Jujube

Ziziphus Jujuba (Chinese Date) is a fruit-bearing plant belonging to the Rhamnaceae family and the Ziziphus genus, with the species of Zizyphus.^[1] The botanical name for this plant is Ziziphus zizyphus, and commonly referred to as either Jujube or Jujuba (with the former being technically correct but as common); other names for the fruit of this plant are Chinese Date, Korean Date, Indian Date, or Red Date.

In Traditional Chinese Medicine (where it is called Da Zao), Jujuba is used for anodyne (pain-killing), antitumor, pectoral, refrigerant, sedative, stomachic, styptic and tonic medication; in Japan, Jujuba is used to treat chronic hepatitis or fullness in the chest and ribs.^[2] It also appears to have antifungal and insecticidal properties,^[3] and in some areas it is also reported to be antidiarrhoeal.^[4]

Traditional Chinese Medicine for effects related to sedation, pain-killing, and relaxation

Jujuba tends to contain as its terpenoid and saponin profile:

• Jujubosides such as Jujuboside A (0.126-0.476mg/g), Jujuboside B (0.106-0.506mg/g)^[5][6] as well as D^[7] and E^[8] as well as the amine compound Jubanine E^[9]
• Zizyphus saponin I and II (2.59-7.24mg/g and up to 3.05mg/g with some undetectable samples in the leaves; respectively)^[10] and zizybeoside II at 130-410mcg/g^[11]
• Ceanothic acid (0.48-5.77mg/g in the leaves; 2.6-4.3mg/100g in berries), epiceanothic acid (0.57-7.63mg/g leaves; 13.8-19.6mg/100g berries), and ceanothenic acid (0.26-0.32mg/g but usually undetectable in leaves)^[10][12]
• Maslinic acid (0.44-1.66mg/g, sometimes undetectable in leaves; 41.5-66.3mg/100g berries), oleanolic acid (0.59-1.47mg/g in leaves; 18.3 -41.7mg/g berries) and Oleanonic acid (37.5-110.5mg/100g in berries)^[10]
• Betulinic acid (1.13-4.35mg/g in the leaves; 7.8-48.7mg/100g usually with one sample reaching 362.2mg/100g^[12]) and zizyberanalic acid (1.13-2.37mg/100g, sometimes undetectable)^[10] and Zizyberenalic acid^[13]
• Ursolic Acid (6.5-26mg/g berries) and 2α-hydroxyursolic acid (0.69-4.02mg/g in leaves)^[13][10]
• Alphitolic acid (0.89-3.99mg/g in leaves; 20.6-41.3mg/100g in berries),^[10] Colubrinic Acid,^[14] and Ursonic acid (22.3-95mg/100g)^[12]
• Coumaroyl compounds 3-O-cis-p-Coumaroylalphitolic acid and 3-O-trans-p-Coumaroylalphitolic acid (aka. Coumaroylmaslinic acid)^[13]
• Pomolic acid, Pomonic acid (10.7-175.4mg/100g in berries; highly variable), and Pomolic acid methyl ester^[15][13]
• Palmatic (1.5-2.4mg/g), Palmitoleic (0.3-1.7mg/g) and Oleic acids (8-50mg/g), no Lauric acid appears to exist in Jujuba^[13][5]
• Linoleic Acid (6-28mg/g), Myristic acid (0.1-0.8mg/g), Stearic acid (0.6-2.8mg/g), Arachidic acid (0.1-0.9mg/g), and Docosanoic acid (2.7-7.7mg/g)^[5]
• Oleanolic/Ursonic acid^[13]
• Various aromatic oils^[16]

Whereas the flavonoid and polyphenolic profile contains:

• Apigenin^[17] and its diglucoside Isovitexin^[17]
• Swertish and Puerarin as monoglucoside flavonoids^[17]
• Spinosin and Isospinosin as diglucoside flavonoids, 6'''-feruloylspinosin and 6'''-feruloylisospinosin as related molecules^[17] and 6'''- sinapoylspinosin^[18]
• (-)-epiafzelechin^[19]
• Rutin (Quercetin-3-O-Rutinoside)^[13] at 15.78-32.74mg/g of the leaves^[20]
• Protocatechuic acid, Chlorogenic Acid, Gallic Acid, and Caffeic Acid^[21]

With various other compounds including:

• Nucleosides and Nucleobases, at 420-550mcg/g and mostly cAMP^[22] and Uridine^[23]
• Dietary minerals such as selenium (0.242mcg/g), zinc (13.8mcg/g), and Iron (38.2mcg/g)^[24]

With some bioactive polysaccharides (totalling 5.1-6.76% total weight in these two studies,^[25][26] reporting a third (not available online) citing 4.42 to 7.91%;^[26] these are 77.1% of dry weight, since the fruits have a high water content^[27]) consisting of:

• Neutral polysaccharide (arabinose, xylose, mannose, glucose and galactose at 0.3:0.2:0.2:1:0.7 ratios)^[26] which appears to have anti-oxidant properties
• Acidic polysaccharides containing rhamnose, arabinose, xylose, mannose, glucose and galactose in a ratio of either 0.3:9.6:0.1:0.4:1:12.1 or 3:16.8:1.2:0.2:1:12.2^[26] that are also anti-oxidant in nature
• Acidic polysaccharide with rhamnose, arabinose, xylose, glucose and galactose at 21:24:2:1:20^[26]

General fruit bioactives including flavanoids, polysaccharides (carbohydrates), and some saponins and alkaloids; a fair bit of the ones in Ziziphus are fairly unique to the fruits

Many compounds are structurally similar to Apigenin, as Swertish is an Apigenin molecule with a methoxy (-OCH3) group at the 7-carbon instead of a hydroxy (-OH) group and a single glucose bound to it; Puerarin is an isomer of Swertish with the glucose bound to the 8 carbon rather than the 6 carbon.^[17]

Spinospin and Isospinosin have a second glucose molecule bound to the first via an oxygen bridge at 4'', with the only differences being that Spinosin is built off of Swertish and Isospinosin off of Puerarin (with a molecule called Isovitexin built off of Apigenin).^[17] Adding 6'''-feruloyl- to these structures is due to adding a ferulic acid molecule to the 6''' carbon on the second glucose.^[17]

Tends to have a unique saponin profile, although some are common among a variety of plants (oleanolic acid, betulinic acid) while the flavonoid profile is also somewhat unique

Although bioactives tend to vary in concentration depending on cultivar, growing conditions, and soil conditions; the pulps tend to have more amino acids on a per gram basis when compared to the seeds and vice versa when it comes to flavonoid content, with the seeds posessing more than the pulp.^[28]

200µg/mL of ziziphus jujuba (fruit) has failed to significantly inhibit acetylcholinesterase in vitro, inhibiting merely 2.4+/-2.6% of activity.^[29]

The seeds of Ziziphus jujube have been implicated in reducing anxiety, in accordance with their traditional usage.^[30] Oral administration of 0.5, 1, and 2g/kg of the ethanolic seed extract in mice was able to exert anxiolytic effects, and although it was equally effective as Buspirone and Diazepam (2mg/kg and 1mg/kg, respectively) at a black and white test (anxiety model^[31]) at 500mg/kg, it appeared to become less potent at anxiolysis at 1 and 2g/kg while becoming more sedative in nature.^[30]

Possible anxiolytic effects that rival Buspirone and Diazepam according to one study, lack of evidence otherwise; subsequently higher doses reduce anxiolysis in favor of sedation

According to one systemic review on insomnia, the Traditional Chinese Medicine called Suan Zao Ren (which is Ziziphus Jujuba) appears to be the most commonly used insomniac treatment; conclusions on its efficacy in humans could not be drawn due to a lack of good evidence, however.^[32]

The ethanolic extract of the seeds has been found to prolong hexobarbital-induced sleeping time at 1g/kg, but not 500mg/kg; no influence was noted on sleep latency (time required to fall asleep) and an impairment of waking locomotion was found at the dose that induces sedation.^[30] This enhancement of sedation may be mediated via the flavonoid spinosin and vicariously through post-synaptic 5-HT(1A) receptors (serotonin receptor), with synergistic augmentation when paired with 5-HT1A antagonists at 15mg/kg spinosin.^[33] This enhancement has also been noted with jujubosides, and was synergstic with 5-HTP at 2mg/kg.^[34]

In a test on what constituents mediated these effects, the saponins and flavanoids (but not polysaccharides) appeared to have anti-locomotion properties but only the saponin component appeared to augment phenobarbitol-induced sleep.^[35] At a dose of phenobarbitol that was seen as suboptimal (able to induce sleep in a minority of animals), the amount of animals who managed to sleep increased from 20% to 90% with the saponins (70% with flavonoids).^[35]

Highly regarded as a sedative in Traditional Chinese Medicine with minimal Western trials on its efficacy, it appears to induce sedation in a relatively dose dependent manner and is synergistic with 5-HTP in this regard

At least one study conducted in rats where a seizure was induced noted that Ziziphus Jujube was able to attenuate the adverse effects of the seizure, including oxidative biomarkers and reducing the subsequent impairment in cognition.^[36] A reduction in physical contractions was also noted, with absolute (100% protection) against pentylenetetrazole-induced seizures and 66.7% in electricity-induced convulsions at 1g/kg (the dose required for sedation), with lower doses being effective but to a lesser degree. Absolute protection was also noted with 300mg/kg Sodium Valproate.^[36]

One study noted anti-convulsant effects, fairly potent according to it

One animal study noted that, using middle-aged mice, 40-100mg/kg of the methanol extract for 30 days resulted in neuronal proliferation.^[37] According to Ki67 and doublecortin immunostaining, neurons in the dendate gyrus were significantly enhanced at 40mg/kg and increased further at 100mg/kg (although not significantly different than 40mg/kg) with the percentage increase being 475% and 672%, respectively and relative to control.^[37] Most of this enhancement was due to increased amounts of tertiary dendrites at both concentrations (354% and 579%, respectively), suggesting dendritic proliferation or an attenuation of dendritic loss associated with aging.^[37] Actual cognition and learning was not assessed in this study despite the results suggesting improvements.^[37]

One study noting cognitive enhancement in older rats, potentially related to dendritic proliferation (although causation not established); unknown potency relative to a reference drug

In response to Ischemia, oral ingestion of a methanolic extract of Ziziphus (dose undisclosed) appears to protect neurons from cell death (with Ischemia having 11.3% of control and ingestion of Ziziphus attenuating this to 58.4% as assessed by neuronal nuclei immunoreactivity four days after Ischemia) and was about as effective as the active control of 100mg/kg Ebselen.^[38] This was thought to be secondary to anti-oxidant effects in the brain.^[38]

Other possible mechanisms associated with neuroprotection could be antagonism of excitotoxicity. Jujuboside A appears to have anti-calmodulin activities in preventing calcium influx into glutaminergic neurons (although the concentration used in this study may not be applicable to oral Jujube ingestion; too high)^[39] although similar effects have been noted at lower concentrations.^[40] When a concentration of 0.5g/L was compared to the active control of phenobarbitol, is was slightly but significantly less effective at suppressing the number and amplitude of neuronal population spikes.^[40] Even lower concentrations (0.05-5mcg/mL) appear to protect neurons from glutaminergic excitotoxicity, secondary to preventing an influx of calcium.^[41]

Jujuboside A has been demonstrated to reduce excitatory postsynaptic potential in hippocampal neurons,^[42] and has been shown to reduce EEG readings in rats given intracerebral injections of Jujuboside A.^[43][40]

Appears to have protective effects in the brain in response to damage, but there is a lack of evidence connecting the in vitro studies (which appear quite promising) to practical interventions with oral Jujube

The traditional method of preparation of Jujubes for the purpose of constipation relief to to boil 50g of Jujube fruits (20 whole fruits of 2–2.5 cm in length) to create a soup or drink, which may be related to extraction of a water soluble polysaccharide noted to have anti-constipative effects, and comprise 77% of the dry weight of jujube fruits.^[27] This study extracted said polysaccharide according to the traditional methods, and when feeding to hamsters (40mg; equivalent to 50g fruits in humans) was able to increase fecal moisture content and decrease transit time in a dose-dependent manner.^[27] Fecal ammonia was decreased in a similarly dose-dependent manner, and levels of short chain fatty acids in the colon increased.^[27] These authors hypothesized that the increase in SCFAs explained the observed effects, as SCFAs have been previously linked to mucosal stimulation^[44] although the decrease in mucinase may also partly explain the moisture content.^[27]

Currently one clinical trial has been conducted with Ziziphus Jujuba and constipation, where in persons with prolonged transit time (indicative of constipation) symptoms normalized in 84% of the Jujube group and 12% of the placebo group with better improvement in quality of life associated with Jujube.^[45]

Jujube appears to be quite beneficial to intestinal motility, increasing fecal moisture and increasing transit time (anti-constipative). These effects are seen with the polysaccharide component, and may not be achieved with concentrated flavonoid capsules

Triterpenoids from Ziziphus fruits and seeds show efficacy in preventing macrophages (immune cells) from converting into foam cells, and may offer protection from atherosclerosis.^[15] This study noted that out of 50 various herbs tested only Ziziphus, Foeniculi Fructus (Fennel Seed), and Hoelen were able to significantly suppress foam cell formation; herbs such as astragalus membranaceus, the fruits of schisandra chinensis, and horny goat weed were ineffective at this role, and the bioactives in Ziziphus appears to be Oleanolic acid, Pomolic acid, and Pomonic acid; Pomolic acid methyl ester was ineffective.^[15]

The hydroalcoholic (alkaloid free) extract of Jujube at 100, 200, or 400mg/kg bodyweight was tested against two inflammatory models in rats (careegnan induced paw edema and cotton-pellet-induced granuloma) and found to dose-dependently reduce inflammation; when compared to 10mg/kg Indomethacin as active control, Ziziphus Jujube extract underperformed.^[46] Serum Nitrate showed similar results, with a dose-dependent reduction with Jujube but more efficacy with Indomethacin.^[46]

Appears to have general anti-inflammatory properties, less potent than the reference drug of Indomethacin (NSAID)

In mice, the essential oil of Jujube seeds at 1-10% is as effective (when applied topically) in suppressing skin inflammation as 1% Hydrocortisone as assessed by thickness and more effective in reducing water content of the ear.^[47] There was not much dose-dependence observed when comparing 1% and 10% Jujube essential oil.^[47]

May be able to exert anti-inflammatory properties topically when the oil is applied

Ziziphus contains a collection of polysaccharides which may interact with the immune system.^[48] In a mouse model fed the crude water-soluble polysaccharides at 50, 150, and 250mg/kg daily the two larger doses caused an increase in nonspecific immunity (as assessed by spleen and thymus index) and was able to proliferate splenocytes and macrophages in vitro.^[48]

In a screening of estrogenicity between medical plants, the fruits of Ziziphus (95% ethanolic extract) failed to show any estrogenic or anti-estrogenic effects at concentrations below 1mg/mL.^[49]

The essential oils from the seeds of Ziziphus Jujuba appear to be able to induce hair regrowth in mice when topically applied.^[50] This study noted that 1% and 10% (content of Ziziphus Jujuba oil in lotion) applied daily to the skin resulted in 11.4% and 12% longer hairs over 21 days, while 0.1% was not significantly effective.^[50] Interestingly, these same doses of essential oils have been linked to fairly potent anti-inflammatory effects,^[47] and may be related to hair growth.

Green Tea Catechins (Green tea extract, GTE) appears to enhance the cytotoxicity of Jujube. This one study noted that in HepG2 cells (liver carcinoma cells) that cytotoxicity at 100ug/mL Jujube (chloroform extract) reduced viability of cells to 80%, and under the influence of 30ug/mL GTE this was enhanced to about 60%.^[51] Green tea at 30ug/mL itself has no affect on viability, and this enhanced cell death was not seen in noncancerous liver cells under any condition.^[51]

Mechanistically, an increased level of ROS (oxidation) occurred in the Jujube condition which correlated with cellular death; this was not enhanced or hindered by GTE^[51] but instead the combination appeared to further change the cell cycle relative to control HepG2, where Jujube in isolation and the combination to a greater degree increased the amount of cells in the G1 phase while reducing the amount in G2/M and S phases.^[51] The authors concluded that the synergism occured via enhancing G1 cellular arrest, which was confirmed by less DNA synthesis and improved Rb protein (mediator of G1) actions.^[51]

Synergistic protection has also been noted when measuring the actions of APRIL, a protein that induces differentiation of HepG2 cells.^[52]

Jujube and Green Tea Catechins appear to have synergistic anti-cancer properties, but the evidence is currently limited in size and only in one cell line

5-HTP is an animo acid derivative that is made from tryptophan, and proceeds to be metabolized into the neurotransmitter serotonin and subsequently melatonin; secondary to melatonin, it may help sleep. Jujube flavonoids have once been found to act synergistically with 2mg/kg 5-HTP in inducing sleep in rats.^[34]

May be synergistic with Jujube in regards to sedation

PHY906 is a term used to refer to a decoction of four herbs that has usage in Traditional Chinese Medicine under the name of Huang-Qin-Tang, one of which is Ziziphus Jujuba. The other three herbs are Paeonia lactiflora, Scutellaria baicalensis, and Glycyrrhiza uralensis; this combination apparently has some limited usage as cancer adjunct therapy.^[53][54]

This combination has been used in vitro in a HepG2 cell line, and at the IC₅₀ concentration of 0.85g/mL it affects 466 genes (amount common between fractions samples) with some of the more significant changes being a 405-fold increase in Carnitine Palmitoyltransferase 1A activity.^[54]

CKBM is a polyherbal formula consisting of Jujube, Glycine Max, Panax ginseng, Shizandra Chinensis, and Fructus crataegi.^[55] This decoction was shown to suppress LPS-induced IFNγ release without inducing IFNγ itself, and induced the activity of ERK (one of the three major MAPK subsets) in one immune cell line while activating all major three subsets (ERK, JNK, p38) in another; suggesting potential immunomodulatory properties.^[55]

The LD₅₀ of an ethyl acetate fraction of Jujube (concentrated flavanoids) appears to be around 2.5g/kg in female mice.^[56]

Jujube has apparently been used to prevent pregnancy, as was mentioned in the introduction of one study.^[47] The only current study on the subject matter is one in female mice given an ethyl acetate fraction of Jujube (consisting of polyphenolics and flavanoids) at 60-240mg/kg bodyweight appeared to reduce the weight of the ovaries and inhibit the estrus cycle, with a greater potency than the other herb tested (Croton roxburghii).^[56] This co-existed with an inhibition of delta-5-3β-HSD in a dose dependent manner, and all parameters were normalized 32 days after supplementation cessation.^[56]

May be acutely anti-fertility, but there is limited evidence to support this notion