [47].

3.2.5. Formulas

The clinical application of Tibetan medicine is mainly as formulas and single herb preparations are very few. Formulas can contain more than 100 drugs, and those with more than 10 drugs are usually common. Similar to traditional Chinese medicine formulas, Tibetan medicine formulas also employ the “Monarch, Minister, Assistant, and Guide” methods. Some drugs must be processed before use to eliminate and reduce their toxicity and improve efficacy. Decoctions, powders, and water pills are the most common dosage forms, of which powders and water pills are the most widely used in a clinical setting [4,55].
According to our statistics, about 56 formulas containing “Jieji”, 53 formulas containing “Bangjian”, 160 formulas containing “Dida”, and 14 formulas containing “Ganggaqiong” were used (Supplement Table S1). “Jieji” has mostly been used in formulas owing to its effect of clearing heat toxins, removing food stagnation, dispelling wind, and eliminating dampness, and purging the liver and gallbladder. “Bangjian” has mostly been used in formulas owing to its effect of clearing lung heat. “Dida” has been mostly used in formulas because of its heat-toxin clearing effect and purging the liver and gallbladder. “Ganggaqiong” has mostly been used in formulas owing to its effect of clearing heat toxins.

3.3. Phytochemistry of Gentianeae

To date, most phytochemical studies have mainly focused on the Gentiana and Swertia genera. Nearly 600 metabolites were identified from the Gentiana genus [56,57,58] and more than 400 metabolites were identified from the Swertia genus [59,60,61,62]. The primary bioactive components isolated from the two genera include iridoids, xanthones, flavonoids, and triterpenoids, of which a few are alkaloids, lignans, and phenolic compounds.

3.3.1. Iridoids

As the main chemical constituents, iridoids are widely distributed within the Gentiana and Swertia genera [16]. Iridoids can be divided into six groups including loganic acid, secologanic acid, morroniside, sweroside, swertiamarin, and gentiopicroside derivatives based on the classic mevalonic acid pathway [63]. Loganic acid derivatives mostly belong to carbocyclic iridoids and most are esters of loganic acid [63]. To date, more than 40 loganic acid derivatives were isolated from Gentiana [56], whereas only 10 were isolated from Swertia [61]. Secologanic acid derivatives are mainly derived from the split C7–C8 bond of carbocyclic iridoids. About 19 secologanic acid derivatives were obtained from Gentiana [56,63] and only two (vogelioside and nervoside) from Swertia [16]. Morroniside derivatives were not the major iridoids in both genera. To date, only 13 morroniside derivatives were isolated from Gentiana and none from Swertia [64]. Sweroside, swertiamarin, and gentiopicroside derivatives were not only the major compounds in Gentiana and Swertia but are also widely distributed [16,56,62]. In the biosynthetic pathway, sweroside, swertiamarin, and gentiopicroside are the precursors of the latter [63]. Gentiopicroside derivatives were characterized in the existence of double bond in C-5 and C-6, whereas sweroside derivatives without the double bond and swertiamarin derivatives with hydroxyl at C-5, 22, 14, and 25 of sweroside, swertiamarin, and gentiopicroside derivatives was obtained, respectively, in Gentiana while were obtained respectively in Swertia [56,61].

3.3.2. Xanthones

Xanthones are rather rare among higher plants and are found almost exclusively in Gentianaceae, Guttiferae, Moraceae, Clusiaceae, and Polygalaceae [16,65]. Unlike iridoids, xanthones are not present in all plant species that have been investigated in the Gentianaceae family [16]. Xanthones isolated from natural sources are classified into six groups, namely, simple xanthones, xanthone glycosides, prenylated xanthones, xanthonolignoids, bisxanthones, and miscellaneous xanthones [66]. Only simple xanthones and xanthone glycosides were reported in Gentianaceae [16,56,58,61]. In Gentianeae, 8-substituted or 2- and 4-substituted xanthones are predominant [16]. Xanthone glycosides were predominantly reported in the Gentianaceae and Polygalaceae families as C- or O-glycosides [67,68]. Mangiferin is the most common C-glycoside xanthone in Gentiana and Swertia [56,61]. Besides, some Mangiferin derivatives such as neomangiferin and mangiferin-6-O-β-d-glucopyranoside have also been obtained from the two genera [69,70]. The first O-glycoside xanthone, norswertianin-1-O-glucosyl-3-O-glucoside, was isolated from S. perennis [71]. Other xanthone O-glycosides such as gentiacauloside from G. acaulis [72], gentioside from G. marcailhouana [73], and swertianolin from S. chirayita [74] have also been isolated.

3.3.3. Flavonoids

The flavonoids in Gentianeae mainly exist as free or in the glycosidic forms. A total of 58 and 12 flavonoids were obtained from Gentiana and Swertia, receptively [56,61,75,76,77]. The majority of the glycosylated flavonoids are isoorientin and isovitexin derivatives, which implies that both might be the key compounds in the biosynthetic pathway of flavonoids in Gentianeae. (2E)-1-(2-Hydroxyphenyl)-3-{5′-[3-(2-hydroxyphenyl)-3-oxopropyl]-2′,6-bis[(3-methylbut-2-en-1-yl)oxy]-biphenyl-3-yl}prop-2-en-1-one isolated from the bark of G. lutea, is the only flavonoid dimer reported from Gentianaceae [78], whereas swertifrancheside from S. franchetiana was the first flavone-xanthone dimer to be isolated [79].

3.3.4. Triterpenoids

Gentianeae is also rich in triterpenoids. A total of 64 triterpenoids were isolated from Gentiana and classified, and 33 were isolated from Swertia [56,61]. The carbon frameworks of triterpenoids in Gentiana include dammarane, oleanane, ursane, lupane, hopane, chiratane, sterol, and squalene skeletons. Carbon skeletons of triterpenoids in Swertia consist of oleanane, ursane, taraxerane, lupane, hopene, isohopane, gammacerane, swertane, chiratane, and lanostane skeletons. Oleanane-type triterpenoids are the most substantial. Oleanolic acid was once recommended as a marker by some researchers to assess the quality of “Dida”, owing to its relatively high concentrations [51].

3.4. Pharmacology of Gentianeae

The bioactivities of plants from Gentianeae include hepatic protection, upper respiratory tract protection, joint and bone protection, glucose regulation, antibacterial, antioxidant, anticancer, and antiviral effects (Table 2).

3.4.1. Hepatic Protection

“Dida” is the most common medicinal material for the treatment of hepatitis, especially icteric hepatitis [48]. The mechanism mainly involves restoring abnormal physiological characteristics and biochemical indexes of liver, improving antioxidants levels and lipid peroxidation, and promoting blood supply to the liver tissue [80,81,82,83]. Plants from “Jieji” also showed similar hepatoprotective effects [84]. Gentiopicroside and Swertiamarin, the main iridoid in “Jieji” plants, can significantly reduce the abnormal biochemical indexes of liver and increase the antioxidants and lipid peroxidation levels [85,86,87].

3.4.2. Protection from Upper Respiratory Tract Infections

“Bangjian” is widely used in the treatment of upper respiratory tract infections. More than 60% of the formulas with “Bangjian” as the primary drug are clinically used for the treatment of respiratory diseases such as bronchitis, emphysema, acute and chronic pharyngitis, cough and asthma, and hoarseness (Table S1). Pharmacological studies reveal that the mechanism involves enhancing p-ERK expression [88] and antioxidant enzymes activities [89], while inhibiting TNF-α, IL-10 and TGF-β1 expression [88,90,91].

3.4.3. Joint and Bone Protection

“Jieji” can effectively protect joints and bones. The extracts of G. straminea, G. macrophylla and Sinogentiana striata were proved to alleviate adjuvant arthritis, synovial inflammation and rheumatoid arthritis by effect on different targets and pathways [92,93,94]. Gentiopicroside and swertiamarin also played an important role in joint and bone protection through inactivation of JNK and NF-кB signaling pathways or interfere with the release of inflammatory factors [95,96,97].

3.4.4. Glucose Regulation

Many compounds from Gentianeae, especially xanthones and iridoid derivatives, were reported to have glucose-regulating effects [98,99,100]. Demethylbellidifolin can stimulate the GLP-1 receptor in a concentration-dependent manner and reduce blood glucose levels [101]. Bellidifolin was observed to reduce blood glucose levels, indicating its hypoglycemic effect [102]. Swertiamarin can significantly reduce the levels of fasting blood glucose, HbA1c, TC, tTG, and LDL; increase the levels of hemoglobin, insulin, TP, and HDL; and significantly promote the regeneration of pancreatic islet tissue in diabetic rats [103]. Swertiamarin may regulate the expression of related genes in the liver and adipose tissue by targeting PPARγ [104].

3.4.5. Antibacterial Effects

The extract of G. veitchiorum is effective against MRSA and MSSA infections [105]. The ethyl acetate extracts of G. algida showed antibacterial activity against Escherichia coli, S. aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Bacillus licheniformis [106]. The volatile oil of S. mussotii exerts antibacterial activity against S. aureus, E. coli, and Salmonella typhi [107]. l,8-Dihydroxy-3,7-dixanthone from S. mussotii was found to have antibacterial effect on Clostridium, P. aeruginosa, B. megalosus, S. aureus, Ocardiococcus, E. coli, and Proteus, especially E. coli [108].

3.4.6. Antioxidant Effects

The extract of S. chirata, S. davidii and G. urnula was found to have the high free-radical scavenging capacity, which is associated with phenolic compounds and synergistic effects with xanthones and glycosides [109]. Xanthones are the major compounds in Swertia and this species may, therefore, prove useful in scavenging OH·and O2. Studies report an increase in radical-scavenging activity when the substituents are present in the ortho-position [110].

3.4.7. Anti-Inflammatory Effects

The extracts of G. macrophylla, G. straminea and S. chirayita all possessed significant anti-inflammatory activities [92,111,112]. Numerus compounds isolated from Gentianeae plants play an important role in anti-inflammatory activity, such as gentiopicroside, swertiamarin 1,5-dihydroxy-3,8-dimethoxy xanthone and Bellidifolin [113,114,115,116].

3.4.8. Anticancer

The triterpenoids (24-hydroxyoleanolic acid, 1a,2a,3b,24-tetrahydroxyolean-12-en-28-oicacid, 2a-hydroxyursolicacid) isolated from G. aristata showed low cytotoxic activities against HL-60 cells [117]. Six compounds (3-antene, arborinone, boehmerol, carotenoside, 3β-acetoxy-28-hydroxy-12-ene-urthulane and swertisin) from G. algida showed different degrees of antitumor activity in HeLa cells [106]. Waltonitone isolated from G. waltonii induces tumor cell cycle arrest through regulating Akt and ERK1/2 pathways, thereby inhibiting tumor cell growth [118]. Swertiamarin had certain inhibitory and pro-apoptotic effects on hepatocellular carcinoma cells in vitro [119]. Swertiamarin and mangiferin from S. davidii are the main active substances that inhibit growth and induce apoptosis in HepG2 human liver cancer cells [120].

3.4.9. Antiviral Effects

Both aqueous and alcohol extracts of G. macropylana significantly inhibit influenza A and B [121,122]. The extracts of G. veitchiorum showed obvious inhibitory effects on RSV both in vivo and in vitro [123]. Lots of compounds isolated from Gentianeae had significantly anti-HBV and anti-HIV activity [79,124,125,126,127].

4. Limitation

This review paper is based on the author’s own analysis and summary of the literature. Although the author tries to keep objective in the analysis process, it is still highly subjective, thus all the findings are based on personal views. This review paper only covers the research results published in mainstream journals from 2000 to 2021, and it is inevitable to overlook some of them. Therefore, readers need to understand the limitations of this review paper in terms of time and sources. There have been previous reviews on the chemical constituents and pharmacological activities of Gentiana and Swertia [56,60]. Nevertheless, in this review, we mainly focused on the related studies of Gentianeae plants used in Tibetan medicine, especially ethnomedicinal usage. Moreover, we also included the latest research results.

5. Conclusions

Due to its complete theoretical system and remarkable therapeutic effect, Tibetan medicine has attracted increasing attention from researchers. However, proper research on Tibetan medicine is scarce. In this study, we employ Gentianeae as a case, aiming to provide good inspiration for the follow-up research in Tibetan medicine.
Species from Gentianeae have been widely and long used as Tibetan medicine. Many species are good sources for chemical and pharmaceutical research owing to the presence of high levels of iridoids, flavonoids, and triterpenoids. However, the ethnomedicinal usage and the phytochemical and pharmacological properties of Gentianeae in Tibetan medicine were not well summarized. In view of this, we systematically summarize the ethnomedicinal usage and the phytochemical and pharmacological properties of Gentianeae in Tibetan medicine.
Although various classes of compounds were identified and their pharmacological activities investigated, systematic studies are lacking for numerous species. Thus, there is the likelihood of the presence of undiscovered compounds. Therefore, phytochemical profiling, bioactivity screening, biosynthetic pathway elucidation, and structure-activity relationship studies should be continued, as these findings could provide a more reasonable foundation for use of Gentianeae species and the maximization of their desired therapeutic benefits.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/plants10112383/s1, Table S1: Formulas containing Gentianeae plants in Tibetan medicine.

Author Contributions

S.C. conceived the project. X.C. and F.Z. summed up the literature and drafted the manuscript. R.X. proofread the structures and figures. Q.G. revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Natural Science Foundation of Qinghai Province (2019-ZJ-959Q), the Second Tibetan Plateau Scientific Expedition and Research (STEP) Program (2019QZKK05020102) and the Construction Project for Innovation Platform of Qinghai province (2021-ZJ-Y05).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

Aktprotein kinase B
ALPalkaline phosphatase
ALTalanine transaminase
ASTaspartate transaminase
BCGBacillus Calmette Guerin vaccine
CATcatalase
COX-2cyclooxygenase 2
D-GalNd-galactosamine
DPPH2,2-Diphenyl-1-picrylhydrazyl
ERKextracellular regulated protein kinase
ERK1/2extracellular regulated protein kinase 1/2
G6Paseglucose-6-phosphatase
GKglucokinase
GLP-1glucagon-like peptide-1
Glut2glucose transporter type 2
Glut4glucose transporter type 4
GOTglutamate oxaloacetate transaminase
GPTglutamate pyruvate transaminase
GPxglutathione peroxidase
GSHglutathione
HbA1cglycosylated hemoglobin
HBVhepatitis B virus
HCG-CoAhydroxymethylglutaryl-coenzyme A
HDLhigh-density lipoprotein
HIVhuman immunodeficiency virus
IKK-βκB kinase-β
IL-10interleukin 10
IL-1βinterleukin 1β
IL-4interleukin 4
IL-6interleukin 6
INF-γTh1-type cytokine interferon γ
iNOSinducible nitric oxide synthase
ITSinternal transcribed spacer
JAK2/STAT3janus kinases 2/signal transducer and activator of transcription 3
JNKJanus kinase
LDLlow density lipoprotein
LPOlipid peroxide
LPSlipopolysaccharide
MAPKmitogen-activated protein kinase
matKmaturase K
MDAmalondialdehyde
MRSAmethicillin-resistant Staphylococcus aureus
MSSAmethicillin-sensitive Staphylococcus aureus
NF-кBnuclear factor kappa-B
NOnitric oxide
P38P38 mitogen-activated protein kinase
PEPCKphosphoenolpyruvate carboxykinase
p-ERKphosphorylated extracellular regulated protein kinase
PGE2prostaglandin E2
PPARγperoxisome proliferators-activated receptors γ
RSVrespiratory syncytial virus
SODsuperoxide dismutase
TBAtotal bile acid
TBILtotal bilirubin
TCtotal cholesterol
TGthyroglobulin
TGF-β1transforming growth factor-β1
TNF-αtumor necrosis factor-α
TPtotal protein
trnLtransfer RNA L

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Figure 1. Representative Gentianeae species used in Tibetan medicine ((A). Gentiana straminea; (B). Gentiana szechenyii; (C). Gentianopsis paludosa; (D). Sinoswertia tetraptera; (E). Swertia mussotii; (F). Gentiana crassicaulis; (G). Gentiana algida; (H). Halenia elliptica; (I). Swertia franchetiana).
Figure 1. Representative Gentianeae species used in Tibetan medicine ((A). Gentiana straminea; (B). Gentiana szechenyii; (C). Gentianopsis paludosa; (D). Sinoswertia tetraptera; (E). Swertia mussotii; (F). Gentiana crassicaulis; (G). Gentiana algida; (H). Halenia elliptica; (I). Swertia franchetiana).
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Figure 2. Mantang (སྨན་ཐང་རྒྱལ་འགྲེལ།) of the representative Gentianeae species in Tibetan medicine ((A). Jiadi [རྒྱ་ཏིག]; (B). Wadi [བལ་ཏིག]; (C). Sangdi [ཟངས་ཏིག]; (D). Jieji·Gabao [ཀྱི་ལྩེ།་དཀར་པོ།]; (E). Jieji·Nabao [ཀྱི་ལྩེ།་ནག་པོ།]; (F). Bangjian·Gabao [སྤང་རྒྱན་དཀར་པོ།]; (G). Bangjian·Nabao [སྤང་རྒྱན་ནག་པོ།]; (H). Ganggaqiong [གང་གྰཆུང་།]) [52].
Figure 2. Mantang (སྨན་ཐང་རྒྱལ་འགྲེལ།) of the representative Gentianeae species in Tibetan medicine ((A). Jiadi [རྒྱ་ཏིག]; (B). Wadi [བལ་ཏིག]; (C). Sangdi [ཟངས་ཏིག]; (D). Jieji·Gabao [ཀྱི་ལྩེ།་དཀར་པོ།]; (E). Jieji·Nabao [ཀྱི་ལྩེ།་ནག་པོ།]; (F). Bangjian·Gabao [སྤང་རྒྱན་དཀར་པོ།]; (G). Bangjian·Nabao [སྤང་རྒྱན་ནག་པོ།]; (H). Ganggaqiong [གང་གྰཆུང་།]) [52].
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Table
Table 1. Gentianeae species used in Tibetan medicine.
Table 1. Gentianeae species used in Tibetan medicine.
No.SpeciesGenusTribesTibetan Medicine Name
1G. algida var. purdomiiGentianaSubtribe GentianeaeBangjian (སྤང་རྒྱན།)
2G. acaulis
3G. algida
4G. altorum
5G. arethusae var. delicatula
6G. atuntsiensis
7G. filistyla
8G. futtereri
9G. lawrencei var. farreri
10G. nubigena
11G. obconica
12G. ornata
13G. purdomii
14G. sinoornata var. gloriosa
15G. stipitata
16G. szechenyii
17G. veitchiorum
18G. yunnanensis
19G. cephalanthaGentianaSubtribe GentianeaeJieji (ཀྱི་ལྕེ།)
20G. crassicaulis
21G. dahurica
22G. erectosepala
23G. hexaphylla
24G. macrophylla
25G. officinalis
26G. rhodantha
27G. robusta
28G. siphonantha
29G. straminea
30G. tibetica
31G. waltonii
32M. stylophorusMegacodonSubtribe SwertiinaeJieji (ཀྱི་ལྕེ།)
33G. pseudosquarrosaGentianaSubtribe GentianeaeGanggaqiong (གང་གྰཆུང་།)
34G. phyllocalyx
35G. urnula
36G. wardii
37G. aristataGentianaSubtribe GentianeaeWengbu (སྔོན་བུ།)
38G. capitata
39G. haynaldii
40G. crassuloidesGentianaSubtribe GentianeaeEbu·youyou (སྔོན་བུ་ཡོལ་ཡོལ།)
41G. lhassicaGentianaSubtribe GentianeaeEdaiwa (སྡོ་དེ་བ།)
42G. rigescensGentianaSubtribe GentianeaeAxue·Dida (ཨ་ཉོག་ཏིག་ཏ།)
43G. spathulifoliaGentianaSubtribe GentianeaeAolamu (སྔོ་ལྟ་མོ།)
44S. angustifolia var. pulchella SwertiaSubtribe SwertiinaeDida (ཏིག་ཏ།)
45S. bimaculata
46S. ciliata
47S. cincta
48S. dichotoma
49S. erythrosticta
50S. franchetiana
51S. leducii
52S. mussotii
53S. nervosa
54S. paniculata
55S. punicea
56S. racemosa
57S. speciosa
58Swertia wardii
59S. younghusbandii
60S. yunnanensis
61G. barbataGentianopsisSubtribe SwertiinaeDida (ཏིག་ཏ།)
62G. grandis
63G. paludosa
64H. ellipticaHaleniaSubtribe SwertiinaeDida (ཏིག་ཏ།)
65H. corniculata
66H. elliptica var. grandiflora
67L. forrestii var. bonatianumLomatogoniumSubtribe SwertiinaeDida (ཏིག་ཏ།)
68L. perenne
69L. forrestii
70L. macranthum
71L. oreocharis
72S. tetrapteraSinoswertiaSubtribe SwertiinaeDida (ཏིག་ཏ།)
73S. bifoliaSwertiaSubtribe SwertiinaeDaiwa (དེ་བ།)
74S. marginata
75S. wolfgangiana
76S. atroviolaceaSwertiaSubtribe SwertiinaeSaibo·Guizhui (སེར་པོ་རྒུ་དྲུས།)
77S. elata
78S. kingii
79S. multicaulis
80C. pedunculatumComastomaSubtribe SwertiinaeJiadi·Jiazha (ལྕགས་ཏིག་ལྕགས་སྦྲག)
81C. traillianum
82C. pulmonarium
83V. baillonii Franch.VeratrillaSubtribe SwertiinaeBae·Sebao (དཔའ་བོ་སེར་པོ)
Table
Table 2. Pharmacological activity of Gentianeae.
Table 2. Pharmacological activity of Gentianeae.
Pharmacological
Activity		AnalytesMethodsModelsEffectsReference
Hepatic protectionEthanolic extract of S. chirataParacetamolSwiss albino miceGPT, GOT, ALP and bilirubin↓, LPO↑, SOD, CAT, GSH and GPx↑[80]
Ethanolic extracts of S. mussotiiCCl4Wistar ratsALT, AST, TBIL and TBA↓[81]
Ethanolic extract of S. mussotiiBCG and LPSKunming miceALT and AST↓[82]
Ethanol extract of S. mussotiiCCl4Wistar ratsGPT↓, NO↑[83]
Aqueous extracts of G. stramineaCCl4Kunming miceALT and TNF-α↓, IL-10↑[84]
GentiopicrosideCCl4Kunming miceALT and AST↓, GSH-Px↑, bilirubin↓[85]
SwertiamarinCCl4SD ratsALT, AST, ALP↓, MDA↓, SOD, GPx and GSH↑[86]
SwertiamarinD-GalNWistar ratsSOD, CAT and GSH↑, MDA↓[87]
Protection from upper respiratory tract infectionsAqueous extract of G. veitchiorum LPSSD ratsTNF-α↓, p-ERK↑[88]
Aqueous extract of G. veitchiorumNH3Kunming miceSOD↑, MDA↓[89]
Ethanol extract of G. veitchiorumNH3Kunming miceSOD↑, TNF-α and IL-10↓[90]
Aqueous extract of G. veitchiorumOvalbuminBABL/c miceTGF-β1↓[91]
Joint and bone protectionEthanol extracts of G. macrophyllaBovine Type II CollagenSD ratsINF-γ, anti-cyclic citrullinafer peptide antibody and TNF-α↓, IL-4↑[92]
Ethyl acetate extract of S. striataXyleneSD ratsPGE2 and NO↓[93]
Ethanol extracts of G. macrophyllaLPSKunming miceIL-1β, IL-6, and TNF-α↓, iNOS and COX-2↓[94]
GentiopicrosideOsteoclastSD ratsNF-κB p65↓[95]
GentiopicrosideIL-1βRat chondrocytesp38, ERK and JNK↓, PGE2 and COX-2↓[96]
SwertiamarinIL-1βfibroblast synovial cellsp38↓, COX-2 and PEG2↓[97]
Glucose regulationSwerchirinGlucoseAlbino ratsblood sugar↓[98]
Hexane fraction of S. chirayita GlucoseAlbino ratsblood sugar↓, plasma IRI↑[99]
Methanolic and aqueous extract of S. chirayitaStarchα-amylase (in vitro)α-amylase↓[100]
Demethylbellidifolin HEK293 cellGLP-1↑[101]
BellidifolinStreptozotocinBABL/c miceblood glucose↓[102]
SwertiamarinStreptozotocinWistar ratsblood glucose, HbA1c, TC, TG and LDL↓, hemoglobin, plasma insulin, TP, body weight and HDL↑[103]
SwertiamarinStreptozotocinNIDDM ratG6Pase and HMG-CoA reductase↑, PEPCK, GK, Glut 2, PPAR-γ, leptin, adiponectin, LPL, SREBP-1c, and Glut 4↑[104]
Antibacterial effectsExtract of G. veitchiorumMRSAKunming miceMRSA and MSSA↓[105]
Ethyl acetate extracts of G. algida in vitroE. coli, S. aureus, S. pneumoniae, P. aeruginosa, and B. li-cheniformis↓[106]
Volatile oil of S. mussotii in vitroS. aureus, E. coli, and S. typhi↓[107]
l, 8-Dihydroxy-3,7-dixanthone in vitroClostridium, P. aeruginosa, B. megalosus, S. aureus, Ocardiococcus, E. coli and Proteus↓[108]
Antioxidant effectsEthanol extract of S. davidii in vitroDPPH and ABTS↓[109]
Ethanol extract of G. urnula in vitroDPPH, O2, OH↓[110]
Anti-inflammatory effectsExtracts of G. macrophylla and G. stramineaLPS p65, p50 and NF-κB↓[111]
Ethanol extract of G. macrophyllaBovine Type II CollagenSD ratsINF-γ, anti-cyclic citrullinafer peptide antibody and TNF-α↓, IL-4↑[92]
Aqueous extract of S. chirayitaFCA Swiss albino miceTNF-α, IL-1β, IL-6, and IFN-γ↓, IL-10↑[112]
GentiopicrosideLPSRAW 264.7 NO, PGE2 and IL-6↓[113]
GentiopicrosidexyleneKunming miceTNF-α, IL-1β, IL-6, iNOS and COX-2↓[113]
GentiopicrosideDextran sulfate sodiumICR miceTNF-α, IL-1β, IL-6, iNOS and COX-2↓[114]
SwertiamarinFCASD ratsIL1, TNF, IL-6, MMPs, iNOS, PGE2, PPARc and COX-2↓, IL-10 and IL-4↑, NF-κB, p65, p-IκBα, p-JAK2 and p-STAT3↓[115]
BellidifolinLPSRAW 264.7 COX-2, Akt, IKK-β, MAPK and NF-κB↓[116]
Anticancer24-hydroxyoleanolic acid, 1a,2a,3b,24-tetrahydroxyolean-12-en-28-oicacid, 2a-hydroxyursolic acid HL-60 ↓[117]
3-antene, arborinone, boehmerol, carotenoside, 3β -acetoxy-28-hydroxy-12-ene-urthulane and swertisin HeLa ↓[106]
Waltonitone bel-7402, PANC-1, BXPC-3, and HeLa ↓[118]
Swertiamarin HepG2↓[119]
Swertiamarin and mangiferin HepG2 ↓[120]
Antiviral effectsEthanol extracts of G. macropylanaInfluenza A and BICR rats↓[121,122]
Aqueous, n-butanol, ethyl acetate, and chloroform extracts of G. veitchiorumRSVKunming mice↓[123]
1,8-dihydroxy-3,5dimethoxy-xanthone, norswertianolin, luteolin neolancerin, and isovitexinHBVHepG2.2.15↓[124]
Swermacrolactones A-CHBVHepG2.2.15↓[125]
(+)-dehydrodiconiferyl alcohol and dehydrozingeroneHBVHepG2.2.15↓[126]
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Chi, X.; Zhang, F.; Gao, Q.; Xing, R.; Chen, S. A Review on the Ethnomedicinal Usage, Phytochemistry, and Pharmacological Properties of Gentianeae (Gentianaceae) in Tibetan Medicine. Plants 2021, 10, 2383. https://doi.org/10.3390/plants10112383

AMA Style

Chi X, Zhang F, Gao Q, Xing R, Chen S. A Review on the Ethnomedicinal Usage, Phytochemistry, and Pharmacological Properties of Gentianeae (Gentianaceae) in Tibetan Medicine. Plants. 2021; 10(11):2383. https://doi.org/10.3390/plants10112383

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Chi, Xiaofeng, Faqi Zhang, Qingbo Gao, Rui Xing, and Shilong Chen. 2021. "A Review on the Ethnomedicinal Usage, Phytochemistry, and Pharmacological Properties of Gentianeae (Gentianaceae) in Tibetan Medicine" Plants 10, no. 11: 2383. https://doi.org/10.3390/plants10112383

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