The old world salsola as a source of valuable secondary metabolites endowed with diverse pharmacological activities: a review

Abstract Salsola is an important genus in the plant kingdom with diverse traditional, industrial, and environmental applications. Salsola species are widely distributed in temperate regions and represent about 45% of desert plants. They are a rich source of diverse phytochemical classes, such as alkaloids, cardenolides, triterpenoids, coumarins, flavonoids, isoflavonoids, and phenolic acids. Salsola spp. were traditionally used as antihypertensive, anti-inflammatory, and immunostimulants. They attracted great interest from researchers as several pharmacological activities were reported, including analgesic, antipyretic, antioxidant, cytotoxic, hepatoprotective, contraceptive, antidiabetic, neuroprotective, and antimicrobial activities. Genus Salsola is one of the most notorious plant genera from the taxonomical point of view. Our study represents a comprehensive review of the previous phytochemical and biological research on the old world Salsola secies. It is designed to be a guide for future research on different plant species that still belong to this genus or have been transferred to other genera.


Introduction
Plants are considered as a latent treasure and a vital source for the discovery of medicines. They include a plethora of secondary metabolites that act as modulators for the enzymes involved in human diseases 1,2 . Plant extracts and their derived natural products or analogues are extensively reported to exert promising effects on human devastating diseases including different types of cancer [3][4][5][6] . They are also reported to protect humans against different types of microbes 7 and recently evolved infectious diseases as COVID-19 8,9 .
The genus Salsola (commonly known as saltwort) belongs to the family Amaranthaceae, previously Chenopodiaceae. The genus name is from the Latin words "salsus" or "sallere" meaning salty because they are halophytes capable of living in saline environments or due to their content of alkaline salts, such as potassium and sodium carbonates [10][11][12] . The old genus Salsola comprised about 150 sp. growing in extreme climatic conditions as arid, semi-arid, and temperate regions worldwide 11,13 . They represented about 45% of the desert plants 11 and some of them are invasive species 14 . Various plants of the genus Salsola are edible and some of them have been used in traditional medicine 15 . Some of them are also reported to be rich in fibre content 16 . They have important value as animal feed and they are beneficial in the reclamation and phytoremediation of soil contaminated with heavy metals 11,14 . Plants belonging to this genus also represent a rich CONTACT  source for endophytic microbes that could be used for potential biological applications 17,18 . Furthermore, different plants of the genus Salsola were reported to have industrial value as the use of S. soda and S. kali as a source of sodium carbonate, in linin, and cotton bleaching, and in glass and soap making 14,19,20 .
Despite the importance of plants belonging to the genus Salsola, they do not receive great research attention. Most of the research is done on the respiratory diseases and the hypersensitivity caused by the pollen grains of some Salsola spp. and developing vaccines for it [21][22][23] . Very limited reviews are made on the genus Salsola such as the one made by Altay and Ozturk 11 that discuss its fodder value. Hanif et al. 14 discussed the environmental, industrial, and traditional uses of Salsola spp. and they mentioned a small fraction of the biological studies made on them. This article addresses almost all the research articles concerning the phytochemistry and the biological activity of the plants belonging to the old genus Salsola until 2021.

Morphological characters
Members of the genus Salsola are shrubs, sub-shrubs, annual or perennial herbs. They are characterised by small, sessile, often succulent leaves that may be opposite or alternate. Most have bisexual axillary flowers that can be solitary or clustered to form loose or dense spikes ( Figure 1). Each flower is subtended by two prominent bracteoles, with a frequently hard 5-segmented perianth (often winged in fruit), and a superior ovary. Seeds are horizontal, subglobose, with a spiral embryo 11,24,25 .

Taxonomic classification
Genus Salsola belongs to the flowering plant family Amaranthaceae descending from the order Caryophyllales 26 . Salsola has a long history of being considered as one of the largest genera within the family Chenopodiaceae containing 100 to 190 sp. 27 . While it is classified now as one of the Amaranthaceae genera after merging family Chenopodiaceae with the family Amaranthaceae according to the angiosperm phylogeny group (AGP-IV) 26,[28][29][30] . Plants belonging to the genus Salsola have the following taxonomic classification 27,[30][31][32] . Family: Amaranthaceae (previously, Chenopodiaceae) Subfamily: Salsoloideae Tribe: Salsoleae Genus: Salsola The taxonomy of Salsola spp. is debateable and confusing due to their diversity and distribution in the Asian and the middle east deserts that lead to difficulties in their collection and investigation 31 . The close relationship between Salsola spp. and the dependence on minor morphological differences in their old classification together with the recent use of molecular techniques in plant systematics led to major changes in the classification of the genus Salsola 27 . The classification of the genus Salsola has been revised by Akhani et al. (2007) and it was spitted into 10 different genera. The transfer of different sp. from the old world Salsola to other genera, such as Caroxylon genus resulted in decreasing the number of its sp. to 25 27 .
The type of the genus Salsola was Salsola soda 27,31 , which has been recently changed by the International Code of Nomenclature into Salsola Kali as suggested by Mosyakin et al. 33 . This resulted in changing the name of many traditionally known Salsola spp. into Soda 28 .
These taxonomical and nomenclatural changes together with the presence of different synonyms for several Salsola spp. would obscure the determination of the phytochemical constituents and the biological activities of the old world Salsola species.
Therefore, in this article, we will review the phytochemical content and the biological activities of the old world Salsola spp. and indicate their current taxonomic status as illustrated in Table 1.

Volatile constituents
Hexahydro-farnesyl acetone and benzoic acid esters were reported as the major constituents of S. cyclophylla volatile oil 15,41 . However, GC analysis of the volatile fractions of different parts of S. vermiculate L. plant revealed that carvone and b-caryophylline were the major components in leaves (52.2% and 5.8%, respectively), while carvone and cuminaldehyde were the major components in roots (49.9% and 4.4%, respectively). Additionally, carvone, limonene, and linalool were detected as the major constituents of the stems of S. vermiculate L. (53%, 17.4%, and 11.3%, respectively) 42 .
Another miscellaneous group of nitrogenous compounds was reported from different Salsola spp., including simple nitrogenous compounds, such as methyl carbamate 1.11 from S. tetrandra, S. kali, S. longifolia and S. rigida 69 57 from S. imbricata Forssk. The alkylamine, tridecanamine 1.21, was also reported from the aerial parts of S. terrandra Forssk 71 .

Cardenolides and steroids
Steroids are a group of natural products biosynthesized from the isoprenoid pathway via the 2,3-oxidosqualene (C 30 ) route. Cardenolides are cardioactive steroidal lactones with a 5-membered (furanones) or 6-membered (pyranone) ring at C-17. They are naturally present free or glycosylated with mono-or multisugar moieties. Several families are known for their high cardenolides content, such as Asclepidaceae, Apocynaceae, and others 72 . However, only one report on cardenolides from the Amaranthaceae family has been described. It addressed the isolation of five cardenolides, salsotetragonin 2.1, calactin 2.2, 12dehydroxyghalakinoside 2.3, desglucouzarin 2.4, and uzarigenin 2.5 from the Algerian plant, Salsola tetragona Delile, Figure 3 50 . Other reported steroids comprised several phytosterols with diversity in the alkyl side chains at C-17, including campesterol 2.6, cholesterol 2.7, and desmosterol 2.8 from S. collina 73 , b-sitosterol 2.9, stigmastanol 2.10, and stigmasterol 2.11, in addition to a combined phytosterol, stigmasterol-3-O-b-D-glucopyranoside 2.12 from the aerial parts of S. inermis 51 . The existence of fatty acid esters or acylated sterols was reported by Mayakova et al. 73 from the genus Salsola. They investigated the contents of the saponified acylsterols fraction of the pentane extract of S. collina. The neutral fraction indicated the presence of four sterols, including b-sitosterol, stigmasterol, cholesterol, and campesterol, whereas the acyl fraction of the hydrolysed esters composed of stearic, palmitic, and oleic acids 73 .

Coumarins and coumarinolignans
Coumarins are bioactive secondary metabolites biosynthesized in plants from the phenylpropanoid (C 6 C 3 ) pathway by cyclisation of cinnamic acid. They contribute to diverse biological activities, such as anticoagulant, antimicrobial, antiviral, and anticancer activities 74 . Several studies reported the presence of simple coumarins in members of the genus Salsola. These reported coumarins are either free or glycosylated with mostly methoxylated C-6 and oxygenated C-7 positions. Two simple coumarins, namely umbelliferone 3.1 and scopoletin 3.2 were reported from the aerial parts of S. inermis 51 . Whereas S. kali showed the presence of fraxidin 3.3 75 . However, the highest record of coumarins from this genus was noted to S. laricifolia that included several simple coumarins

Flavonoids and isoflavonoids
Flavonoids and isoflavonoids are predominant plant polyphenols having a C 6 -C 3 -C 6 skeleton and are considered as one of the frequently studied plant phytochemicals 94 . Flavonoids are yellow-colored compounds possessing a highly distinctive biosynthetic pathway as they are synthesised from the mixed phenylpropanoid (4-coumaroyl-CoA) and polyketide (3 malonyl-CoA) pathway 95 . The isoflavonoids subclass is characterised by the presence of a 2-phenyl instead of 3-phenyl substitution at the benzo-c-pyrone moiety 94 . Concerning the biological activities, flavonoids are the main dietary antioxidants due to their action as scavengers of harmful free radicals. In addition, they act as signalling molecules by their modulatory effect on several protein kinases, such as MAP kinase (mitogen-activated protein kinase). The latter mechanism can explain their neuroprotection, cardioprotection, and anticancer activities 96 . Isoflavonoids are much limited in their distribution in plant families (e.g. Leguminosae) compared to flavonoids and are characterised by their phytoestrogenic activity as in the case of genistein 97 . In the genus Slasola, the reported flavonoids ( The free flavonol aglycone, kaempferol was incompletely identified by UPLC/qTOF-MS analysis of the aerial parts and roots of S. vermiculata and S. Tetrandra plants 68 . The presence of OCH 3 groups (i.e. methoxylated flavonoids) was mainly observed at C-3and C-4 0 in the B-ring of flavones (in tricin and its derivatives 5. 28-5.32), and at C-3 0 of flavonols (in the isorhamnetin derivatives 5.4-5.13). However, diversity in methoxylation positions was recorded for the isoflavonoids group (5.37-5.52), as both the A-ring (positions C-5, 6, 7, and 8) and the B-ring (positions C-2 0 , 3 0 , and 5 0 ) acquired OCH 3 groups. For detailed references and the plant source, see Table 2. Finally, a unique 8,2 0dimethoxylated isoflavan derivative, salisoflavan 5.53, was reported from the arial parts S. imbricata Forssk 57 .

Phenolic acids and simple phenols
Simple phenols are a minor class of natural products defined as aromatic compounds with at least one hydroxyl group attached to a benzene ring, such as catechol, resorcinol, and phloroglucinol. However, phenolic acids/derivatives represent a major class of plant-derived natural products, categorised into benzoic acids, such as protocatechuic and gallic acids (C 6 -C 1 ) and cinnamic acids, such as caffeic and coumaric acids (C 6 -C 3 ) 100 . HPLC analysis of the aerial parts and root of S. kali revealed the presence of two simple phenols viz, catechol 8.6 and resorcinol 8.21 12,75 2, cuneataside C 9.9, and 2-(3,4-dihydroxy)-phenyl-ethyl-b-Dglucopyranoside 9.10 were isolated from the aerial parts of S. komarovii 89 . The cyanogenic glycosides, taxiphyllin 9.17 and 3,4,5trimethoxyphenyl-b-D-glucopyranoside 9.18 were reported in the aerial parts of S. tetrandra 53 . Whereas the isoprenoid glycosides comprised the acyclic monoterpene, 9-hydroxylinaloyl glucoside 9.11 from S. tetrandra 53 , in addition to several ionone derivatives with different unsaturation and oxidation status, such as roseoside A 9.4 and blumenyl B b-D-glucopyranoside 9.5 from S. komarovii 89 and the epoxy derivatives icariside B2 9.12 and lyohebecarpin A 9.14 from S. komarovii and S. tetrandra, respectively 53,89 were reported, Table 2 and Figure 10.

Biphenylpropanoids
Biphenylpropanoids ( Table 2 and Figure 11) were isolated from the aerial parts of S. villosa Delile. ex Schul. and the roots of S. imbricata. They are formed of dimeric C 6 C 3 residues (linked head to head) with a characteristic oxirane ring formed by epoxidation of either one of the side chains' double bond as in biphenylsalsinol 10.

Polyhydric alcohols and carbohydrates
Syrchina et al. 93 described the presence of a few monosaccharide derivatives, including two simple ethyl glucosides namely, ethyl b-D-fructopyranoside 11.1 and ethyl b-D-glucopyranoside 11.2 from S. collina Pall. In addition, they reported the presence of two polyhydric alcohols (D-mannitol 11.5 and myoinositol 11.6) from the same plant 93 , Table 2 and Figure 12.
The whole plant of S. foetida The whole plant of S. foetida                         The aerial parts of S. tetrandra

Miscellaneous group
Only two compounds are included in this group; the first one is a dimeric methylcyclopentenyl alcohol namely, salsolanol 12.1 isolated from the aerial parts of S. villosa Delile. ex Schul. 91 . While, the second compound is an isohexyl 2-pentyl ester of sulphurous acid 12.2 detected by GC-MS analysis of the aerial parts of S. tetrandra 71 , Table 2 and Figure 13.

Pharmacological activities
Plants of the genus Salsola are widely used in the folk medicine of different countries for the treatment of several diseases, such as hypertension, broken bones as well as for boosting the immunity (Table 3).
Research studies showed that extracts of different Salsola spp. and compounds isolated from them exert a wide range of variable pharmacological activities. These activities will be discussed in detail in this section. They are also summarised in Table 4 and Figure 14.

Effect on the cardiac system and blood pressure
One of the early reported pharmacological activities of Salsola spp. is their antihypertensive action. Different Salsola spp. are used as ingredients in different Chinese patents obtained from Faming Zhuanli Shenqing for treating hypertension. Of these, S. collina was the most extensively used sp. as indicated by the number of patents addressed this particular plant. Also, S. ruthenica and S. arbuscula were used in some Chinese patents. Likewise, S. ruthenic, a synonym for S. tragus, was reported as a potential treatment for essential hypertension 105 . Ammon et al. 81 attributed the antihypertensive activity of S. kali and S. longifolia Forsk to salsoline 1.16 and salsolidine 1.19 alkaloids due to their ability to stimulate respiration and to decrease blood pressure 81 .
Loizzo et al. 106 investigated the inhibitory activity of different extracts of the aerial parts of S. oppositifolia Desf., S. soda L., and S. tragus against the angiotensin-converting enzyme (ACE). The ethyl acetate extracts of S. oppositifolia and S. soda showed interesting activities with IC 50 values of 181.04 and 284.27 mg/mL, respectively which further support the traditional antihypertensive use of these species.
The aqueous extract of the whole shrub of S. kali was reported to display a cardioprotective effect against adriamycin-induced cardiotoxicity in male Swiss albino mice 107 . This effect was attributed to lowering the oxidative stress in the heart and inhibiting lipid peroxidation 107 .

Anti-inflammatory, analgesic, and antipyretic activities
Janbaz et al. 108 tested the aqueous-ethanol extract of the aerial parts of S. imbricata to assess its traditional use in inflammatory conditions. They confirmed the anti-inflammatory activity of S. imbricata as it significantly inhibited carrageenan-induced paw edoema in rats. The same research group also tested the analgesic activity of S. imbricata extract using NaCl-induced writhing and formalin-induced paw licking models in rats. Their obtained results indicated that S. imbricata exhibited a dose-dependant analgesic activity by reducing the number of abdominal writhing mediated by 4% NaCl intraperitoneal injection at all tested doses (100, 300, and 500 mg/kg) 108 . Nevertheless, it decreased the time of paw licking by rats only at the dose of 500 mg/kg. Also, S. imbricata showed significant antipyretic activity in the brewer's yeastinduced pyrexia model in rats 108 . The aqueous methanolic extract of S. imbricata leaves and the phenolic compounds isolated from it decreased the NO production levels in in-vitro LPS-induced inflammation in RAW 264.7 macrophage cells and were found to be non-toxic at the concentration of 100 mg/mL 80 . Regarding the tested phenolic compounds, isorhamnetin-3-O-glucopyranoside 5.8 displayed higher activity than its corresponding galactopyranoside glycoside 5.7 and aglycone 5.4 80 .
The anti-inflammatory and antinociceptive activities of S. grandis were tested using the carrageenan-induced paw edoema model in rats and p-benzoquinone-induced nociception tests in mice, respectively 77 . The ethanolic extract obtained from the aerial parts of S. grandis was fractionated and the most bioactive fraction (n-BuOH) was further subjected to a bioassay-guided fractionation to isolate the compounds responsible for S. grandis's activity. The flavonoidal compounds, tiliroside 5.14 and quercetin-3-O-b-Dgalactoside 5.19 displayed the highest activities in the used models 77 .
The anti-inflammatory activity of different extracts of the aerial parts of S. cyclophylla was evaluated by Mohammed et al. 15 using the carrageenan-induced paw edoema method. The aqueous-ethanolic extract showed the highest anti-inflammatory activity among the tested extracts and its activity was close to the well-known anti-inflammatory drug, diclofenac. Mohammed et al. attributed  Ethyl b-D-fructopyranoside S. collina Pall. 93

12.2
Sulphurous acid, isohexyl 2-pentyl ester By GC-MS analysis of the aerial parts of S. tetrandra 71 this anti-inflammatory activity to the antioxidant potential of the phenolic and flavonoid components present in the aqueous-ethanolic extract. The same research group also investigated the analgesic activity of S. cyclophylla using the hot-plate and acetic-acid writhing models in mice. The aqueous ethanolic extract showed the highest activity with 87.50-99.66% pain reduction rates after different time intervals, which was comparable to the diclofenac activity 15 .
Seo et al. 37 reported that the ethanol extract of S. komarovii showed effective anti-inflammatory activity as hydrocortisone by reducing the production of LPS-induced IL-6. It also exerted glucocorticoid receptor binding activity and interfered with NF-jB nuclear translocation 37 .
The synthetic analogue of the active principle of S. tuberculata, 2-(4-acetoxyphenyl)2-chloro-N-methylethylammonium-chloride, was reported to inhibit UVB induced intracellular interleukin-1 alpha (icIL-1a) in the UVB in-vitro model for inflammation 122 . Contrarily, the methanol extract of S. tuberculata exerted a pro-inflammatory activity by boosting the UVB induced-icIL-1a production and enhanced cytotoxicity. While the dichloromethane extract showed no significant effect on skin cells inflammation 122 . The investigated synthetic analouge was also suggested to exert its anti-inflammatory and contraceptive activities by competitive inhibition of glucocorticoid binding to corticosteroid-binding globulin (CBG) leading to increased levels of the in-vivo free corticosterone 123,124 .

Antioxidant and iron chelation activities
The antioxidant potential is one of the most extensively studied activities of Salsola species. It could be concluded from the reported results that the used plant parts and the extraction solvent could greatly affect the antioxidant activity. Flavonoids and their glucosidal derivatives are mostly the responsible compounds for antioxidant activities. While other compounds, such as essential oil components, alkaloids, and biphenylpropanoids showed only moderate activities.
The antioxidant activity of S. cyclophylla extracts was tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH) colorimetric assay method 15 . The best DPPH-free radicals scavenging potential was observed for the aqueous-ethanolic extract that showed comparable activity to the used standard, quercetin. While, the ethyl acetate extract showed the highest ferrous ions (Fe 2þ ) chelating activity using ferrozine-based assay 15 . The same group reported the antioxidant activity of the essential oil obtained by water distillation of S. cyclophylla that showed only one-half of the quercetin activity. They attributed this activity to the benzoic acid esters and the hexahydrofarnesyl acetone components that occur in the essential oil in high concentrations 41 .
Antioxidant and iron chelation activities of the methanolic extract of different plant parts of S. kali were also investigated by Boulaaba et al. 75 using the same methods used for S. cyclophylla extracts. Leaf and stem extracts showed the highest antioxidant activity while leaf and root extracts showed the highest iron chelation activity 75 .
The alkaloidal extracts of S. oppositofolia, S. soda, and S. tragus were prepared by extraction of their aerial parts with methanol, alkalinization with NH 4 OH then extraction with ethyl acetate. The three alkaloidal extracts showed significant antioxidant activity when tested using the DPPH method. Remarkably, S. oppositifolia showed the highest activity with an IC 50 value of 16.30 mg/mL 48 .
The ethyl acetate extract of S. komarovii aerial parts was subjected to HPLC separation and the obtained elutes were tested for antioxidant activity using ABTS þ radical scavenging method. The components responsible for the antioxidant activity were identified by HPLC-MS as the flavonoids, isorhamnetin 5.4, astragalin 5.15, isoquercitrin 5.20, and rutin 5.25 79 .
The ethyl acetate fraction of S. baryosma showed 77% DPPH radicals scavenging activity while other tested fractions showed lower activities below 57% 109 . This result is contradictory with that obtained by Khacheba et al. 125 who reported weak antioxidant activity of S. baryosma ethyl acetate extract using DPPH assay.
The antioxidant activity of 80% (v/v) aqueous-methanol extracts of S. vermiculata and S. baryosma in addition to other Algerian herbs was tested using the hydroxyl (OH ), nitroxide (NO ) and (ABTS þ ) radicals scavenging assays, and Fe 3þ -TPTZ complex reductive power assay. The results showed that S. baryosma exhibited the highest antioxidant activity in OH radical assay with an EC 50 of 0.26 ppm despite its low phenolic content 22 .
Beyaoui et al. 59 investigated the antioxidant activity of two compounds, tetranins A and B, isolated from the ethyl acetate extract of S. tetrandra roots using DPPH and ABTS assays. The dihydrostilbene, tetranin A 8.27 exerted higher antioxidant activity than the isoflavonoid, tetranin B 5.37. However, both compounds showed lower activity than the standard antioxidant, Trolox 59 .
The ethanol extract of S. collina Pall demonstrated anti-oxidative activity through DPPH radical scavenging capacity (Oh et al., 2014).

Cytotoxic activity
Only a few studies were made for investigating the cytotoxic activity of a small number of Salsola spp., including S. cyclophylla, S. oppositifolia, S. collina Pall, and S. baryosma. The cytotoxic activity of 95% aqueous-ethanolic extract of the aerial parts of S. cyclophylla was investigated using MTT assay against M14 melanoma derived epithelial breast cancer (MDA cells), human pancreatic cancer (PANC-1), Michigan Cancer Foundation-7 (MCF-7) breast cancer cells, and the normal human fibroblast cells. The aqueousethanolic extract of S. cyclophylla showed low to moderate cytotoxic activity only at high concentrations (50-400 mg/mL) against the tested cell lines and no significant cytotoxic effect was observed at low concentration (< 50 mg/mL) 15 .
Different fractions obtained from the extract of the aerial parts of S. oppositifolia were screened for cytotoxic activity against a panel of cancer cell lines 85  The ethanol extract of S. baryosma whole plant showed no significant cytotoxic activity when tested with other plant extracts using the brine shrimp method 126 . The same result was reported by Ahmed et al. 109 , while 80% ethanol extract of S. baryosma did not exhibit cytotoxic activity against brine shrimp larvae and only the ethyl acetate fraction showed 50% cytotoxic activity. However, all tested fractions of S. baryosma showed phytotoxicity against Lemna minor plant growth 109 .

Effect on the immune system
Interestingly, S. laricifolia Turcz is reported to be one of the immune system-boosting drugs, and a pharmaceutical product derived from it "Salimon" represents one of the best-selling immunostimulant drugs in the Mongolian drug market 76 .

Effect on the liver and the gallbladder
Lochein, a liquid extract of the Russian thistle S. collina Pall., was reported to show a significant hepatoprotective effect on patients with chronic hepatitis 127 . It also has been approved as an active food supplement by the Ministry of Health of the Russian  Figure 14. Reported pharmacological activities of plants belonging to the old genus Salsola.
Federation 111 . Ethanol extract (25%) of the aerial parts of S. collina Pall. was reported to decrease the signs of paracetamol-induced liver damage in rats and to exert a better hepatoprotective activity than the reference drug, silymarin 111 . It was also reported to decrease the levels of the liver enzymes and lipid peroxidation products and to enhance the detoxification of bilirubin, and ammonia 111 . Moreover, S. collina aqueous extract was reported to protect against cholelithiasis in rabbits through enhancing cholesterol and water absorption and decreasing inflammation and formation of biliary slough 112 .
Oral administration of S. imbricata methanol extract was reported to prevent liver toxicity in CCl 4 -induced hepatotoxicity in mice. This hepatoprotective activity was attributed to the ability of the phenolic content of S. imbricata to enhance the antioxidant capacity of the liver 84 .
Ethanol extracts (70%) of S. tetrandra and S. baryosma showed a prophylactic and therapeutic hepatoprotective activity against paracetamol-induced hepatorenal toxicity in rats 113 . The results showed that S. tetrandra was more active and showed a higher ability to decrease the levels of inflammatory markers, such as interleukin-1b (IL-1b) and tumour necrosis factor alpha (TNF-a) 113 .
The alcoholic extracts of S. volkensii and S. villosa showed hepatoprotective effects with a broad safety margin against CCl 4induced hepatotoxicity in Sprague Dewaly rats indicating their potential use for the treatment of liver damage 114 ,.

Effects on the gastrointestinal system
Different plants of the Salsola genus were reported to exert several effects on the gastrointestinal tract, including gastroprotective activity against ulcer, anthelmintic, and antispasmodic activities.
Alcoholic extract (50%) of S. komarovi in 500 mg/kg concentration was found to significantly protect against gastric ulcer and to be more potent than Ranitidine (300 mg/kg) in 60% HCl-ethanol induced gastritis model 115 . While 70% alcoholic extract of S. tetrandra showed a similar gastroprotective effect to that of Ranitidine against aspirin-induced gastric ulceration in rats 71 .
Chloroform extract of S. imbricata bark demonstrated anthelmintic activity against Haemonchus contortus worms 116 . Ethanol extract (80%) of S. baryosma (synonym for S. imbricata) demonstrated antispasmodic activity as it inhibited the rabbit jejunum contraction at a concentration of 0.3-3 mg/mL 109 . It was suggested to act as a calcium channel blocker because it resulted in 70% inhibition of K þ -induced contractions in rabbit jejunum at the concentration of 1-5 mg/mL 109 . The ethyl acetate fraction of the aerial parts extract of the same sp. showed the highest spasmolytic and bronchorelaxant activities on isolated rabbit jejunum and tracheal preparations which were suggested to be due to its agonist action on b-adrenergic receptors and Ca þ2 antagonising activity 117 .
On the other hand, the ethyl acetate extract of S. collina was reported to increase the gastric motility and gastric emptying rate through activating M-cholinergic receptor, increasing ghrelin and gastrin plasma levels and increasing the expression of the vasoactive intestinal peptide receptors in rats 118,128 .

Antidiabetic activity
Decreasing post-prandial hyperglycaemia by inhibiting digestive enzymes involved in carbohydrate hydrolysis, such as a-amylase and a-glucosidase enzymes is a commonly used therapeutic approach for the management of diabetes. Therefore extensive studies were made on the a-amylase and a-glucosidase inhibitory activity of different Salsola spp. 22,65 .
The a-amylase inhibitory activity of different fractions of the aerial parts of S. kali, S. soda, and S. oppositifolia was investigated by Tundis et al. 65 . The ethyl acetate fraction of S. kali showed the highest a-amylase inhibitory activity with an IC 50 value of 0.022 mg/mL. The bioassay-guided chromatographic separation of this most active fraction resulted in the isolation of two flavonol glycosides, of which isorhamnetin-3-O-rutinoside 5.5 displayed significant a-amylase inhibitory activity with an IC 50 value of 0.129 mM 65 .
Djeridane et al. 22 investigated the antidiabetic potential of the aqueous-methanol extracts of S. vermiculata and S. baryosma by testing their ability to inhibit a-amylase and a-glucosidase enzymes activities. The results indicated that S. baryosma exhibited the highest competitive inhibitory activity with inhibition constant (K i ) values of 7 and 16 mM against a-amylase and a-glucosidase, respectively suggesting its potential for type 2 diabetes management 22 . Similarly, N-acetyltryptophan 1.1 isolated from S. collina Pall by Jin et al. 66 showed 44% inhibition of a-amylase enzyme activity.
Iannuzzi et al. 10 studied the chemical profile of the cultivated buds of S. soda and compared it to that of the wild plant. They also screened the inhibitory activity of the compounds isolated from their n-BuOH fraction against three enzymes of the aldo/keto reductase superfamily, namely aldose reductase (hAKR1B1), aldose-reductase-like protein (hAKR1B10), and carbonyl reductase 1 (hCBR1). They found that quercetin-3-O-glucuronopyranoside 5.22, the only flavonoid identified in both plant types was the most effective inhibitor for the tested enzymes and suggested its use as a functional nutraceutical to counteract diabetic complications 10 .

Effect on neurodegenerative diseases
The effect of the isolated compounds from the methanol extract of S. komarovii aerial parts on the production of the endogenous Nerve Growth Factor (NGF) in C6 glioma cells was investigated by Cho et al. 89 . The lignan derivative, conicaoside 6.3 showed the highest NGF-production stimulating activity and the lowest toxicity among the tested compounds indicating its potential for the regulation of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases 89 . Alzheimer's disease (AD) is one of the most common neurodegenerative diseases that is combined with acetylcholine deficiency. Therefore, it can be improved by inhibiting the enzymes affecting the cleavage of acetylcholine, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).
The ethanolic extract of the aerial parts of S. grandis and the different compounds isolated from its n-BuOH sub-extract were investigated for AChE inhibitory activity by Orhan et al. 70 . Only Nacetyltryptophan 1.1 showed AChE inhibitory activity suggesting its neuroprotective potential against Alzheimer's disease 70 .
The methanolic extract of S. vermiculata root demonstrated strong anti-acetylcholinesterase inhibitory activity which was higher than that of S. vermiculata aerial parts and S. tetrandra roots and aerial parts. It showed an IC 50 of 0.45 ± 0.17 mg/mL. While the standard drug, eserine showed IC 50 of 0.27 ± 0.1 mg/ mL 68 . This activity could be attributed to the rich catecholamines content in S. vermiculata root 68 .
The alkaloidal extracts of S. tragus, S. soda, and S. oppositifolia Desf. were screened for AChE and BChE inhibitory activities 48 90 from the chloroform extract of S. baryosma were reported to inhibit the BChE enzyme 90 .

Effect on fertility
The contraceptive activity of Salsola plants was firstly described by Ploss in 1960. He reported the use of the aqueous extract of an undefined Salsola sp. as an oral contraceptive in Algeria 40 . The aqueous extract of S. tuberculatiformis (previously known as S. tuberculate and commonly known as Gannabos) was reported to be used by Bushmen women as an oral contraceptive and to cause prolonged gestation and foetal post-maturity in Karakul sheep in Namibia region, South Africa 40,119,129 . Swart et al. 40 investigated the phytochemicals responsible for this activity in S. tuberculatiformis. The compound responsible for this activity was reported to be a labile synephrine analogue with a reactive aziridine group. Therefore, they synthesised the compound, 2-(4-acetoxyphenyl)2-chloro-N-methylethylammonium-chloride, as a stable analogue for the active principle of S. tuberculatiformis. This compound was found to disturb the mammalian steroid hormones homeostasis and to inhibit adrenal steroidogenesis 40 .
The ethanolic extract of S. imbricata was reported to cause a slight decrease in the testis weight and to cause a significant decline in the sperm count when administered orally to male albino rats suggesting its potential use as a reversible male contraceptive, with a high safety margin 104 . They attributed this contraceptive activity to the phenolic content of the plant, especially quercitrin 104 .

Effect on melanin biosynthesis
Trans-N-feruloyltyramine derivatives (1.3, 1.4, and 1.8) isolated from S. foetida were reported to exhibit significant tyrosinase enzyme inhibitory activity with IC 50 ranging from 0.40-2.61 mM which was lower than that of the standard tyrosinase inhibitors, kojic acid and L-mimosine, with IC 50 of 16.67 and 3.68 mM, respectively. Therefore, these derivatives could have promising activities on melanocytes and skin pigmentation abnormalities 78 .

Antimicrobial activity
The chloroform extract of the aerial parts of S. villosa and the compounds isolated from it were tested against different bacterial strains using the paper disc diffusion method 91 . The isolated compound biphenylsalsinol 10.1 showed the highest antimicrobial activity against Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa bacterial strains with an inhibitory zone diameter (IZD) ranging from 12.33 to 28.66 mm. While salsolanol 12.1 showed slight activity against S. aureus, E. coli, S. epidermidis with IZD ranging from 9.33 to 12.66 mm 91 . Oueslati et al. 92 also investigated the antibacterial activity of the roots of S. imbricata and the bioactive compounds, biphenylsalsonoid A 10.2 and B 10.3, isolated from its ethyl acetate fraction. The two isolated compounds showed similar antibacterial activity against S. aureus, S. epidermidis and E. coli with MIC values ranging from 16-32 mg/mL 92 . While biphenylsalsonoid A 10.2 was two times more active than biphenylsalsonoid B 10.3 against Micrococcus luteus. It is worth noting that both compounds showed lower activity than the standard drug, Kanamycin which showed MIC values ranging from 2-8 mg/mL 92 The antimicrobial activities of the methanol extract of S. kali leaves and stems were investigated by Boulaaba et al. 75 . The stem extract showed higher activity than the leaf extract. It showed antibacterial activity against P. aeruginosa and M. luteus with an inhibition zone diameter (IZD) of 10 mm. It showed weak or slight activity against other bacterial pathogens and Candida sp. 75 .
Mohammed et al. 41 investigated the antimicrobial activity of S. cyclophylla essential oil against different microorganisms using the agar well-diffusion method. It showed good antibacterial activity against the Gram þ ve, S. aureus and Streptococcus pyogenes, and the Gram -ve, P. aeruginosa, and E. coli. However, it had no activity against S. epidermidis. It also demonstrated powerful antifungal activity against C. albicans 41 .
Gannoun et al. 42 investigated the antimicrobial activities of S. vermiculate leaf, root, and stem extracts and their volatile fractions towards different pathogens. They reported that the ethanolic roots extract showed the highest activity against S. aureus with a MIC value of 0.28 mg/mL 42 . The used extracts showed low antifungal activity against the tested fungal sp. with IZD ranging from 6-9.5 mm 42 . On the other hand, S. vermiculata aqueous extract was reported to be an effective antifungal agent that can be used as a preservative during grain storage. This activity was examined by the decrease of fungal growth on wheat samples that were coated with S. vermiculata aqueous extract, dried, and stored for one year 120 .
Terrestric acid 1.20 isolated from S. collina Pall by Jin et al. 66 showed antifungal activity against Candida albicans with a minimum 80% inhibitory concentration (MIC 80 ) of 8mg/mL 66 . The alkaloid salsoline A (trolline) 1.17, present in S. collina Pall. and the flowers of Trollius chinensis, was reported to exhibit significant antibacterial activity against S. aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae. It also exhibited moderate antiviral activity against influenza viruses A and B 46 .

Insecticidal activity
The ethanol extract of S. baryosma was reported to cause moderate insecticidal activity (22.08% mortality) against Trogoderma granarium insects (Everts) which was lower than the standard insecticidal compound, cypermethrin (37.64% mortality) 121 .

Conclusion
The impressive diversity of the pool of phytochemicals of Salsola spp. is comprehensively studied in this review. Furthermore, upto-date taxonomic classification and description of the important morphological characteristics of the plants of this genus were discussed herein. The phytochemical profile of Salsola spp. is composed of alkaloids, nitrogenous compounds, flavonoids and isoflavonoids, triterpenoids, cardenolides and steroids, coumarins, coumarolignans, lignans and diphenylpropanoids, and simple phenolic acids. These secondary metabolites represent a great interest for the chemotaxonomy of the genus. Furthermore, they would support the diverse traditional medicinal uses and pharmacological activities of Salsola species demonstrated by many reports as antihypertensive, immunostimulant, anti-inflammatory, hepatoprotective, anthelmintic, antispasmodic, and antidiabetic. The current study represents a guiding light for researchers studying such widely distributed wild medicinal plants.

Disclosure statement
No potential conflict of interest was reported by the author(s).