Phoenix dactylifera:traditional uses,chemical constituents,nutritional benefit and therapeutic effects

Ali Esmail Al-Snafi ,Mahdi Murshd Thuwaini

1Department of Pharmacology,College of Medicine,University of Thi-Qar,Nassiyriah P.O.Box 42,Iraq.2Department of Pathology,College of Medical and Healthy Techniques,Southern Technical University,Basrah FQ3F,Iraq.

Abstract Phoenix dactylifera(Fam:Arecaceae)is originated from the Mesopotamia.The date fruit,was eaten fresh,in various processed forms and dried.The fruits were used traditionally as general tonic,for the treatment of liver diseases,memory disturbances,fever,inflammation,paralysis,loss of consciousness,nervous disorders and consumed by pregnant women before and after delivery.However,all parts of the plant were used for some purpose.Dates fruits were considered a complete diet and a very important item of food,with plenty of vitamins and minerals.It contained a wide range of secondary metabolites.It possessed many pharmacological effects included anticancer,antidiabetic,anti-inflammatory,antimicrobial,antiparasitic,antioxidant,anti-toxin,cardiovascular,hypolipidemic,gastrointestinal,immunomodullatory,neural,hepato and reno-protective,reproductive and wound healing effects.This review highlighted the chemical constituents,nutritional and pharmacological effects of Phoenix dactylifera.

Keywords: Phoenix dactylifera;traditional;constituents;nutrition;pharmacology

Highlights

This report presents a comprehensive overview of the traditional uses,chemical constituents,nutritional benefit and therapeutic effects of date palm(Phoenix dactylifera).

Medical history of objective

Date palm has long been one of the most important fruit crops in the arid regions of the Arabian Peninsula.In ancient times,date palms were used traditionally as tonic,to enhance male and female fertility,for labour augmentation and to cure many diseases and infections.

Background

Date palm was originated from Mesopotamia.All parts of the plant were used for some purpose.The trunk and wood were used as timber,wood,or fuel.Fiber of the trunk and leaves were used to make baskets,bags,cords,camel saddles,crates,food covers,furniture,mats,fans,trays,paper,ropes,and twine.Dried bundles of leaves were used to make shades,separating walls,roofs,and enclosures.Ribs of the leaves were used to make fishing traps and boats.The base of the leaves and fruit stalks were used as fuel.The date fruit,can be eaten fresh,dried,or in various processed forms.Date palm contained many nutritional and therapeutic constituents,and it possessed a wide range of pharmacological effects.In the current review,databases including PubMed,Web Science,Science Direct,Researchgate,Academia.edu and Scopus were searched to investigate the chemical constituents,nutritional and pharmacological effects ofPhoenix dactylifera.

Synonyms

Palma majorandPalma dactylifera[1].

Taxonomic classification

Kingdom:Plantae

Subkingdom:Viridiplantae

Infrakingdom:Streptophyta

Superdivision:Embryophyta

Division:Tracheophyta

Subdivision:Spermatophytina

Class:Magnoliopsida

Family:Arecaceae

Genus:Phoenix

Species:Phoenix dactylifera[2].

Common names

Arabic:nakhl,nakheel,nakheel altamr,tamr,ratab,ajwa, balah;English:date,date palm;French:palmier dattier;German:Dattelpalme;Hindi:Khajur;Italian:Date;Portuguese:tamareira;Spanish:palmera datilera;Swedish:dadelpalm [3].

Distribution

Date was cultivated in the Middle East for more than 5,000 years(Figure 1) [4].According to the earliest record from Iraq(Mesopotamia),it was originated from the Mesopotamia [5].It was depicted in ancient Babylonian and Assyrian tablets,including theCode of Hammurabi[6,7].Dates were one of the important fruits in the dry regions of the Arabian Peninsula,Middle East and North Africa.Over the past 3 centuries,it has been introduced in Pakistan,India,Australia,Mexico,South America,United States and Southern Africa.Dates were the staple food and essential income source in many countries [7].Now,it was cultivated in wide areas.Long summers with high day and night temperatures,and mild,sunny,dry winters without prolonged frost are the ideal climatic conditions for this species[8-10].

Figure 1 Date palm tree (Balaram Mahalder,CC-BY-SA-3.0) and fruits. (https://www.britannica.com/plant/date-palm)

Traditional uses

The date fruit,was eaten fresh,in various processed forms and dried.Fruits were harvested when they were fully ripened(Tamar and Rutab stages),which were low in moisture,high in sugar and low in tannin,but in North Africa,the dates were eaten during the Khalal stage,which contained high tannin and very astringent [11-13].All parts of the plant were used for some purpose.The trunk and wood were used as fuel.Fiber of the trunk and leaves were used to make baskets,bags,cords,food covers,crates,camel saddles,furniture,mats,fans,trays,ropes,paper,and twine.The dried leaves bundles were used to make shades,separating walls,roofs,and enclosures.Ribs of the leaves were used to make fishing traps and boats.The base of the leaves and fruit stalks were used as fuel.Palm heart was eaten as a salad.Oil of date seeds was used for soap manufacturing.Date fruit also used medicinally [6,11,14].It was used as nutrient,heart tonic,aphrodisiac,laxative,demulcent and expectorant.It was traditionally used in fatigue,diabetes,hypertension,chest complaints,cough,asthma and gastroenteritis[15-17].In traditional medicine,the use of date fruit is recommended for treatment of liver diseases and to be consumed by pregnant women before and after delivery [18].The dates fruits and pollen grain were used to improve fertility in women[19].Fruits were also used for fever,inflammation,loss of consciousness,memory disturbances,nervous disorders and paralysis[20].

Chemical constituents

Dates ripen in four stages: Kimri (the immature green),Khalal (the mature full-colored,crunchy),Rutab (ripe,soft),and Tamar (ripe,hard,reduced moisture).The stages were differed in their constituents[21].Dates are considered a complete diet and a very important item of food,with plenty of vitamins and minerals.The proximate composition,of the fruit flesh was: moisture 8.3-29.5,ash 1.4-2.3,protein 1.8-2.5,lipids 0.1-0.5,glucose 14.8-36.7,fructose 12.3-36.5,sucrose 0-38,fiber 2.7-23.8 (g/100 g fresh weight) and energy 239-322 (kcal/100 g fresh weight) [22].Proximate analysis of of 21 date palm accessions in Nigeria,revealed that they contained moisture 2.25-7.65,ash 1.56-2.7,protein 3.36-6.26,lipids 2.69-5.46 and carbohydrate 64.55-82.85% [23].Proximate composition of dried dates (Phoenix dactylifera) from Pakistan were: moisture 0.84-9.8%,ash 1.82-2.39%,protein 32.50-41.25%,lipid 9.05-24.08%,carbohydrate 37.79-45.94%,oxalate 0.192-1.128 g/100 mL,fiber 62.11-86.08% and energy 352.329-425.147 kcal/100 g [24].The main fatty acids in date palm cultivars were lauric acids 18.5-23.2 %and oleic 38.5-42.3%.Fractionation of the lipids ofPhoenix dactyliferaseed oil gave neutral lipids 98.3-97.3%,phospholipids 0.25-0.18%,triglycerides 97.26-96.9% and sterols 0.36-0.31% [25-28].The main fatty acids in the seeds were 36.69%oleic,20.49%lauric acids.While,the main fatty acids in the pollen were 22.27 % palmitic,33.4%linoleic and 17.055% linolenic acids[29].

The amino acids extracted from the date palm fruits were: proline 491.798,arginine 364.478,histidine 210.789,glutamic acid 147.538,aspartic acid 106.247,glycine 103.286,valine 66.425,leucine 57.894,isoleucine 41.333,lysine 33.68,phenylalanine 30.095,serine 27.786,threonine 21.364,tyrosine 17.010,ammonia 14.532,methionine 12.082 and alanine 1.942 μg/mL [30].Minerals identified in the date palm included: magnesium 31-150,sodium 1-261,calcium 5-206,phosphorus 35-74,potassium 345-1287,manganese 0.01-0.4,iron 0.1-1.5,zinc 0.02-0.6,copper 0.01-0.8 and selenium 0.24-0.4 mg/100 g [31].Vitamins contents per 100 g of the fruit were:riboflavin: 0.066 mg,niacin: 1.274 mg,pantothenic acid: 0.589 mg,thiamine: 0.052 mg,vitamin B6: 0.165 mg,folate: 19 μg,vitamin C:0.4 mg,vitamin E: 0.05 mg,vitamin K: 2.7 μg[32-36].

The total phenolic compounds content of the aqueous extract of the(Tamer stage)fruit was 14.80 ±0.61 and ethanolic extract was 10.31± 0.29 mg gallic acid equivalent/g [37].However,the highest phenolic quantity was recorded in the methanol extract of the leaves 74.4 mg/g,lethanol extract of the leaves 67.3 mg/g,and the methanol extract of the seeds 64.7 mg/g [38].Phenolics identified in date fruits were included: benzoic acids and derivatives (p-hydroxybenzoic acid,protocatechuic acid,gallic acid,syringic acid,sinapic acid and vanillic acid);cinnamic acid and its derivatives (hydrocaffeic acid,caffeic acid,p-coumaric acid,ferulic acid,dactyliferic acid,syringic acid,3-caffeoylshikimic acid,2-caffeoylshikimic acid hexosides,4-caffeoylshikimic acid,5-caffeoylshikimic acid,dicaffeoylsinapoyl hexoside and caffeoylsinapoyl hexoside);flavonoid glycosides and esters (rutin,luteolin,apigenin,quercetin,quercetin hexoside sulfate,quercetin acetyl-hexoside,quercetin rhamnosyl-hexoside,isorhamnetin hexoside,isorhamnetin acetyl-hexoside,isorhamnetin-3-O-rutinoside,chrysoeriol rhamnosyl-hexoside,chrysoeriol hexoside sulfate,chrysoeriol hexoside,and isoquercitrin),(-)-epicatechin and flavan-3-ols ((+)-catechin);proanthocyanidins(procyanidin B1,procyanidin B2,procyanidin pentamer,procyanidin trimer,procyanidin tetramer,and anthocyanins cyanidin) [33-36,39-43] (Table 1).

Table 1 Some polyphenols identified in date palm fruits

However,many flavonoids were isolated from the date palm seeds extract,included isoquercetrin,apigenin 7-O-β-D-apiofuranosyl-(1 2)-O-β-D-glucopyranoside,apigenin 7-O-β-D-apiofuranoside,luteolin 7-O-β-D-neohesperopyranoside,luteolin 7-O-β-D-neohesperopyranoside 3-O-methylether,acacetin 7-O-β-D-neohesperopyranoside,genistein 8-C-β-D-glucopyranoside,quercetin and rutin [45].Dates contain high levels of pectin,6.7% in the unripe and 2.3% in the ripe fruits [46].The yellow color characteristic of the dates is flavon or flavenol,the red color is anthocyanins,and the color of Jamri is carotene mixed with chlorophyll [47].Carotenoids (beta-carotene,lutein,lycopene,violaxanthin,flavoxanthin,neoxanthin,leukoxanthin) were identified in the date palm fruits [40,48-49].

Pharmacological effects

Antimicrobial effects

The results of an antibacterial assay revealed that the methanolic extract of the seeds of date palm inhibited the growth ofPseudomonas fluorescens,Escherichia coli,Staphylococcus aureusandBacillus subtilis,(zone of growth inhibition 7-14.5 mm) [44].

The antibacterial effects of different extracts of the fruit and leaves of date palm were studied againstEscherichia coli,Staphylococcus aureus,Bacillus subtilis,andPseudomonas aeruginosa.The extract of the date palm leaves possessed inhibitory activity against the growth ofStaphylococcus aureusandBacillus subtilis,whilePseudomonas aeruginosaandEscherichia coliresisted the extract.Minimum inhibitory concentration of ethanolic (70%) and methanolic leaves extract was 250 and 100 mg/mL againstStaphylococcus aureusandBacillus subtilis,respectively [38].

The antibacterial effect of date palm pits was studied againstKlebsiella pneumoniaandEscherichia colidate palm possessed antibacterial activity against the tested pathogenes mediated by changing of membrane permeability [50].

The antimicrobial activity of the seeds of dates cultivars from Tunisia was studied against 5 pathogenic bacteria (Staphylococcus epidermis,Staphylococcus aureus,Escherichia coli,andSalmonella typhinurium).The extracts showed antibacterial activity against all the tested pathogens exceptEnterococcus feacalis[51].

The extract of 4 date cultivars possessed variable antibacterial properties.Only the Ajwa methanol extract exerted antibacterial effects against all the tested bacteria (Escherichia coli,Bacillus cereus,Staphylococcus aureusandSerratia marcescens)[52].

The antibacterial activity of the essential oil extracted form spathe(by-product from date palm) was evaluated against food-borne bacteria.The essential oils inhibited the growth ofEscherichia coli,Salmonella enteric,Listeria monocytogenes,Staphylococcus aureus(11-13 mm).Escherichia coliandStaphylococcus aureuswere not recorded in the meat of chicken treated with essential oils 1% (v/w) and stored at 20°C for 18 h [53].

The antimicrobial effect of the fruit extracts was investigated against 5 pathogenic bacterial isolates.The date palm fruits extracts(aqueous and ethanolic) showed strong antibacterial activity against

Salmonella enterica(20 and 14 mm),Escherichia coli(20 and 16 mm),andBacillus sabtilis(18 and 15 mm) respectively,and showed moderate activity againstEnterococcus faecalis(5 and 2 mm) andStaphylococcus areues(8 and 5 mm) respectively [37].

The aqueous extracts of 5 date fruit possessed potent antibacterial activity (62-76%) againstStaphylococcus aureus,Bacillus subtilis,Salmonella typhimurium Escherichia coli,andPseudomonas aeruginosa[54].

The antimicrobial activity of date palm seed cake hexane and ethyl-acetate extracts was studied againstEscherichia coli,Pseudomonas aeruginosa,Klebsiella pneumonia,Proteus mirabilis,Proteus vulgaris,methicillin-resistantStaphylococcus aureus,andEnterococcus faecalis.Methicillin-resistantStaphylococcus aureuswas highly sensitive to the seed extract,followed byEnterococcus faecalis.Mild activity was recorded againstPseudomonas aeruginosaandEscherichia coli,whileProteus mirabilisshowed more sensitivity [55].

A non-randomized controlled trial was performed to determine the effects of Ajwa (Phoenix dactylifera) intake against many infections associated with neutropenia,fever,and pediatric cancer mortality in King Abdulaziz Hospital (Saudi Arabia,Jeddah).26 patients were given Ajwa (3 pieces/day,7.33 ± 0.399 g) and 30 patients were served as controls.The Ajwa group had a better survival rate in comparison to the non-Ajwa group,the progression of the infections(77) was the major death cause in the non-Ajwa group [56].

Organic extract of Deglet Nour date palm seeds exerted potent antibacterial effect againstEscherichia coli.The pollen extract possessed potent activity againstStaphylococcus aureus,methicillin resistantStaphylococcus aureus,Escherichia coliandEnterococcus faecalis.Aqueous extracts of the seeds and pollen showed antifungal effect at 6-12 mg/mL.The organic extracts of pollen at a concentration of 90 μg/mL induce an inhibition of the growth of five species ofFusarium oxysporum[57].

The best antifungal effect was exerted by the cultivar Bent-Cherk’rachis dichloromethanic extract (6.5 mm) and the cultivar Rotbi’rachis ethyl acetate extract (6mm) [58].However,the antifungal effect of water,acetone and methanol extracts of leaves and pits ofPhoenix dactyliferaL.var.Barhee and Rothana were evaluated againstFusarium oxysporum,Fusarium sp.,Fusarium solani,Aspergillus flavus,Alternaria alternata,Alternariasp.andTrichodermasp.Alternaria alternatawas the most sensitive fungi (growth inhibition 51.6%).The IC50 of methanol pits extract againstFusariumandAlternataspecies was 6.7-2.8 mg/mL [59].

The acetone extract of date palm pit reduced thePseudomonasphage infectivity and completely inhibited the lysis ofPseudomonas aeruginosa.The antiviral effect was mediated through binding with the phage (minimum inhibitory concentration: ＜10 μg/mL) [60].

Antiparasitic effect

The anti-Toxoplasmaeffects of silver nanoparticles synthesized in combination with extracts of natural plants (Phoenix dactyliferaandZiziphus spina-christi) were studied in mice.Pretreatment with nanoparticles prevented hepatic damage,it maintained the activity of the liver enzymes,significantly inhibited liver nitric oxide levels and significantly increased hepatic superoxide dismutase (SOD) and catalase activities,significantly decreased inflammatory cytokines[61].

The anti-Leishmanialeffect of the methanolic extracts of date palm pit and fruit was investigated againstLeishmania majorpromastigotes.After 48 hours of exposure,IC50s of methanolic extracts of fruit and pit were 500 mg/mL and 23 μg/mL,respectively.Both extracts possessed time and dose-dependent effects againstLeishmania majorpromastigotes[62].

The effect of the water extract of Khodary date fruit (4 mL/kg) on the outcome ofEimeria papillatainduced coccidiosis was investigated in mice.The extract reduced the faecal output of the oocysts/g.The extract reduced the parasitic stages number in the intestinal villi to about 52%.It also reduced the histopathological lesions of the murine jejunum [63].

Antioxidant effect

The polyphenol,flavonoid contents and activity of the seeds of 11 dates cultivars were studied in Tunisia.Khadhouri cultivar showed the highest phenolic content (9.532 g/100 g),flavonoids content (3.82 g/100 g)and antioxidant activity (55.47%) [64].

In studying of total phenolics and antioxidant effects of five Algerian date,it appeared that the total phenolic content was 5.9-23.05 mg gallic acid equivalents/100 g.The IC50 on superoxide anion radical was 33.17-85.23 mg/L [65].

The radical scavenging effect of lyophilized extract (6.5-100 mg)was investigated using 1,1-diphenyl-2 picrylhydrazyl radical-scavenging activity test.The ethanol and aqueous extract showed high free radical scavenging effect and antioxidant activity.The percentage inhibition of the aqueous fruit extract were 19.52-79.32 for concentrations 6.5-100 mg.The inhibition(%) of the ethanolic extract of the fruit was 10-66.51 for concentrations 6.5-100 mg[37].

The antioxidant effect of the fruit extract was evaluated by 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)method.Different varieties showed different antioxidant effects (IC50:11.3-19.1 mmol equivalents/100 g dry weight) [54].

The maximum total antioxidant activity was recorded in biser,followed by unripe stage and soft and ripped.A sharp decrease in antioxidant activity was found to be associated with the fruit ripening[66].

The antioxidant activities of the aqueous extract of the fruits of the date palm were investigated in vitro.The extract possessed inhibited dose-dependently the hydroxyl and superoxide radicals [67].

ThePhoenix dactyliferahydroethanolic extract possessed potent scavenging activity by 1,1-diphenyl-2 picrylhydrazyl radical-scavenging activity(IC50 value of 0.15 mg/mL) [68].

Date fruit phenolic-acid or flavonol fractions of two date(Amari and Hallawi) varieties were examined in vitro for antioxidant effect.All fractions possessed different abilities to decrease scavenge radicals,ferric ions,and inhibit oxidation [69].

The essential oils extracted from date palm spathe showed potent radical scavenging effect (IC50: 0.61 μg/mL) [70].

Cardiovascular effects

Date fruit provide protective effects against cardiovascular disease,by reducing blood pressure,serum lipids,lipid oxidation,and amelioration of oxidative stress.The anti-hypertensive effect of date palm was mediated by inhibition of the activity of angiotensin converting enzyme,the effect which attributed to the phenolic contents of the fruits [71-72].

The effect of the extracts of date palm fruits of four varieties in repairing tissue injury following myocardial infarction using the in vivo isoproterenol model in rats.The extracts,which showed high levels of phenolic and flavonoid compounds,have the potential to mobilize endogenous circulating progenitor cells,which can promote tissue repair following ischemic injury [73].

The preventive role of oral hydroethanolic extract of thePhoenix dactyliferaheart (250 and 500 mg) in nephro and cardiotoxicity induced by adriamycin was investigated in rats.At adose of 500 mg/kg,the extract possessed significant decline in nephro and cardiotoxicity serum markers,apoptosis,cyclooxygenase-2,caspase-3 and improved the antioxidant status in kidney and heart homogenate[74].

The cardioprotective activity of lyophilized extract of Ajwa date was studied in vivo and in vivo.In vivo cardioprotective activity was evaluated against DCFH-induced toxicity of cardiomyoblast cells.In vivo cardiac function,hemodynamics,cardiac enzymes activities,myocardial apoptotic,inflammatory,antioxidant biomarkers and histopathological finding were investigated in cardiomyopathy induced by isoproterenol in rat.In vitro,the extract (250 μg/mL)enhanced the proliferation of cardiomyoblast cells and ameliorated the cytotoxic effect of DCFH.While 250 and 500 mg/kg,of the extract orally,reduced the depletion of antioxidants,enzymes marker of myocyte injury,reduced lipid peroxidation,downregulated of the proinflammatory cytokines expressions and apoptotic markers.The extract also reduced the histopathological changes associated with isoproterenol [75].

The Ajwa nanoformulated bioactive compounds (quercetin and rutin) protected against doxorubicin-mediated cardiomyopathies in mice.It significantly reduced doxorubicin induced weight loss in mice,significantly reduced the elevated cardiac troponin-I,and decreased the doxorubicin induced histological changes in heart muscles of micen [76].

Hypolipidemic effect

The antihyperlipidemic effect of the polyphenols extract of Ajwa date(25-100 mg/kg) was investigated in cholesterol-rich fed rats.Cholesterol-rich diet elevated liver and body weights significantly,increased lipid in the serum and in the liver,and decreased HDL content and antioxidant enzyme activities.The extract,when administered orally,it decreased liver and body weight,hepatic contents of lipids,improved HDL level and antioxidant enzyme activity significantly [77].

The methanolic extract of the date seed at 200 mg/kg,decreased the serum lipids,increased serum HDL and prevented body weight gain in hyperlipidemia induced by high fat diet in rats,significantly [45].

The ameliorative role of date fruit suspension,300 and 600 mg/kg for 14 days in hyperlipidemia and fatty liver,was studied in rats.Fasting serum lipids and blood glucose,and the activity of hepatic enzymes,were significantly reduced at the low and high doses [78].

Freeze-dried dates fruit extracts were tested in modulation of nuclear receptor-mediated transactivation.The activity on potent farnesoid X receptor (FXR)-target genes which regulated bile acid transport and absorption was tested in Caco-2 cells.The results revealed that the extract acts as a co-agonist ligand for FXR,activating bile acid-binding FXR more than that seen with bile acid alone.Accordingly,dates could be exerted hypolipidemic activity by modulation of the homeostasis of bile acid [79].

The activity of the date seeds methanolic extract on arylesterase and paraoxonase activities was investigated in hyperlipidemic rats.Administration of seed extract significantly increased serum arylesterase and paraoxonase activities in treated hyperlipidemic rats.However,the extract did not change the total antioxidant capacity in hypercholesterolemic groups significantly [80].

The effect of consumption of two varieties of dates: Medjool and Hallawi (100 g/day for 4 weeks) was investigated on serum oxidative status,glucose and lipid levels in healthy human subjects.The consumption of date did not affect the body mass index and lipid profile significantly.The consumption of date reduced triacylglycerol levels while serum glucose was not elevated.The serum oxidative status was reduced by 33%,in comparison to that recorded before consumption,after Hallawi date consumption.Hallawi date consumption increased the antioxidant enzyme paraoxonase 1 by 8%[81].

Antidiabetic effects

The antidiabetic effectofPhoenix dactyliferaseeds aqueous suspension was studied in rats.Oral administration of the suspension significantly ameliorated the elevated levels of glucose,urea,creatinine,ALT,and AST in streptozotocin-induced diabetic rats.It also significantely augmented the activities of antioxidant enzymes,and improved the histological structure of the kidney and liver of diabetic rats [82].

The hypoglycemic effects of date fruit (variety Aseel) oral suspension (300 and 600 mg/kg) were evaluated in normoglycemic and alloxan induced hyperglycemic rats.The results reveal that Aseel dates possessed significant anti-hyperglycemic effects in diabetes rats[83].

The antidiabetic activity of date palm leaves hydroalcoholic extract was investigated in vitro and in mice models of type II diabetes.The in vitro investigation revealed that the extract possessed potent inhibition of α-glucosidase (IC50: 20 μg/mL),and less inhibition of α-amylase (30 ± 0.8 μg/mL).In diabetic mice,the extract at 20 mg/kg reduced the glucose after 60 min.Marked hypoglycemic activity in alloxan-induced diabetic mices,was recorded by the extract(orally,20 mg/kg) for 28 days [84].

The effects of aqueous and methanolic extracts of palm dates (fruits and seeds,for 15 weeks)on diabetic nephropathy were studied in a rat model of type 2 diabetes mellitus.The fruit extracts,especially aqueous extract possessed potent hypoglycemic effect than seed extracts[85].

The hydroethanolic extract fromPhoenix dactyliferaparthenocarpic dates possessed more specific inhibition of α-glucosidase than α-amylase (IC50: 0.6 and 2.5 mg/mL,respectively).The extract decreased postprandial hyperglycemia in vivo after 30 minutes [86].

Anticancer effect

The anticancer activity of the hydroethanolic extract ofPhoenix dactyliferawas evaluated against MCF-7 and MDA-MB-231 cancer cell lines.The extract inhibited MDA-MB-231 and MCF-7 multiplication(IC50: 18 and 8 mg/mL,respectively,after 72 h) [68].

The extract of the date fruit inhibited the mutagenecity induced by benzo(a)pyrene on Salmonella TA-100 and TA-98 in a dose-dependent manner [67].

The antiproliferative activity of the Ajwa date methanolic extract was investigated in vitro against MCF-7 cell line.The extract significantly and dose-dependently inhibited MCF-7 cell proliferation from 35% to 95% by arresting the cell cycle and induction of apoptosis[87].

The anticancer effect ofPhoenix dactyliferaleaves hydroalcoholic extract of against human melanoma-derived cell line.At a dose of 35 and 75 μg/mL,the extract inhibited the growth of the cell line[88].

The effect of Ajwa date fruit (Phoenix dactylifera) extract (at 400,800 mg/kg body weight/d) was studied after 7,12-dimethyl benz(a)anthracene induction for 30 days to study its activity in modulation of NK cells,TNF-α,and development of breast cancer.The Ajwa date fruit extract normalize the level of circulatory CD161 NK cells and breast tissue TNF-α,cell size and proliferation,and improve overall survival rates [89].

The induction of apoptosis by the Ajwa date pulp ethanolic extract was studied against HepG2 cells.Treated human hepatocellular carcinoma cells revealed morphological characteristics of apoptosis under phase contrast microscopy.The extract caused significant doseand time-dependent inhibition of human hepatocellular carcinoma cell growth[90].

The protective effect of a date-pit extract (1.5 mL/day,orally for 2 weeks) was investigated against azoxymethane-induced colonic carcinogenicity and oxidative stress in rats.Date-pit extract contained phytonutrients that were capable of inhibiting chemically-induced oxidative stress in the rat colonic cells [91].

The water,ethanol,acetone,and ethyl acetate extracts of date palm fruit were studied for anticancer effect in TNF stimulated pancreatic stellate cells in vitro.The pancreatic stellate cell proliferation was significantly reduced by acetone,ethyl acetate,and ethanol extracts but not by an aqueous extract[92].

Gold and silver nanoparticles were prepared from the date palm pollen extract.The nanoparticles possessed anticancer effect against MCF-7 cells.The extract down-regulated the anti-apoptotic protein Bcl-2 and upregulated the pro-apoptotic protein p53[93].

However,the of various concentrations of n-hexane and aqueous extracts of date palm fruit was studied against HFFF2,A172 and A2780 cell lines.N-hexane and aqueous extracts of date enhanced cell proliferation in a dose dependent manner.The authors mentioned that the disagreements with the previously recorded cytotoxic effect of date fruits could be attributed to different characteristics of cell lines,different extraction solvents and different type of date fruits[94].

Hepato-and reno protective effect

The protective effects of aqueous extracts of the flesh and pits of dates against hepatotoxicity induced by CCl4 in rats.The aqueous extracts of the flesh and pits of dates decreased CCl4-induced elevation of bilirubin level and liver enzymes activities and restored the histological structure of the liver [95].

The hepatoprotective effect ofPhoenix dactyliferaseeds aqueous suspension and the proanthocyanidin rich extract of the seeds was studied in CCl4-induced liver toxicity in rats.The deterioration of liver functions by CCl4 was improved by the extract significantly.It also attenuated the deterioration in the oxidative status and the histological lesions triggered by CCl4.However,the aqueous extract of flesh or pits,also decreased hepatic inflammation and oxidative DNA damage induced by CCl4 in rats [96-98].

The hepatorotective effect of the extract of Ajwa date was studied against CCl4-induced hepatic toxicity in rats.Ajwa date significantly reduced the serum ALP,ALT and AST,triglycerides,total cholesterol,LDL,lipid peroxidation and elevated hepatic antioxidant parameters[99].

The role of date palm fruit extract in protection against oxidative damage and hepatotoxicity induced by subchronic exposure to dimethoate (20 mg/kg/day) were studied in rats.Date palm fruit extract ameliorated the dimethoate induced hepatic damage,as revealed by reducing of lipid peroxidation,enhanced antioxidant status and improved histopathology changes [100].

The hepatoprotective and hypolipidemic effects of the extract of the Ajwa date seed was studied against the toxicity of atorvastatin in hyperlipidemia induced by high-fat diet in rat.Ajwa seed extract decreased the serum cholesterol in high-fat diet rats and ameliorated atorvastatin hepatotoxicity by reduction of the levels of hepatic enzymes and enhancement of antioxidant parameters [101].

The protective activity of date palm fruit aqueous extract on hepatotoxicity induced by trichloroacetic acid was investigated in rats.The fruit extract alliviated the liver injury induced by trichloroacetic acid,it reduced lipid peroxidation,enhanced antioxidant parameters and improved histopathology changes[102].

The protective effect of aqueous suspension(50,100 mg/kg)of date palm pollen and aqueous and methanolic leaves extracts on paracetamol triggered hepatorenal damage was investigated in rats.Pretreatment with date palm pollen aqueous suspensions significantly prevented paracetamol induced hepatic and renal toxicity,as determined by biochemical,antioxidant and histological investigation[103-104].

The hepatoprotective effect of date flesh and pits extracts was studied in CCl4-induced liver fibrosis.Treatment by both extract significantly attenuated the CCl4-induced elevation of the levels of caspase 3,Bax,Fas,and CYP2E1.The extracts also elevated the decline levels of HO-1,HGF,Bcl2,and the anti-apoptotic factors in liver [105].

The hepato-and reno-protective activities of date palm ethanolic and aqueous extracts (300 mg/kg,for 7 days) in hepato-and reno-toxicity induced by azithromycin were investigated in rabbits.Lipid profile,liver function and kidney fuction tests,were improved significantly in comparison with untreated azithromycin group [106].

Nephro-protective effect of the extract of the flesh and pits of dates was investigated in gentamicin induced nephrotoxicity in rats.The date flesh and pits significantly reduced gentamicin induced elevation of plasma creatinine and urea and ameliorated the damage to proximal tubular [107].

Radioprotective effect

Rats pretreated with date fruit syrup showed reduction of the tissue damage induced by whole body radiation at 6 Gy.Date fruit syrup improved antioxidant status,liver biomarkers,and reduced DNA damage,serum MMP-9 activity and the expression of liver TNF-α[108].The pretreatment of rats prior to irradiation with date pits extract caused higher survival rate after exposure to γ-irradiation at different doses.The extract also improved the hepatic redox status significantly,markedly elevated HDL,testosterone,insulin,and the activity of the liver glucose 6 phosphate dehydrogenase.It also positively modulated the hepatic enzyme activities [109].

The radioprotective effect of date palm seed extract was investigated in mice after total body gamma irradiation.The results showed that the extract injected into mice before irradiation has no toxicity and could protect mice from lethal effects of total body irradiation.It increased the number of mice surviving at the termination of the experiment [110].

Lung protective effect

The protective effect of date palm sap on bleomycin-induced lung fibrosis was investigated in rats.Bleomycin increased lipid peroxidation and SOD levels and decreased CAT activity.It also induced inflammation and accumulation of bundles of collagen in lung.Date palm sap normalized MDA,SOD,and CAT levels,decreased hydroxyproline level and morphological lesions induced by bleomycin[111].

Reproductive effects

The past and recent literature regarding the effect of date consumption on infertility-related problems showed that the date palm possessed marked beneficial effects on the male reproductive functions,included semen quality and pituitary and testicular hormones.On the other hand,date fruits possessed beneficial effect on female reproductive functions included regulation of pituitary and ovarian hormones,oogenesis process,strengthening of pregnancy,decreasing of the requirement for augmentation and induction of labor,and prevention of postpartum hemorrhage[112].

Estrone was identified in date palm seeds,pits and pollen [113].Investigation of date pits of eight cultivars grown in the Kingdom of Saudi Arabia showed that,only two cultivars contained estrone[114].

The effects of the ethanol extract (140,280,and 560 mg/kg,for 34 days)ofPhoenix dactyliferafruit in Khalal stage,on male fertility were investigated in mice compared with propolis.Ethanol extract of Khalal date fruit and propolis increased sperm count,sperm motility,and weight of testes.Ethanol extract of Khalal date fruit can increase sperm quality higher than propolis [115].

The effects of date palm pollen (120,240 and 360 mg/kg,orally for 35 days) on fertility were studied in healthy adult male rats.Date palm pollen significantly raised the relative testis and epididymis weights,sperm count and motility and the diameter of seminiferous tubules.Testosterone and luteinizing hormone (LH) levels significantly increased at 120 mg/kg of date palm pollen [116].

The protective effect of the extract of date palm pollen (0 or 40 mg/kg/day for 56 consecutive days,orally) in averting the reproductive damage induced by CdCl2 was studied in male rats.CdCl2 exposure induced significant reduced the weight of the reproductive tissues,decreased the level of testosterone,reduced sperm count and sperm motility,increased sperm malformation ratio,increased oxidative stress,and induced histological changes.The extract attenuated all the adverse effects of CdCl2 on the reproductive organs and restored the normal limits[117].

The effects of the suspension of the pollen ofPhoenix dactyliferaon the blood glucose,antioxidant defense system and testicular dysfunctions,were studied in male rat diabetes induced by streptozotocin.Diabetic rats showed significantly hyperglycemia deterioration of antioxidant status,and testicular and pancreatic histological damage.Streptozotocin also significantly reduced the weights of the body,pancreas and testis,serum LH,follicle-stimulating hormone(FSH),testosterone,insulin,sperm count,sperm viability,and sperm motility.The suspension of date palm pollen significantly improved of all these parameters,and enhanced the testicular antioxidant system [118].

Date palm pollen (500 mg iq) alone and in a combination of zinc sulphate significantly elevated serum testosterone,LH and FSH levels in infertile men.Date palm pollen also,increased sexual desire,sperm count and motility significantly.The occurrence of the pregnancy was increased in wives of men treated by date palm pollen [119-120].

The protective effect of date palm pollen extract(56 days treatment with 150 mg/kg daily) on thyroid disorder-induced testicular dysfunction was investigated in rats.L-thyroxine or propylthiouracil lowered genital sex organs weight,sperm count and motility,serum LH,FSH,testosterone,testicular function markers and activities of testicular 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase.The extract protected against the adverse effects of L-thyroxine or propylthiouraci on fertility parameters [121].

The protective effect of the aqueous extract of date fruit,against the toxic effect of atrazine on testes,was studied in rats.Atrazine caused a significant reduction in the sperm count,sperm malformation ratio,sperm motility,testicular weight,with significant increase in the testicular lipid peroxidation and significant decline in the antioxidant enzymes and increased.The fruit aqueous extract restored the antioxidant enzymes levels,increased sperm count,sperm motility and testicular weight,and decreased sperm malformation ratio and testicular lipid peroxidation [122].

The prophylactic effect of 4 mg/kg for 35 days of date palm fruit extract against testicular toxicity induced by formaldehyde was investigated in male mice.Formaldehyde increased the percentage of sperm malformation and decreased sperm count,sperm viability,sperm motility,and the level of testosterone in comparison to the control group.Formaldehyde also induced histological changes(germinal epithelium destruction and tubules vacuolization).The consumption of date palm fruit extract before formaldehyde partially ameliorate the decreased testosterone and testicular parameters deterioration caused by formaldehyde[123].

The effect of date palm pit powder on spermatotoxicty induced by nicotine was investigated in male mice.Partial recovery from nicotine-induced spermatotoxicity was recorded after withdrawal of nicotine treatment,whereas near normal restoration was achieved after administration of date palm pit powder after the stopping of nicotine[124].

The protective effect of aqueous date extract (4 mL/kg for 2 months) was studied in testicular injury induced by dichloroacetic acid in rats.The absolute weights of testes and epididymis were decreased following the dichloroacetic acid administration.The testosterone,FSH and LH levels were also decreased.The antioxidant status was declined.Severe histopathological changes were recorded,included seminiferous tubules degeneration and germ cells depletion.The extract was markedly ameliorated the deteriorated antioxidant status induced by dichloroacetic acid and restored the testicular parameters to normal values[125].

Pollen grain aqueous extract supplemented mice follicles maturation media showed that the extract significantly increased the maturation [126].

A prospective study was performed on 69 women consumed 6 date fruits in the last 4 weeks of pregnancy,to determine the effect on delivery outcomes.Compared with non-consumers,the women consumed date fruit showed significantly more cervical dilatation(3.52 cm vs 2.02 cm),higher percentage of healthy membranes(83% vs 60%) more spontaneous labor (96% vs 79%),lower prostin/oxytocin usage (28% vs 47%) and shorter latent phase of the first stage of labor (510 min vs 906 min) [127].

A meta-analysis was performed on six clinical studies to investigate the effects of date palm fruit on labor outcomes (duration of labor stages,bishop score and frequency of cesarean section).The date fruit consumption significantly reduced active phase of labor,duration of the first stage of labor and significantly improved the bishop score and insignificantly reduced the frequency of cesarean section [128].

In a clinical trial investigated the effect of consumption of date fruit during late pregnancy on the onset of labour and requirment for augmentation of labor.The dates-consumer nulliparous females showed less need for labour augmentation,but the date consumption didn’t hasten the onset of labor [129].

The analysis of studies investigated the effects of consumption of date fruits on pregnancy,labor,and delivery outcomes showed that date consumption significantly decreased the duration of pregnancy,increased cervical dilation on admission,and decreased the duration of the first and second stages of labor [130].

The preventive effect of daily intake of seven Ajwa dates on preeclampsia,before and after 8-week intervention period,was investigated using the roll-over test and the mean arterial pressure.The mean arterial pressure and roll-over test were significantly decreased after 8-week intervention period in the intervention group[131].

Gastrointestinal effect

The aqueous and ethanolic undialyzed and dialyzed extracts(4 mL/kg for 14 consecutive days) from date fruit and pits were evaluated for gastroprotective effect in rat model of ethanol-induced gastric ulceration.The ethanolic and aqueous extracts of the fruit and date pits,ameliorated gastric ulceration severity and mitigating the increased histamine and gastrin induced by ethanol,and the decrease in gastric mucin levels [132].

It has been known since ancient times that dates have a laxative effect,and their laxative effect may be due to its fiber content,as the fibers lead to the absorption of water and increase the volume of stool,which stimulates the intestinal movement.An adult human needs 6 g of fiber per day,and it was noted that this amount reduces the period of passage of stool in the intestine by 29% and increases the weight of stool by 21% [133-135].

In addition,the consumption of foods containing fiber reduces digestive system problems,and the dates was used for this purpose.On the other hand,it was noted that the consumption of fiber in large doses did not cause any disturbance in the digestive system[136-138].

The activity of ethanolic and aqueous extracts of date flesh and pits(0.01,0.02 or 0.04 mL/kg) on the gastrointestinal transit was studied in mice using charcoal test.The ethanolic and aqueous extracts of date flesh and pits increased gastrointestinal transit 4 to 22% [139].

The effect of palm sap and pulp aqueous extract on gastrointestinal transit activity was investigated in adult rats.The aqueous pulp extract increased the gastrointestinal transit activity significantly,while,it was slightly increased by the palm sap[140].

Pectin possessed a protective effect against toxins,and its protective effect is due to it adsorbant effect.It also has a chelating effect,it binds to toxins and prevents their absorption,and because it absorbs and prevents the absorption of bacterial toxins,it is used for the treatment of diarrhea.Many pharmaceutical preparations contained pectin,such as Amogel,Diabismul,Dior Aid,Diarkote,Dia-quel,Diatrol,Donnagel,Infantol,Kaodene,Kaodonna,Kaopectate,Kaopectine,Kaypectrol,Parelixirk,Paelixirk.Pektamalt,Polymagma and Quiagel were prepared for these purposes [46].

Neural effects

The neurobehavioral activity of the date fruits methanolic extract was studied in mice.The fruits methanolic extract decreased the exploration time in closed arms and increased exploration in open arms,increased the discrimination index,increased the time spent in mirrored chamber,decreased the onset of death by respiratory arrest induced by sodium nitrite and potentiated the catalepsy induced by haloperidol [141].

The benefits of the aqueous extract (100,200 and 400 mg/kg) of date fruits in prevention of scopolamine and streptozotocin induced memory deficit was studied in mice.The extract possessed nootropic activity in absence of cognitive deficit and was also successful in preventing the chemically induced memory deficits in experimental mice.The authors concluded that these effect could be attributed to its antioxidant,neuroprotective effects,its choline content or activation of acetylcholine system in brain [142].

All the alterations induced by cerebral ischemia in rats (neuronal damage of the brain tissue,high lipid peroxidation,declined antioxidant enzymes),were significantly attenuated with pretreatment with date palm fruits methanolic extract (100 and 300 mg/kg,for 15 days) [143].

The potential of date palm pits in decreasing the adverse effect of methyl prednisolone on brain neurotransmitter,and testosterone hormone were studied in rats.A maximal elevation in the gamma-aminobutyric acid,dopamine and norepinephrine transmitters content (which decreased by methyl prednisolone) in the brain stem was recorded after oral administration of date palm pits for 2 weeks.The date palm pits also significantly elevated the serum testosterone level [50].

The neuroprotective effect of date seed extract(80 mg/kg,ip,for 12 days) was investigated in hippocampal impairments induced by β-amyloid in male rats.The extract restored β-amyloid-induced memory and learning impairments significantly,and significantly reduced the caspase-3 expression level and the number of hippocampal degenerated neurons[144].

The role of date seed extract (80 mg/kg,ip) in protection against cerebral ischemic damages induced by middle cerebral artery occlusion,was investigated in rats.Middle cerebral artery occlusion significantly decreased SOD and total antioxidant activity activities.Malondialdehyde content was significantly elevated by occlusion.Motor coordination was also decreased due to transient ischemia.Treatment with the extract attenuated all alterations and neuronal damage induced by occlusion [145].

Wound healing effect

The efficacy of the sap of date palm for wound healing was studied using mechanically wounded rats.The sap accelerated cell proliferation and enhanced faster healing compared to Cicaflora(®).The sap possessed high total antioxidant capacity and exerted marked radical scavenging activity [146].

Immunomodullatory effect

The antiallergic effect of a hot water extract of date palm matured fruit were investigated in mite-sensitized mice.Nose rubbing and sneezing were significantly less than that recorded in control.The total IgE and mite antigen-specific immunoglobulin IgE,IgE+B220+,spleen interleukin (IL)-4+CD4+,and FcεRIα+CD117+cells were significantly lower than control [147].

The immunomodulatory activity of matured date palm fruit hot aqueous extract were investigated in mice.Mice given date extract-added diet showed elevated IFN-γ+CD49b+,spleen IFN-γ+CD4+,and IL-12+CD11b+cells.Polyphenols of the date extract stimulated IFN-γ mRNA expression significantly in mouse Peyer’s patch cell cultures.Caffeic acid and chlorogenic acid also significantly elevated IFN-γ+CD4+cells.Some polyphenols significantly elevated IL-12+CD11b+cells and the number of IFN-γ+CD49b+.The trypsin treated-ethanol-insoluble date extract elevated IL-12+CD11b+cells and the number of IFN-γ+CD49b+significantly [148].

Anti-inflammatory effects

The aqueous and methanol extracts of the fruit pulp of date palm and the methanolic extract of date palm seeds showed anti-inflammatory effect in adjuvant arthritis model in rats.The methanol extracts showed more potent antiinflammatory activity than that produced by the aqueous extract [149].

The antiinflammatory activity of the parthenocarpic dates hydroethanolic extract was studied via its inhibitory effect on the activity of phospholipase A2 in vitro,and on paw oedema in mice induced by carrageenan.A2 activity was inhibited by the extract(IC50: 130 μg/mL) and significantly reduced the mice paw oedema after 1 h[68].

The studying of the effects of date palm seed extract on the metabolome of the LPS-IFN-γ-induced RAW 264.7 cells indicate the possibility of application of the extract of date seeds as a functional food with anti-inflammatory activity [150].

The effect of dietary supplementation ofPhoenix dactyliferaseeds on CCl4-induced pro-inflammatory mediators was studied in rats.Administration of steeped date seeds at a dose of 5 g/kg can increase glutathione reductase and IFN-γ,and decrease TNF-α,the strongest inflammatory marker in CCl4-induced rats[151].

Date syrup polyphenols suppressed inflammation and reduced several stages of angiogenesis (invasion,endothelial cell migration,tube formation,and matrix metalloproteinase activity) without cytotoxicity.Date syrup polyphenols also significantly reduced the TNF-α induced expression of VEGF and COX-2 [152].

The anti-toxin effects

In addition,to its high content of pectin,which is characterized by its ability to absorb toxins,because of its chelating effect,and it covers the intestinal mucosa and prevents absorption [46].The flavonoids contained in dates have a strong affinity for heavy metal ions [153].Therefore,dates contain many active molecules that have the ability to bind with toxins and inhibit their absorption,as well as they line the intestines and prevent the absorption of toxins.

Side effects and toxicity

No toxicity and side effects were recorded in mice up to the dose of 2,000 mg/kg of the methanolic extract ofPhoenix dactyliferafruits without any mortality [141].

Conclusion

Plants generally produce many secondary metabolites which were constituted an important source of many pharmaceutical drugs.Phoenix dactyliferacontained many essential nutritional components and possessed many therapeutic effects.The current review discusses the chemical constituent,pharmacological and therapeutic effects ofPhoenix dactyliferaas promising nutraceutical and natural drug because of its safety and effectiveness.