Introduction

Several plant genera are known for their impact on traditional and modern medicine. One of these is the Ziziphus genus, which belongs to the Rhamnaceae family (Ji et al. 2017). The genus Ziziphus includes several species of subtropical and tropical origins and are mostly economically valuable. The genus encompasses sweet edible fruits that serve as nectars producing honey with premium quality, exemplified as Sidr honey (Maaiden et al. 2020). The most well-known species are Ziziphus jujuba Mill, Ziziphus xylopyrus (Retz.) Willd, and Ziziphus spina-christi (Mill.) Georgi, which originate from Southwest Asia, Ziziphus lotus subsp. saharae Maire, which belongs to the Mediterranean region, Ziziphus glabrata B. Heyne ex Roth, and Ziziphus nummularia var. saharae (Maire) A. Chevfound in India and western Africa, Ziziphus joazeiro Mart grows in Brazil (Caatinga), whereas Ziziphus celata Judd & D.W. Hall is listed as a scarce type in many of the United States’ forests (Mroczek 2015; Ahmad et al. 2017).

The genus is especially prevalent in subtropical and warm-temperate regions worldwide, with diverse species exhibiting different shapes, i.e., spiky flowers or tiny leaves, usually armed with stipular spikes (Maaiden et al. 2020; Wojdyło et al. 2016). The leaves of most of the genus species have three prominent basal veins that are characteristic of the genus. Ziziphus leaves are also highly aromatic and are used in many applications. Besides, flowers are mostly tiny, inconspicuously shaped, and colored yellow to green (Stoli and Stanica 2021; Ahmad et al. 2017). The fruit is edible, very sweet, and is considered a high source of energy as it contains large amounts of sugars. The fruit, which can range in color from yellowish brown to red or black, is cultivated and eaten in fresh and dried forms. The fruits’ pulp is also added as a base in diverse meals asides from manufacturing of candies (Stoli and Stanica 2021).

Certain species among genus Ziziphus have been traditionally used for several decades for medicinal uses, especially for the treatment of diverse ailments such as common colds, skin infections (e.g., eczema), diabetes, etc. (Ji et al. 2017). It was also reported that most of the genus’ species possess antioxidant, anti-inflammatory and antiviral activities (Ouelbani et al. 2016; Maaiden et al. 2020). Modern phytochemical investigations have revealed that genus Ziziphus fruits, seeds, leaves, barks, and roots encompass 431 phytochemicals belonging to flavonoids, saponins, triterpenes, alkaloids, etc. (Maaiden et al. 2020). Such rich complex composition imparts vast biological functions, e.g., antioxidant, anti-inflammatory, antibacterial, antipyretic, antidiabetic, antidiarrheal, anticancer, antinociceptive activities, etc. (Ji et al. 2017).

Terpenoids are found ubiquitously among the plants of the genus Ziziphus. Until now, ca. 43 triterpenes have been extracted from fruits, flowers, leaves, and seeds of Z. celata, Z. spina Christi, Z. mauritiana, Z. jujuba, Z. lotus, etc., of which several triterpenes exhibit promising biological activities (Ríos et al. 2000; Ahmad et al. 2017). In addition, saponins as sugar conjugates of triterpenes are widely distributed throughout the genus Ziziphus. These phytochemicals are often associated with defensive functions in most plants’ species. Saponins exert several functional properties (e.g., emulsification, solubilization, foaming, sweetness, bitterness) and biological (e.g., antimicrobial, antioxidant, molluscicide, haemolytic, insecticide) of potential to be exploited in diverse applications, e.g., food, cosmetics and pharmaceutical industries, as well as in soil bioremediation (Ji et al. 2017). Approximately 31 saponins were reported in the roots, leaves, fruits, and seeds of Z. mauritiana, Z. joazeiro, Z. jujuba, Z. spina christi, etc. (Bozicevic et al. 2017; Dubey et al. 2019).

Given the importance of naturally occurring phytochemicals to human health and the scarcity of review papers reported on the detailed triterpenes and saponins characterization within genus Ziziphus, this study was undertaken. This review summarizes and critically analyses Ziziphus species' pharmacological effects in the context of its triterpenoids and saponins composition for the first time.

Methodology of the literature review

An extensive literature survey from this review was conducted using different search engines and online databases like SciFinder Scopus, PubMed, Google Scholar, Web of Science, and Science Direct. The keywords used were ´´Ziziphus, triterpenes, saponins, antioxidant, antidiabetic activity, anti-inflammatory, and biological activit´´. Prior to 2022, both review articles and original research studies on the topic of the review were included, with more emphasis on reports published within the last 10 years. We did not consider papers with only abstracts, unpublished manuscripts, conference proceedings, and non-English-language publications. The review is structured as follows: initially, the bioactive phytochemicals of Ziziphus in different plant parts (i.e., leaves, fruits, roots, and seeds) are presented, highlighting their triterpenoids and saponins. Then, the biological effects of different Ziziphus species are discussed. These include their antioxidant, antibacterial, antihypertensive, and anti-inflammatory activities.

Ziziphus phytochemistry

Major bioactive phytochemical classes in planta include triterpenes, saponins, alkaloids, phenolics, flavonoids, and polysaccharides. The species of the genus Ziziphus entail 43 terpenoids, 31 saponins, 165 alkaloids, 151 flavonoids, and 40 other miscellaneous compounds (Ahmad et al. 2017; Ji et al. 2017). The current review focuses on the triterpenoids and saponins composition of the genus Ziziphus. Investigated organs for these classes in the Ziziphus genus include its fruit, wood, bark, stem, seed, and leaf as the most usual organs subjected to phytochemical investigations (Maaiden et al. 2020; Mroczek 2015), as clarified in the next subsections for each triterpene subclass.

Lupane-type triterpenoids

Lupanes, a group of pentacyclic triterpenoids found in planta, are reported to exhibit promising pharmacological activities, including anti-inflammatory, antioxidants, anti-HIV, and antitumor activities. Lupanes are very common in the Rhamnaceae family, including Zizyphus. Based on our literature survey, 22 lupane-type triterpenoids (1–22), mainly betulinic, alphitolic acid, and their derivatives, were isolated and identified from the genus Ziziphus (Table 1 and Fig. 1). Betulinic acid (1) is a widely distributed lupane triterpene reported in different species of Ziziphus. It was extracted from stem bark (Kundu et al. 1989), root (Kang et al. 2016), and seed (Wu et al. 2013) of Z. jujube. Betulinic acid (1) was also purified from different crude extracts of other Ziziphus species such as Z. spina-christi aerial part, Z. xylopyrus stem wood (Jagadccs et al. 2000), Z. cambodiana root bark (Suksamrarn et al. 2006), stem bark of Z. joazeiro (Leal et al. 2010) and root of Z. mauritiana (Ji et al. 2012). Betulinic acid (1) exhibits cytotoxic activity with ED50 values of 7.2–15.0 µM against different human cancer cells, including colorectal adenocarcinoma (HT-29), liver carcinoma (HepG2), alveolar basal epithelial (A549), breast adenocarcinoma (MCF-7), the leukemic cells (K562), melanoma cell lines (SK-MEL-2 and LOX-IMVI), prostate cancer (PC-3) and murine melanoma cells B16-F10 (Myung Lee et al. 2003). Several pentacyclic betulinic acid derivatives (Table 1 and Fig. 1) such as 7β-(4-hydroxy-benzoyloxy)-betulinic acid (3), 7β-(4-hydroxy-3’-methoxybenzoyloxy)-betulinic acid (4) and 27-(4-hydroxy-3’-methoxy-benzoyloxy)-betulinic acid (5) were reported from the dichloromethane extract of Z. joazeiro stem bark (Schühly et al. 1999). Compounds 3 and 4 have a benzoyloxy moiety linked to C-7 of betulinic acid, whereas compound 5 encompasses a vanillyl group connected to C-27 of compound 1 and suggested for acyl transferases in Ziziphus involved in their biosynthesis that have yet to be annotated. Acylation of flavonoids with phenolic acids is known to improve their pharmacokinetic and biological effects and is not as explored in triterpenes (Mroczek 2015). Compounds 3–5 revealed an antibacterial effect against a Gram-positive Staphylococcus epidermidis. Other acylated triterpenes with fatty acids were isolated from Z. jujube. For example, 3-O-[9(Z)-octadecenoyl] betulinic acid (9) has a Z-unsaturated fatty acid ester attached to the C-3 of betulinic acid (Su et al. 2002). Betulinaldehyde (6) and betulin (7) were isolated as a reduced derivative of betulinic acid (1) from Z. cambodiana and Z. jujube, respectively (Suksamrarn et al. 2006; Wu et al. 2013). The methyl ester of betulinic acid, methylbetulinate (8) was isolated for the first time from Z. joazeiro stem bark (Leal et al. 2010), identification of reductase enzyme involved in its production has yet to be reported. Betulonic acid (10) and terminic acid (11) were obtained from Z jujuba (Bai et al. 2016; Myung Lee et al. 2003), with terminic acid (11) to exhibit anticancer potency against MCF-7, A549, HepG2 and HT-29 cancer cells (Bai et al. 2016). Alphitolic acid (12) (Table 1 and Fig. 1) is another chief pentacyclic triterpenoid with a lupane skeleton isolated from the genus Ziziphus. This triterpene has been found in both fruit and root of Z. jujube (Guo et al. 2011; bin Kang et al. 2016; Myung Lee et al. 2003), Z. joazeiro bark (Leal et al. 2010; Schühly et al. 2000), and root of Z. cambodiana (Suksamrarn et al. 2006). Several alphitolic acid acylated analogues (13–16) with cis- and trans-p-coumaroyl moieties linked to C-2 and C-3 of alphitolic acid (12) were reported from different parts of Z. jujube and Z. cambodiana (Suksamrarn et al. 2006; Bai et al. 2016; Kang et al. 2016; Myung Lee et al. 2003) as in case of betulinic acid. The two isomers of 3-O-p-coumaroyl alphitolic acids (15 and 16) showed cytotoxic effect against B16-F-10, SK-MEL-2, PC-3, LOX-IMVI and A549 cancer cells (Myung Lee et al. 2003). A series of other esterified derivatives of alphitolic acid (17–22) were also isolated from Z. jujube roots (Kang et al. 2016; Shoei-Sheng, Buh-Fang, and Karin 1996), among which 2-O-p-hydroxybenzoyl alphitolic acid (21) showed potential anticancer activity against the human hepatocellular carcinoma cell line (HepG2) with an IC50 value reported at 2.9 µM.

Table 1 Lupane-type triterpenoids isolated from genus Ziziphus
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Fig. 1
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Lupane-type triterpenoids isolated from genus Ziziphus

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Ceanothane-type triterpenoids

Ceanothane triterpenes were isolated from plants belonging to the genus Ziziphus and suggested to serve as chemotaxonomic markers for this family (Kang et al. 2016; Sakna et al. 2019). To date, 33 ceanothane-type triterpenoids, 23–56, were reported from the genus Ziziphus (Table 2 and Fig. 2). These compounds are regarded as the rearranged derivatives of lupane-type triterpenoids with a five-membered A-ring. Ceanothic acid (23) is one of the most common triterpenoids belonging to this class that was isolated from Z. spina christi (Ikram and Tomlinson 1976), Z. jujuba (Guo et al. 2011; Kang et al. 2016; Kundu et al. 1989), Z. glabrata (Ganapaty et al. 2006), Z. cambodiana (Suksamrarn et al. 2006) and Z. mauritiana (Ji et al. 2012). Likewise, isoceanothic acid (30) as an isomer of ceanothic acid (23) was reported from Z. xylopyrus (Jagadeesh et al. 2000). The most famous esters of ceanothic acid in Ziziphus plants are 3-O-protocatechuoyl ceanothic acid (24) (Kang et al. 2016; Shoei-Sheng et al. 1996), 3-O-vanilloyl ceanothic acid (26) (Suksamrarn et al. 2006), ceanothic acid 28-methyl ester (27) (Fujiwara et al. 2011; Leal et al. 2010) and ceanothic acid 2-methyl ester (28) (Fujiwara et al. 2011). The compound 27 contributed to the antibacterial activity of Z. joazeiro extract against Staphylococcus epidermidis (ATCC 12,228) and S. aureus (ATCC 29,213) with MIC values of 16 μg/mL and 32 μg/mL, respectively (Leal et al. 2010). Several ceanothane-type triterpenes with aldehyde group at C-1 such as zizyberanalic acid (29) (Kundu et al. 1989; Myung Lee et al. 2003; Suksamrarn et al. 2006), its O-methyl derivative (45) (Kang et al. 2016) and zizyberanal acid (31) (Guo et al. 2009) were extracted from Z. jujuba and Z. cambodiana extracts. Zizyberenalic acid (32) that possessed α, β-unsaturated aldehyde was also obtained from the root bark of Z. cambodiana (Suksamrarn et al. 2006), fruit and root of Z. jujuba (Kang et al. 2016; Myung Lee et al. 2003). Ceanothenic acid (33) and nortriterpenes have different A-nor-E-seco spiro-lactone ceanothane-type triterpene, zizimauritic acids A–C (34–36), were extracted from roots of Z. mauritiana. Besides that, compounds 33–36 showed antibacterial activity against Staphylococcus aureus and cytotoxic effect against A549, BGC-823, and Hela cancer cell lines with IC50 values reported to range from 5.05 to 11.94 µg/mL (Ji et al. 2012). Epigouanic acid A (37) with carbinol methylene group at C-1 was reported first time from Z. joazeiro stem bark (Leal et al. 2010). Kang et al. 2016, purified several ceanothane triterpenes (38 − 53) from roots of Z. jujube, of which compounds 50 and 51 showed a unique E-ring γ-lactone structure, whereas 52 was assigned as the first naturally occurring dinorlupane-type triterpenoid derivative in planta (Kang et al. 2016). Other ceanothane-based triterpenoids isolated from same species included ent-epicatechin oceanothic acid A (54), ent-epicatechin oceanothic acid B (55), and epicatechino-3-deoxyceanothetric acid A (56) (Kang et al. 2016). Compounds 54–56 contained unusual C–C bond linkages between ceanothane-type triterpenoids and flavonoid moieties, and likely to exert potential biological effects of both classes, i.e., catechins and triterpenes. Identification of biosynthetic pathways leading to such C–C coupling in a such rare catechin-bound ceanothane-type triterpenoid derivatives in Ziziphus should be followed. Compounds 43, 44, 47 and 52 showed a cytotoxicity against the human hepatocellular carcinoma HepG2 cells (IC50 = 1.9 ~ 4.9 μM), whereas ent-epicatechinoceanothic acid A (53) showed anti-proliferative activity toward hepatic stellate HSC-T6 cells (IC50 = 43.5 μM).

Table 2 Ceanothane-type triterpenoids isolated from genus Ziziphus
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Fig. 2
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Ceanothane-type triterpenoids isolated from genus Ziziphus

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Ursane-type triterpenoids

Ursane triterpenes are phytochemicals that are quite rare in nature compared to oleanane (Mukhtar et al. 2005). Genus Ziziphus was found to encompass ursane triterpenes in most of its species, represented by isozizyphursolic acid, ursolic acid, isozizyphursolic acid pomolic acid, and corosolic acid. Studies in the genus Ziziphus led to the identification of 19 different ursane triterpenes (57–75), as shown in Table 3 and Fig. 3. Ursane-type triterpenoids and in particular ursolic acid (57), pomolic acid (58) and corosolic acid (59) are known compounds of Z. jujuba found at higher levels in roots (Bai et al. 2016; Qiao et al. 2014; Guo et al. 2009; Guo et al. 2011). Schühly et al. also isolated ursolic acid (57) from the stem bark of Brazilian medicinal plant Z. joazeiro (Schühly et al. 2000), which is moderately active against Staphylococcus epidermidis (MIC = 128 µg/ml). In 2005, zizyphursolic acid (60) and isozizyphursolic acid (61) having an extra hydroxy group at C-2 were isolated from Z. vulgaris roots collected from Indian local markets (Mukhtar et al. 2005). A detailed phytochemical study led to the isolation of 12 ursane-type triterpenoids from the fruits of sour jujube (Z. jujuba var. spinosa) (Qiao et al. 2014). The isolated compounds were identified as 3β,13β-dihydroxy-urs-11-en-28-oic acid (62), 2α,3β,13β-trihydroxy-urs-11-en-28-oic acid (63), 2α,3β,13β,23-tetrahydroxy-urs-11-en-28-oic acid (64), 3β,19α-dihydroxyurs-12-en-28-oic acid (65), 2α,3β,-dihydroxy-urs-12-en-28-oic acid (66), 2α,3β,19α-trihydroxy-urs-12-en-28-oic acid (67), 3β-hydroxy-urs-20(30)-en-28-oic acid (68), 2α,3β-dihydroxy-urs-20(30)-en-28-oic acid (69), 2α,3β,28-trihydroxy-urs-20(30)-ene (70), 3β,12β,13β-trihydroxy-ursan-28-oic acid (71), 2α,3β,12β,13β-tetrahydroxy-ursan-28-oic acid (72) and ursonic acid (73). Among isolated ursanes, compounds 67, 69 and 70 showed a strong inhibitory activity towards the proliferation of HepG2 cells (IC50 < 5 μM). The ursane-type triterpenoids 67 and 69 also displayed distinct anticancer activity against breast adenocarcinoma (MCF-7) cells with IC50 values of 0.8 and 031.5 μM, respectively. A rare triterpenoid named as pomonic acid (74) and 2-oxo-pomolic acid (75) were isolated for the first time from Z. jujuba fruit (Guo et al. 2011; Bai et al. 2016).

Table 3 Ursane-type triterpenoids isolated from genus Ziziphus
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Fig. 3
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Ursane-type triterpenoids isolated from genus Ziziphus

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Oleanane-type triterpenoids

Oleanane-type triterpenoids are the largest group within triterpenes to encompass many active compounds, several of which were from the fruits of the genus Ziziphus. As shown in Table 4 and Fig. 4, oleanonic acid (73) (Lee et al. 2003), maslinic acid (74) (Guo et al. 2011), 3-β-O-(E-p-coumaroyl) maslinic acid (75) (Lee et al. 2003; Lee et al. 2004; Bai et al. 2016), 3-β-O-(Z-p-coumaroyl) maslinic acid (76) (1978; Lee et al. 2004; Lee et al. 2003), oleanolic acid (77) (Lee et al. 2003; Lee et al. 2004; Bai et al. 2016) and hydroxyoleanonic acid lactone (78) (Guo et al. 2011) are abundant in fruits of Z. jujuba. The chemical structure of compound 78 showed the presence of lactone moiety in oleanonic acid carbon skeleton. Compounds 75, 76, and 77 showed anti-complement activity with IC50 values of 101.4, 143.9, and 163.4 µM, respectively, with the p-coumaroyl moieties at C-3 in triterpenes 75 and 76 likely to improve its activity compared to that of oleanolic acid (77). Generation of other phenolic acid acyl derivatives, i.e., caffeic and ferulic acid, should identify better analogues with regards to anti complement effect (Table 4 and Fig. 4).

Table 4 Oleanane-type triterpenoids isolated from genus Ziziphus
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Fig. 4
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Oleanane-type triterpenoids isolated from genus Ziziphus

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Dammarane-type triterpenes/saponins

Dammarane is a tetracyclic triterpene that was firstly isolated from and named after dammar resin (Mroczek 2015). These compounds exhibit potential activities, including anti-inflammatory, antidiabetic, antioxidants, antitumor, etc. (Bozicevic et al. 2017). Dammarane sugar conjugates are saponins that are distributed in the Rhamnaceae family, including Ziziphus (Bhandari, et al. 2020; Wang et al. 2020). Based on our literature survey, 59 dammarane-type saponins (79—138) were isolated and identified from the genus Ziziphus (Table 5 and Fig. 5) belonging to jujubogenin, trevoagenin D, protojujubogenin, and siconigenin aglycones with different sugar units linked through O-glycosidic bond to C-3 of the aglycones. The most common sugars include α -L-rhamnopyranosyl, β-D-glucopyranosyl, β -D-xylosepyranosyl, α-L-arabinopyranosyl, α-D-fucopyranosyl, 6-deoxy- α-L-talopyranose and β-D-galactopyranosyl. Jujuboside A (79) and jujuboside B (80) containing jujubogenin as aglycone (Fu et al. 2016; Lee et al. 2005; Yu, Wang, and Hu 2014) were isolated from Z. jujuba seed (Fu et al. 2016) and root bark (Renault et al. 1997), seed (Otsuka et al. 1978) and leaf (Maciuk et al. 2004) of Z. lotus and Z. jujuba. Both saponins exhibit antitumor, anti-lipoxygenase-inhibiting activities and moderate inhibitory effects against pro-inflammatory cytokine TNF-α release in LPS-induced RAW 246.7 macrophages. Christinin A (81) is another jujubogenin saponin isolated from the leaf and stem of Z. vulgaris as well as from Z. spina-christi (L.) willd leaf (Glo et al. 1994; Bozicevic et al. 2017). This class of dammarane-type saponins showed an efficient antidiabetic activity in albino rats. Ziziphus saponin I (82), Ziziphus saponin II (83) and Ziziphus saponin III (84) are three types of dammarane-type saponins isolated from Z. jujuba Mill. Fruits, leaves and seeds (Devkota, Watanabe, and Yahara 2013). Zizynummin (85) (Sharma and Kumar 1983) and ziziphin (89) isolated from Z. nummularia and Z. jujuba leaves showed potential anti-sweat activities (Yoshikawa, Shimono, and Arihara 1991). Likewise, jujubasaponin I (90), jujubasaponin II (91) and jujubasaponin III (92) isolated from Z. jujuba leaf showed anti-sweat activities (Yoshikawa et al. 1991). Jujuboside A1 (98), jujuboside C (99), jujuboside B1 (101), and jujuboside I (106) all isolated from Z. jujuba seeds (Wang et al. 2013) showed promising effects on the neonatal rat cardiomyocyte injury induced by hydrogen peroxide in vitro. Jujuboside D (108) isolated from Z. jujuba Mill. seeds showed lipoxygenase-inhibiting activity (Yu et al. 2014); besides that, jujuboside F (110) was found in Z. jujuba Mill. seeds and revealed a moderate inhibitory effect against pro-inflammatory cytokine TNF-a release in LPS-induced RAW 246.7 macrophages (Fu et al. 2016). 22α-Acetoxy christinin A (114), christinin A1 (115) and christinin A2 (116) were isolated from Z. spina-christi (L.) Desf. leaves (Bozicevic et al. 2017). Compounds 114 and 115 contain acetyl group linked to the aglycon and sugar moiety, respectively. (20R,22R)-16β,22:16α,30-Diepoxydammar-24-ene-3β,20-diol is another saponin isolated from the genus Ziziphus, which entailed jujubasaponin IV (117), from Z. jujuba Mill. leaves, jujubasaponin V (118) from Z. jujuba Mill. seeds, sulfated derivative of jujubasaponin IV (119) from Z. lotus. leaves (Maciuk et al. 2004). Jujubasaponin VI (122) which is the glycosylated derivative of the aglycon trevoagenin D [16α,18:16β,22R:20R,24R-triepoxydammarane-3β,25-diol] was extracted from Z. jujuba Mill. leaves and it showed anti-sweat properties (Yoshikawa, Shimono and Arihara, 1992). This compound was considered the first glycosylated trevoagenin D derivative in nature. Lotogenin [(20R,22R)-16,22-epoxydammar-24-ene-3β,15α,16α,20–tetrol] with two hydroxyl groups at C-15 and C-16 represented another type of dammarane-type saponin extracted from various Ziziphus species. Several lotogenin glycosides such as lotosides I (123) and II (124) were reported in Z. lotus (L.) root bark (Renault et al. 1997), as well as lotoside A (125) which was extracted from Z. joazeiro Mart. stem barks (Schühly et al., 2000). Some of these dammarane-type saponins showed biological activities, including possessing sweetness inhibition. Protojujubogenin (3β,20S,23R,30-tetrahydroxydammar-24-en-16-one) was found in Ziziphus genus. It included protojujubosides A (128), B (129) and B1 (130); all of which were isolated from Z. jujuba var. spinosa seeds and revealed potent immunological adjuvant activities (Matsuda et al. 1999). Pseudo-jujubogenin-3-O-β-eudo-jujubogenind (133) was isolated from Z. glabrata Heyne leaves and to possess significant anti bactericidal activities (Ganapaty et al. 2006). Mabioside D (134) with the aglycone (17ξ,20R,22R)16,22-epoxydammar-24-ene-3β,15α,16α,20 –tetrol was separated from Z. incurva aerial parts (Devkota et al. 2013). Jujuboside II (135) with (20R,23S)-16β,23:16α,30-diepoxydammar-24-ene-3β,20-diol linked to α-L-rhamnose, β-D-xylose, β-D- glucose, and α-L-arabinose was also isolated Z. jujuba var. spinosa seeds and showed protective effects on neonatal rat cardiomyocyte injury (Wang et al. 2013).

Table 5 Dammarane-type saponins isolated from genus Ziziphus
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Fig. 5
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Dammarane-type saponins isolated from genus Ziziphus

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Ziziphus pharmacological reports related to triterpenes/saponins composition

Previous studies have indicated for several medicinal uses of most species within the genus Ziziphus either as extracts or chemical ingredients using in vitro and in vivo bioassays (Mahajan et al. 2022). The genus Ziziphus has been well characterized for its antibacterial, antioxidant, antiplasmodial, anti-inflammatory, hepatoprotective, antidiabetic, antidiarrheal, antifungal, and antinociceptive activities (Borgi et al. 2008). The main biological activities are presented in more details in the following subsections and summarized in Table 6 and Fig. 6. The main phytochemicals that are abundantly present in the genus and to account for its biological activities are terpenoids (Maaiden et al. 2020; Mroczek 2015). Notably, the triterpenes isolated from the genus Ziziphus have a wide range of biological activities, including antimicrobial, antioxidant, cytotoxic, anti-inflammatory, etc. (Ríos et al. 2000). Additionally, saponins, sugar conjugates of triterpenes, are widely distributed throughout Ziziphus; and to account for its antimicrobial, hemolytic, antidiabetic, antiasthmatic, anti-inflammatory activities. In this part of the review, we shall focus on the major pharmacological effects of triterpenes, i.e., antioxidant, cytotoxic, antidiabetic and anti-inflammatory.

Table 6 Reported biological activities in genus Ziziphus in relation to its triterpene and saponin content
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Fig. 6
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Main Biological activities of triterpenes and saponins isolated from the genus Ziziphus

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Antioxidant activity

Damage to the ordinary antioxidant structure can lead tothe production of reactive oxygen species’ accumulations in human bodies, leading to diverse diseases, including neurodegeneration, diabetes, and cancer. Antioxidants can either deactivate or renovate the damage caused by harmful reactive oxygen species (Abdullah et al. 2021). Most of the genus Ziziphus’s plants have been reported to be potential antioxidants attributed to their polyphenolics, saponins, and triterpenoids, which are known to exhibit antioxidant activity (Sakna et al. 2019). Modern studies have confirmed that triterpenes and triterpenic acids, isolated from Ziziphus exert biological functions, the most important of which is antioxidant activity (Song et al. 2020). In one study, triterpenoids isolated from Z. jujube fruit, including maslinic acid, ursolic acid, oleanolic acid, betulinic acid, and alphitolic acid, as major forms. A positive correlation was revealed between major triterpenic acids and genus’s antioxidant activity, suggesting that Z. jujube is a possible source of triterpenic acids as natural antioxidants. FRAP values were reported at 0.35, 0.94 mM/100gm for betulinic acid, alphitolic acid, respectively (Song et al. 2020). Z. oxyphylla has been traditionally consumed in Pakistan folk medicine as anti-inflammatory and analgesic agent in addition for curing chronic liver ailments, e.g., hepatitis. The antioxidant activity of pentacyclic triterpenes isolated from Z. oxyphylla Edgew was determined using DPPH and H2O2 scavenging assays. The results demonstrated a potential antioxidant activity of triterpenes isolated from Z. oxyphylla roots with a DPPH scavenging activity reported at 52.8% for 100 mg/ml (Abdullah et al. 2021). Another study investigated the antioxidant potential of fruits from different Ziziphus species using ABTS, DPPH and FRAP antioxidant assays. The in vitro assays showed that among all studied Ziziphus fruits, Z. spina-christi showed the strongest antioxidant action attributed to its highest triterpenoid levels (Sakna et al. 2019). Kou et al., (2015) evaluated the antioxidant activity of 15 Z. jujube cultivars late in their maturation stages (i.e., red stage) using in vitro DPPH, FRAP, and ABTS antioxidant assays in relation to their metabolic composition. Results revealed variations in the bioactive compounds and antioxidant capacities among Z. jujube species. Additionally, the correlation analysis showed that ascorbic acid and polyphenols but not triterpenes, accounted more for the antioxidant activity (Kou et al. 2015). Despite these efforts, much more research is needed to investigate the effect of pentacyclic triterpenes from various Ziziphus species on cell signalling pathways that activate antioxidant enzymes such as SOD or catalase, as there have been few reports on triterpenes (Simian et al. 2011).

The antioxidant capacity of Z. mauritiana leaf saponin was also evaluated using a reducing power assay, with IC50 at 82.12 µg/ml though higher than that of ascorbic acid (Dubey et al. 2019). A study investigated the in vitro antioxidant assays of saponins from two Ziziphus species namely, Z. mauritiana and Z. spinachristi using DPPH, hydroxyl radical, superoxide radical and lipid peroxidation assays. Results of the DPPH inhibition were reported at 68.2 and 80.2% per 300 ug of extract for Z. mauritiana and Z. spinachristi, respectively. The elevated DPPH radical scavenging of both ethanolic leaf extracts was due to saponins rich content (Oadeyemo 2011).

Several studies investigated the antioxidant capacity of decoction and hydroethanolic extract of Z. mistol fruits in correlation to their phytochemical content. The ethanolic extract was found to be more active as an electron donor than decoction; the decoction was more effective as a superoxide and hydroxyl scavenger than ethanolic extract. Polyphenols and not saponins though that revealed a dose–response relationship (R2 > 0.90) with an antioxidant potency in alcoholic beverage and the decoction as well (Cardozo et al. 2011).

Antidiabetic activity

Diabetes is a widespread disease among all age groups characterized by either deficiency in insulin or malfunction of insulin activity, and clinically by hyperglycemia or impaired glucose tolerance. Hyperglycemia occurs due to a lack of insulin secretion or even due to the resistance of the human body cells to the normal action of insulin. All metabolic disorders cause an acute or long-term diabetic illness (Dubey et al. 2019). Recent studies have indicated that some plant extracts possess a strong antidiabetic effect; these can be employed for diabetic conditions to decrease blood glucose levels. The literature revealed that several saponins and terpenoids isolated from the genus Ziziphus could be used to cure or alleviate diabetes, i.e., betulic /ceanothic acids (Niamat et al. 2012).

Saponin isolates from Z. Mauritiana leaf were tested for their antidiabetic action using amylase enzyme assay. Saponin extract showed significant α-amylase enzyme inhibition and has yet to identify exact saponins mediating such effect of potential as antidiabetic agent (Dubey et al. 2019). The effect of Z. spina-christi extract form the leaves and its major saponin christinin-A, glycoside on in vivo serum glucose/insulin levels was experimented in non-diabetic control, type-I (insulin-dependent) as well as type-II (non-insulin-dependent) rats with diabetic conditions. The results demonstrated that butanol extract of Z. spina-christi leaf and its chief saponin glycoside (i.e., christinin-A) showed similar effects in reducing glucose concurrent with increased insulin levels of non-diabetic control and streptozocin-induced diabetic rats. In addition, the insulinotropic and enhanced glucose-lowering effects of glibenclamide counteracted the hypoinsulinemic and hyperglycemic effects of diazoxide.

Further, the vasodilatation effect of diazoxide was inhibited entirely by a combination of glibenclamide and christinin-A posing Z. spina-christi leaf as potential substitute for lowering blood glucose attributed to its sulfonylurea-like potency (Abdel-Zaher et al. 2005). In addition, the antidiabetic potential of saponins extracted from Z. nummlaria and Z. Mauritiana leaves was likewise assayed using alpha amylase enzyme showing significant enzyme inhibition with IC50 values reported at 114.16 and 137.87 µg/ml, respectively. In the future, saponin extracts should be subjected to further isolation of active agents with the determination of its molecular mechanism or cellular target to be more conclusive (Imran et al. 2016). An investigation targeted to assess the antidiabetic activity of Z. spina-christi leaf butanol extract rich in saponins, namely christinin-A, B, C, D. Oral administration of Z. spina-christi leaf extracts enhanced both glucose utilization and controlled hyperglycemia in streptozocin induced diabetic rats likely mediated via rich saponin and polyphenolic contents in Z. spina-christi leaves. Furthermore, in vitro investigation of the extract against α-amylase enzyme showed a dose-dependent activity likewise with an IC50 of 300 µg/mL, further proving the genus to be a good antidiabetic source (Michel et al. 2011).

Glombitza et al. (1994) investigated the influence Z. spina-christi (leaf) butanol isolates and its major saponin glycoside (christinin-A) in streptozocin and normal rats with diabetic conditions. Conversely, minimal changes were recorded in normal rats, suggesting its safety in normal individuals (Glo et al. 1994). Kim (2011) observed that oral administration of Z. jujuba seed aqueous extract for 4 weeks improved blood glucose level and serum lipid profile in hyperlipidemic rats. Hussein et al. (2006) assessed the effect of Z. spina-christi and Z. jujuba root methanol extract oral administration on alloxan diabetic rats, with both extracts effective in reducing hyperglycemia, hyperlipidemia, and lipid peroxidation presenting an added value.

Anti-inflammatory activity

Inflammation is a defense reaction of the human body to eliminate the spread of an injurious agent and is characterized by leukocyte infiltration, edema formation, granuloma formation, etc. It is primarily triggered by the release of some pro-inflammatory mediators, e.g., nitric oxide induction of inducible nitric oxide synthase leading to acute or chronic inflammatory pathological diseases (Rotelli et al. 2003). Studies have investigated the anti-inflammatory potencies of pentacyclic triterpenes extracted from Z. oxyphylla to mediate for the genus’s anti-inflammatory potency. Ceanothic acid and zizybrenalic acid exerted an anti-inflammatory effect as observed from a decrease in paw volume in vivo. At 50 mg/kg, the observed anti-inflammatory effect was 51.33%. Similarly, zizybrenalic acid exhibited higher inhibition of xylene induced ear edema of 58.6% at 50 mg/kg (Abdullah et al. 2021). Yu et al., (2012) investigated the anti-inflammatory activity of Z. jujuba alcoholic extracts against inflammation induced by Euphorbiaceae plants. The obtained results revealed that triterpene acids enriched fraction was the most active with pronounced inhibitory action on activated inflammatory cells proven by their interference on TNF-alpha production reported at 126.2 pg/ml (Yu et al. 2012). Additionally, extracts from Z. jujube have long been consumed as an antidote agent in belated Chinese formula (Shi Zao) decoction, primarily to alleviate inflammatory irritant nature of Euphorbia species. An in vivo anti-inflammatory capacity of Z. jujube extracts was assessed with triterpene acid fraction found as the most active ingredient in inhibiting effects on the inflamed cells (Li et al. 2017). Additionally, structurally diverse triterpenes were extracted from the fruits of Z. jujuba Mill and assayed for inflammatory effects targeting NF-κB signaling pathway. Although all triterpenes showed anti-inflammatory activities, oleanane and ursane type triterpenes showed more significant nitric oxide inhibitory activities than betulinic acid-type and pomolic acid-type triterpenes (Ruan et al. 2021). Alhakmani et al. (2014) investigated the anti-inflammatory potential of Z. spina-christi seed and fruit extracts via the protein denaturation method showing significant anti-inflammatory activities compared with a standard diclofenac drug. The protein denaturation was reported at 118.07% for the seed extract and 98.98% for the fruit extract versus 120% for diclofenac (Alhakmani et al. 2014). The ethanolic extract of Z. spina-christi bark inhibited COX-2-induced prostaglandin production by 58–97%, whereas COX-1-induced prostaglandin production was not inhibited at all (Eldeen and Staden 2008).

The effect of flavonoids and saponins from the roots and leaves of Z. lotus was examined on carrageenan-induced paw edema in rats and acetic acid-induced algesia in rats. Two methanolic extracts (1 mg/ear) were experimented on an oxazolone-induced contact-delayed hypersensitivity in rats and also in vitro on nitrites production (RAW 264.7 macrophages). Both saponin and flavonoid enriched extracts considerably decreased the algesia, paw edema, and nitrite production. Moreover, methanol extracts of the leaves and roots of Z. lotus were found to considerably constrain the hypersensitivity stimulated by oxazolone, with the root extract found to be more active than that of the leaf (Borgi et al. 2008). Whether such an effect is due to saponins being more enriched in roots than in leaves has yet to be determined using chemical assays and identification of bioactive saponins. In contrast, anti-inflammatory effect of Z. mauritiana methanol leaf extract was investigated in carrageenan-induced paw edema rat models. The leaves’ extract showed 71.8% reduction in inflammation at a concentration of 400 mg/kg body weight of rats suggesting that it can be used as a source of functional ingredients in pharmaceutical drug industries to treat inflammation (Abdallah et al. 2016). Several bioactive phytochemicals were identified in Z. mauritiana extracts, including terpenoids, saponins, tannins, and phenolics likely to account for its efficacy.

Miscellaneous activities

The different parts of the genus Zizyphus have been used to treat or alleviate diverse ailments due to many other biological activities, e.g., anticancer, cytotoxic, antibacterial, antidiarrheal, antiviral activities, etc. A study was undertaken to examine the potential anticancer activities in vivo and in vitro of triterpenes isolated from genus Z. nummularia root bark against carcinoma cell lines. An in vivo test in female Swiss albino rats against an Ehrlich ascites carcinoma has been experimented as well. Both in vivo and in vitro tests proved that Z. nummularia root extract is rich in triterpenes and can be used as an effective anticancer agent (Dey Ray and Dewanjee 2015). Furthermore, the cytotoxic activity of triterpenoids isolated from Z. jujuba fruit was evaluated for 11 triterpenoic acids, namely betulinic acid, 3-O-Z-p-coumaroylalphitolic acid, oleanonic acid, colubrinic acid, alphitolic acid, oleanolic acid, betulonic acid, 3-O-Z-p-coumaroylmaslinic acid, 3-O-E-p-coumaroylmaslinic acid, 3-O-E-p-coumaroylalphitolic acid, and zizyberenalic acid. An in vitro cytotoxicity of triterpenoic acids was assessed against tumor cell lines (i.e., K562, B16(F-10), SK-MEL-2, PC-3, LOX-IMVI, and A549) with lupane-type triterpenes showing the highest cytotoxic effect (ED50 reaching up to 15.01 uM). Cytotoxic potency of 3-O-p-coumaroylalphitolic acids were better than non-acylated triterpenoids proving that p-coumaroyl moiety at C-3 position of lupane-type triterpene may play a significant role in boosting cytotoxic activity. The results suggested that lupane-type triterpene extracted from genus Z. jujuba can be used as an efficient cytotoxic agent or synergize with another classical chemotherapeutic to lower its therapeutic dose (Myung Lee et al. 2003). The anti-asthmatic potential of Z. jujuba extract was also investigated to understand its potential in healing asthma and related diseases (Ninave and Patil 2019).

Conclusions

Previous literature highlighted for genus Ziziphus potential medicinal purposes due to its diverse phytochemicals. The genus different species are found in several locations of the world to encompass Z. mistol, Z. vulgaris, Z. jujuba, Z. xylopyrus, Z. spina-christi, Z. lotus, Z. mauritiana, Z. celata, etc. The genus Ziziphus has been used for long to treat diverse ailments, e.g., diarrhea, hypertension, diabetes, fever, and skin diseases. Diverse phytochemicals have been extracted and identified proving for the broad therapeutic uses of extracts from different organs of the genus Ziziphus. The genus Ziziphus extracts own cytotoxic, anti-inflammatory, antioxidant, antipyretic antimicrobial, anticancer, antidiabetic, antiasthmatic activities, etc. Terpenoids and saponins are ubiquitous in the genus Ziziphus and were thus the focus of this review. Both phytochemicals exerted antioxidant, antidiabetic, antimicrobial, antihypertensive, anti-inflammatory, anticancer, anti-inflammatory effects. This review recapitulated the chemical composition of the genus Ziziphus and utilization of its bioactive compounds as therapeutic agents. In conclusion, Ziziphus species present a valuable medicinal resource mostly based on cell-based assays warranting more in vivo assays and clinical studies to elucidate the relation between the modern uses and the traditional applications of the species. Determination of structural motifs critical for triterpenes/saponins biological effects should be considered especially aided through in silico structure–activity relationship (SAR) models using machine learning tools, i.e., single-target-oriented SAR methodologies and chemogenomics. There are also no reports focusing on the Ziziphus toxicity, warranting for more evaluation of toxicity associated with the species to be considered in nutraceuticals. Inclusions of triterpenoid saponins in pharmaceutical formulations as valuable phytochemicals are recommended as a promising source of new drugs, especially for health effects well reported for these triterpenes such as anticancer, antiulcer, anti-inflammatory, and anti-diabetic.