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1. Introduction

The Nitraria genus, a member of the family Zygophyllaceae, is one of the dominant species in the Mediterranean and central Asian deserts. The English name Nitre-bush is from the Latin word saltpetre, referring to the fact that it can thrive in saline soil. It serves an key ecological role due to its superior tolerance to severe drought and high salinity. Nitraria are shrubs 25–200-cm tall, with spiny branches at the apex and simple serrated leaves. The flowers are yellowish-gray or white, 2–4 cm pubescent, with five petals and five sepals, while the fruit is a fleshy drupe. The Nitraria genus consists of 13 species across the world, which are mainly distributed in Asia, Europe, Africa and Australia (Table I).

Table I Species of the Nitraria genus and the geographical distribution.

Table I

Species of the Nitraria genus and the geographical distribution.

No.	Species	Geographical distribution
1	N. schoberi	China, Europe
2	N. sibirica	China, Siberia
3	N. senegalensis	Africa
4	N. billardieri	Austraria
5	N. retusa	Mediterranean coast
6	N. sphaerocarpa	Northwest China
7	N. roborowskii	Northwest China, Russia
8	N. komarovii	Europe caspian coast
9	N. tangutorum	Northwest China
10	N. praevisa	Northwest China
11	N. pamirica	China
12	N. sinensis	China
13	N. tridentate	Africa

A growing body of evidence now demonstrates that Nitraria extract has numerous biomedical properties, including antifatigue, antitumor, anti-oxidative and antimutagenic activities. In addition, the fruit of Nitraria sibirica is extensively used to treat hypertension, menstrual disorders and gastroenteritis in folklore medicines of Northwest China (1,2). The leaves of Nitraria retusa also serve as supplement tea and are used as a poultice in Africa (3,4).

To provide further support and evidence for the clinical use of this genus, a systematic review of the modern phytochemical and pharmacological properties of Nitraria was performed. The available information on the pharmacology and phytochemistry of the Nitraria genus was collected via libraries and electronic searches using PubMed (http://www.ncbi.nim.nih.gov/pubmed), ScienceDirect (http://sciencedirect.com), Springer (http://springer.com), EMBASE (http://elsevier.com/online-tools/embase) and CNKI (http://www.cnki.net).

2. Phytochemical studies

Currently, the following six species of the Nitraria genus have been observed for their phytochemical properties: N. komarovii, N. schoberi, N. sibirica, N. tangutorum, N. retusa and N. billardieri. These investigations suggested that members of the Nitraria genus contain numerous components categorized as alkaloids, flavonoids and phenolic acid, of which alkaloids and flavonoids are the most abundant constituents. An overview of ingredients contained in the Nitraria genus is presented in Table II.

Table II Compounds isolated from the Nitraria genus.

Table II

Compounds isolated from the Nitraria genus.

A, Alkaloid compounds
No.	Compound	Species	Part of plant	Reference
1	Nitraricine	N. komarovii	Epigeal	5
2	Nitrarizine	N. komarovii	Epigeal	5
3	Isokomarovine	N. komarovii	Epigeal	6
4	Komarovidinine	N. komarovii	Epigeal	6
5	Komarovinine	N. komarovii	Epigeal	7
6	Peganine N-oxide	N. komarovii	Epigeal	8
7	Nallylschoberine	N. komarovii	Epigeal	8
8	Dehydronitramidine	N. komarovii	Epigeal	8
9	Komavicine	N. komaroviii	Epigeal	9
10	Deoxypeganine	N. komarovii	Epigeal	10
11	Nitraramine	N. schoberi/N. komarovii	Epigeal	11
12	Komarovine	N. komarovii	Epigeal	12
13	Komarovidine	N. komarovii	Epigeal	12
14	Komaroine	N. komarovii	Epigeal	13
15	Nitraraine	N. schoberi	Epigeal	14
16	Nitrabirine	N. sibirica	Epigeal	14
17	Nitramine	N. sibirica	Epigeal	15
18	Isonitramine	N. sibirica	Epigeal	16
19	Sibirine	N. sibirica	Epigeal	17
20	Vasicinone N-oxide	N. komarovii	Epigeal	18
21	Deoxyvasicinone N-oxide	N. komarovii	Epigeal	18
22	Dihydronitraraine	N. komarovii	Epigeal	19
23	Deoxyvasicinone	N. komarovii	Epigeal	20
24	Vasicinone	N. komarovii	Epigeal	20
25	Peganine	N. komarovii	Epigeal	20
26	Deoxypeganine	N. komarovii	Epigeal	20
27	Dehydroschoberine	N. komarovii	Epigeal	20
28	Nitraroxine	N. komarovii	Epigeal	20
29	Tryptamine	N. komarovii	Epigeal	20
30	Schoberine	N. komarovii	Epigeal	20
31	Schoberidine	N. komarovii	Epigeal	21
32	Nitrarine	N. schoberi	Epigeal	22
33	Tetramethylenetetrahydro-β-carboline N-oxide	N. komarovii	Epigeal	23
34	Sibirinine	N. sibirica	Epigeal	24
35	Dihydroschoberine	N. sibirica	Aerial	25
36	Nitrabirine N-oxide	N. sibirica	Aerial	25
37	O-acetylnitraraine	N. schoberi	Aerial	26
38	N-methylnitrarine	N. schoberi	Aerial	27
39	Komavine	N. komarovii	Aerial	28
40	Acetylkomavine	N. komarovii	Aerial	28
41	N-allylnitrarine	N. komarovii	Aerial	29
42	Komarovidinine N-oxide	N. komarovii	Aerial	29
43	Sibiridine	N. sibirica/N. schoberi	Aerial	30
44	Nitraramidine	N. sibirica	Aerial	31
45	Nitraraidine	N. sibirica	Aerial	31
46	Komarin	N. komarovii	Aerial	32
47	Peganol N-oxide	N. komarovii	Aerial	32
48	N-allylisonitrarine	N. schoberi	Aerial	33
49	Nitraridine	N. komarovii	Aerial	34
50	Dihydronitraridine	N. komarovii	Aerial	34
51	Tetrahydronitraridine	N. Komarovii	Aerial	34
52	Schobericine	N. Schoberi	Aerial	35
53	Komaroidine	N. Komarovii/N. Schoberi	Aerial	35
54	Acetylkomaroidine	N. Komarovii/N. Schoberi	Aerial	35
55	Tetrahydronitramarine	N. Komarovii.	Epigeal	36
56	Tetrahydrokomarovinine	N. Komarovii	Epigeal	36
57	Dihydroisokomarovine	N. Komarovii	Epigeal	36
58	Tetrahydroisokomarovine	N. Komarovii	Epigeal	36
59	Nazlinin	N. Schoberi	Epigeal	39
60	Tangutorine	N. Tangutorum	Leaves	40
61	Nitrarine	N. Billardieri	Aerial	41
62	1-Epinitraramine	N. Billardieri	Aerial	41
63	3-Epinitrarine	N. Billardieri	Aerial	41
64	5,7-Dihydroxy-3-deoxy-vasicine	N. Retusa	Aerial	42
65	7-Hydroxy-3-deoxy-1-vasiciene	N. Retusa	Aerial	42
66	Allantoin	N. Tangutorum	Seed	48
B, Flavanoid compounds
No.	Compound	Species	Part of plant	Reference
67	Narcissin	N. Komarovii	Leaves	28
68	Rutin	N. Retusa	Leaves and stems	43
69	Kaempferol	N. Retusa	Leaves and stems	43
70	Isorhamnetin 3-O-4rham-galactosylrobinobioside	N. Retusa	Leaves and stems	44
71	Isorhamnetin 3-robinobioside	N. Retusa	Leaves and stems	44
72	Isorhamnetin 3-rutinoside	N. Retusa	Leaves and stems	44
73	Isorhamnetin 3-galactoside	N. Retusa	Leaves and stems	44
74	Isorhamnetin 3-glucoside	N. Retusa	Leaves and stems	44
75	Isorhamnetin	N. Retusa	Leaves and stems	44
76	Isorhamnetin 3-xylosylrobinobioside	N. Retusa	Leaves and stems	44
77	Isorhamnetin-7-O-α-L-rhamnoside	N. Tangutorum	Seeds	45
78	Isorhamnetin-7-O-β-D-glucoside	N. Tangutorum	Seeds	45
79	Kaempferol-7-O-α-L-rhamnoside	N. Tangutorum	Seeds	45
80	Quercetin-7-O-α-L-rhamnoside	N. Tangutorum	Seeds	45
81	Quercetin	N. Tangutorum	Seeds	45
82	3,5-Dimethylether-kaempfrol-7-O-β-D-glucoside	N. Tangutorum	Leaf	46
83	3-Methylether-kaempferol-7-O-β-D-glucoside	N. Tangutorum	Leaf	46
84	Isorhamnetin-3-O-β-D-glucopyranosyl-(1–2)-α-L-rhamnopyranoside	N. Tangutorum	Fruit	47
85	5,7,2′-Trihydroxyflavonol	N. Tangutorum	Fruit	47
86	Cyaniding 3-[6′-(6-trans-p-coumaroyl-β-D-glucopyranosyl)-β-D-galactopyranoside]	N. Tangutorum	Fruit	47
87	Apigenin 5-O-(2′-O-E-P-coumaroyl)-β-D-glucopyranoside	N. Tangutorum	Fruit	47

Numerous studies (5–36) have been conducted to explore the alkaloids contained in the members of the Nitraria genus. Nearly all known alkaloids (Table II, nos. 1–36) identified in plants of the Nitraria genus were initially isolated in these studies. These studies also observed that the content of alkaloids in the leaves is higher than the content in the roots, stems and seeds of Nitraria komarovii and Nitraria sibirica (37–38). There are also various types of alkaloids that have been isolated and purified in other studies. In the crude MeOH extracts of N. rhoberi, nazlinin was purified by Üstunes et al (39). In a proceeding study, tangutorine was isolated from the leaves of N. tangutorum (40). Three novel alkaloids, 3-epinitrarine, 1-epinitraramine and nitrarine (41) were identified in N. billardieri, which is a species that is mainly distributed in Australia. Phytochemical studies of the aerial sections of N. retusa reported the novel alkaloids 5,7-dihydroxy-3-deoxy vasicine and 7-hydroxy-3-deoxy-1-vasiciene (42) (Fig. 1). Nitraria was also reported by Saleh et al (43) to contain the flavonoids rutin, kaempferol and isorhamnetin. The flavonoids isolated in other studies are listed in Table II, nos. 67–87 (44–48) (Fig. 2).

Figure 1 Chemical structures of the main alkaloids from the genus Nitraria. Chemical structure of main alkaloids from the genus Nitraria.

Figure 2 Chemical structures of flavonoids from the genus Nitraria.

Wang et al (49) determined fatty acids in N. tangutorum seed by supercritical carbon dioxide extraction and high-performance liquid chromatography/atmospheric pressure chemical ionization/mass spectrometry. Using gas chromatograph-mass spectrometry, numerous volatile substances were detected in the extract of the stem, leaves and fruits of N. tangutorum and N. sibirica (50–52). Additionally, Wu et al (53) isolated phenolic acid from the water extraction of N. tangutorum.

3. Pharmacological effects

Antifatigue activity

The antifatigue activity of polysaccharides from the fruits of N. tangutorum was assessed in mice using the forced swim test (FST). The results demonstrated that the FST-induced reductions in glucose, superoxide dismutase (SOD) and glutathione peroxidase (GPx), and the increases in creatine phosphokinase, lactic dehydrogenase, blood urea nitrogen, triglyceride (TG) and malondialdehyde (MDA) levels, were inhibited by the polysaccharides from N. tangutorum. Additionally, at the same dosage, the extract of N. tangutorum is more potent than Hippophae rhamnoides and Lycium ruthenicum, which are traditionally used as medicinal foods with antifatigue and antioxidant potential in Tibet (54). Fruit extracts of N. tangutorum markedly prolonged the swimming time, climbing time and survival time in low temperature of mice compared with the control group in a study by Suo et al (55). The seed oil of N. tangutorum, when extracted by supercritical CO2, displayed similar effects as the fruit, and upregulated the contents of serum urea-nitrogen and hepatic glycogen, but downregulated the serum lactic acid contents, consequently improving the swimming and climbing time. This result has been repeated in other studies (56,57).

Antitumor activity

Boubaker et al investigated the apoptotic potential of N. retusa ethyl acetate (EA) extract and isorhamnetin 3-O-rutinoside (I3-O-R) isolated from the ethyl acetate extract, in K562 human chronic myelogenous erythroleukemia cells. After 48 h incubation with N. retusa extract and I3-O-R, K562 cell viability was significantly suppressed by inducing apoptosis, and the caspase 3 and caspase 8 activity was increased (58). The extract and the component inhibited the genotoxicity induced by hydroxyl radicals in K562 cells (59). Another similar study indicated that EA extract of N. retusa and I3-O-R have a strong antiproliferative effect on TK6 human lymphoblastoid cells, possibly due to their involvement in the apoptotic pathway (60).

The hexane (Hex), chloroform (Chl) and methanol (MeOH) extracts of N. retusa were utilized to test their antiproliferative effects on K562 cells. The Hex and Chl extracts were demonstrated to induce stronger antiproliferative effects than the MeOH extracts, by ameliorating the DNA fragmentation, poly ADPribose polymerase cleavage, and caspase 3 and caspase 8 activity (61). In another study, 3H-thymidine incorporation-induced proliferation of the HT29 human colon cancer cells was reduced in a dose-dependent manner following treatment with tangutorine, a β-carboline alkaloid from the leaves of N. tangutorum. Tangutorine may induce p21 suppression of all cyclins and their associated kinases, such as the topoisomerase II, and thus inhibit normal DNA replication and mitosis (62). The activities of fractions/extracts of N. retusa were compared with their flavanoid contents, which consisted of the following four major flavonoids: Isorhamnetin; isorhamnetin-3-O-glucoside (I3-O-G); I3-O-R; and isorhamnetin-3-O-robinobioside (I3-O-Rb). They inhibited the proliferation of Caco-2 cells in vitro (63).

The total flavones from the N. tangutorum fruits repress proliferation of the SGC-7901 human gastric adenocarcinoma cell line and A-704 human kidney adenocarcinoma cell line by regulating the levels of Ca2+, K+ and P3+ in the cell (64–65). The in vivo experiment demonstrated that flavones, in addition to the aqueous extract of N. tangutorum, combined with 5-fluorouracil, induced a significantly increased inhibitory rate in the Hep human throat cancer cell line and U14 human cervical cancer cell line by regulating the weight of immune organs, the formation value of serolysin and phagocytic index (66–67). Additionally, the lipids of N. tangutorum were cytotoxic against the MGC-803 human gastric carcinoma cell line (68).

Antioxidant activity

EA extract of N. retusa and I3-O-R indicated a protective effect against lipid peroxidation induced by H2O2. It demonstrated significant antioxidant effects on oxidation induced by 2,2′-azobis (2-amidinopropane) dihydrochloride in K562 cells with 50% inhibitory concentration values (IC50) of 0.225 mg/ml and 0.31 mg/ml (59). Sterols, the main constituents of Hex extract, and sterol and polyphenolic compounds, the main constituents of Chl extract, may participate in the protective effect against lipid peroxidation induced by H2O2 in K562 cells (61). Chl extract exhibited the highest ability to protect plasmid DNA against hydroxyl radical-induced DNA damage, and the highest antioxidant capacity, with 0.95 mM trolox equivalent capacity when tested using the ferric reducing/antioxidant method (69). Furthermore, the extract of fruits from N. tangutorum displayed a significantly different antioxidant activity when assessed with the 1,1-diphenyl-2-picrylhydrazy (DPPH), 2,2′-Azinobis (3-ethylbenzothiaz-oline-6-sulfonate) (ABTS) and ferric-reducing antioxidant power assays (70).

The DPPH scavenging activity, xanthine oxidase inhibition and superoxide scavenging activity of various N. retusa extracts and compounds, including isorhamnetin, I3-O-G, I3-O-R and I3-O-Rb, were evaluated to confirm the association between the activities of the fractions and their flavonoid contents. The EA extracts were identified to be most effective at scavenging the DPPH stable free radical, and the CHCl3 extracts exhibited the highest xanthine oxidase inhibition activity; however, only BuOH extract exhibited a scavenging activity toward superoxide radicals. Overall, all the compounds exhibited some level of DPPH and superoxide scavenging and xanthine oxidase inhibition activity, and the aglycone compounds were more active than their glycosylated derivatives (63). Antiradical activities against DPPH, and β-carotene and Fe-reducing power were more efficient in leaf non-polar fractions compared with polar fractions of N. retusa (61). Similar studies investigating anti-oxidant properties were also performed by Bouaziz et al (71) and demonstrated that the EA fraction and MeOH fraction of N. retusa indicated DPPH scavenging activity and reduction of the ABTS radical cation.

Anthocyanins have also been demonstrated to elicit scavenging effects against O2, OH and DPPH in a dose-dependent manner. Notably, these scavenging capacities were greater than those of vitamin C according to results of in vitro anti-oxidative tests (72). Nazlinin isolated from Nitraria and its derivative 1-(4-butylamino)-3,4-dihydro-β-carboline have been indicated to be inhibitors of pig kidney diamine oxidase, while 1-(4-butylamino)-β-carbolin was demonstrated as a substrate (73).

Antimicrobial activity

The EA, ethanol and Chl extracts from the fruits of N. tangutorum had antibacterial effects against Escherichia coli, Bacillus subtilis and Staphyloccocus aureus. The EA fraction presented the highest level of antibacterial activity (74,75). In addition, Chl extract from N. retusa leaves was more efficient against all human pathogen strains, particularly Escherichia coli and Staphylococcus aureus (76). The EA and MeOH extracts of N. retusa revealed antimicrobial effects against Pseudomonas aeruginosa and Aspergillus niger in vitro (71). The ethanol extracts of N. retusa also exhibited cytotoxicity in brine shrimp with LC50 values of 6.2 μg/ml (77).

Antimutagenic activity

The protection of N. retusa against mutagenicity induced by methyl methanesulfonate and 2-aminoanthracene in Salmonella typhimurium TA102 and TA104 strains was observed. The highest protection was elicited by Chl and MeOH extracts of N. retusa, with inhibition percentages of 44.93% at 50 μg/plate in the presence of TA102 strain and 38% at 10 μg/plate in the presence of TA104 strain. Hex and Chl extracts have been demonstrated to reduce the mutagenicity induced by 2-aminoanthracene with 83.4% in TA104 and 65.3% in the TA102 strain (69).

Hypotensive effects

Senejouxa et al conducted a study on the vasorelaxant activity and underlying mechanisms of hydroalcoholic extract from the fruits of N. sibirica on thoracic aortic rings isolated from Wistar rats. The study revealed that the hydroalcoholic extract was more effective in the induction of vasodilation of phenylephrine- than high KCl-pre-contracted aortic rings with respective Emax values of 82.9±2.2 and 34.8±3.6%. The acute intravenous injection of hydroalcoholic extract induced an immediate and transient hypotensive effect in anesthetized spontaneously hypertensive and control rats through an endothelium-dependent pathway involving nitric oxide synthase (NOS) activation, endothelium-derived hyperpolarizing factor production and muscarinic receptor stimulation (78). Flavonoids of different concentrations increased the repair of impaired human umbilical vein endothelial cells induced by high glucose or H2O2 by increasing the ratio of NOS, SOD and GPx activity, and NO level (79,80). Notably, the inhibition activity of ethanol extracts from 10 halophytes on angiotensin converting enzyme (ACE) has been investigated extensively. The Nitraria sibirica fraction has been demonstrated to significantly inhibit ACE with an IC50 value of 69.36 g/l (81).

Hypoglycemic effects

The fruit of N. tangutorum at a dosage of 1.8 g/kg and 3.6 g/kg not only had a therapeutic action in a mouse diabetes model induced by alloxan, but also led to an increase in the glucose-toleration in similar models in rats. It has also been demonstrated to reduce glucose levels in hyperglycemic animal models induced by epinephrine and glucose (82). Shabana et al (83) investigated the hypoglycemic activity of 31 desert plants from different Egyptian localities in normal fasting and alloxanised rats, and Nitraria retusa had hypoglycemic effects in normal fasting rats.

Lipid lowering effects

An in vivo study on the effects of the fruit extracts of N. tangutorum on rat and mouse models of hyperlipermia induced by high lipid levels was conducted by Suo et al. N. tangutorum significantly reduced the serum level of total cholesterol (TC) and TG in a rat hyperlipermia model, and the level of low-density lipoprotein (LDL) in Kunming strain rats. It also increased the ratio of high-density lipoprotein cholesterol (HDL)/TC, HDL/LDL and SOD activity, and reduced the MDA content in vivo and in vitro (84,85).

Hepatoprotective effects

A study by Zhang et al (86) indicated that seed oil of N. tangutorum alleviated the increased levels of aspartate aminotransferase, alanine aminotransferase and MDA induced by CCl4, and it also enhanced the level of GPx in liver.

4. Conclusion

The studies summarized above strongly support the theory that the Nitraria genus has favorable therapeutic properties, indicating its potential for clinical use. The present review presents and assesses the previous pharmacological and phytochemical studies published on the Nitraria genus, and may aid the easy identification and further research into properties of members of the Nitraria genus.

Nitraria as a halophyte, is ecologically central in stabilizing wind-blown sand and loess soils and thus reduces erosion. Hence, combined with the pharmacological effects, the rational development and utilization of Nitraria may be beneficial for the local environment and public health.

Numerous alkaloids have been isolated from the Nitraria genus. However, there is currently no research on the pharmacological properties of the alkaloid components, which are the most abundant constituents in nature. Further studies on the antitumor and anti-oxidative activities of these components are required. Furthermore, few molecular mechanisms are known, which may hamper the further clinical application of Nitraria. The possible synergistic action among the bioactive compounds of the plants must be evaluated prior to their use in clinical practice.

Acknowledgements

The current study was supported by grants from the National Natural Science Foundation of China (grant no. U1203104).

References