Potential Benefits of Jujube (Zizyphus Lotus L.) Bioactive Compounds for Nutrition and Health

Zizyphus lotus, belonging to the Rhamnaceae family, is a deciduous shrub which generally grows in arid and semiarid regions of the globe. In traditional medicine, Z. lotus is used as antidiabetes, sedative, bronchitis, and antidiarrhea by local populations. Recently, several scientific reports for health benefit and nutritional potential of bioactive compounds from this jujube have been reported. This plant is rich in polyphenols, cyclopeptide alkaloids, dammarane saponins, vitamins, minerals, amino acids, and polyunsaturated fatty acids. These identified compounds were supposed to be responsible for most of Z. lotus biologically relevant activities including antimicrobial, anti-inflammatory, hypoglycemic, antioxidant, and immunomodulatory effects. The aim of the present review was to give particular emphasis on the most recent findings on biological effects of the major groups of Zizyphus lotus components and their medical interest, notably for human nutrition, health benefit, and therapeutic impacts.


Classification of Natural Biomolecules of Z. lotus
As a source of polyphenols, fatty acids, vitamins, and other natural compounds, Z. lotus seems to be a potential candidate for human nutrition, health promoting, and disease preventing. An overview of bioactive compounds for each part of Z. lotus is presented thereafter.
In summary, aerial parts (leaves and fruits) of Z. lotus are the most important source of polyphenols and flavonoids (3630-8144 mg/100 g) [26], while the seeds are rich in fats [19]. These variations in Z. lotus biomolecules content might be due to the environment, soil type, climate, or age of the plant.
Numerous studies reported that all parts of Z. lotus particularly, seeds, pulp, fruits, leaves, almond, root, and stem, were rich in palmitic, stearic, linoleic, and oleic acid [11,13,19,28]. Oleic acid was the most important fatty acid of Z. lotus fruits [13], seeds [11], and almond [19] at 88.12%, 61.93%, and 49.88%, respectively. In vivo studies in rabbit LDL model provided evidence that oleic acid is responsible of the potent antioxidant properties attributed to many edible oils rich in this fatty acid [45]. Moreover, it has been reported that oleic acid upregulated the expression of breast cancer resistance protein and thereby modulates intestinal retention  Figure 1: Common structure of jujubogenins (a), lotogenins (b), and lotusines (c) found in Z. lotus [12,[15][16][17]20].
of several food toxicants [46]. Z. lotus almond also presented moderate level of linoleic acid (22.97%). This fatty acid is the precursor of arachidonic acid, which has inhibitory effect of colon cancer [47]. Other fatty acids were also present in this plant like linolenic acid (9.15%) particularly in Z lotus leaves. Linolenic acid is the precursor of docosahexaenoic acid, known to have potential benefit for health and for other diseases like cardiovascular diseases.

Vitamins Composition of Z. lotus.
The pulp of Z. lotus is rich in vitamin C in amounts up to 190.65 mg/100 g, followed by Z. lotus seeds, leaves, root, and stem, containing 170.84, 63.40, 47.20, and 24.65 mg/100 g, respectively (Table 4). Z. lotus leaves content is high in vitamin E with 155.71 mg/100 g [28], while Z. lotus's seeds are enriched in -tocopherols with 130.47 mg/100 g [11]. A little amount of carotenoids (1.47 mg/100) was found only in Z. lotus fruits. Vitamins B1 and B2 were present in Z. lotus seeds with 0.03 and 0.08 mg/100 g. Several parts of Z. lotus are rich in vitamin A, ranging from 3.8 to 71.63 mg/100 g. Collectively, these data provide evidence that Z. lotus might be considered as a source of many vitamins for human food.

Sterols Composition of Z. lotus.
Plant-derived sterols have been reported to decrease LDL cholesterol level in blood [58]. The quality of vegetable oil is correlated with its sterol contents. The sterol analysis of Z. lotus seed oil showed that seven compounds have been identified [11]. Δ 7 -Campesterol was the major compound with 147.82 mg/100 g (51.86% of total sterol), along with -sitosterol and campesterol with 82.10 and 31.89 mg/100 g, respectively (Table 5). Other sterols notably stigmasterol, Δ 5 -avenasterol, Δ 5 , 24-stigmatadienol, and cholesterol are present in small quantities. Total sterols content in Z. lotus seed oil was 285.03 mg/100 g. Compared to other vegetable oils, this content is better than Z. jujuba oil (18.56 mg/100 g) [10] and virgin oil (150 mg/100 g) [59] but lower than those measured in Z. zizyphus (291.82 mg/100 g) [54] and soy oil (350 mg/100 g) [60]. It is important to indicate that there is no available data on the sterol content in the other parts of Z. lotus; this issue remains to be determined.

Mineral Composition of Z. lotus.
The mineral analysis of Z. lotus fruit showed that calcium, magnesium, and potassium were the predominance compounds with 490.84, 397.91, and 134.99 mg/100 g, respectively, [55] (Table 6). Similar amounts for magnesium and calcium were found in Z. lotus pulp [19], while higher contents of these three minerals are present in Z. lotus seeds, with amounts ranging from 92.41 to 1349.06 mg/100 g [11,19].

Amino Acids
(／ 3 SO  Journal of Nutrition and Metabolism  major amino acid in this part with 26.73% of total amino acid content, followed by glutamic acid (17.28%), leucine (13.11%), arginine (9.47%), aspartic acid (7.76%), and alanine (4.56%) (  [61]. In addition, the powder of dried leaves and fruit mixed with water or milk is used for the treatment of boils [62] and the root bark for the treatment of diabetes [16]. The juice from Z. lotus root would be efficient in the treatment of eye leucomas [63]. The fruits and the leaves of Z. lotus are used as emollient [61] and in the treatment of diarrhea and intestinal diseases [63].

Z. lotus in Nutrition.
Z. lotus fruits would still be consumed by local population in North Africa. The fruits are dried and processed into flour to make pancakes with very pleasant flavor [64]. The nutritional virtue of Z. lotus is mainly based on its composition rich in vitamin E, vitamin C, fibers, fatty acids, amino acids, calcium, magnesium, and considerable amounts of sugars as mentioned above. The vegetable oils are widely consumed in our diet. They contribute to foods flavor, taste, and texture. Consistent with this, it has been reported that Z. lotus oil is of high quality, because of its content in unsaturated fatty acids and other bioactive compounds [11].

Pharmacological and Biological Activities of Z. lotus Compounds
Therapeutic benefits of Z. lotus compounds or extracts have been highlighted by several experimental models (cell and animal) through in vivo and in vitro studies.

Antioxidant and Anti-Inflammatory.
Several studies report that the extracts of Z. lotus exhibit anti-inflammatory and antioxidant properties. As shown in Table 1, Z. lotus is rich in many antioxidant compounds such as phenolic acids, flavonoids, alkaloids, and saponins. These components have been shown to prevent oxidative stress and inflammation by reducing reactive oxygen species (ROS) [69]. Interestingly, numerous in vitro studies have demonstrated the capacity of the different parts of Z. lotus for scavenging free radicals, for instance, in lipid peroxidation, resulting in cell damage prevention [4,13,21,23,24,26]. Moreover, in diabetic rats, the aqueous extract of Z. lotus roots and leaves strongly increases the rate of haemolysis and glutathione reductase and decreases catalase activity, glutathione peroxidase, and the status of antioxidant, suggesting that this plant corrected diabetes-induced antioxidant status [22]. Besides, the involvement of glutathione in protein and DNA synthesis, cellular detoxification, and inflammation has been reported [70]. For this reason, Z. lotus extract might have potential benefit for cellular protection. In vitro data on human T cells suggest that Z. lotus fruits have higher antioxidant activities compared to other parts of this plant, followed by leaves, root, and stem [28]. Furthermore, the secondary metabolites of Z. lotus administrated orally in carrageenan-induced rat paw edema presented anti-inflammatory effects in dosedependent manner [62] by inhibiting paw edema and the production of nitrite in lipopolysaccharide-activated RAW 264.7 macrophages without cytotoxicity [18]. These studies sustained that Z. lotus biomolecules might have beneficial effects for human health, for example, to reduce or prevent inflammation and oxidative damage.

Antimicrobial and Antifungal.
In vitro studies have elucidated the effects of Z. lotus extracts on the growth of several bacteria and fungi species (see Table 8). They demonstrated that the extracts of Z. lotus fruits under etheric and methanolic solvents presented the most bactericidal effects to induce growth inhibition [13,25]. These antimicrobial activities of Z. lotus fruits seem to be mediated by phenolic compounds content in this part of Z. lotus as shown elsewhere [71]. Altogether, these reports provided evidence that Z. lotus with antibacterial effects might be considered as source of natural biomolecules for producing synthetic bactericides and fungicides.

Antidiabetic and Hypoglycemic.
In a Wistar rat model of streptozotocin-induced hyperglycemia [72], hypoglycemic effects of Z. lotus indicate that the aqueous extracts of roots presented the most efficient activities compared to Z. lotus leaves [22]. This beneficial effect might be correlated with the high quantities of vitamin A observed in leaves and roots of Z. lotus. Indeed, it has been reported that insulin sensitivity was improved by vitamin A through activation of insulin receptor and protein tyrosine phosphatase 1B [73]. Moreover, lower amounts of vitamins were observed in diabetic animals compared to control animals [74].

Antiulcerogenic and Gastroprotective.
Gastric ulcer is part of gastrointestinal disorder involving inflammation and default of defense mechanism. In many in vivo studies, protective effects of aqueous extracts of Z. lotus (root bark, leaves, and fruit) administered orally were observed in the lesions of several ulcerogenic induced models in Wistar rat [21,27]. These reports suggest that the extracts of this plant act as antiulcer agent by reducing gastric acidity and juice secretion. Helicobacter pylori is the most common bacterium that can survive in the highly acidic environment of the human stomach involving different digestive diseases such as peptic ulcer, dyspepsia (heartburn, acid indigestion, and nausea) [75,76], the stomach cancer (adenocarcinoma) [77,78], and MALT lymphoma [79]. Interestingly, the effect of methanol extract of Z. lotus (fruits) has been studied in vitro on 22 clinical strains of Helicobacter pylori, indicating that this plant has bactericidal effects on these clinical strains [21].

Analgesic and Antispasmodic.
In Swiss mice, analgesic effects of aqueous extract of Z. lotus root barks were observed in a dose-dependent manner [62]. In acetic acid-induced algesia in mice, analgesic activities were also reported by flavonoid and saponin extracts from Z. lotus leaves and root bark in vivo, while in vitro, this effect is modulated by nitrite production in RAW 264.7 macrophages [18]. In addition, ex vivo studies on isolated rat duodenum show that aqueous extract of Z. lotus leaves and root bark exerts antispasmodic activities by modulating Ca 2+ signaling via cholinergic receptors [32].

Z. lotus Phenolic Compounds and Immune System: Mechanisms of Action
Beneficial effects of Z. lotus polyphenols on health might be generated by their antioxidant and radical scavenging properties. Interestingly, our previous studies demonstrated that Z. lotus polyphenols also modulate human immune cell signaling and exert immunosuppressive effects [14]. As shown in Figure 3, in human T cells, Z. lotus polyphenols (ZLP) upregulate thapsigargin-(TG-, inhibitor of Ca 2+ -ATPase) mediated calcium signaling at endoplasmic reticulum level, modulate plasma membrane, and, thus, block the entry of ions, decrease ERK1 and ERK2 activation, diminish cell proliferation and IL-2 expression by arresting S cell cycle, and increase intracellular acidification in dose-dependent manner [14]. ZLP alone do not induce elevation of intracellular calcium concentration, [Ca 2+ ] i , in these cells. Consistent with this, Z. lotus might have a potential benefit in human autoimmune diseases. Antidiabetic

Z. lotus aqueous extracts from roots and leaves
In vivo studies in diabetic wistar rats pancreas, liver, and erythrocytes. [22] Hypoglycemic Aqueous extract of leaf and root from Z. lotus In vivo studies in wistar rats [22] Gastroprotective Z. lotus (fruits) methanol extract In vivo studies in wistar rats [21] In vitro studies in 22 clinical strains of helicobacter pylori j99

Conclusion
Collectively, this review provides updated comprehensive information on Z. lotus as a source of several bioactive compounds which hold therapeutic potentialities for human nutrition, health promoting, and disease preventing. As mentioned in Table 8, several scientific papers have clearly reported many biological properties of the different parts of this plant and its constituents through in vitro and in vivo studies. The potent antioxidant, antimicrobial, and antiinflammatory effects of Z. lotus have been distinctly elucidated. On another side, Z. lotus extracts present beneficial effects on metabolic disorders via antidiabetic and hypoglycemic actions. In vivo studies showed that Z. lotus supplementation might be used to treat gastrointestinal disorders. On the nutritional level, this plant is rich in many nutriments which may be used in various fields such as food, cosmetics, and pharmaceutics.

Future Perspectives
Although several studies reported the benefit effects of Z. lotus in many facets of human nutrition, health, and disease, the exact mechanisms by which Z. lotus bioactive compounds exert their biological and pharmacological activities are not yet entirely elucidated.
Therefore, further studies are required to elucidate the effects of Z. lotus extracts and active compounds in some unexplored domains such as cancer, metabolic disorders, inflammation, and age-linked diseases as well as their mechanisms of actions.