The Jujube (Ziziphus Jujuba Mill.) Fruit: A Review of Current Knowledge of Fruit Composition and Health Benefits

Pain is a term that refers to a spectrum of sensations of varying types and intensities, ranging from unpleasant to intolerable. The struggle to relieve pain began with the advent of mankind. Analgesics can be defined as drugs that reduce the sensation of pain without losing consciousness. Analgesics act in different ways on the peripheral and central nervous systems. They differ from anesthetics in that they reversibly eliminate sensation, acetaminophen [known in the US as acetaminophen, or simply APAP], non-steroidal anti-inflammatory drugs [NSAIDs] such as salicylates, morphine and opioids such as opiates. When choosing an analgesic, the severity and response to other drugs determine drug choice. World Health Organization [WHO] pain ladder. Herbal medicines have less side effects and less harm, so they have a higher market value. The nutritious jujube fruit (Ziziphus jujube Mill.) is a member of the Rhamnaceous family and grows mainly in inland areas of Europe, southern and eastern Asia, Australia and especially northern China. Jujubes have a long history as fruit and medicinal. The main bioactive components are vitamin C, phenols, flavonoids, triterpenoids and polysaccharides. Recent phytochemical studies of jujube fruit have highlighted the following biological effects: B. Anticancer, anti-inflammatory, anti-obesity, immunostimulatory, antioxidant, hepatoprotective and gastrointestinal protective activity in macrophages and inhibition of foam cell formation. Further focus on clinical trials and phytochemical definitions of jujube fruit will be essential for future research efforts. In this study, an attempt was made to evaluate the analgesic potential of Ziziphus jujube hydroalcoholic fruit extract.

An endophytic fungus, Neofusicoccum parvum JS-0968, was isolated from a plant, Vitex rotundifolia. The chemical investigation of its cultures led to the isolation of a secondary metabolite, (3R)-5-hydroxymellein. It has been reported to have antifungal, antibacterial, and antioxidant activity, but there have been no previous reports on the effects of (3R)-5-hydroxymellein on atherosclerosis. The oxidation of lipoproteins and foam cell formation have been known to be significant in the development of atherosclerosis. Therefore, we investigated the inhibitory effects of (3R)-5-hydroxymellein on atherosclerosis through low-density lipoprotein (LDL) and high-density lipoprotein (HDL) oxidation and macrophage foam cell formation. LDL and HDL oxidation were determined by measuring the production of conjugated dienes and malondialdehyde, the amount of hyperchromicity and carbonyl content, conformational changes, and anti-LDL oxidation. In addition, the inhibition of foam cell formation was measured by Oil red O staining. As a result, (3R)-5-hydroxymellein suppressed the oxidation of LDL and HDL through the inhibition of lipid peroxidation, the decrease of negative charges, the reduction of hyperchromicity and carbonyl contents, and the prevention of apolipoprotein A-I (ApoA-I) aggregation and apoB-100 fragmentation. Furthermore, (3R)-5-hydroxymellein significantly reduced foam cell formation induced by oxidized LDL (oxLDL). Taken together, our data show that (3R)-5-hydroxymellein could be a potential preventive agent for atherosclerosis via obvious anti-LDL and HDL oxidation and the inhibition of foam cell formation.

Atherosclerosis is a major cause of morbidity and mortality in developed societies, and begins when activated endothelial cells recruit monocytes and T-cells from the bloodstream into the arterial wall. Macrophages that accumulate cholesterol and other fatty materials are transformed into foam cells. Several epidemiological studies have demonstrated that a diet rich in carotenoids is associated with a reduced risk of heart disease; while previous work in our laboratory has shown that the 9-cis β-carotene rich alga Dunaliella inhibits atherogenesis in mice. The effect of 9-cis β-carotene on macrophage foam cell formation has not yet been investigated. In the present work, we sought to study whether the 9-cis β-carotene isomer, isolated from the alga Dunaliella, can inhibit macrophage foam cell formation upon its conversion to retinoids. The 9-cis β-carotene and Dunaliella lipid extract inhibited foam cell formation in the RAW264.7 cell line, similar to 9-cis retinoic acid. Furthermore, dietary enrichment with the algal powder in mice resulted in carotenoid accumulation in the peritoneal macrophages and in the inhibition of foam cell formation ex-vivo and in-vivo. We also found that the β-carotene cleavage enzyme β-carotene 15,15’-monooxygenase (BCMO1) is expressed and active in macrophages. Finally, 9-cis β-carotene, as well as the Dunaliella extract, activated the nuclear receptor RXR in hepa1-6 cells. These results indicate that dietary carotenoids, such as 9-cis β-carotene, accumulate in macrophages and can be locally cleaved by endogenous BCMO1 to form 9-cis retinoic acid and other retinoids. Subsequently, these retinoids activate the nuclear receptor RXR that, along with additional nuclear receptors, can affect various metabolic pathways, including those involved in foam cell formation and atherosclerosis.

Because foam cell formation in macrophages is believed to play an essential role in the progression of early atherosclerotic lesions in vivo, prevention of foam cell formation is considered to be one of the major targets for the treatment of atherosclerosis. The present study examined the inhibitory effect of 50 crude plant extracts on foam cell formation. Among those crude extracts, Zizyphi Fructus (ZF) and Zizyphi Semen (ZS) extracts significantly inhibited the foam cell formation induced by acetylated LDL. Furthermore, triterpenoids such as oleanonic acid, pomolic acid, and pomonic acid were the major active compounds, and triterpenoids containing a carboxylic acid at C-28 play an important role in the inhibitory effect on foam cell formation in human macrophages. These data suggest that triterpenoids in Zizyphus jujuba , the plant source of ZF and ZS, may therefore be useful for the prevention of atherosclerosis.

PPARalpha, beta/delta, and gamma regulate genes involved in the control of lipid metabolism and inflammation and are expressed in all major cell types of atherosclerotic lesions. In vitro studies have suggested that PPARs exert antiatherogenic effects by inhibiting the expression of proinflammatory genes and enhancing cholesterol efflux via activation of the liver X receptor-ABCA1 (LXR-ABCA1) pathway. To investigate the potential importance of these activities in vivo, we performed a systematic analysis of the effects of PPARalpha, beta, and gamma agonists on foam-cell formation and atherosclerosis in male LDL receptor-deficient (LDLR(-/-)) mice. Like the PPARgamma agonist, a PPARalpha-specific agonist strongly inhibited atherosclerosis, whereas a PPARbeta-specific agonist failed to inhibit lesion formation. In concert with their effects on atherosclerosis, PPARalpha and PPARgamma agonists, but not the PPARbeta agonist, inhibited the formation of macrophage foam cells in the peritoneal cavity. Unexpectedly, PPARalpha and PPARgamma agonists inhibited foam-cell formation in vivo through distinct ABCA1-independent pathways. While inhibition of foam-cell formation by PPARalpha required LXRs, activation of PPARgamma reduced cholesterol esterification, induced expression of ABCG1, and stimulated HDL-dependent cholesterol efflux in an LXR-independent manner. In concert, these findings reveal receptor-specific mechanisms by which PPARs influence macrophage cholesterol homeostasis. In the future, these mechanisms may be exploited pharmacologically to inhibit the development of atherosclerosis.

Transport of cholesterol out of macrophages is critical for prevention of foam cell formation, the first step in the pathogenesis of atherosclerosis. Proteins involved in this process include cholesterol 27-hydroxylase and adenosine 5'-triphosphate-binding cassette transporter A1 (ABCA1). Proinflammatory cytokines and immune complexes (IC) down-regulate cholesterol 27-hydroxylase and impede cholesterol efflux from macrophages, leading to foam cell formation. Prior studies have suggested occupancy of the anti-inflammatory adenosine A2A receptor (A2AR) minimizes early atherosclerotic changes in arteries following injury. We therefore asked whether A2AR occupancy affects macrophage foam cell formation in response to IC and the cytokine interferon-gamma. We found that the selective A2AR agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido-adenosine (CGS-21680) inhibited foam cell formation in stimulated THP-1 human macrophages, and the effects of CGS-21680 were reversed by the selective A2AR antagonist 4-(2-[7-amino-2-(2-furyl) [1, 2, 4]triazolo[2,3-a] [1, 3, 5]triazin-5-ylamino]ethyl)phenol. In confirmation of the role of A2AR in prevention of foam cell formation, CGS-21680 also inhibited foam cell formation in cultured murine peritoneal macrophages but did not affect foam cell formation in A2AR-deficient mice. Agents that increase foam cell formation also down-regulate cholesterol 27-hydroxylase and ABCA1 expression. Therefore, we determined the effect of A2AR occupancy on expression of these reverse cholesterol transport (RCT) proteins and found that A2AR occupancy stimulates expression of message for both proteins. These results indicate that one mechanism for the antiatherogenic effects of adenosine is stimulation of the expression of proteins involved in RCT. These findings suggest a novel approach to the development of agents that prevent progression of atherosclerosis.

Triterpenoid compounds are one of the main functional components in jujube fruit. In this study, the optimal process for ultrasound-assisted extraction (UAE) of total triterpenoids from jujube fruit was determined using response surface methodology (RSM). The optimal conditions were as follows: temperature of 55.14 °C, ethanol concentration of 86.57%, time of 34.41 min, and liquid-to-solid ratio of 39.33 mL/g. The triterpenoid yield was 19.21 ± 0.25 mg/g under optimal conditions. The triterpenoid profiles and antioxidant activity were further analyzed. Betulinic acid, alphitolic acid, maslinic acid, oleanolic acid, and ursolic acid were the dominant triterpenoid acids in jujube fruits. Correlation analysis revealed a significant positive correlation between the major triterpenic acids and antioxidant activities. The variations of triterpenoid profiles and antioxidant activity within the jujube fruits and the degree of variation were evaluated by hierarchical cluster analysis (HCA) and principal component analysis (PCA), respectively. The results provide important guidance for the quality evaluation and industrial application of jujube fruit.

Jujube (Ziziphus jujuba Mill.), a highly nutritious and functional fruit, is reported to have various health benefits and has been extensively planted worldwide, especially in China. Many studies have shown that bioactive components derived from jujube fruit have significant nutritional and potential biological effects. In this paper, the latest progress in research on major bioactive compounds obtained from jujube is reviewed, and the potential biological functions of jujube fruit resources are discussed. As a dietary supplement, jujube fruit is well recognized as a healthy food which contains a variety of bioactive substances, such as polysaccharides, polyphenols, amino acids, nucleotides, fatty acids, dietary fiber, alkaloids, and other nutrients. These nutrients and non-nutritive phytochemicals obtained from jujube fruit have physiological functions including anticancer, antioxidant, anti-inflammatory, anti-hyperlipidemic, anti-hyperglycemic, immunoregulatory, neuroprotective, sedative, and antiviral functions. Of note is that new constituents, including alkaloids, dietary fiber, and other bioactive substances, as well as the antiviral, hypoglycemic, lipid-lowering, and neuroprotective effects of jujube fruit, are systematically reviewed here for the first time. Meanwhile, problems affecting the exploitation of jujube fruit resources are discussed and further research directions proposed. Therefore, this review provides a useful bibliography for the future development of jujube-based products and the utilization of jujube nutritional components in functional foods.

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to play a protective role against atherosclerosis in both animal models and patients with type 2 diabetes (T2D). However, since T2D is associated with dyslipidemia, hypertension and insulin resistance, part of which are ameliorated by DPP-4 inhibitors, it remains unclear whether DPP-4 inhibitors could have anti-atherosclerotic properties directly by attenuating the harmful effects of hyperglycemia. Therefore, we examined whether a DPP-4 inhibitor, teneligliptin, could suppress oxidized low-density lipoprotein (ox-LDL) uptake, foam cell formation, CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) gene expression of macrophages isolated from streptozotocin-induced type 1 diabetes (T1D) mice and T1D patients as well as advanced glycation end product (AGE)-exposed mouse peritoneal macrophages and THP-1 cells. Foam cell formation, CD36 and ACAT-1 gene expression of macrophages derived from T1D mice or patients increased compared with those from non-diabetic controls, all of which were inhibited by 10 nmol/L teneligliptin. AGEs mimicked the effects of T1D; teneligliptin attenuated all the deleterious effects of AGEs in mouse macrophages and THP-1 cells. Our present findings suggest that teneligliptin may inhibit foam cell formation of macrophages in T1D via suppression of CD36 and ACAT-1 gene expression partly by attenuating the harmful effects of AGEs.

Two beta-1,3-glucanase genes were cloned from jujube (Ziziphus jujuba Mill) fruit and designated Glu-1 and Glu-2 (GenBank accession numbers DQ012940 and DQ093571), respectively. The expression of Glu-1 and Glu-2 in jujube fruit in response to wounding and microbial biocontrol agent was evaluated by semi-quantitative reverse-transcription polymerase chain reaction analysis. Wounding and treatment with Cryptococcus laurentii stimulated an increase in beta-1,3-glucanase (EC 3.2.1.39) activity in jujube fruit. Analysis of gene expression proved that Glu-1 was highly induced both by wounding and C. laurentii, whereas Glu-2 was broadly not responsive to the yeast. The expression of Glu-1 was noticeably enhanced with increased concentrations of C. laurentii, suggesting that Glu-1 may play a role in defense responses to fungal pathogens. The results hold true at the levels of gene activation and enzyme accumulation in jujube fruit treated by both stimuli, resulting in a significant decrease in disease incidence and lesion diameter, thus providing evidence that changes in beta-1,3-glucanase activity are related to expression of the genes. Taken together, these findings suggest the possible use of beta-1,3-glucanase activity as a biochemical marker for screening jujube fruit against fungal pathogens, and also provide a mechanistic framework for the functions of beta-1,3-glucanase in defense responses.

The fruit Malus prunifolia (Malus micromalus Mak.), which belongs to the Rosaceae family, grows mostly in the upper-middle reaches of the Yellow River area. It has long been popular as a fruit commodity and as a natural remedy. Its main biologically active components include vitamin C, phenolics, flavonoids, polysaccharides, and triterpenic acids. Recent phytochemical studies on the fruit have shed some light on its biological activities, such as anticancer, immunomodulatory, antioxidant, immunostimulating, hepatoprotective, and gastrointestinal protective activities. A stronger focus on clinical studies and phytochemical characterization of the fruit will be essential for future research efforts. This minireview could be useful for predicting its other medicinal uses and its potential drug or food interactions, and it could be beneficial for people living in areas where the fruit is endemic and where healthcare resources are scarce.

Content variations of triterpenic acid, nucleoside, nucleobase, and sugar in jujube (Ziziphus jujuba) fruit during ripening

Fruits of two jujube (Ziziphus jujuba Mill.) cultivars were collected at four stages of ripening and analyzed in terms of chemical compounds. The cultivars were grown under the climatic conditions of the Sub-Carpathian area Ramnicu-Valcea in Romania (45°6′17″N, 24°22′32″E). Total phenols content, total flavonoids content, organic acids from jujube fruits and related antioxidant activities were investigated during the ripening stages. The antioxidant activity of alcoholic extracts was investigated by the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method. Total phenolic content was determined by using the Folin-Ciocalteu assay, while determination of flavonoids was done by aluminium nitrate colorimetric method, and organic acids were separated by reversed phase chromatography. The results obtained have indicated significant differences (p < 0.05) found in bioactive compounds and antioxidant activity, depending on cultivars and ripening stage. Total phenolic content ranged from 1634.44 to 472.38 mg GAE/100 g in methanolic extracts of the two varieties studied, while total flavonoids content ranged from 19.9 to 48.5 mg QE/100 g. As regards the influence of ripening stage, the results show that the highest antioxidant activity was recorded in the stage of white maturity. The impact of maturity stage was significant on organic acid distribution of jujube extracts, and ascorbic acid is the major organic acid found in jujube fruits, followed by malic acid and lactic acid. Jujube fruits are rich in bioactive compounds and can be a complement in human’s healthy eating.

This study was conducted to determine the effects of addition of jujube (Ziziphus jujuba Mill.) fruit at different rates into the mixed feed on intestinal morphology, antioxidant and some blood parameters of broiler chickens. A total of 160 male broiler chickens (Ross-308), including 40 in each group, were used in the study. The groups were divided into 4 sub-groups, each of which include 10 broiler chickens. The study groups were the control group ( the group without jujube fruit), the H-0.5% group (the group with 0.5% jujube fruit), the H-1 group (the group with 1% jujube fruit), and the H-2 group (the group with 2% jujube fruit). At the end of the experiment (42nd day), the control group had the highest levels of blood glucose, triglycerides, total cholesterol, VLDL cholesterol, ALT, AST, and uric acid, and the lowest level of creatine (P<0.05). While the lowest MDA level was detected in the H-2 group (P<0.001), the highest GSH (P<0.01) and CAT (P<0.05) levels were observed in the H-1 and H-2 groups. The control group also had the lowest values for villus height and crypt depth and the highest values for villus height/crypt depth (P<0.001). As a result, it was concluded that jujube fruit, which is mainly used for its antioxidant properties, can be used in poultry compound feeds especially at the level of 1% due to its positive effects on antioxidant and blood parameters and intestinal morphology.

We investigated the effects of T-2591, a new ureidophenol derivative, on low density lipoprotein (LDL) oxidation, acyl CoA: cholesterol acyltransferase (ACAT) and foam cell formation of macrophages in vitro. T-2591 inhibited both copper ion--and endothelial cell--induced LDL oxidation with higher potencies than probucol did. It inhibited ACAT from rabbit intestine, liver and aorta, the respective IC50 values being 0.26, 4.6 and 4.1 microM. It also inhibited ACAT from the mouse macrophage cell line J774 A.1, and its IC50 value (0.067 microM) was much lower than that of CI-976 (4.1 microM). This probably accounts for the inhibition of foam cell formation measured as cholesteryl ester formation in both mouse peritoneal macrophages and J774 A.1 cells at low concentrations (IC50; 0.06 and 0.44 microM, respectively). These observations suggest that T-2591 should be evaluated as a potential tool to retard atherosclerosis in animal models.