Gleditsia species: An ethnomedical, phytochemical and pharmacological review

Gleditsia species: An ethnomedical, phytochemical and pharmacological review

Author’s Accepted Manuscript Gleditsia species: An ethnomedical, phytochemical and pharmacological review Jian-Ping Zhang, Xin-Hui Tian, Yong-Xun Yang...

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Author’s Accepted Manuscript Gleditsia species: An ethnomedical, phytochemical and pharmacological review Jian-Ping Zhang, Xin-Hui Tian, Yong-Xun Yang, Qing-Xin Liu, Qun Wang, Li-Ping Chen, HuiLiang Li, Wei-Dong Zhang www.elsevier.com/locate/jep

PII: DOI: Reference:

S0378-8741(15)30245-2 http://dx.doi.org/10.1016/j.jep.2015.11.044 JEP9843

To appear in: Journal of Ethnopharmacology Received date: 28 August 2015 Revised date: 24 November 2015 Accepted date: 24 November 2015 Cite this article as: Jian-Ping Zhang, Xin-Hui Tian, Yong-Xun Yang, Qing-Xin Liu, Qun Wang, Li-Ping Chen, Hui-Liang Li and Wei-Dong Zhang, Gleditsia species: An ethnomedical, phytochemical and pharmacological review, Journal of Ethnopharmacology, http://dx.doi.org/10.1016/j.jep.2015.11.044 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Title Gleditsia species: An ethnomedical, phytochemical and pharmacological review Authors Jian-Ping Zhanga, Xin-Hui Tiana, Yong-Xun Yanga, Qing-Xin Liua, Qun Wanga, Li-Ping Chena, Hui-Liang Lia,*, Wei-Dong Zhanga,b,* Affliliation a

School of Pharmacy, Second Military Medical University, Shanghai 200433, China

b

School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200030, China

* Correspondence Address: School of Pharmacy, Second Military Medical University, 325 Guo-He Road, Shanghai 200433, PR China. Associate Prof. Hui-Liang Li, E-mail: [email protected] Tel./fax.: +86 21 81871245 Abbreviations AFGS, the ethanol extract from the anomalous fruits of Gleditsia sinensis Lam.; ALI, acute lung injury; AML, acute myelogenous leukemia; AP-1, activator protein-1; ARDS, acute respiratory distress syndrome; bFGF, basic fibroblast growth factor; CDK, cyclin-dependent kinase; CML, chronic myelogenous leukemia; DNP, dinitrophenyl; DPPH, 2,2-diphenyl-1-picrylhydrazyl; EA, echinocystic acid; EDN1, endothelin 1; EEGS, the ethanol extract of Gleditsia sinensis Lam. thorns; EPCs, endothelial progenitor cells; ESCC, esophageal squamous cell carcinoma; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinase; FGS, the fruit hull of Gleditsia sinensis Lam; GAE, the aqueous extract of Gleditsia sinensis Lam. fruit; GCLC, glutamatecysteine ligase catalytic subunit; GSE, the extract of Gleditsia sinensis Lam. fruit;

HO-1, heme oxygenase 1; HUVEC, human umbilical vein endothelial cell: iNOS, inducible nitric oxide

synthase;

JNK,

c-Jun

N-terminal

kinases;

LPS,

lipopolysaccharide;

MAP,

mitogen-activated protein; MEGT, Gleditsia triacanthos L. methanolic fruit extract; MIC, minimal

inhibitory

concentration;

MMP,

matrix

metalloproteinase;

MNNG,

1-methyl-3-nitro-1-nitrosoguanidine; NO, nitric oxide; Nrf2, NF-E2-related factor 2; NF-κB, nuclear factor κB; NQO-1, 4-nitroquioline-1-oxide 1; oxLDL, oxidised low-density lipoprotein; PCA, passive cutaneous anaphylaxis; ROS, reactive oxygen species; RPMC, rat peritoneal mast cell; RT-PCR, reverse transcription-polymerase chain reaction; SFGS, the saponin fraction from the Gleditsia caspica Desf. methanolic fruit extract; SFGT, the saponin fraction from the Gleditsia triacanthos L. methanolic fruit extract; TCM, traditional Chinese medicine; TNF-, tumor necrosis factor-; TUNEL. transferase-mediated dUTP nick-end labelling; VEGF, vascular endothelial growth factor; WEGS, the water extract of Gleditsia sinensis Lam. thorns; Keywords Fabaceae, Gleditsia, Triterpenoid saponins, Bioactivity, Ethnopharmacology

Abstract Ethnopharmacological relevance: The plants in the genus Gleditsia, mainly distributed in central and Southeast Asia and North and South America, have been used as local and traditional medicines in many regions, especially in China, for the treatment of measles, indigestion, whooping, smallpox, arthrolithiasis, constipation, diarrhea, hematochezia, dysentery and carbuncle, etc. This present paper systemically reviews the miscellaneous information surrounding its traditional use, phytochemistry and pharmacology to provide opportunities and recommendations for the future research.

Materials and Methods: The scientific literatures were systematically searched from scientific databases (PubMed, Scopus, Elsevier, SpringerLink, SciFinder, Google Scholar and others). In addition, the ethnopharmacological information on this genus was mainly acquired from Chinese and Korean herbal classics, and library catalogs. Results: More than 60 compounds including triterpenes, sterols, flavonoids, alkaloids, phenolics and their derivatives were isolated from Gleditsia japonica Miq., Gleditsia sinensis Lam., Gleditsia caspica Desf. and Gleditsia triacanthos L. Among these compounds, triterpenoid saponins were the main constituents of Gleditsia species. Moreover, the crude extracts and purified molecules were tested, revealing diverse biological activities such as anti-tumor, anti-inflammatory, anti-allergic, anti-hyperlipidemic, analgesic, antimutagenic, antioxidant, anti-HIV, antibacterial and antifungal activities, etc. Among these biological studies, the possible mechanisms of antitumor action are stressed in this review, and these include causing cytotoxicity to cancer cells, inhibition of proliferation of cancer cells by affecting their growth, regeneration and apoptosis, inhibition of basic fibroblast growth factor (bFGF) and nitric oxide (NO), modulation of the oncogenic expression and telomerase activity results, inhibition of the expression of pro-angiogenic proteins, as well as down-regulation of intra/extracellular proangiogenic modulators, etc. Conclusions: On the basis of preliminary research on Gleditsia genus it could be stated that saponins investigations may be more promising in future. Although 32 compounds of 67 identified compounds were saponins, modern pharmacological research on saponins were not a priority in Gleditsia species. Therefore, more bioactive experiments and in-depth mechanisms of action are required for elucidating their roles in physiological systems. Moreover, the present review also

highlights that analgesic, anti-tumor and anti-HIV activities should have priority in saponins research. Additionally, it is imperative to explore more structure-activity relationships and possible synergistic actions of triterpenoid saponins for revaluating their pharmacological activities.

1.

Introduction

The genus Gleditsia (Fabaceae) comprises 14 species, and grows throughout the world as well as mainly in central and Southeast Asia, and North and South America (Editorial Board of Flora of China, 2007; Huxley et al., 1992). According to Flora of China, morphology of this genus is described as: deciduous tree or shrub; stem and branch usually with branches of rough spines; rachis and pinna rachis with groove; leaves, usually leaflet, edge with a thin, serrated or blunt tooth; stipules, small and caduceus; flowers unisexual or polygamous, pale green or green white, usually clustered in axillary, few to terminal inflorescences or racemes, and panicle; phycostemones mitriform, outside puberulent, inside glabrous; sepals 35, slightly different from each other, slightly longer than calyx lobes; stamen 610, protrudent; the middle following of filaments, flat and wide with long curly hair; ovary superior, sessile or with short handle, stylus short, stigma terminal; ovule, more than one; pod flat, straight, bending or torsion, no crack or delayed cracking; seeds one and more, ovate or elliptic, flat or nearly cylindrical (Editorial Board of Flora of China, 2007). Gleditsia species have been widely used for centuries in local and traditional medicine. G. sinensis is documented in various editions of the Pharmacopoeia of the People’s Republic of China from 1965 to 2015, and also used as local medicines in Korea (Chinese Pharmacopoeia

Commission, 2015a, 2015b; Bensky et al., 2004). The thorns of G. sinensis are used in China and Korea for treatment of carbuncle, scabies and skin diseases, while the mature pods and anomalous fruits are mainly used for treating apoplexy, headache, productive cough and asthma in China (Jiangsu New Medical College, 1977a; Bensky et al., 2004; Zhang, 1987; Kuang et al., 2005). G. japonica, which grows in many areas of China such as HuNan, JiangXi, LiaoNing, ShanDong and JiangSu provinces, as well as Korea and Japan, has long been known as a diuretic and expectorant (Jiangsu New Medical College, 1977b). G. triacanthos, which grows in China and America, is mainly used as the fancy breed. However, G. triacanthos has also been used as local medicine for treatment of whooping, ache, measles, smallpox and difficult labour in the Native American (Miguel et al., 2010; Durk et al., 1981). In addition, it is well known that some herbal prescriptions such as Gleditsia ointment, Gleditsia pulvis, Gleditsia pill, “Zao Jia Tong Luo Pian”, “Liu Wei Tong Luo Yin”, which are mainly composed of G. sinensis, are effective in some diseases (Zhang, 1987; Wang, 1958; Zhao, 2011; Lai, 2011; Xing and Wu, 1996; Sun and Li, 1998). With the increasing interest paid to the pharmacologically active phytochemicals from the Gleditsia herbs, a lot of studies related to the phytochemical and pharmacological aspects of this genus have been carried out. In recent decades, phytochemical studies were carried out on G. japonica, G. sinensis, G. caspica and G. triacanthos, and that found the existence of triterpenes, sterols, flavonoids, alkaloid, phenolics and their derivatives (Mohammed et al., 2014; Melek et al., 2014; Saleh et al., 2015; Kajimoto et al., 2010; Zhang et al., 1999a, 1999b). Pharmacological studies revealed that the crude extracts and purified molecules possess a wide spectrum of biological activities, involving in anti-tumor, anti-inflammatory, anti-allergic, anti-hyperlipidemic,

analgesic, antimutagenic, anti-HIV, antioxidant, antibacterial and antifungal activities, confirmed by various in vivo animal, and in vitro studies (Ha et al., 2008; Lai et al., 2011; Shin et al., 2000; Zhou et al., 2007a, 2007b; Saleh et al., 2015; Farouk et al., 2015; Mohammed et al., 2014; Wu et al., 2010). Moreover, among these isolated compounds, triterpenoid saponins were considered as the main constituents of Gleditsia species, and triterpenoid saponins present in Gleditsia members mainly acted on anti-tumor effect (Zhang et al., 1999a, 1999b, 1999c; Miyase et al., 2010; Melek et al., 2014; Konoshima, 1995; Zhong et al., 2003). Additionally, the structure–activity relationship of triterpenoid saponins has also been investigated to acquire more potential anti-tumor drugs, but the possible synergistic action is still unknown and required to be researched (Lu et al., 2014). This review comprehensively summarized the chemical constituents and the ethnomedical and pharmacological effects, as well as revealed Gleditsia plants′ potential therapeutic effects and gaps establishing a solid foundation for the exploration of novel and effective pharmaceutical agents.

2. Ethnopharmacology

Gleditsia species have been widely used in traditional medicine. The medicinal use of Gleditsia species dates back over 2000 years, and more than fifteen classical pharmaceutical books written by distinguished medical experts in China contain records of this genus (Table 1). An important medical compendium, “Sheng Nong′s herbal classic”, in 200 A.D., is one of the earliest medical monographs in China. This book was also the first to record Gleditsia plants, as well as their effects in treating apoplexy, headache, carbuncle, swelling, suppuration, scabies, productive cough and asthma (Wu, 1955). According to the “Compendium of Materia Medica” (Ming Dynasty, A.D.

1590), another authoritative encyclopaedia of TCM, the seeds of Gleditsia species were used in arthrolithiasis, constipation, diarrhea, hematochezia, dysentery, carbuncle, swelling, salivation in children and dystocia in women, and the thorns of Gleditsia plants were described as having the activities related to treating scrofula, dysuria, acute mastitis, retained afterbirth, etc (Li, 1982). In Han dynasty (A.D. 480-498), another famous TCM monograph, “Bencaojing Jizhu”, described the thorns of Gleditsia plants as treating wandering arthritis, muscular death, epiphora induced by wind, pathogenic factor, abdominal distension, etc (Tao, 1955). According to Bencao Mengquan (Ncmm) (Ming Dynasty, A.D. 1565), the thorns of Gleditsia plants were an effective medicine in chirurgery, and used for treating various exelcosis (Chen, 1988). In Elementary Medicine, Gleditsia plants were used to disperse phlegm, suppress cough and treat headache in Ming dynasty (Li, 2006). Another ancient Chinese medical book, “Bencao Yanyi”, recorded the species′ uses, which include the treatment of pestilence, eczema, wind-heat and anemogenous salvation (Kou, 1990). In addition, some Chinese ancient medical monographs such as Qianjin Yi Fang, Tang materia medica, Tangye Bencao, etc, also recorded the treatment of some similar symptoms such as cough, abdominal distension, exelcosis, swelling, cystic node, etc (Sun, 2011; Wang, 2008; Jiangsu New Medical College, 1977; Tang,1982; Tao, 1986; Zhang, 1996). Except for the information mentioned above, Gleditsia species were also described as the main components in some noted prescriptions. Gleditsia pill, mainly composed of G. sinensis, has been applied as a classic TCM formula in the treatment of retention of turbid phlegm in the lung, cough with dyspnea, hemorrhoids, etc (Zhang, 1987; Wang, 1958; Zhao, 2011). Moreover, a classic formula, Gleditsia pulvis, which ranks G. sinensis as one of the major ingredients, has been used for expelling parasite (Zhao, 2011). Gleditsia ointment (the constituents: G. sinensis, Li Zi,

mulberry root and tengyuch euonymus bark) was used to treat various sores (Zhao, 2011). The prescriptions involving in “Zao Jia Tong Luo Pian”(≥40% of G. sinensis)and “Liu Wei Tong Luo Yin” (30g G. sinensis thorn), have been used as the antithrombosis agents (Lai, 2011; Xing and Wu, 1996; Sun and Li, 1998). In the Pharmacopoeia of the People′s Republic of China, the thorns of G. sinensis have been listed in the various editions for the function of expelling phlegm, detoxication, apocenosis and expelling parasite, and the treatment of ulcer, sepsis, scabies and Hansen's disease; The mature pods and anomalous fruits are also recorded in the various editions of Chinese Pharmacopoeia and mainly used for treating aphasia from apoplexy, coma, epilepsia, pharyngitis, cough, asthma, dry feces and ulcer (Chinese Pharmacopoeia Commission, 2015a, 2015b). In the Korea monograph, the thorns of G. sinensis are widely distributed in the Gyeongju city area in Korea and have been used for treatment of carbuncle, swelling, suppuration, scabies and skin diseases, while the mature pods and anomalous fruits, produced by old or injured plants, are mainly used for treating apoplexy, cough, asthma, and as an expectorant and pesticide (Ahn et al., 2003). Additionally, the dried fruits of G. japonica have long been used as a diuretic and expectorant known in China and Japan (Jiangsu New Medical College, 1977b). The G. triacanthos has been widely used in the Native American. The G. triacanthos tree has been used in traditional remedy due to its anesthetic, antiseptic, antitumor and stomachic activities; the pods of G. triacanthos are used as a local medicine for dyspepsia, measles and indigestion; the G. triacanthos bark has been used in the treatment of whooping, measles, smallpox and dyspepsia; the whole plant of G. triacanthos has been reported to possess mydriatic, anodyne, narcotic and experimentally oxytocic effects, and has been used as a local medicine for dyspepsia and measles

(Miguel et al., 2010; Durk et al., 1981).

Table 1 Medicinal uses in Chinese classical pharmaceutical books Monograph

Dynasty

Species

Function

Reference

Sheng Nong′s herbal classic; Tangye Bencao; Tang Ben Cao

Qin, A.D. 200 Yuan, A.D. 1289 Tang, A.D. 657

Gleditsia species

The effects in treating apoplexy, headache, carbuncle, swelling, suppuration, scabies, productive cough and asthma

Wu, 1955; Wang, New Medical Col

Compendium Medica

Ming, A.D. 1590

The seeds of Gleditsia species

Treating arthrolithiasis, constipation, diarrhea, hematochezia, dysentery, carbuncle, swelling, salivation in children and dystocia in women; Treating scrofula, dysuria, acute mastitis, retained afterbirth, etc

Li. (1982)

of

Materia

The thorns of Gleditsia species Bencaojing Jizhu

Han, A.D. 498

The thorns of Gleditsia plants

Treating wandering arthritis, muscular death, epiphora induced by wind, pathogenic factor, abdominal distension, etc

Tao. (1955)

Ncmm

Ming, A.D. 1565

The thorns of Gleditsia plants

An effective medicine in chirurgery

Chen. (1988)

New Compilation of Materia Medica

Qing, A.D. 1757

Gleditsia species

Treating sequela of apoplexy, vomiting phlegmatic savliva, thoracic obstruction, pharyngitis, anemogenous constipation, etc

Wu. (2012)

Bencao Yanyi

Song, A.D. 1116

Gleditsia species

Exorcizing pestilence and treating eczema, wind-heat, anemogenous salvation, etc

Kou. (1990)

Qianjin Yi Fang

Tang, A.D. 682

Gleditsia species

Treating wandering arthritis, epiphora induced by wind, polypepsia, cough, abdominal distension, cystic node, etc

Sun. (2011)

Elementary Medicine

Ming, A.D. 1575

Gleditsia species

Dispersing phlegm, suppressing cough and treating headache

Li. (2006)

Bencao Chengya Banji

Qing, A.D. 1647

Gleditsia species

Treating wandering arthritis, putrid flesh, epiphora induced by wind, and benefiting nine orifices

Lu and Leng (198

Bencao Tujing

Song, A.D. 1061

Gleditsia species

Treating thoracic retention of phlegm, pyrosis and tinea sores

Su. (1994)

Chong xiu zheng he jing shi zheng lei bei yong ben cao Mingyi Bielu Bencao Congyuan

Song, A.D. 1116

Gu Songyuan Yijing

Qing, A.D. 1618

Gleditsia species

Han, A.D. 498 Qing, A.D. 1674 Gleditsia species

Treating wandering arthritis, putrid flesh, epiphora induced by wind, polypepsia, cough, abdominal distension, cystic node, salivation in children, dystocia in women, and benefiting nine orifices Treating epilepsy, pharyngitis, coprostasis, carbuncle and tinea

3. Phytochemistry

So far, more than 60 compounds have been isolated and elucidated from Gleditsia genus. These chemical constituents contain triterpenes, sterols, flavonoids, phenolics and alkaloids. However, triterpenoid saponins, the most characteristic constituents of Gleditsia fruits, account for a large proportion in isolated compounds. The chemical structures, previously reported from this genus, are shown in Figs. 1–4.

3.1. Triterpenes and Sterols

Gleditsia species are rich in triterpenes, particularly in triterpenoid saponins, and these saponins may be appropriate chemotaxonomic markers for this genus (Table 2; Fig. 1). Structural characteristics of triterpenes are listed as follows: (1) these triterpenes can be divided into two major types due to their basic skeletons, and oleanane-type and lupane-type compounds were found in the genus Gleditsia; (2) 32 triterpenes are commonly glycosylated at C-3 or C-3,-28 positions with one or more sugar moieties; (3) among 32 triterpenoid saponins, 17 triterpenoid glucosides possess one, two or three monoterpenic acids to the sugar moieties. In 1995, the bioassay-guided fractionation of the bioactive extract led to the isolation and identification of one known active compound, gleditsia saponin C (1) (Konoshima, 1995). Besides,

Tang,1982; Tao, 1996

Gu. (2014).

eleven new and one known oleanane-type triterpenoid saponins (213) were isolated from the fruits of G. sinensis in 1999 (Zhang et al., 1999a, 1999b, 1999c). These bisdesmosidic triterpenoid saponins are acylated with one or two monoterpenic acids to the sugar moieties. More recently, some literatures have reported the isolation and characterization of eleven novel bisdesmosidic triterpenoid saponins (1424) from G. caspica (Miyase et al., 2010; Melek et al., 2014). The common structures mentioned above are expected, but some triterpenoid glucosides unexpectedly contain three monoterpenic acids to the sugar moieties; whether the change influences their bioactivity remains unknown. In addition, eight triterpenoid glucosides (2532), which are not acylated with monoterpenic acids, were found and isolated from G. sinensis (Zhang et al., 1999a, 1999d). Except for these triterpenoid saponins mentioned above, and one new triterpene along with four known triterpenes (3337) were also isolated from this genus (Li et al., 2007; Lim et al., 2005; Zhang et al., 1999a). Sterols yielded from the genus Gleditsia can be classified into two types: lanostane-type and lupane-type compounds. Li et al. (2007) isolated four known lupane-type sterols, betulic acid (38), alphitolic acid (39), 3-O-trans-p-coumaroyl alphitolic acid (40) and 2-hydroxypyracrenic acid (41) (Li et al., 2007). In addition, searching for bioactive compounds, Lim et al. (2005) investigated the thorns of G. sinensis, and found several active lanostane-type compounds (4245) (Lim et al., 2005).

Fig. 1. Triterpenes and Sterols from genus Gleditsia

Table 2 Compounds from Gleditsia species Classification

No.

Compound

Source

Reference

Triterpenoid saponin

1

Gleditsia saponin C

G. japonica G. sinensis

Konoshima (1995) Zhang et al. (1999a)

Triterpene

Sterol

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

Gleditsioside E Gleditsioside F Gleditsioside G Gleditsia saponin B Gleditsioside N Gleditsioside O Gleditsioside P Gleditsioside A Gleditsioside B Gleditsioside C Gleditsioside D Gleditsioside Q Caspicaoside A Caspicaoside B Caspicaoside C Caspicaoside D Caspicaoside E Caspicaoside F Caspicaoside G Caspicaoside H Caspicaoside I Caspicaoside J Caspicaoside K Prosapogenin 1a Prosapogenin 1b Gleditsioside H Gleditsioside I Gleditsioside J Gleditsioside K Saponin C′ Saponin E′ 2β-carboxyl,3β-hydroxyl-norlupA (1)-20 (29)-en-28-oic acid Zizyberanalic acid Echinocystic acid 1d (EA) Echinocystic acid 2d D:C-friedours-7-en-3-one Betulic acid Alphitolic acid 3-O-trans-p-coumaroyl alphitolic acid 2-hydroxypyracrenic acid Stigmast-4-ene-3,6-dione Stigmast-3,6-dione Stigmasterol

G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis

Zhang et al. (1999a) Zhang et al. (1999a) Zhang et al. (1999a) Zhang et al. (1999a) Zhang et al. (1999b) Zhang et al. (1999b) Zhang et al. (1999b) Zhang et al. (1999c) Zhang et al. (1999c) Zhang et al. (1999c) Zhang et al. (1999c) Zhang et al. (1999b) Miyase et al. (2010) Miyase et al. (2010) Miyase et al. (2010) Miyase et al. (2010) Melek et al. (2014) Melek et al. (2014) Melek et al. (2014) Melek et al. (2014) Melek et al. (2014) Melek et al. (2014) Melek et al. (2014) Zhang et al. (1999c) Zhang et al. (1999c) Zhang et al. (1999d) Zhang et al. (1999d) Zhang et al. (1999d) Zhang et al. (1999d) Zhang et al. (1999d) Zhang et al. (1999d) Li et al. (2007)

G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis

Li et al. (2007) Zhang et al. (1999c) Zhang et al. (1999c) Lim et al. (2005) Li et al. (2007) Li et al. (2007) Li et al. (2007) Li et al. (2007) Lim et al. (2005) Lim et al. (2005) Lim et al. (2005)

Flavonoid

Phenolic

45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Alkaloid

61 62 63 64 65 66 67

β-sitosterol Dihydrokaempferol Quercetin 3,3′,5′,5,7-pentahydroflavanone Apigenin Luteolin Vicenin-I Vitexin Isovitexin Orientin Isoorientin Iuteolin-7-O-β-glucopyranoside Iuteolin-7-O-β-galactopyranoside Apigenin-7-O-β-glucopyranoside 3-O-methylellagic acid-4′-(5′′-acetyl)-α-L-arabinofuranoside 3-O-methylellagic acid-4′-O-α-L-rhamnopyranoside Ethyl gallate

G. sinensis G. sinensis G. sinensis G. sinensis G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. sinensis

Lim et al. (2005) Zhou et al. (2007a) Zhou et al. (2007a) Zhou et al. (2007a) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Moon and Zee. (2010a)

G. sinensis

Zhou et al. (2007b)

()-epicatechin Caffeic acid Triacanthine

G. sinensis G. sinensis G. sinensis G. horrida

Saikachinoside A Locustoside A Cytochalasin H

G. japonica G. japonica G. sinensis

Zhou et al. (2007b) Zhou et al. (2007a) Zhou et al. (2007a) Morimoto and Oshio (1965) Kajimoto et al. (2010) Kajimoto et al. (2010) Lee et al. (2014)

3.2. Flavonoids

Gleditsia plants also contain flavonoids, and approximately 13 of the compounds have been isolated and elucidated (Table 2; Fig. 2). The largest group of flavonoids, which were found in the genus Gleditsia, is flavone glycosides. In 2007, three flavones (4648) were isolated and identified from G. sinensis (Zhou et al., 2007a). In another study conducted seven years later, Mohammed et al. (2015) isolated eight flavone glycosides (5158) and two flavone aglycones (49, 50) from the ethanol extract of G. triacanthos leaves (Mohammed et al., 2015).

Fig. 2. Flavonoids from genus Gleditsia

3.3. Phenolics and their derivatives

Table 2 contains 5 phenolic compounds isolated from the Gleditsia species. Aiming to search for antimicrobial constituents, two ellagic acid glycosides, which were assigned as 3-O-methylellagic

acid-4′-(5′′-acetyl)-α-L-arabinofuranoside

(59)

and

3-O-methylellagic

acid-4′-O-α-L-rhamnopyranoside (60), were isolated from G. sinensis (Zhou et al., 2007b). In addition, Zhou et al. (2007a) isolated three active phenolic acid relatives (6264) from the spines of G. sinensis, and identified them as ethyl gallate and caffeic acid (Zhou et al., 2007a). The structures of phenolic compounds are presented in Fig. 3.

Fig. 3. Phenolics from genus Gleditsia

3.4. Alkaloids

Alkaloids are relatively rare in Gleditsia species, and only four such compounds were reported in this genus (Table 2; Fig. 4). Morimoto and Oshio (1965) found one alkaloid triacanthine from Gleditsia horrida Willd. (Morimoto and Oshio, 1965). In addition, Kajimoto et al. (2010a)

isolated a novel isoguanine glucoside (64) from the seeds of G. japonica, and the compound was identified as saikachinoside A (65) (Kajimoto et al., 2010a). In another research, bioassay-guided fractionation of the active extract of the seeds of G. japonica resulted in a novel purine alkaloid glucoside designated locustoside A (66) in 2010 (Kajimoto et al., 2010b). Additionally, Lee et al. (2014) isolated cytochalasin H (67), using activity-guided fractionation (Lee et al., 2014). Their structures were confirmed by X-ray crystallographic analysis. The investigations revealed the potential for the occurance of alkaloids in this genus.

Fig. 4. Alkaloids from genus Gleditsia

4. Pharmacology

The genus Gleditsia as the traditional medicine has the wide medicinal uses. Many researchers investigated its pharmacological actions in traditional records, and have validated the therapeutic potential of some species in modern methods. Bioactive studies revealed that the extracts or active compounds of this genus exhibited a wide spectrum of pharmacological activities such as

anti-tumor, anti-inflammatory, anti-hyperlipidemic, anti-HIV, antiallergic, antibacterial, antifungal, analgesic, antimutagenic and antioxidant activities (Table 3 and 4).

4.1. Anti-tumor activities and the mechanisms of action

First anti-cancer study began in 2000s, and Gleditsia species were considered as effective antitumor candidates against various cancer cells involving in breast cancer MCF-7, negative breast cancer MDA-MB231, hepatoblastoma HepG2, nasopharyngeal darcinoma CNE-2, prostatic cancer LNCaP, colon cancer HCT116, colon cancer HT29, oesophageal squamous carcinoma SLMT-1, gastric cancer SNU-5, gastric cancer BGC-823, oral squamous cell carcinoma KB, hepatoma Bel-7402, lung cancer A549 and cervical cancer HeLa cells. Chow et al. (2002) investigated the antiproliferative activity of the fruit extract of G. sinensis (GSE). The MTT proliferation assay was carried out against the four solid tumor cell lines (MCF-7, MDA-MB231, HepG2 and SLMT-1 cells). GSE exhibited appreciable growth inhibition with the MTS50 values ranging from 16 to 20 μg/mL comparing with a positive control cisplatin ranging from 22 to 28 μg/mL. Besides, the anchorage-independent clonogenicity assay also found that GSE cloud incur the loss of the four solid tumor cell lines of regeneration potential. The mechanism of action was further investigated that GSE (20μg/mL) could cause the increasing oligonucleosomal DNA formation in MDA-MB231 cells with the increasing time intervals from 4 to 24h, and revealed that DNA fragmentation suggestive of apoptosis existed. Subsequently, the mechanism of apoptosis was further confirmed by flow cytometry using the transferase-mediated dUTP nick-end labelling (TUNEL) assay and found that GSE can induce apoptosis in time course- and dose-dependent (Chow et al., 2002). In 2003, GSE was investigated on chronic and acute

myelogenous leukemia. The extract was evaluated for the mean concentration in MTS50 against K562 chronic myelogenous leukemia (CML) and HL-60 acute myelogenous leukemia (AML) cell lines according to the MTS assay. The result showed that GSE possessed potent antitumor activity against K562 CML cells (MTS50 18 ± 1.6 μg/mL) and HL-60 AML cells (MTS50 12 ± 1.3 μg/mL), comparing with a mean MTS50 from 1328 μg/mL for patient samples and a mean MTS50 from 4553 μg/mL for non-malignant hematological disorder bone marrow samples (Chow et al., 2003b). Through the further research on the antiproliferative activity of GSE, Chui et al. (2004) demonstrated that the growth inhibition induced by GSE in these solid tumour cell lines including MDA-MB231, CNE-2 and LNCaP cells involved both bFGF and NO regulations (Chui et al., 2004). In addition, Teo et al. (2004) demonstrated that apoptotic activity was involved in the cancer therapy of GSE, and revealed that the GSE-induced apoptosis was via reactive oxygen species (ROS) pathway to result in an early decrease of intracellular superoxide anion (Teo et al., 2004). Moreover, Chui et al. (2005) demonstrated that activation of the signaling pathway of caspase 3 involved in the mechanistic action of GSE inducing apoptosis (Chui et al., 2005). Tang et al. (2007) evaluated GSE for the inhibitory actions on the esophageal squamous cell carcinoma (ESCC) cell lines (MTS50 21μg/mL) after 48h of GSE treatment. The result was compared with non-tumor mouse embryonic fibroblast NIH 3T3 cells (MTS50 163 μg/mL), and indicated that GSE was effective against ESCC cell lines with low cytotoxicity on non-tumor cells. The mechanism of GSE was that modulation of the oncogenic expression and telomerase activity resulted in exerting the antitumor activity. However, the further molecular mechanisms of GSE was unknown, and further research is still needed (Tang et al., 2007). Lee et al. (2009) found that the ethanol extract of G. sinensis thorns (EEGS) could effectively inhibit the growth of HCT116

cells in a concentration-dependent manner, and induced apoptosis by significantly increasing the cytoplasmic DNA-histone complex of HCT116 cells. Subsequently, Lee et al. (2009) investigated and revealed that the further mechanism of EEGS on the treatment of colon cancer was as follows. EEGS activated ERK (extracellular signal-regulated kinase) via p27-mediated G2/M-phase cell cycle arrest, and incurred the inhibition of cell growth. Moreover, EEGS strongly inhibited tumor necrosis factor- (TNF-)-induced matrix metalloproteinase-9 (MMP-9) expression by suppressing nuclear factor κB (NF-κB) and activator protein-1 (AP-1) binding activities. Finally, the in vivo growth of HCT116 cells, which is associated with changed levels of ERK, MMP-9 and p27 expression, was suppressed by EEGS. Although EEGS are effective in treating colon cancer, further in vivo assay is necessary for exploring the molecular mechanism of the effective EEGS constituents (Lee et al., 2009). Apart from the study about EEGS, Lee et al. (2010) also tested the water extract of G. sinensis thorns (WEGS) for antitumor activity, and demonstrated that WEGS exhibited modest antitumor effect against HCT116 cells (IC50 800 μg/mL). The mechanisms of WEGS were also revealed. When HCT116 cells were treated with WEGS, a decrease in cell growth and an increase in the G2/M-phase arrest related to the increasing p53 levels and down-regulation of the check-point proteins including cyclin B1, Cdc 2 and Cdc25c, were observed. In addition, Lee et al. (2010) also found that the treatment with WEGS could induce phosphorylation of ERK, p38 mitogen-activated protein (MAP) kinase and JNK (c-Jun N-terminal kinases), as well as the treatment of HCT116 cells with the ERK-specific inhibitor PD98059 could inhibit ERK, and resulted in blocking the expression of WEGS-mediated p53, reversing cell-growth inhibition and decreasing cell cycle proteins. In addition, further in vivo study also found that the treatment with WEGS could inhibit the cell-growth in nude mice without any

negative side effects including the loss of body weight (Lee et al., 2010). Lee et al. (2013) assessed the antiproliferative effect of EEGS against SNU-5 cells. They observed that EEGS exhibited appropriate growth inhibitory effects on cells with the IC50 value of 400 μg/mL in a concentration-dependent manner, and cytoplasmic DNA-histone complexes was on the increase in the EEGS-treated cells. Subsequently, a novel mechanism was identified. EEGS inducing the inhibitory growth of SNU-5 cells linked to p38 MAP kinase pathways activated through p21WAF1-mediated G1 phase cell cycle arrest. Further study found that the decrease in the cyclin and cyclin-dependent kinases (CDK) complexes was associated with p21WAF1 expression in SUN-5 cells. Moreover, EEGS inhibited the binding activities of NF-κB and AP-1 cis-elements in TNF-α-treated cells, and caused the suppression of MMP-9 expression (Lee et al., 2013). In 2014, the ethanol extract of G. triacanthos leaves was characterized for its cytotoxicity on the following cancer cells. The extract showed potent antitumor activity against the liver, cervix, larynx and colon cancer cell lines, with IC50 values of 1.68, 0.74, 1.28 and 0.67 μg/mL (Mohammed et al., 2014). Except for the extracts obtained, several compounds, which were isolated from these extracts, were also tested for cytotoxicity. Compound 2 was isolated from G. sinensis, and the cytotoxicities were tested against Bel-7402, BGC-823, HeLa, HL-60, KB and MCF-7 cell lines with the IC50 values of 3.1 ± 2.8, 8.0 ± 1.2, 5.0 ± 3.4, 3.0 ± 1.3, 34.3 ± 1.5, 6.6 ± 2.3 μM, respectively. In addition, the compound was compared with the positive control paclitaxel (IC50 0.3 ± 0.1, not tested, 33.0 ± 6.1, 4.1E-4 ± 1.1 E-4, >100, 15.3 ± 2.6 μM, respectively), and the data demonstrated that compound 2 exhibited potent cytotoxicity against Bel-7402, BGC-823, HeLa, HL-60 and MCF-7 cell lines. The mechanism of action involved that compound 2 could block the

G2/M phase of HL-60 cells incurring an prominent accumulation of the sub-G1 peak, and finally caused early apoptosis in HL-60 cells (Zhong et al., 2003). In another research, compounds 1417 were isolated from G. caspica, and these compounds were tested for cytotoxicity against HepG2 cells (IC50 4.5, 2.5, 2.2, 5.4 μM ), A549 cells (IC50 30.0, 6.5, 3.7,16.3 μM) and HT29 cells (IC50 23.0, 3.9, 1.5, 11.3 μM). The data were compared with the positive control, adriamycin (IC50 6.9, 7.9, 6.4 μM). The result showed that compounds 14 and 17 exhibited potent cytotoxic activities against HepG2 cells, and compounds 15 and 16 showed strong cytotoxicity against HepG2, A549 and HT29 cells. However, the molecular mechanism for these compounds remains unknown and requires further research (Miyase et al., 2010). In addition, some studies found that the unabatedly continuing development of new blood vessels is a key step for the formation of solid and liquid (leukaemgenesis) tumors, and blocking angiogenesis could be necessary in cancer therapy (Matsunaga et al., 2010). Chow et al. (2003a) evaluated the vascular endothelial growth factor (VEGF) mRNA expression level, and found that GSE could suppress VEGF mRNA expression in MDA-MB23 and HepG2 cells. Enzyme-linked immunosorbent assay further demonstrated that GSE could decrease the VEGF secretion in MDA-MB231, HepG2, HL-60 and eleven primary cultured leukaemia cells. In addition, the in vivo chorioallantoic membrane assay showed that GSE could suppress the angiogenic activity of bFGF. Taken together, the information indicated that GSE could be potentially served as an angiogenic inhibitor in solid tumour and leukaemia therapy (Chow et al., 2003a). Yi et al. (2012) explored the effects of EEGS on angiogenesis towards primary endothelial cells with the function of forming blood vessels. They found that EEGS could inhibit the proliferation of HUVEC primary cells in vitro (the IC50 values ≥50 μg/mL), and inhibit the vessel formation in vivo (the

IC50 values ≥50 μg/mL) in a dose-dependent manner. However, the antiproliferative activity was not related to cytotoxicity, and further research found that EEGS suppressed the action of pro-angiogenic proteins, as well as the effects linked to down-regulation of intra/extracellular proangiogenic modulators such as endothelin-1 (EDN1) and matrix metalloproteinase-9 (MMP9) enzymes (Yi et al., 2012). Aiming to explore the antiangiogenic constituents of EEGS, Lee et al. (2014) identified an active compound, cytochalsin H (67), two years later. Compound 67 suppressed cell growth and mobility in HUVECs partly by decreasing expression of pro-angiogenic factor, such as EDN1. Additionally, the compound inhibited the pro-angiogenic protein-induced formation of new blood vessels in vivo. Taken together, compound 67 showed significant antiangiogenic effect in vitro and in vivo, and was proved to be an active anti-angiogenic constituent (Lee et al., 2014). Subsequently, Lee et al. (2015) observed that EEGS and its active constituent, compound 67, effectively inhibited the tumor growth in an in ovo xenograft model, and not exhibit significant toxicity. In addition, Lee et al. (2015) also repeatedly found EEGS with the anti-tumor and anti-metastatic effects in these representative animal models. These results further revealed that EEGS and compound 67 are potential anti-angiogenic cancer candidates (Lee et al., 2015). Another research found that the saponin fraction from the fruits of G. sinensis (SFGS) could significantly suppress the proliferation, migration, and tube formation of HUVECs induced by bFGF (10 ng/mL) with the concentrations of 1, 3 and 10 μg/mL, and the potent cytotoxicity was not observed on endothelial cells. Moreover, SFGS could greatly induce cell apoptosis by increasing the expressions of apoptosis regulatory proteins: caspase-3, caspase-8 and Fas except for caspase-9 in HUVECs, and not affect the bFGF-induced autosecretion of VEGF from endothelial cells. Additionally, 13 saponin compounds along with the sapogenin

oleanolic acid from SFGS were tested for their antiangiogenic activity according to tube formation assay of HUVECs. The result exhibited that compounds 7, 10, 13, 28, and 29 could potently inhibit the tube formation with the concentration of 3 μΜ. The structure-activity relationship of these five compounds revealed that glucosylation of the C-28 carboxyl is essential and important. Moreover, the numbers and structures of monoterpene groups on the sugar chain, and the existence of hydroxyl chain at C-16 as well as the sugar chain length of the hydroxyl at C-3 also affect the activities of compounds (Lu et al., 2014). Table3 Anti-tumor effects of this genus Pharmacological detail

Compounds/extracts

Concentration

Reference

Antiproliferative activity against the four solid tumor cell lines (MCF-7, MDA-MB231, HepG2 and SLMT-1 cell lines); inducing apoptosis in time course- and dose-dependent

The extract of G. sinensis

MTS50 (ranging from 16 to 20 μg/mL)

Chow et al. (2002)

The growth inhibitory activity against K562 CML and HL-60 AML cell lines

The extract of G. sinensis

MTS50 (18 ± 1.6, 12 ± Chow 1.3 μg/mL) (2003b)

The growth inhibition involving in both bFGF and NO regulations

The extract of G. sinensis

Chui et al. (2004)

The GSE-induced apoptosis being via ROS pathway to result in an early decrease of intracellular superoxide anion

The extract of G. sinensis

Teo et al. (2004)

Activation of the signaling pathway of caspase 3 involving in the mechanistic action of GSE inducing apoptosis

The extract of G. sinensis

Chui et al. (2005)

Cytotoxicity on Bel-7402, BGC-823, HeLa, HL-60, KB and MCF-7 cell lines; blocking the G2/M phase of HL-60 cells incurring an prominent accumulation of the sub-G1 peak, and finally causing early apoptosis in

Compound 2

IC50: 3.1 ± 2.8, 8.0 ± 1.2, 5.0 ± 3.4, 3.0 ± 1.3, 34.3 ± 1.5, 6.6 ± 2.3 μM

et

al.

Zhong et al. (2003)

HL-60 cells The inhibitory actions on the ESCC cell line; exertion of the antitumor activity by modulation of the oncogenic expression and telomerase activity

The extract of G. sinensis

Incurring apoptosis by modulating the cytoplasmic DNA-histone complex; the inhibition of cell growth induced by EEGS related to activate ERK via p27-mediated G2/M-phase cell cycle

The ethanol extract of G. sinensis thorns

MTS50 = 21 μg/mL

Tang et al. (2007)

Lee et al. (2009)

arrest; inhibiting TNF--induced MMP-9 expression by suppressing NF-κB and AP-1 binding activities; inhibiting the growth of HCT116 cells by changing levels of ERK, MMP-9 and p27 expression IC50 = 800 μg/mL

Antitumor effect against HCT116 cells

The water extract of G. sinensis thorns

Lee et al. (2010)

A appropriate decrease in cell growth and a dramatically increase in the G2/M-phase arrest related to the increasing p53 levels and down-regulation of the check-point proteins, including cyclin B1, Cdc 2 and Cdc25c; inducing phosphorylation of ERK, p38 MAP kinase and JNK; inhibiting the cell-growth in nude mice without any negative side effects including the loss of body weight

The water extract of G. sinensis thorns

Cytotoxicity against HepG2, A549 and HT29 cells

Compounds 1417

HepG2 (IC50 4.5, 2.5, 2.2, 5.4 μM ); A549 (IC50 30.0, 6.5, 3.7,16.3 μM); HT29 (IC50 23.0, 3.9, 1.5, 11.3 μM)

Miyase (2010)

The antiproliferative effect against human SNU-5 gastric cancer cells; the

The ethanol extract of G. sinensis thorns

IC50 = 400 μg/mL

Lee et al. (2013)

Lee et al. (2010)

et

al.

inhibitory growth of SNU-5 gastric cancer cells related to p38 MAP kinase pathways activated through p21WAF1-mediated G1 phase cell cycle arrest; the decrease in the cyclin and CDK complexes associated with p21WAF1 expression in SUN-5 cells; the inhibition of the binding activities of NF-κB and AP-1 cis-elements in TNF-α-treated cells, and incurring the significant suppression of MMP-9 expression

The ethanol extract of G. sinensis thorns

The cytotoxicity on liver, cervix, larynx and colon cancer cell lines

The ethanol extract of G. triacanthos leaves

Treating solid tumour and leukaemia by inhibiting angiogenic

The extract of G. sinensis

The effects of EEGS on angiogenesis towards primary endothelial cells

The ethanol extract of G. sinensis thorns

Suppressing cell growth and mobility in HUVEC partly by decreasing expression of pro-angiogenic factor, such as endothelin-1; inhibiting the pro-angiogenic protein-induced formation of new blood vessels in vivo;

Compound 67

Lee et al. (2014)

Inhibiting the tumor growth in an in ovo xenograft model without significant toxicity

The ethanol extract of G. sinensis thorns and compound 67

Lee et al. (2015)

Suppressing the proliferation, migration, and tube formation of HUVECs induced by bFGF; inducing cell apoptosis by increasing the expressions of apoptosis regulatory proteins: caspase-3, caspase-8 and Fas

The saponin fraction isolated from the fruits (SFGS) of G. sinensis

IC50: 1.68, 0.74, 1.28 and 0.67 μg/mL

Mohammed et al. (2014) Chow (2003a)

The proliferation of HUVEC primary cells in vitro (the IC50 values of ≥50 μg/mL); The vessel formation in vivo (the IC50 values of ≥50 μg/mL)

The concentrations of 1, 3 and 10 μg/mL

et

Yi et al. (2012)

Lu et al. (2014)

al.

except for caspase-9 in HUVECs Inhibiting the tube formation

Compounds 7, 13, 10, 28 and 29

The concentration of 3 μΜ.

Lu et al. (2014)

4.2. Anti-inflammatory activities

In traditional records, the G. sinensis thorns have been used as traditional medicine for treatment of some inflammatory diseases, such as swelling, carbuncle, suppuration and skin diseases in China and Korea. The fruit hull of G. sinensis (FGS) has been used as a traditional anti-inflammatory medicine for treatment of some respiratory system diseases caused by inflammation (Zhang, 1987). So far, the anti-inflammatory action has been confirmed by modern studies. Ha et al. (2008) investigated the anti-inflammatory mechanism of G. sinensis thorns, and the action was as follows. WEGS inhibited NO release and inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, and that these anti-inflammatory effects were mediated by suppression of the activation of NF-κB, the degradation of IκB- and the phosphorylation of ERK1/2 and JNK (Ha et al., 2008). Choi et al. (2012) investigated the effect of FGS pretreatment for the LPS-induced acute lung injury, and explored the anti-inflammatory mechanism of FGS. Pretreatment of C57BL/6 mice with FGS protected from the LPS-induced neutrophilic lung inflammation, the hallmark of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), and that FGS enhanced the activation and expression of the anti-inflammatory NF-E2-related factor 2 (Nrf2)-regulated genes including glutamatecysteine ligase catalytic subunit (GCLC), 4-nitroquioline-1-oxide 1 (NQO-1), and glutamatecysteine ligase catalytic subunit (HO-1) without affecting NF-κB activity. These results indicated that FGS inhibited neutrophilic lung inflammation by activating anti-inflammatory

factor Nrf2 (Choi et al., 2012). Kim et al. (2014) carried out the similar assay and provided the experimental evidence that the FGS of post-treatment suppressed the LPS-induced lung inflammation in ALI mouse model, at least partly by the mediation of Nrf2 activation (Kim et al., 2014). Based on the pretreatment and post-treatment of FGS, the information suggested that FGS possessed the therapeutic potential and could be a therapeutic option for treating inflammatory lung diseases. In a research, the 70% ethanol extract from the anomalous fruits of G. sinensis (AFGS) exhibited the appropriate inhibition on the ear swelling in mice and hind paw edema in rats with the concentrations of 500 and 1000 mg/kg. The study also revealed that AFGS (with a dose of 1000 mg/kg) could suppress the vascular permeability triggered by acetic acid in mice. These findings suggested that AFGS possessed modest inhibitory effect on acute inflammation that can be mediated by weakening the inflammatory effects of mediators such as serotonin (Dai et al., 2002).

4.3. Anti-hyperlipidemic activities

G. sinensis, a major agent of many polyherbal prescriptions, has been used for treating obesity and thrombosis in TCM (Xie, 1995). Modern pharmacological studies have been shown correlations to the traditional use. In 2011, the G. sinensis fruit aqueous extract (GAE), mainly composed of compound 35 (EA), was evaluated against hyperlipidemia and atherosclerosis in the white rabbits with a high fat diet. Lai et al. (2011) demonstrated that oral administration of GAE had a potent hypolipidemic activity by decreasing the lipid levels of liver, serum and aorta and that can effectively inhibit the aortic atherosclerosis of formation and enhance aortic remodeling

without the significant muscle and liver toxicity. Although EA exhibited significant attenuation of atherosclerosis in zoopery, the potentially molecular mechanism was unknown and remained to be identified (Lai et al., 2011). Lai and Liu (2014) investigated the relationship between EA and endothelial progenitor cells (EPCs), and elucidated the mechanism. The study demonstrated that oxidised low-density lipoprotein (oxLDL) could make EPCs induce apoptosis, migration and impaired adhesion. However, the treatment of EPCs with EA could attenuate the harmful effects of oxLDL on EPCs via up-regulating the expression of endothelial nitric oxide synthase (eNOS) protein as well as repression of Akt/eNOS phosphorylation (Lai and Liu, 2014). Taken together, EA exerts its protective effects on EPCs through oxLDL via the Akt/eNOS pathway.

4.4. Antiallergic activities

Shin et al. (2000) investigated the action of WEGS in the mast cell-dependent anaphylaxis. WEGS inhibited systemic anaphylaxis induced by compound 48/80 with a mean ranging from 0.005 to 1 g/kg in a concentration-dependent manner. In addition, WEGS (the concentrations of 0.1 and 1 g/kg) also showed the effective inhibition of passive cutaneous anaphylaxis (PCA) activated by anti-dinitrophenyl (anti-DNP) lgE. Moreover, WEGS (the means ranging from 0.001 to 1 mg/mL) could dose-dependently inhibit the release of histamine from rat peritoneal mast cells (RPMC) triggered by compound 48/80 or anti-DNP lgE. Taken together, WEGS was effective in the mast cell-dependent anaphylaxis. Although the findings suggested that WEGS could be used for inhibiting the mast cell-dependent, the in vivo effect of WEGS on the production of mast cell cytokine such as lgE-induced TNF- remains to be explored (Shin and Kim, 2000).

Dai et al. (2000) carried out a study to explore the 70% ethanol extract from the anomalous fruits of G. sinensis (AFGS). In vivo, AFGS dose-dependently exhibited the inhibitory effect on the systemic anaphylactic shock by compound 48/80 and cutaneous anaphylaxis induced by the release of histamine/serotonin in rats at doses of 200, 500 and 1000 mg/kg. In vitro, immediate allergic reactions could be mediated by suppressing the release of histamine from rat peritoneal mast cells induced by compound 48/80 at concentrations of 20 and 50 μg/mL. These results suggested that AFGS possessed the antiallergic activities, and the activities were mediated by suppressing the release of some mediators such as histamine from mast cells. However, further studies are necessary for elucidating the precise mechanism of action and exploring the effective constituents of this plant (Dai et al., 2000). Based on the research status mentioned above, Fu et al. (2000) explored the inhibition of the n-butanol fraction from the anomalous fruits of G. sinensis (NBGS) on the experimental allergic rhinitis. NBGS (the means of 100, 200 and 400 mg/kg) inhibited the nasal symptoms including sneezing and rubbing, as well as dye leakage induced by ovalbumin challenge into the nasal cavity in actively sensitized rats. In vitro, NBGS (the concentrations of 30 and 100 mg/ml) significantly reduced the release of histamine from rat peritoneal mast cells induced by compound 48/80. Furthermore, NBGS (200 and 400 mg/kg) reduced both nasal symptoms such as sneezing and nasal rubbing, and the amount of nasal vascular permeability induced by antigen or histamine in rats. These findings suggested that NBGS possessed the inhibitory effect on experimental allergic rhinitis, probably by inhibiting both the release of histamine from mast cells and the increase of nasal vascular permeability (Fu et al., 2000).

4.5. Antibacterial and antifungal activities

In 2007, the ethanol crude extract of the G. sinensis spines showed significant inhibitory activity against Bacillus subtilis and Xanthomonas vesicatoria based on the sizes of inhibitory zones of 9.5 and 9.2 mm, by comparing with streptomycin (the diameter of inhibitory zones of 21.5 and 13.8 mm, respectively). Among the ethanol extract fractions, the acetidine fraction exhibited the more significant inhibitory effect on Bacillus subtilis and Xanthomonas vesicatoria with the diameters of inhibitory zones of 14.5 and 11.3 mm, and the lowest minimal inhibitory concentration (MIC) of 1.25 and 5 mg/mL, respectively. Therefore, further isolation and elucidation of antimicrobial compounds was conducted to the acetidine fraction by column chromatography, and seven compounds were separated. Among these compounds, compounds 47, 48 and 63 were evaluated antibacterial activities against Bacillus subtilis (MIC 0.5, 0.5, 0.125 mg/mL) and Xanthomonas vesicatoria (MIC 0.75, 0.75, 0.125 mg/mL). These data were compared with the positive control with the MIC values of 0.078 and 0.010 mg/mL, and exhibited the appreciable antibacterial activities (Zhou et al., 2007a). In 2007, the antimicrobial ethyl acetate fraction from the ethanol extract of G. sinensis spines yielded two ellagic acid glycosides. The two compounds were tested for antifungal activity against the spore germination of rice blast fungus, Magnaporthe grisea. The result was that compounds 59 and 60 showed modest inhibitory activity with the IC50 values of 13.56 and 16.14 μg/mL, respectively (Zhou et al., 2007b).

4.6. Analgesic activities

G. triacanthos has been reported as local medicine for anodyne, narcotic, mydriatic, and

experimentally oxytocic (Duke et al., 1981). Recently, some studies have accounted for the uses in local remedy. The G. triacanthos methanolic fruit extract (MEGT) and its saponin-containing fraction (SFGT) were tested for analgesic activity by Saleh et al. (2015). In the writhing test, the six mice groups were treated with MEGT and SFGT with the ED50 values of 268.2 and 161.2 mg/kg, respectively. The results showed that these mice groups (three dose levels of 140, 280, and 560 mg/kg) displayed a remarkable decrease in writhing count compared with the group by treatment with standard drug indomethacin (14mg/kg). This research also found that SFGT displayed 64.94 and 70.78% protection with the dose levels of 280 and 560 mg/kg, respectively, which are more than double protection caused by indomethacin (31.82%). In addition, the subcutaneous injection of formalin produced a distinct biphasic nociceptive response including phase I and phase II. MEGT and SFGT at the dose of 400 mg/kg were conducted to the formalin test with the ED50 values of 287.6 and 283.4 mg/kg for phase I as well as 295.1 and 290.4 mg/kg for phase II, respectively. The data were compared with indomethacin (56.0 and 32.29%) at 10 mg/kg and demonstrated that MEGT and SFGT exhibited appropriate inhibitory effect in both phase I (18.86 and 52.57%) and phase II (39.36 and 44.29%). Furthermore, the tested animals were orally administered with MEGT and SFGT at the three dose levels of 100, 200, and 400 mg/kg, and carried out the hotplate test with ED50 values 155.4 and 200.6 mg/kg, respectively, at 30, 60 and 120 min. The test results were compared with indomethacin (10 mg/kg), and showed that SFGT and MEGT could cause significant delay in responses in hotplate model. Taken together, these results revealed that SFGT and MEGT exhibited appropriate both peripheral and central analgesic activities (Saleh et al., 2015).

4.7. Antimutagenic activities

Lim et al. (2005) carried out the antimutagenic activity-guided isolation from G. sinensis, and led to the isolation and identification of compounds 37, 4245. These compounds were tested for their antigenotoxic activities through the SOS chromotest. Compound 44 caused the 51.2% and 64.2% decrease of the mutagens 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) and NQO, respectively, and showed more potent antimutagenic activity against the induction factors among these isolated compounds (Lim et al., 2005). In 2015, the saponin fraction from the G. caspica methanolic fruit extract (SFGS) was evaluated for genotoxic and antigenotoxic activities in vivo. SFGS significantly reduced the number of cyclophosphamide-induced chromosomal aberrations in bone marrow and germ cells when applied before or after administration of cyclophosphamide, and the reduction of chromosomal aberrations were 59% and 41% for bone marrow and 48% and 43% for germ cells, respectively. These data demonstrated that SFGS could possess significant antigenotoxic activities. Moreover, further research found that the fraction caused no DNA damage in Swiss albino male mice upon treatment with the dose of 45 mg/kg body weight for 24 h (Farouk et al., 2015).

4.8. Other bioactivities

In 1995, compound 1, isolated from G. triacanthos, was evaluated the anti-HIV activity against HIV replication in H-9 cells. Compound 1 exhibited the significant anti-HIV activity with the EC50 value of 1.1 μM (Konoshima, 1995). Li et al. (2007) tested compound 33 against HIV-1 replication in C8166 cells, and found that the compound (EC50 < 0.064 μg/mL) possessed the potent anti-HIV activity (Li et al., 2007).

Mohammed et al. (2014) carried out the antioxidant assay in the extracts and compounds from G. triacanthos leaves. In vivo, the ethanol and successive extracts of G. triacanthos leaves were tested for antioxidant activity by the raise in glutathione level and comparison with diabetic control. The result demonstrated that the ethanol extract at 100 mg exhibited the higher antioxidant activity (64.05% change from diabetic control) followed by the successive extracts (the values of ranging from 57.14 % to 61.75%) compared with vitamin E (65.43%). In vitro, compounds 52, 54, 56, 58 were evaluated for the free radical scavenging activity by 2,2-diphenyl-1-picrylhydrazyl (DPPH). Among these compounds, compounds 52, 54, 56 showed no antioxidant activity while compound 58 showed the potent activity with the 91.8% free radical scavenging (Mohammed et al., 2014). In another research, a pentacyclic triterpene, compound 35 (EA) was isolated from the fruits of G. sinensis. EA was evaluated for protective effects in acute myocardial ischemia triggered by isoproterenol and vasopress in rat models. In the electrocardiogram of anesthetized rats, EA dose-dependently suppressed the ST-segment depression induced by isoproterenol and vasopressin. Furthermore, the Bcl-2 mRNA isolated from infarcted tissue induced by isoproterenol in rats was analyzed by reverse transcription-polymerase chain reaction (RT-PCR), and EA showed a raise in the mRNA expression of Bcl-2. These results demonstrated that EA could reduce myocardial ischemia by the decrease in apoptotic cell death in myocardial tissue, and may be a natural drug (Wu et al., 2010).

Table4 Various effects of Gleditsia species Pharmacological effects

Detail

Compounds/extracts

Reference

Anti-inflammatory effect

NO release and inducible iNOS expression in LPS-induced RAW 264.7 macrophages causing inflammation; mediating anti-inflammatory effects by the suppression of the activation of NF-κB, the

The aqueous extract of G. sinensis thorns

Ha et al. (2008)

Enhancing the activation and expression of the anti-inflammatory Nrf2-regulated genes including GCLC, NQO-1, and HO-1 without affecting NF-κB activity.

The fruit hull of G. sinensis

Choi et al. (2012)

Suppressing the LPS-induced lung inflammation in ALI mouse model, at least partly by the mediation of Nrf2 activation.

The fruit hull of G. sinensis

Kim et al. (2014)

An appropriate inhibitory effect on acute inflammation being mediated by weakening the inflammatory effects of mediators such as serotonin.

The 70% ethanol extract from the anomalous fruits of G. sinensis

Dai et al. (2002)

Inhibiting the aortic atherosclerosis of formation and enhancing aortic remodeling without the significant muscle and liver toxicity.

The G. sinensis fruit aqueous extract

Lai et al. (2011)

Attenuating the harmful effects of oxLDL on EPCs via up-regulating the expression of eNOS protein as well as the repression of Akt/eNOS phosphorylation

Compound 35 (EA)

Lai and Liu (2014)

The inhibition of systemic anaphylaxis (0.005 to 1 g/kg); The significant inhibition of local anaphylaxis (0.1 and 1 g/kg); The inhibition of the release of histamine from rat peritoneal mast cells ((0.001 to 1 g/kg)

The aqueous extract of G. sinensis thorns

Shin and Kim (2000)

Mediating the antiallergic activity by suppressing the release of some mediators such as histamine from mast cells

The ethanol extract from G. sinensis

Dai et al. (2000)

The inhibitory effect on experimental allergic rhinitis, probably by inhibiting both the release of histamine from mast cells and the increase of nasal vascular permeability

The n-butanol fraction from the anomalous fruits of G. sinensis

Fu et al. (2000)

Against Bacillus subtilis (MIC 0.5, 0.5, 0.125 mg/mL)

The ethanol crude extract of the

Zhou et al. (2007a)

degradation of IκB-, and the phosphorylation of ERK1/2 and JNK

Anti-hyperlipidemic effect

Antiallergic effect

Antibacterial effect

and Xanthomonas vesicatoria (MIC 0.75, 0.75, 0.125 mg/mL)

G. sinensis spines

Against Magnaporthe grisea (IC50 13.56 and 16.14 μg/mL)

Compounds 59 and 60

Zhou et al. (2007b)

Analgesic effect

Exhibiting both peripheral and central analgesic activities (the ED50 values of 268.2 and 161.2 mg/kg in the writhing test,; the ED50 values of 287.6 and 283.4 mg/kg for phase I, and 295.1 and 290.4 mg/kg for phase II; the ED50 values 155.4 and 200.6 mg/kg in the hotplate test)

The G. triacanthos methanolic fruit extract (MEGT) and its saponin-containing fraction (SFGT)

Saleh et al. (2015)

Antimutagenic effect

Causing the 51.2% and 64.2% decrease of the mutagens MNNG and NQO, respectively

Compound 44

Lim et al. (2005)

Causing the 59% and 41% reduction of chromosomal aberrations for bone marrow, and 48% and 43% for germ cells before or after administration of cyclophosphamide

The saponin fraction from the G. caspica methanolic fruit extract

Farouk et al. (2015)

The significant anti-HIV activity with the EC50 value of 1.1 μM

Compound 1

Konoshima (1995)

The significant anti-HIV activity (EC50 < 0.064 μg/Ml)

Compound 33

Li et al. (2007)

Antioxidant activity

Scavenging DPPH (91.8%)

Compound 58

Mohammed et al. (20

Effects on acute myocardial ischemia

Reducing myocardial ischemia by the decrease in apoptotic cell death in myocardial tissue

Compound 35 (EA)

Wu et al. (2010)

Anti-HIV effect

5. Conclusion

The genus Gleditsia (family Fabaceae) has been used as traditional herbal medicine for a long time, and an increasing number of studies have been carried out on chemical constituents and pharmacological activities recently. Several reasons could contribute to the increasing research interests of this genus: (1) a widely distribution across the world, (2) a extensively traditional use for various diseases, (3) an abundance of triterpenoid saponins with promising pharmacological

actions, (4) a potential source of novel, pharmacologically active compounds from the bioactive extracts. Moreover, part traditional uses of this genus have been well known to be highly associated with modern pharmacological studies, and the results exhibited that the ethnomedical uses of wandering arthritis and swelling are connected with anti-inflammatory activities; the ethnological uses of suppuration, scabies, carbuncle and skin diseases are associated with antibacterial and antifungal activities; the uses of anodyne, anesthetic link to the analgesic activity; the treatment of apoplexy is affected by the hypolipidemic activity. Although phytochemical and pharmacological studies on Gleditsia species have received considerable interest, the following gaps are still noteworthy. First, regarding the chemical constituents contributed to therapeutic values, the active constituents are ambiguous mostly attributed to the crude extracts or the saponins fractions, and there is not enough evidence regarding purified molecules and their pharmacological actions. Therefore, further study is required to elucidate the bioactive actions of the exact pure constituents. Secondly, the modern studies mainly focused on four Gleditsia species—G. japonica, G. sinensis, G. triacanthos and G. caspica. The relationships of the chemistry and bioactivities to other Gleditsia species were not investigated. Therefore, a comprehensive investigation of triterpenoid saponins from different Gleditsia species is necessary. Thirdly, various pharmacological activities of the extracts and compounds were mainly conducted to test in in vitro assays, and less carried out in vivo assays using laboratory animals. Therefore, there are few reported data focused on toxicity, side effects and clinical efficiency, and the results obtained may not be accurate and applicable in humans. Therefore, comprehensive well-controlled and double-blind clinical trials are therefore urgently required to re-evaluate the efficacy and safety. Fourthly, the pharmacological studies are still

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Table

Table 1 Medicinal uses in Chinese classical pharmaceutical books Monograph

Dynasty

Species

Function

Reference

Sheng Nong′s herbal classic; Tangye Bencao; Tang Ben Cao

Qin, A.D. 200 Yuan, A.D. 1289 Tang, A.D. 657

Gleditsia species

The effects in treating apoplexy, headache, carbuncle, swelling, suppuration, scabies, productive cough and asthma

Wu, 1955; Wang, 2008; New Medical College, 1

Compendium Medica

Ming, A.D. 1590

The seeds of Gleditsia species

Treating arthrolithiasis, constipation, diarrhea, hematochezia, dysentery, carbuncle, swelling, salivation in children and dystocia in women; Treating scrofula, dysuria, acute mastitis, retained afterbirth, etc

Li. (1982)

of

Materia

The thorns of Gleditsia species Bencaojing Jizhu

Han, A.D. 498

The thorns of Gleditsia plants

Treating wandering arthritis, muscular death, epiphora induced by wind, pathogenic factor, abdominal distension, etc

Tao. (1955)

Ncmm

Ming, A.D. 1565

The thorns of Gleditsia plants

An effective medicine in chirurgery

Chen. (1988)

New Compilation of Materia Medica

Qing, A.D. 1757

Gleditsia species

Treating sequela of apoplexy, vomiting phlegmatic savliva, thoracic obstruction, pharyngitis, anemogenous constipation, etc

Wu. (2012)

Bencao Yanyi

Song, A.D. 1116

Gleditsia species

Exorcizing pestilence and treating eczema, wind-heat, anemogenous salvation, etc

Kou. (1990)

Qianjin Yi Fang

Tang, A.D. 682

Gleditsia species

Treating wandering arthritis, epiphora induced by wind, polypepsia, cough, abdominal distension, cystic node, etc

Sun. (2011)

Elementary Medicine

Ming, A.D. 1575

Gleditsia species

Dispersing phlegm, suppressing cough and treating headache

Li. (2006)

Bencao Chengya Banji

Qing, A.D. 1647

Gleditsia species

Treating wandering arthritis, putrid flesh, epiphora induced by wind, and benefiting nine orifices

Lu and Leng (1986)

Bencao Tujing

Song, A.D. 1061

Gleditsia species

Treating thoracic retention of phlegm, pyrosis and tinea sores

Su. (1994)

Chong xiu zheng he jing shi

Song, A.D. 1116

Gleditsia species

Treating wandering arthritis, putrid flesh,

Tang,1982; Tao, 1986;

zheng lei bei yong ben cao Mingyi Bielu Bencao Congyuan

Han, A.D. 498 Qing, A.D. 1674

Gu Songyuan Yijing

Qing, A.D. 1618

Gleditsia species

epiphora induced by wind, polypepsia, cough, abdominal distension, cystic node, salivation in children, dystocia in women, and benefiting nine orifices Treating epilepsy, pharyngitis, coprostasis, carbuncle and tinea

1996

Gu. (2014).

Table 2 Compounds from Gleditsia species Classification

No.

Compound

Source

Reference

Triterpenoid saponin

1

Gleditsia saponin C

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

Gleditsioside E Gleditsioside F Gleditsioside G Gleditsia saponin B Gleditsioside N Gleditsioside O Gleditsioside P Gleditsioside A Gleditsioside B Gleditsioside C Gleditsioside D Gleditsioside Q Caspicaoside A Caspicaoside B Caspicaoside C Caspicaoside D Caspicaoside E Caspicaoside F Caspicaoside G Caspicaoside H Caspicaoside I Caspicaoside J Caspicaoside K Prosapogenin 1a Prosapogenin 1b Gleditsioside H Gleditsioside I Gleditsioside J Gleditsioside K Saponin C′ Saponin E′

G. japonica G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. caspica G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis

Konoshima (1995) Zhang et al. (1999a) Zhang et al. (1999a) Zhang et al. (1999a) Zhang et al. (1999a) Zhang et al. (1999a) Zhang et al. (1999b) Zhang et al. (1999b) Zhang et al. (1999b) Zhang et al. (1999c) Zhang et al. (1999c) Zhang et al. (1999c) Zhang et al. (1999c) Zhang et al. (1999b) Miyase et al. (2010) Miyase et al. (2010) Miyase et al. (2010) Miyase et al. (2010) Melek et al. (2014) Melek et al. (2014) Melek et al. (2014) Melek et al. (2014) Melek et al. (2014) Melek et al. (2014) Melek et al. (2014) Zhang et al. (1999c) Zhang et al. (1999c) Zhang et al. (1999d) Zhang et al. (1999d) Zhang et al. (1999d) Zhang et al. (1999d) Zhang et al. (1999d) Zhang et al. (1999d)

Triterpene

Sterol

Flavonoid

Phenolic

33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Alkaloid

61 62 63 64 65 66 67

G. sinensis

Li et al. (2007)

G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. sinensis G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. triacanthos G. sinensis

Li et al. (2007) Zhang et al. (1999c) Zhang et al. (1999c) Lim et al. (2005) Li et al. (2007) Li et al. (2007) Li et al. (2007) Li et al. (2007) Lim et al. (2005) Lim et al. (2005) Lim et al. (2005) Lim et al. (2005) Zhou et al. (2007a) Zhou et al. (2007a) Zhou et al. (2007a) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Mohammed et al. (2014) Moon and Zee. (2010a)

G. sinensis

Zhou et al. (2007b)

(-)-epicatechin Caffeic acid Triacanthine

G. sinensis G. sinensis G. sinensis G. horrida

Saikachinoside A Locustoside A Cytochalasin H

G. japonica G. japonica G. sinensis

Zhou et al. (2007b) Zhou et al. (2007a) Zhou et al. (2007a) Morimoto and Oshio (1965) Kajimoto et al. (2010) Kajimoto et al. (2010) Lee et al. (2014)

2β-carboxyl,3β-hydroxyl-norlupA (1)-20 (29)-en-28-oic acid Zizyberanalic acid Echinocystic acid 1d (EA) Echinocystic acid 2d D:C-friedours-7-en-3-one Betulic acid Alphitolic acid 3-O-trans-p-coumaroyl alphitolic acid 2-hydroxypyracrenic acid Stigmast-4-ene-3,6-dione Stigmast-3,6-dione Stigmasterol β-sitosterol Dihydrokaempferol Quercetin 3,3′,5′,5,7-pentahydroflavanone Apigenin Luteolin Vicenin-I Vitexin Isovitexin Orientin Isoorientin Iuteolin-7-O-β-glucopyranoside Iuteolin-7-O-β-galactopyranoside Apigenin-7-O-β-glucopyranoside 3-O-methylellagic acid-4′-(5′′-acetyl)-α-L-arabinofuranoside 3-O-methylellagic acid-4′-O-α-L-rhamnopyranoside Ethyl gallate

Table3 Anti-tumor effects of this genus Pharmacological detail

Compounds/extracts

Concentration

Reference

Antiproliferative activity against the

The extract of G. sinensis

MTS50 (ranging from 16

Chow et al. (2002)

four solid tumor cell lines (MCF-7, MDA-MB231, HepG2 and SLMT-1 cell lines); inducing apoptosis in time course- and dose-dependent

to 20 μg/mL)

The growth inhibitory activity against K562 CML and HL-60 AML cell lines

The extract of G. sinensis

The growth inhibition involving in both bFGF and NO regulations

The extract of G. sinensis

Chui et al. (2004)

The GSE-induced apoptosis being via ROS pathway to result in an early decrease of intracellular superoxide anion

The extract of G. sinensis

Teo et al. (2004)

Activation of the signaling pathway of caspase 3 involving in the mechanistic action of GSE inducing apoptosis

The extract of G. sinensis

Chui et al. (2005)

Cytotoxicity on Bel-7402, BGC-823, HeLa, HL-60, KB and MCF-7 cell lines; blocking the G2/M phase of HL-60 cells incurring an prominent accumulation of the sub-G1 peak, and finally causing early apoptosis in HL-60 cells

Compound 2

IC50: 3.1 ± 2.8, 8.0 ± 1.2, 5.0 ± 3.4, 3.0 ± 1.3, 34.3 ± 1.5, 6.6 ± 2.3 μM

Zhong et al. (2003)

The inhibitory actions on the ESCC cell line; exertion of the antitumor activity by modulation of the oncogenic expression and telomerase activity

The extract of G. sinensis

MTS50 = 21 μg/mL

Tang et al. (2007)

Incurring apoptosis by modulating the cytoplasmic DNA-histone complex; the inhibition of cell growth induced by EEGS related to activate ERK via p27-mediated G2/M-phase cell cycle

The ethanol extract of G. sinensis thorns

arrest; inhibiting TNF-a-induced MMP-9 expression by suppressing NF-κB and AP-1 binding activities; inhibiting the growth of HCT116 cells by changing levels of ERK, MMP-9

MTS50 (18 ± 1.6, 12 ± Chow 1.3 μg/mL) (2003b)

et

Lee et al. (2009)

al.

and p27 expression Antitumor effect against HCT116 cells

The water extract of G. sinensis thorns

A appropriate decrease in cell growth and a dramatically increase in the G2/M-phase arrest related to the increasing p53 levels and down-regulation of the check-point proteins, including cyclin B1, Cdc 2 and Cdc25c; inducing phosphorylation of ERK, p38 MAP kinase and JNK; inhibiting the cell-growth in nude mice without any negative side effects including the loss of body weight

The water extract of G. sinensis thorns

Cytotoxicity against HepG2, A549 and HT29 cells

Compounds 14-17

HepG2 (IC50 4.5, 2.5, 2.2, 5.4 μM ); A549 (IC50 30.0, 6.5, 3.7,16.3 μM); HT29 (IC50 23.0, 3.9, 1.5, 11.3 μM)

Miyase (2010)

The antiproliferative effect against human SNU-5 gastric cancer cells; the inhibitory growth of SNU-5 gastric cancer cells related to p38 MAP kinase pathways activated through p21WAF1-mediated G1 phase cell cycle arrest; the decrease in the cyclin and CDK complexes associated with p21WAF1 expression in SUN-5 cells; the inhibition of the binding activities of NF-κB and AP-1 cis-elements in TNF-α-treated cells, and incurring the significant suppression of MMP-9 expression

The ethanol extract of G. sinensis thorns The ethanol extract of G. sinensis thorns

IC50 = 400 μg/mL

Lee et al. (2013)

The cytotoxicity on liver, cervix, larynx and colon cancer cell lines

The ethanol extract of G. triacanthos leaves

IC50: 1.68, 0.74, 1.28 and 0.67 μg/mL

Mohammed et al. (2014)

Treating solid tumour and leukaemia by inhibiting angiogenic

The extract of G. sinensis

IC50 = 800 μg/mL

Lee et al. (2010)

Lee et al. (2010)

Chow (2003a)

et

et

al.

al.

The effects of EEGS on angiogenesis towards primary endothelial cells

The ethanol extract of G. sinensis thorns

Suppressing cell growth and mobility in HUVEC partly by decreasing expression of pro-angiogenic factor, such as endothelin-1; inhibiting the pro-angiogenic protein-induced formation of new blood vessels in vivo;

Compound 67

Lee et al. (2014)

Inhibiting the tumor growth in an in ovo xenograft model without significant toxicity

The ethanol extract of G. thorns and sinensis compound 67

Lee et al. (2015)

Suppressing the proliferation, migration, and tube formation of HUVECs induced by bFGF; inducing cell apoptosis by increasing the expressions of apoptosis regulatory proteins: caspase-3, caspase-8 and Fas except for caspase-9 in HUVECs

The saponin fraction isolated from the fruits (SFGS) of G. sinensis

The concentrations of 1, 3 and 10 μg/mL

Lu et al. (2014)

Inhibiting the tube formation

Compounds 7, 13, 10, 28 and 29

The concentration of 3 μΜ.

Lu et al. (2014)

The proliferation of HUVEC primary cells in vitro (the IC50 values of ≥50 μg/mL); The vessel formation in vivo (the IC50 values of ≥50 μg/mL)

Yi et al. (2012)

Table4 Various effects of Gleditsia species Pharmacological effects

Detail

Compounds/extracts

Reference

Anti-inflammatory effect

NO release and inducible iNOS expression in LPS-induced RAW 264.7 macrophages causing inflammation; mediating anti-inflammatory effects by the suppression of the activation of NF-κB, the

The aqueous extract of G. sinensis thorns

Ha et al. (2008)

The fruit hull of G. sinensis

Choi et al. (2012)

degradation of IκB-a, and the phosphorylation of ERK1/2 and JNK Enhancing the activation and expression of the anti-inflammatory Nrf2-regulated genes including GCLC, NQO-1, and HO-1 without affecting NF-κB

activity.

Anti-hyperlipidemic effect

Antiallergic effect

Antibacterial effect

Analgesic effect

Suppressing the LPS-induced lung inflammation in ALI mouse model, at least partly by the mediation of Nrf2 activation.

The fruit hull of G. sinensis

Kim et al. (2014)

A appropriate inhibitory effect on acute inflammation being mediated by weakening the inflammatory effects of mediators such as serotonin.

The 70% ethanol extract from the anomalous fruits of G. sinensis

Dai et al. (2002)

Inhibiting the aortic atherosclerosis of formation and enhancing aortic remodeling without the significant muscle and liver toxicity.

The G. sinensis fruit aqueous extract

Lai et al. (2011)

Attenuating the harmful effects of oxLDL on EPCs via up-regulating the expression of eNOS protein as well as the repression of Akt/eNOS phosphorylation

Compound 35 (EA)

Lai and Liu (2014)

The inhibition of systemic anaphylaxis (0.005 to 1 g/kg); The significant inhibition of local anaphylaxis (0.1 and 1 g/kg); The inhibition of the release of histamine from rat peritoneal mast cells ((0.001 to 1 g/kg)

The aqueous extract of G. sinensis thorns

Shin and Kim (2000)

Mediating the antiallergic activity by suppressing the release of some mediators such as histamine from mast cells

The ethanol extract from G. sinensis

Dai et al. (2000)

The inhibitory effect on experimental allergic rhinitis, probably by inhibiting both the release of histamine from mast cells and the increase of nasal vascular permeability

The n-butanol fraction from the anomalous fruits of G. sinensis

Fu et al. (2000)

Against Bacillus subtilis (MIC 0.5, 0.5, 0.125 mg/mL) and Xanthomonas vesicatoria (MIC 0.75, 0.75, 0.125 mg/mL)

The ethanol crude extract of the G. sinensis spines

Zhou et al. (2007a)

Against Magnaporthe grisea (IC50 13.56 and 16.14 μg/mL)

Compounds 59 and 60

Zhou et al. (2007b)

Exhibiting both peripheral and central analgesic activities (the ED50 values of 268.2 and 161.2 mg/kg in the writhing test,; the ED50 values of 287.6 and 283.4 mg/kg for phase I, and 295.1 and 290.4 mg/kg

The G. triacanthos methanolic fruit extract (MEGT) and its saponin-containing fraction (SFGT)

Saleh et al. (2015)

for phase II; the ED50 values 155.4 and 200.6 mg/kg in the hotplate test) Causing the 51.2% and 64.2% decrease of the mutagens MNNG and NQO, respectively

Compound 44

Lim et al. (2005)

Causing the 59% and 41% reduction of chromosomal aberrations for bone marrow, and 48% and 43% for germ cells before or after administration of cyclophosphamide

The saponin fraction from the G. caspica methanolic fruit extract

Farouk et al. (2015)

The significant anti-HIV activity with the EC50 value of 1.1 μM

Compound 1

Konoshima (1995)

The significant anti-HIV activity (EC50 < 0.064 μg/Ml)

Compound 33

Li et al. (2007)

Antioxidant activity

Scavenging DPPH (91.8%)

Compound 58

Mohammed et al. (2014)

Effects on acute myocardial ischemia

Reducing myocardial ischemia by the decrease in apoptotic cell death in myocardial tissue

Compound 35 (EA)

Wu et al. (2010)

Antimutagenic effect

Anti-HIV effect

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