Abstract

Background: Ziziphus spina-christi of family Rhamnaceae is a terrestrial tree often recognized as Christ's thorn jujube. The plant of Ziziphus spina-christi grows in the South and East of Asia as well as in the Middle East zone. Nearly in most of the Arabic countries, Levant, and Saudi Arabia, Ziziphus spina-christi tree is called Sidr mentioned in the Holy Quran. It contains nutritional components that render the plant one of the principal food sources. The plant possesses diverse phytochemical active compounds mostly spinanine A, β sitosterol, rutin, quercetin, betulinic, and kinetic acid. In Saudi Arabia, the Sidr tree has an important therapeutic value as each part of the tree was used to maintain a healthy life. Objective: The present review aimed to collect the different nutritional values, pharmacologic, and biological activities that were linked with the utilization of different parts of Ziziphus spina-christi extracts, which have been reported in the literature. Results: Findings collected from the previously published studies showed that Ziziphus spina-christi extract possesses many pharmacological and biological activities such as hepato, cardio and nephroprotective, antidiabetic, antimicrobial, antiparasitic, anticancer, antiasthma, and antinociceptive activities. Many of these biological activities were attributed to the antioxidant action of Ziziphus spina-christi plant extract. Conclusion: It was experimentally proven that Ziziphus spina-christ extract from the Sidr tree mentioned in the Qur'an has many nutritional values and pharmacological effects that could qualify it to be the subject of other studies in humans until it is used as a supplement or alternative treatment in the future.

1. Introduction

Ziziphus spina-christi (family Rhamnaceae, order of Rosales) is a wild tree commonly famous as Christ's thorn jujube. The family of Rhamnaceae involves 52 genus and 925 species spread around the world, especially across warm areas. The Ziziphus species of deciduous, evergreen trees and shrubs comprise of nearly 100-170 types that tolerate dryness and heat ¹. The plants usually grow in dry regions, deserts, semi-desert washes, savannahs as well as valleys ². The tree cultivated in the East and South areas of Asia and the Middle East region ³. Generally, in Arabic, the fruits have been given the same tree name ⁴. In most Arabic countries such as in Saudi Arabia, Ziziphus spina-christi tree was commonly named Sidr (related to the Lote-trees of the Quran) while the fruit was called Nabka ^{5, 6}. This Sidr tree is one of the paradise trees. It is one of the most important types of native trees planted in the Arabian Peninsula, which has historical, medicinal and religious values ⁷. The tree is referred to in the Holy Quran in four sites (Surat Saba {16}, Surat al-Najm {14 and 16}, and Surat Al- Waqi’ah {28}). This demonstrated that this tree is of great importance ⁸.

Ziziphus spina-christi contains multiple nutritional components that render the plant one of the greatest food sources. The plant has been utilized in traditional medicine in Middle East, mainly the fruits, seeds, leaves, roots and bark ⁹. The fruit of Ziziphus spina-christi is small, orange-yellow with spiked branches ¹⁰ that considers a rich source for important dietary components ¹¹. The dry fruits are wealthy in energy compounds (80.6% carbohydrates: starch, sucrose, glucose, and fructose) ^{4, 12}. Furthermore, there are 0.9 g fat, 4.8 g protein, 140 mg calcium, 0.13 mg riboflavin, 0.04 mg thiamine, and 3.7 mg niacin per 100 gm dried fruit ^{13, 14}. The fruit also contains high amount of vitamin C (98 mg) which is a considerably larger amount compared to those present in strawberry (59 mg), orange (50 mg), and grape (38 mg) ¹⁵. It was reported that the fruits has rich amount of polyphenols (24.62 mg/g of gallic acid equivalent of dry extract) ¹⁶. Phenolic compounds are important natural antioxidants that possess scavenging activity against free radicals ^{17, 18, 19, 20}.

The seeds of Ziziphus spina-christi hold 28.5% fats (mostly linoleic and linolenic acid ), and 18.6% protein (mostly sulphur-rich amino acids) ²¹. The seeds have sedative effect and could be used to relieve pregnancy-related nausea , vomiting, and abdominal discomfort ²². The Ziziphus spina-christi stem bark has been marked to have antifungal, antibacterial, and cytotoxic actions ²³. A study examining the antibacterial properties of Ziziphus spina-christi stem bark revealed the efficacy of stem bark to treat burns, wounds, stomach discomfort as well as urinary tract infection ²⁴. The leaves of the plant contain a substantial amount of calcium, iron, and magnesium ⁴. They are traditionally utilized for the treatment of eye illness, atopic dermatitis, bronchitis, skin disease, ulcers, and wounds ^{22, 25, 26}.

Ziziphus spina-christi owns a sundry of phytochemicals bioactive constituents mostly cyclopeptide, alkaloids (spinanine A), tannins, sterols (β sitosterol), peptide, flavonoids (rutin and quercetin), saponins (betulinic and kinetic acid), triterpenoids, sapogenins, quercetin, and triterpenic acids ^{27, 28, 29, 30, 31, 32}. The extract of Ziziphus spina-christi leaf comprises four saponin glycosides known as (christanin A, B, C, and D) ²¹.

In Saudi Arabia, the Sidr tree possesses much curative importance as each division of the tree was utilized to support a healthy way of life ^{16, 33}. Ziziphus spina-christi was observed to produce antibacterial, antifungal, antinociceptive, antioxidant, anti-inflammatory action, antiallergic, and anti-influenza ^{10, 16, 34, 35, 36, 37, 38, 39}. Previous research on the beneficial activities of Ziziphus spina-christi related to the nervous system of being anxiolytic, analgesic, and anti-depressant have been also determined ^{5, 40, 41}.

Due to the medical and curative significance of this blessed tree, the present review aimed to collect the different pharmacologic and therapeutic activities that were associated with the use of diverse parts of Ziziphus spina-christi extract that have been published in the literature.

2. Hepatoprotective Activity

Research study aimed to investigate the preventive action of Zizyphus spina-christi fruits on carbon tetrachloride associated liver damage in Wistar rats. The results revealed that feeding the rats with a diet containing 2.5, 5, 10, and 15% Zizyphus spina-christi fruits powder for 42 days produced a significant decrease in liver function markers of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP). The addition of Ziziphus spina-christi fruits powder to the group of hepatotoxic rats diet produced significant decrease in Malondialdehyde (MDA) levels. Ziziphus spina-christi fruits powder was also able to maintain the actions of antioxidant enzymes (glutathione peroxides (GSH-Px) and Superoxide dismutase (SOD)) ³.

The study also concluded that the protective effect resulted from the overwhelming mechanism of antioxidant enzymes and their scavenging effect on the free radicals ³. The flavonoids antioxidant properties from different medical plants exert their stimulating actions on antioxidant enzymes ⁴². Ziziphus spina-christi extract has been observed to contain high amounts of flavonoids and polyphenols ⁴³. Defensive effects of flavonoids and polyphenols against oxidative stress-related diseases have been evident in previous research ^{44, 45, 46, 47, 48, 49}.

In a study performed to examined the probable protective action of Zizyphus spina-christi leaves extract versus Plasmodium chabaudi that caused hepatic illness, the authors concluded a marked decline in the blood parasite titre and a marked amelioration of the blood picture (RBCs and haemoglobin level), liver function markers (ALP, AST, and ALT), and liver histopathology. The discussed mechanism was related to the antioxidant catalase (CAT) effect of Zizyphus spina-christi ⁵⁰.

A study reported hepatoprotective action of Ziziphus spina-christi aqueous extracts in rat model of hepatic fibrosis induced by carbon tetrachloride. The extract at 0.125, 0.250 and 0.350 g/kg was administered for eight weeks. Zizyphus spina-christi extract produced a marked decline in the hepatic function enzymes (AST, and ALT) impeding hepatic fibrosis progression. Ziziphus spina-christi aqueous extracts also helped to restore the normal levels of MDA and maintained endogenous antioxidants activities of CAT, GSH, and SOD. In addition, the extract diminished α-smooth muscle actin expression and types I and III collagen deposition in the infected rats, showing improvement in the quantity and quality regarding to the distribution of type I collagen ⁵¹.

The protective impact of the methanolic extract of Ziziphus spina-christi leaves on hepatic and splenic injury was examined in male C57BL/6 mice model of cecal ligation and puncture induced sepsis. The study results indicated that daily oral administration of Ziziphus spina-christi leaf extract at doses of 100, 200, and 300 mg/kg for five days significantly inhibited liver and spleen injury induced by sepsis. The study findings suggests a therapeutic potential of Ziziphus spina-christi leaf extract for sepsis by enhancing antioxidant and anti-inflammatory effects ⁵².

3. Cardio and Nephroprotective Activity

A study reported that different doses at 100, 200, and 300 mg/kg of Ziziphus spina-christi leaves extract exerted a protective impact versus multiple-organ toxicities that accompanied sepsis on male mice. These findings could be relaying on the antioxidant, antiapoptotic, and anti-inflammatory actions of Ziziphus spina-christi leaf extract. Sepsis was produced by cecal ligation and puncture. This study discussed the protective impacts to be attributed to the antioxidant (decreased MDA, myeloperoxidase (MPO), and nitric oxide (NO)), anti-inflammatory (decreased, interleukin 1 beta (IL-1β), tumour necrosis factor alpha (TNF-α), and nuclear factor kappa B (NF-κB)), and antiapoptotic (decreased caspase-3 and Bax mRNA) activities ⁵³.

4. Antidiabetic Activity

A study investigated the impact of hydroalcoholic extract of Zizyphus spina-christi fruit on the serum insulin level and blood glucose of diabetic dogs induced by alloxan compared to antidiabetic agent of glibenclamide. Oral administration for 10 days with 500 mg/kg Zizyphus spina-christi fruit hydroalcoholic extract produced a marked decline in blood sugar concentration associated with a marked elevation in serum insulin concentration in alloxan model of diabetes in the dogs. The effect is better than that produced from the application of glibenclamide at a dose of 0.2 mg/kg ⁵⁴.

One of the rmechanisms by which the Ziziphus fruit regulate glucose homeostasis could be due to inhibition of glucose uptake in rats’ small intestine ⁵⁵. This mechanism was reported in previous research of some medical plants ^{56, 57}. Another mechanism of Improving the liver function and subsequently increasing the uptake of blood glucose was also proposed action of Ziziphus vulgaris ⁵⁵.

Oral feeding with 200 mg/kg Ziziphus spina-christi leaves extract to Sprague Dawley male rats with diabetes induced by streptozotocin (50 mg/kg) for one month showed significant results. It lowered serum glucose; raised insulin and C-peptide; and ameliorated glycated haemoglobin (HbA1C%) levels. The saponin and polyphenols active constituents of Ziziphus spina-christi leaf extract were recognized to be responsible for the amended glucose utilization observed in this context. Besides, the extract significantly increased the total antioxidant capacity ⁶.

In another study, the hypoglycaemic, antidiabetic, antioxidant actions, in addition to the phenolic composition of different fractions of Ziziphus spina-christi were examined in Streptozotocin (60 mg/kg)-induced diabetes in male Swiss albino mice. The results revealed that the most significant antidiabetic effect was provoked next to the administration with 500 mg/kg n-butanol fraction. The total flavonoid in the n-butanol extract has been estimated as 28.2 mg/g while the total phenolic contents has been 68.3 mg/g ⁵⁸.

5. Antihyperlipidemic Activity

Two months oral feeding of Ziziphus spina-christi leaves powder (500 mg/kg) to hypercholesterolemic rats exhibited a significant decline in lipid profile parameters. The antihyperlipidemic effect may be induced through inhibiting oxidative stress by its content of phenolic compounds ⁵⁹.

Another study of the Ziziphus spina-christi leaf extract showed beneficial effects on lipid peroxidation, lipid profile, as well as liver function enzymes in rats with diabetes. The increasing doses of Ziziphus spina-christi leaf extracts at 50, 75, and 100 mg/kg for four weeks significantly lowered the mean of blood cholesterol, triglyceride, LDL-cholesterol, AST and ALT. On the other hand, the mean of HDL-cholesterol in diabetic rats was increased. The phenolic constituents of the extract suppressed the oxidative stress and reduced the hypercholesterolemia effect ⁶⁰.

In addition, a study examining the impact of Ziziphus spina-christi and Ziziphus mauritiana fruits extract in diabetic rats induced by alloxan, revealed that both plants exerted dose-dependent hypolipidemic and hypoglycemic properties ⁶¹. The fruit extract of Ziziphus spina-christi manifested more influence than Ziziphus mauritiana. This finding support the beneficial effect of plant fruits in the management of hyperlipidemia associated with diabetes ^{61, 62, 63}. Saponins present in Ziziphus spina-christi have been reported to exert hypolipidemic effect to lower total cholesterol, LDL cholesterol, and triglycerides. This mechanism could be explained by the fact that saponins create an insoluble compound with cholesterol, which increases the excretion of lipid ⁶⁴. They also rise the activity of liver LDL receptor, and also reduces triglyceride synthesis ⁶⁵.

6. Antimicrobial Activity

An early conducted study revealed that both alcoholic extract of Ziziphus spina-christi fruits and aqueous extract of Ziziphus spina-christi leaves induced a marked antiviral action versus Herpes simplex type 1. The chloroform extract of Ziziphus spina-christi leaves inhibits the Gram-positive pathogens Streptococcus pyogenes and Bacillus cereus. Furthermore, the petroleum ether extract of Ziziphus spina-christi leaves inhibits the growth of Streptococcus pyogenes. The chloroform extract of Ziziphus spina-christi seeds inhibits the growth of Bacillus cereus, Streptococcus pyogenes and Staphylococcus aureus. The chloroform extract of Ziziphus spina-christi leaf instigated a modest antifungal activity against Trichphyton rubrum ⁶⁶.

Another previously published in vitro study showed that the chloroform, methanol, and petroleum ether extract of the fruits, leaves, stems, and seeds of Ziziphus spina-christi produced significant effects of antibacterial action against Gram positive of Staphylococcus aureus and Bacillus subtilis; and Gram negative of Proteus vulgaris, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. It was indicated that the methanolic extract was the most potent. The chloroform extract comes next whereas the petroleum ether extract exerted the least effect. All the extracts of the different herbal parts showed no fungicidal effects versus Aspergillus niger and Candida albicans ⁶⁷.

Recently, the alcoholic extract of the aerial division of Ziziphus spina-christi has been found to exhibit an in vitro dose-dependent antimicrobial activity versus many Gram-positive bacteria (Clostridium perfringens, Listeria monocytogenes, Bacillus cereus, and Staphyllococcus aureus) and against some Gram-negative bacteria (Vibrio parahaemolyticus and Proteus vulgaris) ⁶⁸.

7. Antiparasitic Activity

The antischistosomal and hepatoprotective impact of the alcoholic roots extract of Ziziphus spina-christi was examined in male albino mice infected with Schistosoma mansoni. The study findings showed that application of Ziziphus spina-christi on the infected mice significantly decreased MDA concentration and increased antioxidant enzymes activity. Furthermore, the Ziziphus spina-christi extract significantly lowered the worm and egg counts and thus providing an evidence for antischistosomal efficacy ⁶⁹.

Another study determined the antischistosomal activity of Ziziphus spina-christi leaf extract on CD-1 Swiss male mice infected with Schistosoma mansoni. Treatment with the extract of Ziziphus spina-christi leaves showed significantly lowered hepatic fibrosis, apoptosis, and oxidative stress in the infected mice. The extract of Ziziphus spina-christi activated antifibrinogenic as well as Nrf2 pathways ⁷⁰.

A study by Alzahrani et al., investigated the Ziziphus spina-christi leaves extract at different doses of 100, 200 and 300 mg/kg, to have anti-eimeria and anthelmintic activity. Experimental mice were infected with 1.2×103 E. papillata-sporulated oocysts. The anthelmintic influence of Ziziphus spina-christi leaves extract was determined against adult earthworm, Allolobophora caliginosa. The treatment with Ziziphus spina-christi leaves extract significantly reduced the oocytes shed, and was able to recover the affected jejunum caused by E. papillata infection. A fewer number of parasitic stages was shown in the jejuna villi after the treatment. The number of goblet cells in the jejuna villi was significantly increased after treatment with 100 and 300 mg /Kg Ziziphus spina-christi leaves extract. Moreover, the in vivo experiment exhibited dose-dependent effect, with the increase of Ziziphus spina-christi leaves extract, there was a decreased in time taken to induce paralysis and death ⁷¹.

8. Anticancer Activity

In a study aimed to examine the antiproliferative impact of Ziziphus spina-christi on MCF-7 cells (human breast cancer). Ethanolic extract of Ziziphus spina-christi leaves possess the smallest IC50 value, producing cell cycle arrest at the G1/S phase and apoptosis determined 48 h post treatment ²⁸.

Another study performed also on MCF-7 cell line revealed a significant cytotoxic impact of various concentrations of Ziziphus spina-christi leaf hydroalcoholic extract (0.01, 0.1, 1, and 10 mg/ml). However, only the MCF-7 cell line exposed to 1 mg/ml Ziziphus spina-christi extract induced a marked increase in the apoptotic marker (Bax) expression and decreased the antiapoptotic marker (Bcl2) expression ⁷².

In a study of male Sprague-Dawley rats treated with Aflatoxin to induce hepatic carcinogenicity, the Zizyphus extract showed a protective role against aflatoxicosis. Zizyphus fruit extract of (5mg/kg b.w.) alone caused significant decline in AST, triglycerides, cholesterol, and uric acid. In addition, Zizyphus extract alleviated the activities of GPX and SOD caused by aflatoxin, promising as a rich-antioxidants plant ⁷³.

Another study evaluated the antitumor effect of Ziziphus spina-christi leaf extract (100 and 300 mg/kg) against hepatic carcinoma in rats induced with diethylnitrosamine. The expressions of Bcl2, hepatocyte growth factor, matrix metalloproteinase-9 oncogenes, and insulin-like growth factor-1 receptor were quantified in liver samples. Ziziphus spina-christi leaf extract exerted a dose-dependent medicinal effect versus diethylnitrosamine-induced hepatic carcinoma by ameliorating oxidative stress and oncogenes ⁷⁴. Therefore, Ziziphus spina-christi is a promising candidate for developing anticancer medications ⁷⁵.

9. Antiasthma Activity

A clinical trial aimed to investigate the therapeutic activity of the extract of Ziziphus spina-christi leaf in asthmatic subjects. The study was conducted on 50 asthmatic subjects where 25 served as control group (placebo) and 25 served as treatment group (Ziziphus spina-christi leaf extract). Both groups are treated with the conventional asthma medication plus either placebo or Ziziphus spina-christi extract. The extract was indicated to be inhaled two times daily every other day for a period of eight weeks. Patients treated with the extract showed better pulmonary function tests, ameliorated life quality, and decreased asthma frequency ⁷⁶.

10. Anticonvulsant Activity

An early conducted study revealed that the Ziziphus spina-christi fruit extract (50 mg/kg) induced a significant reduction in neurotransmitter content (gamma-aminobutyric acid, serotonin, dopamine, and norepinephrine) in different areas of the brain in male rats. This finding could be due to the ascorbic acid content in fruit extract of Ziziphus spina-christi of which induced release of neurotransmitter from presynaptic by improved Ca²⁺ influx ⁷⁶.

In a study aimed to examine the neuroprotective impact of Ziziphus spina-christi leaf extract against pentylenetetrazol induced seizure in rats. Three weeks administration of Ziziphus spina-christi leaf extract in a dose of 50 mg/kg induced a significant improve in dopamine, norepinephrine and serotonin contents in different regions in the brain (cerebral cortex, hippocampus, brainstem, cerebellum, striatum, and hypothalamus). The neuroprotective activity of the Ziziphus extract could be related to the presence of cyclopeptide alkaloids, and peptide which inhibit neurotransmitter release ⁷⁷.

In another study the neuroprotective effect of Ziziphus spina-christi leaves extract (50, 100, and 299 mg/kg) on cerebral ischemia/reperfusion-induced brain damage was examined in rats. The findings showed that the Ziziphus extract enhanced the motor balance and coordination as well as improved serum and brain antioxidant capacity in a dose-based manner. The mechanism involved may associated with inhibited oxidative stress and increased antioxidant defence system ⁴¹.

11. Antinociceptive and Anxiolytic Activity

The aqueous extract of Ziziphus spina-christi leaves (250 mg/kg) lowered the number of abdominal cramps induced with acetic acid in rats, and the effect was similar to pethidine (10 mg/kg) ⁷⁸. The analgesic activity of Ziziphus spina-christi root extract has been studied experimental animals utilizing both formalin and hot plate experiments. Ziziphus spina-christi root bark extract at doses of 50 and 100 mg/kg demonstrated a dose-dependent analgesic action ⁷⁹.

The impact of Ziziphus spina-christi extract on anxiety related behaviour in rats induced with scopolamine was investigated. The hydroalcoholic extract of Ziziphus spina-christi doses of 50, 100 and 200 mg/kg showed anxiolytic activity linked to modulation of oxidative stress against DPPH free radicals. Previous research reported Scopolamine to induce oxidative stress in the brain of rats ⁸⁰. The progress of neurodegenerative diseases has been linked to oxidative stress that could result in accelerating aging process and anxiety-related behaviour ⁸¹. The anxiolytic activity identified in this study may be associated with antioxidant effects of the extract.

12. Conclusion

From the collected studies, it could be concluded that Ziziphus spina-christi extract possesses many pharmacological and biological activities such as hepato, cardio and nephroprotective, antidiabetic, antihyperlipidemic, antimicrobial, antiparasitic, anticancer, antiasthma, anticonvulsant, and antinociceptive activities. It was experimentally proven that Ziziphus spina-christi extract from the Sidr tree mentioned in the Qur'an has many nutritional values and pharmacological effects that could qualify it to be the subject of other studies in humans until it is used as a supplement or alternative treatment in the future.

References