A Comprehensive Review on Genus Zygophyllum

Objectives: This study aimed to make a broad review of the chemical constituents and biological activities of genus Zygophyllum. Methods: This review covers the peer reviewed articles between 1977 and August, 2018, retrieved from PubMed, Science Direct, Sci-Hub, Springer and Wikipedia Results: In traditional medicine, plants of genus Zygophyllum have been employed and utilized as anti-rheumatic, anti-gout, antidiabetic, anti-hyperlipidemic, antimicrobial, antioxidant, antihypertensive, antiseptic, anti-eczema and antidiarrheal. Zygophyllum species have been phytochemically studied leading to the identification of various classes of compounds including triterpenes, flavonoids, saponins, sterols, simple phenolic compounds, and esters. Biological studies on Zygophyllum species have also indicated various bioactive potentials including antioxidant, antidiabetic, antimicrobial antitumor and anti-inflammatory effects. The reported medicinal Zygophyllum species were selected and summarized on basis of their; geographical distribution, traditional uses, chemical constituents and biological activities. Conclusion: It would therefore be important to extensively investigate their phytochemicals and pharmacologically determine their activities for future drug discovery and development.


INTRODUCTION
Zygophyllaceae (Caltrop family) is a family of approximately 25 genera and 240 species adapted to semi desert and Mediterranean climates 1 .Species belonging to genus Zygophyllum represent a group of succulent plants that are drought resistant and/or salt tolerant, living under severe, dry climatic conditions 2 .Moreover, it is recorded by many authors as one of the important components of the desert vegetation 3 .The abundance of species related to this genus could be attributed to their high tolerance to environmental stresses as well as to their unpalatability 4 .The growth and distribution of Zygophyllum species are attributed to their dependence on the chemical nature of the soil of their habitats 5 .The genus Zygophyllum consist of 100 species, distributed in desert and steppe habitats from the Mediterranean to central Asia, South Africa and Australia 4 .Most of plants of genus Zygophyllum are small perennial herbs with fleshy leaves and flowers, as in cases of Z. simplex, Z. cocceniem, Z. album, Z. fabago and Z. dumosum 6 .Nine species are widespread in the deserts and salt marshes in Egypt and Sinai Peninsula 5 .They have been utilized in traditional medicine for various ailments, such as treatment of rheumatism, gout, diabetes, asthma, hypertension, dysmenorrhea, as well as fungal infection [7][8][9][10][11] .Biological studies on Zygophyllum species have indicated significant antioxidant, antidiabetic, antitumor, antimicrobial and antiinflammatory activities [12][13][14][15][16][17] .Such activities were contributed to their phytochemical constituents.Various classes of compounds including triterpenes, flavonoids, saponins, sterols, phenolic, essential oils and esters have been isolated from different Zygophyllum species [18][19][20][21][22][23] .

Pakistan
Alzheimer's disease and brain diseases with deficiency in cholinergic function Z. coccienium 9,26 Egypt, Kuwait, Saudi Arabia Gout, Rheumatic pain and hypertension Z. cornutum 10 Algeria Diabetes, hypertension and dermatitis Z. decumbens 27 Egypt, Syria, Sudan Hypotension, fever and GIT spasm Z. dumosum 23,28,29 Egypt Rheumatism, gout, asthma and hypertension Z. fabago 19 China, Spain, Turkey, Iran, Kazakhstan and Iraq Fungal infections, Parasitic worms, constipation, product cough, inflammation, and asthma Z. gaetulum 11 Morocco GIT spasms, hyperglycemia accompanying diabetes and eczema Z. geslini 12 Algeria Hyperglycemia accompanying diabetes Z. hamiense 30 Deserts of Asia and Africa As hepato-protective Z. macropodum 31 China Pain and inflammation Z. melongena 20 Mongolia Snake poisoning (as it inhibits of the snake venom phosphodiesterase) Z. qatarense 13 Iran Fungal infections Z. simplex 32 Egypt, Saudi Arabia, India and Pakistan Glaucoma, inflammation, fungal infections and hyperglycemia accompanying diabetes

MATERIALS AND METHODS
This review covers the peer reviewed articles between 1977 and August, 2018, retrieved from PubMed, Science Direct, Sci-Hub, Springer and Wikipedia.

Distribution and traditional use
Data reported on Zygophyllum species used mostly in folk medicine is summarized in Table 1 according to their geographical distribution and traditional uses.

Phytochemical constituents:
It was reported that the plants belonging to genus Zygophyllum are rich in essential oil, sterols, triterpenes, phenolic compounds, flavonoids and saponins.The previously isolated compounds from reported Zygophyllum species are labeled together with their chemical classes in Table 2 and their chemical structures are shown below.

Biological studies
Reported biological activities of various Zygophyllum species included antioxidants, antidiabetic, antimicrobial, antitumor and other effects are illustrated in Table 3.

Antioxidant activity
One of the most remarkable effects of the members of Zygophyllum genus is their antioxidant activity (Table 3).Such activity is attributed to the presence of the phenolic compounds as reported in cases of Z. cornutum 10 , Z. album 6,8,38 , Z. cocceniem 7 , Z. hamiense 28 , Z. simplex 16,64 and Z. fabago 46 .The most active extracts with the highest antioxidant activity; were those of the alcohol (methanol and ethanol) ones followed by dichloromethane extracts while the hexane extracts were poorly active 6 .Consequently, Zygophyllum genus represents an important economical source of antioxidant agents.

Antidiabetic activity
The antidiabetic activity of members of the Zygophyllum genus have been reported in several studies (Table 3).The aqueous and butanol extract of Z. gaetulum in alloxan-induced diabetic rats (n=6) caused a continuous marked reduction of blood glucose levels particularly 6-9 hr {hours} after treatment.Significant difference was observed; (P˂0.001) (  18,24 Isorhamnetin-    mg/dl at 3 hr and to 182±34 mg/dl at 6 hr 11,61 .In another study , the ethanol extract of Z. album to diabetic mice significantly decreased the level of blood glucose and increased plasma insulin gain to near normal level by (p < 0.05, post hoc Dunnett's test) 14,35,56 .The ethanol extract of Z. album with IC50 {concentration of 50% inhibition} value (43.48 μg/ml) evidenced a better pancreatic α-amylase inhibition than that of the other fractions.Meanwhile, it was observed that the pancreatic α-amylase inhibitory activities increased in the order of hexane fraction, butanol fraction & ethanol extract 14 .The pancreatic and serum α-amylase activities of essential oil of Z. album in treated diabetic rats were noted to undertake considerable reductions of 43 and 38%, respectively 35 .The IC50 value of essential oil of Z. album against αamylase was 43.17 μg/ml and that against pancreatic lipase was 85.95 μg/ml 56 .Also, diabetic rats treated with methanol extract of Z. cornutum, a significant decrease of glycaemia was noted from the second week and the value recorded after six weeks was 145 ± 12.3 mg/dL.The hypoglycemic effect of methanol extract of Z. cornutum may be attributed to its saponins content 58 .

Antimicrobial and antifungal activities
One of the most attracting activities of the extracts of genus Zygophyllum is the antimicrobial activity against gram positive, gram negative bacteria and several fungi (Table 3).A good example is the effectiveness of the aqueous methanol roots extracts of Z. dumosum, Z. coccineum and Z. qatarense on inhibition of the spore germination of Verticillium alboatrum and Fusarium oxysporum 13,15,29 .
The shoot extract using the same solvent showed variable toxicity among the extracted Zygophyllum 13,15,29 such that the extracts of Z. dumosum were suppressive only to Fusarium oxysporum 29 .On the other hand, the extract of Z. coccineum was inhibitory only to Verticillium albo-atrum 15 .In another study, the ethanol extract of Z. coccineum has antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae, Candida albicans, Microsporum canis and Trichophyton mentagrophytes 57 .The antifungal activity of the isolated compounds of Z. coccineum was investigated against Colletotrichum acutatum, Colletotrichum fragariae, Colletotrichum gloeosporioides, Botrytis cinerea, Phomopsis obscurans, Phomopsis viticola, and Fusarium oxysporum.The observed results were recorded against Phomopsis viticola after 144 hr exposure 57 .The methanol extract of Z. simplex showed marked antimicrobial activity against seven standard bacteria (Proteus vulgaris, Escherichia coli, Bacillus cereus, Salmonella typhi, Klebsiella pneumonia, Pseudomonas aeruginosa and Staphylococcus aureus) and one standard fungus (Candida albicans) 17 .Also, the nanoparticles of the methanol extract of Z. qatarense leaf exhibited antifungal activity against Aspergillus nigra and Penicillium digitatum was evaluated by standard disk diffusion, the results showed minimum inhibitory concentration {MIC} and minimum fungal concentration {MFC} against Aspergillus nigra equal to 16 and 128 μg/ml respectively and against Penicillium digitatum equal to 32 and 64 μg/ml respectively 13 .Leaves', seeds' and roots' extract of Z. fabago were evaluated evaluated their antimicrobial activities against Bacillus subtilis showing MIC equal to 10, 1, 20 mg/ml respectively, Staphylococcus aureus showing MIC equal to 20, 1, 30 mg/ml respectively, Escherichia coli showing MIC equal to 30, 10, 50 mg/ml respectively, Pseudomonas aeruginosa MIC were 50, 20, 30 mg/ml respectively and Candida albicans, which was the most resistant for all extracts 59 .The ethyl acetate extract of Z. cocceniem showed antibacterial activities against; Pseudomonas aeruginosa with inhibition zone 20 mm, Fusarium moniliforme with inhibition zone 22 mm, and Klebsiella pneumonia showed inhibition zone 22 mm 57 .

Cytotoxic activity
Recent study showed that the cytotoxic activity of dichloromethane fraction of Z. simplex showed powerful effect against cancer cell lines; Human lung carcinoma cells {A-549} and Human colon adenocarcinoma cells {DLD-1} with important IC50 values of 37 and 48 µg/ml, respectively 6 .Also Z. coccinium extracts showed maximum cytotoxic activity of the acetone extract against Human cervix epithelioid carcinoma {HeLa cell line}, whereas methanol extract showed maximum cytotoxic activity on breast cancer cell line {MCF-7 cell line} with cell line viability 13.36 and 35.19%. 15

Other effects
Other activities have also been reported on members of genus Zygophyllum Table 3. Antiinflammatory activity best results were recorded for Z. album and measured by serum level of C-reactive protein and pancreatic tumor necrosis factor were decreased by 59 % and 64 %, respectively 14 .Also, the analgesic activity was reported for the ethanol extract of Z. macropodum (ZME) in acetic acid induced writhing method.The inhibition percentages of ZME 100, 300, and 600 mg/kg were 8.7%, 24.9%, 51.3%, respectively having significant inhibitory effect on increased vascular permeability induced by acetic acid in mice (P < 0.05 and P < 0.001, respectively) compared to normal control 31 .Hypoglycemic and hypolipidemic activities of the aqueous extract of Z. gaetulum showed hypoglycemic and hypolipidemic activities in Streptozotocin induced-diabetic rats 11,61 , these effects may be due to the antioxidant potential of this plant.Moreover, Z. gaetulum aqueous extract prevented lipid peroxidation by enhancing PON1 {paraoxinase activity} and LCAT {Lecithin cholesterol acyltransferase} activities.In addition, it reduced oxidative stress in the liver and kidney by decreasing thiobarbituric acid reactive substances levels and increasing antioxidant enzyme activities 11 .Oral administration of Z. simplex to hyperlipidemic rats were appreciably effective in decreasing the levels of serum total cholesterol, low-density lipoprotein cholesterol, triacylglycerol and tissue lipid accumulation while increasing the levels of serum high-density lipoprotein cholesterol, adjusting the metabolic disturbance of lipoprotein and increasing the antioxidant enzyme activity and repressing the development of atherosclerosis 66 .

CONCLUSION
In the review, chemical investigations and biological activity have been reported for only 16

ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Shawky et al., 2019, 3 (1), 1-16 http
out of 100 known Zygophyllum species.However, members of Zygophyllum, such as Z. album and Z. simplex, revealed significant biological activity, especially as anti-inflammatory and antioxidant.Investigation of the chemical constituents of plants of genus Zygophyllum showed diverse compounds, including triterpenes, 14 saponins, flavonoids, sterols and simple phenolic compounds.It should be emphasized that phenolic compounds from Z. cornutum, Z. album, Z. cocceniem, Z. hamiense, Z. simplex and Z. fabago had particularly prominent anti-oxidant activity, in addition to some other biological properties.Also, the presence of essential oils and saponins in Z. cornutum contributed to its antidiabetic activity.Previous studies have provided a base for the medicinal use of Zygophyllum species.It is important to note that the safety and toxicity of Zygophyllum species have not been explored.Therefore, the toxicities of traditional remedies and isolated chemical compounds should be further assessed as well. ://aprh.journals.ekb.eg/