Genus Salsola: Chemistry, Biological Activities and Future Prospective—A Review

The genus Salsola L. (Russian thistle, Saltwort) includes halophyte plants and is considered one of the largest genera in the family Amaranthaceae. The genus involves annual semi-dwarf to dwarf shrubs and woody tree. The genus Salsola is frequently overlooked, and few people are aware of its significance. The majority of studies focus on pollen morphology and species identification. Salsola has had little research on its phytochemical makeup or biological effects. Therefore, we present this review to cover all aspects of genus Salsola, including taxonomy, distribution, differences in the chemical constituents and representative examples of isolated compounds produced by various species of genus Salsola and in relation to their several reported biological activities for use in folk medicine worldwide.


Introduction
The genus Salsola L. (Russian thistle, Saltwort), a genus of from semi-dwarf to dwarf shrubs and woody tree species, is a halophyte plant, which is considered one of the largest genera in the family Amaranthaceae. The genus can also help with the restoration and reclamation of degraded salty areas and saline soils [1][2][3][4]. The genus name derives from the Latin word salsus, which means "salty", in reference to the salt-tolerant plants [5,6]. Moreover, this genus is recognized as a cosmopolitan group of plants, which are distributed and naturalized worldwide. The exact number of species that belong to this genus has yet to be determined. Over 64 species have been reported, which are widespread in arid and semi-arid regions of Central Asia, Middle East, Africa, and Europe ( Figure 1) [3,[7][8][9]. Salsola species have a variety of features that contribute to their recognition as a potential forage species in from semi-arid to dry settings along sea beaches, such as extensive seed production, and resistance to extreme climatic conditions including high temperature and extended drought conditions [8,10,11]. These plants typically grow on flat, generally dry and/or slightly saline soils, with some species occurring in salt marshes. Easy-to-vegetates on dry soil and is resistant to pH fluctuation and harsh weather. Salsola is found to be an allelopathically active species, which also decreased the growth of selected associated species during its decaying process [12]. It is autotoxic, but its germination is not inhibited by any of the isolated phytotoxins applied [13]. The genus is rich in vast classes of phyto-constituents, mainly flavonoids, phenolic compounds, nitrogenous compounds, saponins, triterpenes, sterols, volatile constituents, lignans, coumarins and cardiac glycosides. Moreover, it shows different biological activities, including analgesic, anti-inflammatory, antiviral, antibacterial, anticancer, cardioprotective and hepatoprotective activities. The genus Salsola is frequently overlooked, and few people are aware of its significance. The majority of studies focus on pollen morphology [14] and species identification [15] while little research has looked at its phytochemical makeup or biological effects. There is very little information on the adaptation characteristics of Salsola plants for their efficient use in drought-prone, semi-arid to arid settings, as well as their uses re-mediating degraded salt soils.
Therefore, we present this review to cover all aspects of the genus Salsola including taxonomy, distribution, chemical constituents and reported biological activities. This review is based on the literature obtained through a computer search in different databases, including ScinceDirect, Web of Knowledge, SCOPUS, Pub Med and Google Scholar, using the keywords "Salsola and chemistry", "Salsola and phyto-constituents", "Salsola and taxonomy" and "Salsola and biological activities", from 2010 to 2021.

Taxonomy and Distribution
From the taxonomic perspective, Salsola belongs to tribe Salsoleae of subfamily Salsoloideae in family Amaranthaceae [16]. It includes about 64 species (Table 1) but, due to the physical similarity between many species, this genus is generally regarded as exceedingly tough [17,18]. Many writers researched the anatomy of the genus Salsola; however, they all focused on C3-C4 Kranz anatomy in the genus and allied genera's leaves. [19]. Mostly, Salsola species are shrubs, subshrubs, or trees. The leaves are alternate, small, simple, entire, and sessile. They are usually succulent, hairy, and thickly packed, which helps to protect the branches [20]. The genus' stem anatomy was unusual and has been studied in few species, such as S. kali and S. crassa (synonym of Climacoptera crass) [18,19,21]. This is because of the difficulties in sectioning the woody, hard stem, as well as the aberrant secondary growth seen in many Amaranthaceae species [22]. The genus is rich in vast classes of phyto-constituents, mainly flavonoids, phenolic compounds, nitrogenous compounds, saponins, triterpenes, sterols, volatile constituents, lignans, coumarins and cardiac glycosides. Moreover, it shows different biological activities, including analgesic, anti-inflammatory, antiviral, antibacterial, anticancer, cardioprotective and hepatoprotective activities. The genus Salsola is frequently overlooked, and few people are aware of its significance. The majority of studies focus on pollen morphology [14] and species identification [15] while little research has looked at its phytochemical makeup or biological effects. There is very little information on the adaptation characteristics of Salsola plants for their efficient use in drought-prone, semi-arid to arid settings, as well as their uses re-mediating degraded salt soils.
Therefore, we present this review to cover all aspects of the genus Salsola including taxonomy, distribution, chemical constituents and reported biological activities. This review is based on the literature obtained through a computer search in different databases, including ScinceDirect, Web of Knowledge, SCOPUS, Pub Med and Google Scholar, using the keywords "Salsola and chemistry", "Salsola and phyto-constituents", "Salsola and taxonomy" and "Salsola and biological activities", from 2010 to 2021.  Furthermore, Salsola leaves are classified into two anatomical types: the Salsoloid-type leaf, with continuous layers of chlorenchymatous cells with a vascular bundle at the center of the leaf and small peripheral vascular bundles that adhere to chlorenchyma [22], and Sympegmoid-type leaves, with two or three palisade layers and a discontinuous layer of indistinctive bundle sheath cells (typically non-Kranz) around water-storage tissue [22]. Flowers are bisexual, with five petals, five stamens, and a pistil with two stigmas. Finally, fruit is spherical, carrying seeds with a spiral embryo [9].
The genus resists soil salinity; therefore, it is known to grow in hypersaline, arid and semiarid regions [23]. The genus is native to Africa (Mediterranean region), Euro Asia, California, and Australia ( Figure 2) [18]. It was introduced to South Africa, and some territories in North and South America [4].
The genus resists soil salinity; therefore, it is known to grow in hypersaline, arid and semiarid regions [23]. The genus is native to Africa (Mediterranean region), Euro Asia, California, and Australia ( Figure 2) [18]. It was introduced to South Africa, and some territories in North and South America [4].

Traditional Uses of Genus Salsola
Plants from the genus Salsola are known to be used in traditional medicine in treatment of different aliments. S. somalensis is used as hypotensive, antibacterial, anticancer agents and frequently used in traditional medicine to treat a variety of conditions, such as skin diseases and cure tape worm infestation [24][25][26]. In addition, the dried roots of S. somalensis are sold as an anthelmintic by conventional medication distributors in a variety of markets in Ethiopia [27]. The buds of S. soda, the main edible parts of the plant, are consumed as vegetables in Italy and called "agretti" or "barba di frate". The plant was once utilized as a source of impure sodium carbonate, which gave it the name "soda" [26]. Other species, such as S. tragus and S. baryosoma, are utilized as livestock fodder in arid and dry areas [4]. The whole plant of S. kali is used as an infusion by indigenous people residing in the Rif region, Northern Morocco to treat digestive system disorders [28]. The local population in the Mongolian People's Republic traditionally used the S. laricifolia herb for the treatment of stomach diseases, fractured bones, healing wounds, itching, and swelling joints [29,30]. In sheep, some members of the Salsola genus produce prolonged gestation (pregnancy), and, in female rats, they cause contraception (birth control) [31]. Bushmen women in Namibia and South Africa consume the aqueous extracts (tea infusion) of S. tuberculatiformis (synonym of Caroxylon tuberculatiforme (Botsch.) Mucina) as an oral contraceptive in traditional medicine by inhibiting the P450c11 and reducing the biosynthesis of corticosteroids [32]. Meanwhile, in the Cholistan desert, Southern Punjab, Pakistan, S. baryosma has a folklore reputation for treating indigestion, diarrhea, dysentery, itching, sores, colds, improve maleness, asthma, migraine, headache, and inflammations [14,17,20]. Moreover, in the Middle East, S. baryosma is used against some inflammatory diseases [33]. S. imbricata has several folk medicinal applications in the treatment of painful and inflammatory conditions [22], where the bark extract showed a higher potency than fruit extract as an anthelmintic [34]. In China and Korea [34][35][36], the whole fresh herb of S. collina is widely used to treat hypertension [35], headache, insomnia, constipation [37,38] and as a herbal drink or medicine [34,35]. In Russia, S. collina was a component of the biologically active food additive "Heparon", which is recommended as a hepatoprotective when the hepatic cells are exposed to alcohol, medications and various toxins [38]. Hyperpyrexia, hypertension, inflammation, jaundice, and gastrointestinal illnesses have all been treated using S. komarovii in the past [37]. In addition, Bedouins and locals alike are familiar with S. cyclophylla, an edible halophyte, and its traditional medical usage in the treatment of inflammation and pain [36], as well as its other health benefits, including nutritional values

Traditional Uses of Genus Salsola
Plants from the genus Salsola are known to be used in traditional medicine in treatment of different aliments. S. somalensis is used as hypotensive, antibacterial, anticancer agents and frequently used in traditional medicine to treat a variety of conditions, such as skin diseases and cure tape worm infestation [24][25][26]. In addition, the dried roots of S. somalensis are sold as an anthelmintic by conventional medication distributors in a variety of markets in Ethiopia [27]. The buds of S. soda, the main edible parts of the plant, are consumed as vegetables in Italy and called "agretti" or "barba di frate". The plant was once utilized as a source of impure sodium carbonate, which gave it the name "soda" [26]. Other species, such as S. tragus and S. baryosoma, are utilized as livestock fodder in arid and dry areas [4]. The whole plant of S. kali is used as an infusion by indigenous people residing in the Rif region, Northern Morocco to treat digestive system disorders [28]. The local population in the Mongolian People's Republic traditionally used the S. laricifolia herb for the treatment of stomach diseases, fractured bones, healing wounds, itching, and swelling joints [29,30]. In sheep, some members of the Salsola genus produce prolonged gestation (pregnancy), and, in female rats, they cause contraception (birth control) [31]. Bushmen women in Namibia and South Africa consume the aqueous extracts (tea infusion) of S. tuberculatiformis (synonym of Caroxylon tuberculatiforme (Botsch.) Mucina) as an oral contraceptive in traditional medicine by inhibiting the P450c11 and reducing the biosynthesis of corticosteroids [32]. Meanwhile, in the Cholistan desert, Southern Punjab, Pakistan, S. baryosma has a folklore reputation for treating indigestion, diarrhea, dysentery, itching, sores, colds, improve maleness, asthma, migraine, headache, and inflammations [14,17,20]. Moreover, in the Middle East, S. baryosma is used against some inflammatory diseases [33]. S. imbricata has several folk medicinal applications in the treatment of painful and inflammatory conditions [22], where the bark extract showed a higher potency than fruit extract as an anthelmintic [34]. In China and Korea [34][35][36], the whole fresh herb of S. collina is widely used to treat hypertension [35], headache, insomnia, constipation [37,38] and as a herbal drink or medicine [34,35]. In Russia, S. collina was a component of the biologically active food additive "Heparon", which is recommended as a hepatoprotective when the hepatic cells are exposed to alcohol, medications and various toxins [38]. Hyperpyrexia, hypertension, inflammation, jaundice, and gastrointestinal illnesses have all been treated using S. komarovii in the past [37]. In addition, Bedouins and locals alike are familiar with S. cyclophylla, an edible halophyte, and its traditional medical usage in the treatment of inflammation and pain [36], as well as its other health benefits, including nutritional values [36,39]. Thus, the plant is used as a tea and concoction for medicinal purposes by both tribes and traditional healers to treat many diseases, particularly inflammation and pain. The plant is also used as a diuretic, laxative, and anthelmintic by the locals [40]. To find novel medications from the identified genus, more phytochemical, pharmacological, and toxicological research should be carried out.

General Procedures for Isolation of Bioactive Compounds from the Genus
Genus Salsola is rich in different types of phytoconstituents, for which different techniques are required to isolate their active compounds. Generally, dried plant material is extracted with a suitable organic solvent, such as methanol or aqueous ethanol. Total extract is fractionated with different solvents, viz. hexane, chloroform, ethyl acetate and butanol. Hexane fraction is rich in nonpolar constituents, including sterols and triterpenes, which are separated on silica gel columns using an eluting system formed from Hexane:Ethyl acetate with a gradual increase in polarity [43][44][45]. Meanwhile, the chloroform fraction is rich in coumarins, phenolic compounds and flavonoid aglycones. The separation of these compounds is also performed on silica gel columns using chloroform-methanol mixtures with a gradual increase in polarity [46]. Sephadex may be used to purify the isolated compounds using methanol as an eluting agent [46][47][48]. The flavonoid glycosides, as well as saponins, could be detected in ethyl acetate or butanol fractions. These fractions could be treated on Diaion or polyamide columns to remove sugars and obtain flavonoids and their glycosides in a less contaminated form [49,50]. Flavonoid glycosides could be then isolated on normal silica gel using mixtures of chloroform:methanol, with a gradual increase in polarity, or by reverse-phase silica (RP-18) using water:methanol mixtures in isolation [49,50]. Saponins need different treatment, as they were detected in the butanol fraction and could be purified using silica gel columns and chloroform:methanol with a gradual increase in polarity [51]. Alkaloids are usually detected in chloroform or ethyl acetate fractions and separated on silica gel columns using mixtures of chloroform:methanol with a gradual increase in polarity [47,52,53]. Cardinolides are usually detected in chloroform (aglycones) or in butanol (glycosides). Aglycones are separated on silica gel columns using mixtures of chloroform:methanol with gradual increase in polarity; meanwhile, their glycosides are isolated on RP-18 eluted with H 2 O-MeOH [54].     S. baryosma has tested positively for alkaloids [55], flavonoids coumarins and sterols [46]. Phytochemical investigation of the chloroform soluble fraction of S. baryosma resulted in the isolation of polyoxygenated triterpenes named salsolin A (142) and salsolin B (143), along with 2α,3β,23,24-tetrahydroxyurs-12-en-28-oic acid (144) [44]. In addition, salsolide (64), p-hydroxyphenylglycol derivative, coumarins as scopoletin (211), bergaptol (218), daphnoretin (208), bergaptol-5-O-β-D-glucopyranoside (219), daphnorin (209) and a flavonoid, chrysoeriol-7-O-β-D-glucopyranoside (30), have been isolated from the ethyl acetate soluble fraction of the whole plant [46,56]. Meanwhile, salsolic acid (140), an oleane-type triterpene, was isolated from the chloroform fraction of S. baryosma [44]. Kaempferol (18) and quercetin (1) have been isolated from the root, shoot and fruit of S. baryosma. Among plant parts, a maximum content of total flavonoids (kaempferol (18) and quercetin (1)) was observed in fruits, followed by shoot and roots [57]. The following section will outline the important isolated and identified compounds in different Salsola species, as well as the general procedures of their isolation.

S. cyclophylla (Baker) (Synonyme of Caroxylon cyclophyllum (Baker) Akhani and Roalson)
Volatile constituents from S. cyclophylla herb were identified by GC and GC/MS and showed thirty-two volatile compounds (98.16%). A total of 34.59% belonged to ketones, aldehydes, and ester, and 27.97% accounted for benzoic acid ester derivatives including mainly benzyl salicylate (194) (9.07%). Furthermore, the ketone hexa hydrofarnesyl acetone (195) made up 27.14% of the constituents of S. cyclophylla volatile oils. In addition, saturated, and unsaturated hydrocarbons were also detected in the volatile constituents. Therefore, benzoic acid ester derivatives, as well as saturated hydrocarbons, are the major constituents of essential oil from S. cyclophylla [39]. Benzoate esters were found in S cyclophylla, although cinnamate esters have been found in other species. It is now necessary to identify the biochemical pathways involved in the formation of benzoates versus cinnamates.

S. tomentosa (Moq.) Spach
Phenolic components (tannins, flavonoids, and total phenols), and saponins were detected as major constituents of the aerial parts of S. tomentosa collected from Qum province in Iran. Methanol extraction, either by soxhelt or maceration, provided the highest concentration of total phenolic and flavonoid [84].

S. villosa Schult. (Synonym of Caroxylon villosum (Schult.) Akhani and Roalson)
The phytochemical screening of the 95% ethanol extract of the whole plant of S. villosa revealed the presence of alkaloids, saponins, tannins, flavonoids, sterols/terpenes and coumarins [87]. Previous work led to the isolation of secondary cyclic alcohol, salsolanol (225) and biphenylsalsinol (60) from the chloroform fraction of the aerial parts of S. villosa [88]. Compared to other reports on aerial parts' chemical composition, few studies have looked at root organs in most Salsola species.

Overview of the Benefits, Uses and Medicinal Properties of Salsola Genus
There have only been a few chemical and biological studies of Salsola genus. Halophytic plants have been used for medicinal purposes due to the presence of healthpromoting bioactive compounds [89]. In this regard, members in Salsola genus have a significant therapeutic value (Figures 18 and 19). Salsola species have a variety of constituents, with a wide range of biological activities, and have been reported to be utilized in folk medicine all throughout the world, according to the literature. In the following sections, we will go through the different medicinal uses of this genus. The authors will outline the benefits and medicinal uses of different species in the genus Salsola.
have a significant therapeutic value (Figures 18 and 19). Salsola species have a variety of constituents, with a wide range of biological activities, and have been reported to be utilized in folk medicine all throughout the world, according to the literature. In the following sections, we will go through the different medicinal uses of this genus. The authors will outline the benefits and medicinal uses of different species in the genus Salsola.  have a significant therapeutic value (Figures 18 and 19). Salsola species have a variety of constituents, with a wide range of biological activities, and have been reported to be utilized in folk medicine all throughout the world, according to the literature. In the following sections, we will go through the different medicinal uses of this genus. The authors will outline the benefits and medicinal uses of different species in the genus Salsola.

Anti-Inflammatory, Analgesic and Anti-Nociceptive Activity
The incidence of inflammatory diseases is becoming common in almost all countries around the world. Despite their well-known side effects, non-steroidal anti-inflammatory drugs are most commonly used to relieve inflammatory pain [90]. Natural products and traditional medicines, as alternatives to these drugs, offer great hope in the development of efficient agents for the treatment of inflammatory diseases [91]. In this regard, total methanol extract, together with petroleum ether, chloroform, and ethyl acetate fractions of S. kali, were investigated for their anti-inflammatory activity using rat paw edema test. The petroleum ether fraction demonstrated the highest activity (60%). Meanwhile, the chloroform, ethyl acetate fractions and methanol extract led to a 35.0%, 20% and 40% reduction in rat-paw, respectively, relative to indomethacin [45]. The significant anti-inflammatory activity produced by the petroleum ether fraction was attributed to its sterols' contents lupeol (139), ursolic acid (141), β-sitosterol (149) and β-sitosterol-3-O-glucoside (150), which were detected in petroleum ether extract of S. kali. Moreover, these compounds were proven to be anti-inflammatory by different mechanisms [92][93][94]. Moreover, phenolic acid, ferulic (90), which was also identified in S. kali, is known for its strong anti-inflammatory activity [12,95].
COX and other mediators implicated in the pathophysiology of pain alleviation, as well as anti-nociceptive activity, are inhibited by a hydroalcoholic extract from the aerial portions of S. inermis [96].
Using carrageenan-induced paw edema and p-benzoquinone-induced nociception models, the anti-inflammatory and anti-nociceptive effects of the ethanol extract and BuOH fraction of S. grandis, as well as their major constituents, were examined in vivo on male Swiss albino mice. The inhibitory effect of the BuOH fraction on carrageenan-induced paw edema was 27.8-32.9%. On the other hand, a 37.6% inhibition was detected in the p-benzoquinone-induced nociception model. Tiliroside (22) and quercetin-3-O-galactoside (4) were shown to have the most powerful inhibitory effects in the employed models, according to the findings [49].
S. komarovii ethanol extract exhibited anti-inflammatory effects by significantly decreasing lipopolysaccharide (LPS)-induced interleukin IL-6 production, such as hydrocortisone. This worked by a different mechanism to glucocorticoids' induction, which is the main side effect of gluococorticoids [97].
In addition, the aqueous-ethanolic extract of the aerial parts of S. cyclophylla exhibited strong analgesic activity in mice in a hot plate model of pain induction, as well as a carrageenan-induced paw edema model. The activity was attributed to the high phenolic contents of the plant [36].

Antibacterial Activity
Salsoline A (114), an alkaloid isolated from S. collina, as well as ferulic acid (90), a phenolic acid identified in S. kali, showed appreciable anti-bacterial activity [95,98,99]. The antibacterial activity of the methanol extract of S. kali aerial parts was evaluated using the agar-well diffusion method against seven pathogenic bacterial strains at a concentration of 0.5 µg/mL. The highest activity was against Staphylococcus aureus, Streptococcus mutans, Bacillus subtilis and Streptococcus pneumoniae, while moderate bactericidal activity was shown against Pseudomonas aeruginosa. The growth of Escherichia coli and Sarcina lutae was inhibited. Pure methanol was used as a negative control, while Ampicillin, Amoxicillin, Levofloxin, Tetracycline, Vancomycin, Ciprofloxacin, and Penicillin were positive controls [100].
The in vitro anti-bacterial activity of the ethyl acetate extract from the roots of S. imbricata and the two biphenylpropanoids A (62) and B (61) was evaluated by the minimum inhibitory concentration (MIC) method. The two compounds had a similar effectiveness against the tested bacteria, with MIC values ranging from 16 to 64 µg/mL. On the other hand, biphenylsalsonoid B (61) showed higher potency than biphenylsalsonoid A (62) against M. luteus [72].
It was found that 95% ethanol extract of the whole plant of S. villosa, which contains a high concentration of alkaloid and flavonoid, showed a wide spectrum of anti-microbial activity at different concentrations against S. aureus and P. aeruginosa using the agar diffusion method and antibiotics discs of Streptomycin and Chloramphenicol as positive controls [87]. Different fractions of S. villosa revealed different degrees of anti-microbial activity against gram-positive and -negative micro-organisms [101]. Meanwhile, Oueslati and Al-Ghamdi et al., 2015, stated that salsolanol (225) and biphenylsalsinol (60) from S. villosa exhibited anti-bacterial activities. The highest anti-microbial effect was observed for biphenylsalsinol (60) [88].
The anti-microbial activity of extracts prepared from different organs of S. vermiculate (10 mg/mL) was evaluated using the microdilution technique to determine the (MIC). E. faecalis and S. aureus were the most affected by S. vermiculate extracts (MICs 0.28 to 4.16 mg/mL). Ethanol extract of the root was the most effective on S. aureus, while E. coli and P. aeruginosa were the most resistant bacteria. The antibacterial activity was referred to as carvone (187) [102]. It has the ability to destabilize the phospholipid bilayer, interact with enzymes and proteins in the membrane, and reduce pH gradient across the membrane [103].
The agar diffusion method was used to perform the antimicrobial assay of S. cyclophylla. Positive control drug disc 10 µg/mL Amoxicillin and Gentamycin, inhibition zone diameter (IZD) and a broth micro-dilution test were chosen to determine the MIC for selected microorganisms. This had no effect on Staphylococcus epidermidis, but was effective against Staphylococcus aureus and Streptococcus pyogenes with 16 and 11 mm IZD, and an MIC equal to 45 and 72 mg/mL, respectively. Furthermore, it showed activity against Pseudomonas aeruginosa Gram-negative strain with 11 mm IZD and 75 mg/mL MIC, respectively. In contrast, it showed 10 mm IZD with an MIC equal to 79 mg/mL against E. coli. As a result, potent anti-microbial activity was proven, which is remarkable, as this herb is a common camel feed [39]. It should be noted that most results for extracts and or compounds assessed for antimicrobial assays were based on in vitro or agar diffusion assays, with no animal models tested to confirm efficacy. These studies should now follow.

Anti-Viral Activity
Salsoline A (114), an alkaloid in S. collina, showed moderate anti-viral activity against influenza virus A and B [98]. The activity was assessed by infection of Madin-Darby canine kidney (MDCK) cell monolayers with influenza virus A or B using ribavirin as a standard antiviral agent. Salsoline A (114), showed antiviral activity against influenza virus A with IC 50 56.8 µg/mL [98].

Anti-Fungal Activity
The petroleum ether fraction of the whole plant of S. kali exhibited a significant in vitro anti-fungal activity against Rhizoctonea solani and Nattrassi mangifera (21.1 mm and 25.3 mm, respectively) using the agar disc diffusion assay [104]. Mahasneh et al. (1996) studied the anti-fungal activity of the whole aerial parts of the butanol extract of S. villosa which showed significant anti-fungal activity (13-14 mm inhibition zones) against Candida albicans and Fusarium oxysporum, with comparable results to the anti-fungal Miconazole nitrate [101].
The anti-fungal activity of S. vermiculate leaf, root, and stem extracts (100 mg/mL) was tested against three pathogenic Candida species; C. glabrata, C. krusei and C. parapsilosis using the diffusion method in a solid medium (Sabouraud Chloramphenicol). The results showed that the activity varied according to the pathogen and the plant extract. It also appears that these activities were weak with inhibition zone diameters ranging from 6.5 to 9.5 mm. The butanol fraction of root methanol extract was the most active on C. parapsilosis (ϕIZ = 9.5 mm). The richness of S. vermiculate leaves, stems and roots volatile fractions in carvone (187) (52.2%, 53% and 49.9%, respectively) could explain its anti-fungal activity [86].
S. cyclophylla volatile oil demonstrated a powerful effect against C. albicans fungus compared with Clotrimazole standard, with an inhibition zone of 16 mm IZD and 14.5 mg/mL MIC, respectively [39]. Terrestric acid (119) from S. collina showed positive anti-fungal activity when evaluated by the standard broth micro-dilution method of the NCCLS [47].

Anti-Oxidant, Hepato-Protective and Cardio-Protective Activity
Active polymers such as free radicals (reactive oxygen species or reactive nitrogen species) are overproduced or eliminated too slowly under oxidative stress. A variety of chronic disorders, such as diabetes mellitus (DM) and Alzheimer's disease, are linked to an oxidation-antioxidation imbalance [105][106][107]. As long as the body maintains a dynamic balance between oxidation and anti-oxidation, excess ROS and RNS can rapidly be removed from the body. Cellular damage occurs as a result of overproduction of RNS and ROS, resulting in damage to all cellular components, including DNA, proteins, and lipids [108], which causes disordered cell function and metabolism. Excess ROS and RNS have been reported to be eliminated by natural antioxidants, as well as preventing free radicals from oxidizing and harming cells.
Salsola is an important halophytic genera of the family Amaranthaceae and is considered as a genera of plants containing anti-oxidants compounds with low caloric composition [4]. It has been reported that the ethanol extract of S. collina has anti-oxidant activity through its DPPH radical scavenging capacity [109]. Ethyl acetate extract of S. collina alleviates diabetic gastroparesis (DGP), possibly by promoting gastric emptying in DGP Male Sprague-Dawley rats, due to its oxidative stress inhibition ability, and increasing the number of gastric neurons, combined with its hypoglycemic and lipid-lowering effects [64].
The in vitro DPPH radical scavenging activity of the methanol extract of the aerial parts of S. tetrandra exhibited a strong anti-oxidant activity, with an IC 50 of 24.98 µg/mL, comparable with ascorbic acid standard (24.7 µg/mL). This finding agrees with the enrichment of the extract with polyphenols, particularly flavonoids [26]. Tetranins A (59) (bibenzyl derivative) and B (48) (isoflavonoid) were isolated from the EtOAc extract of S. tetrandra roots. They demonstrated a significant anti-oxidant effect in DPPH free-radical scavenging activity and ABTS assays. In the DPPH assay, tetranin A (59) possessed a higher anti-oxidative capability than tetranin B (48), with an IC 50 of 0.17 mM and 1.09 mM, respectively. In the ABTS assay, tetranin A (59) had slightly lower anti-oxidant effects than tetranin B (48) with a Trolox-equivalent anti-oxidant capacity (TEAC) of 2.39 mM and 2.06 mM, respectively [42].
The hydroalcoholic extract from the aerial parts of S. inermis exhibited anti-oxidant activity [96]. Methanol and acetone extract of the aerial parts of S. tomentosa showed good in vitro anti-oxidant activity using the DPPH and β-carotene bleaching methods [84].
The qualitative measurement of anti-oxidant activity using a DPPH spraying reagent revealed that S. cyclophylla essential oils exhibit some anti-oxidant activity, as fading purple color spots appeared as positive anti-oxidant activity. The scavenging effect of essential oils was 32% when compared with the standard quercetin and Trolox. The anti-oxidant activity may be attributed to the presence of a noticeable proportion of benzoic acid ester derivatives (27.97%) and ketone hexahydrofarnesyl acetone (27.14%) [39].
The ferulic acid (90) identified in S. kali is known for its strong anti-oxidant activity [12]. It decreases the synthesis of cholesterol and lipids levels and protects against coronary disease [95]. Pretreatment with aqueous extract of S. kali (200 mg/kg orally) had a potential anti-oxidant activity, which ameliorated adriamycin (ADR)-induced cardiotoxicity in male Swiss albino mice. These protective mechanisms may be caused by inhibiting lipid peroxidation (LPO) and enhancing anti-oxidant status in the heart [111].
The in vitro, anti-oxidant activity of an alkaloid extract of S. oppositofolia, S. soda and S. tragus was determined by the DPPH method, using ascorbic acid (IC 50 2 µg/mL) as a positive control. The results revealed a significant anti-oxidant effect, with an IC 50 value of 16.3 µg/mL, for S. oppositifolia. In comparison, S. soda and S. tragus extracts exhibited an IC 50 value of 24.3 µg/mL and 26.2 µg/mL, respectively [112].
The significant anti-oxidant activity of the aqueous ethanolic extract of S. cyclophylla aerial parts is expressed as DPPH free-radical scavenging reactivity at IC 50 0.615 ± 0.06 mg/mL) [36].

Contraceptive Effect
It is usually possible to classify contraceptive methods as either traditional or modern. Herbal medicine has always supported the potential health benefits of plants. Today, they are highly regarded as a source of safe phyto-pharmaceuticals [67].
Oral administration of the ethanolic extract (cold maceration in 70% ethanol) of the whole plant of S. imbricata at two doses (250 and 500 mg/kg b.wt) over a 65-day period was used to examine the contraceptive effect in male albino rats. Prior to biological evaluation, an acute toxicity study was conducted to ensure its safety. It was found to be safe up to a dose of 5 g/kg. The male contraceptive activity was related to its phenolic contents, especially quercitrin (5) [67].
Ethyl acetate extract of S. collina has significant prokinetic activity. It was effective in vivo, in promoting gastric-emptying and small-intestinal propulsion in normal male Sprague Dawley rats, showing a dose-dependent effect via a mechanism that mainly involves modulating plasma ghrelin and gastrin, as well as the expression of vasoactive intestinal peptide receptor 2 in the duodenum. In vitro, atropine promoted the contraction of both normal and relaxed gastric antrum strips, thus activating M-cholinergic receptor. This establishes a pharmacological foundation for treating gastrointestinal motility problems with S. collina extract [99].
Total extract, as well as the EtOAc and aqueous fractions of S. imbricata, caused relaxation effect on gut and tracheal tissues through the Ca 2+ antagonist, as well as βadrenergic receptor agonist effects. This explains its medicinal value in gastrointestinal and respiratory problems such as stomach colic, diarrhea, cough, and asthma [116]. The ethyl acetate fraction was found to be more effective in relaxing smooth muscle spasms than the original extract and its aqueous fraction.
The 80% ethanol extract of the whole plant of S. baryosma growing in Cholistan desert demonstrated anti-spasmodic activity in isolated rabbit jejunum preparations. When compared to the control verapamil, it also suppressed K+-induced contractions by 70% at 1-5 mg/mL, implying a calcium-channel-blocking activity [48].

Anti-Ulcer Activity
GIT disorders, which are among the leading causes of human illness, are widespread public health issues worldwide [117]. S. imbricata has a legendary reputation for treating a variety of gastrointestinal problems [116].
The alcoholic extract (70% alcohol in H 2 O) of the aerial parts of S. tetrandra showed an ulcer-protective effect like that of Ranitidine against Aspirin-induced gastric ulceration in rats in a dose-dependent manner. The ulcer index significantly decreased (p < 0.05) in the Salsola-treated rats, according to histopathological and histochemical data. In contrast, stomach mucus production increased while mucosa erosion decreased [82].
The ameliorating effect of 500 mg/kg of 50% alcohol extract of S. komarovii against gastritis and gastric ulcers induced by the HCl-ethanol-gastritis model was studied. It showed inhibitory effects against gastritis and gastric ulcers, which were more potent than 300 mg/kg of Ranitidine and could be used to develop a novel anti-gastric ulcer medication [37].

Cytotoxic Activity
The ethanol extract of S. collina was shown to have anti-cancer properties on human colon carcinoma HT29 cells in a dose-dependent manner by cell-cycle regulation [109]. Different fractions (n-hexane, CH 2 Cl 2 , EtOAc and diethyl ether) and isolated flavonols (from EtOAc fraction) from S. oppositifolia aerial parts were evaluated for their cytotoxic activity against five human tumor cell lines: renal adenocarcinoma ACHN, hormone-dependent prostate carcinoma LNCaP, human breast adenocarcinoma MCF-7, amelanotic melanoma C32 and large cell lung carcinoma COR-L23. The n-Hexane fraction was more selective against lung carcinoma compared with amelanotic melanoma cell lines, with IC 50 values of 19.1 µg/mL and 24.4 µg/mL, respectively. Lower activity was found against renal adenocarcinoma and hormone-dependent prostate carcinoma cells (IC 50 value of 43.4 µg/mL and 45.1 µg/mL, respectively). Additionally, the dichloromethane fraction showed the most interesting biological activity on large-cell lung carcinoma (IC 50  The remarkable cytotoxic effect of the two non-polar fractions (n-hexane and diethyl ether), specifically against COR-L23 and C32 cells, may be attributed to the presence of fatty acids and methyl esters, based on their chemical makeup [80].
The IC 50 of the ethyl acetate fraction of the whole plant of S. baryosma was determined using a brine shrimp assay, and the number of larvae that survived after the addition of various amounts of test sample, using Permethrin (236 g/cm 3 ) as a standard, was calculated to be 1 mg/mL. On the other hand, all fractions of S. baryosma (ethanol 80%, n-hexane, EtOAc and n-BuOH) were found to be phytotoxic to a varying degree, from 52% to 100%, which was assessed by the inhibition of Lemna minor plant growth in a dose-dependent manner, using paraquat as standard drug (0.9025 µg/mL) [48]. Finally, taxiphyllin (229) from S. tetrandra showed high cytotoxic activity in the Artemia salina lethality bioassay, with an ED 50 value of 0.96 µM [70]. Likewise, most cytotoxic results are based on cell-based inhibition, with no tumor xenografted animal model to prove efficacy. This should be considered as a next step.

Vaso-Activity Effect
The ethanol extract of Salsola was shown to have hypotensive activity in rats, induced by Nω-Nitro-L-Ariginine (L-NNA) [118].
The alkaloids salsoline (110) and salsolidine (112) were isolated from S. kali and used for the treatment of hypertonia, hypertension and headache (as hydrochloride) by stimulating the activity of sleep and as a nervous system tonifier [12].
Captopril was used as a reference ACE inhibitor to examine the ethyl acetate extracts of the aerial parts of S. oppositifolia, S. soda, and S. tragus for their hypotensive activities. With IC 50 values of 181.04 and 284.27 g/mL, S. oppositifolia and S. soda showed an interesting suppression of ACE activity. S. tragus, on the other hand, showed minimal action, with an inhibition percentage of 36.21 ± 0.4%. Furthermore, using water as a negative control, a gelatin salt block test was used to reduce the false-positive effect caused by tannins. Thus, tannins are not the only factor affecting the efficacy of S. oppositifolia and S. soda EtOAc extracts in inhibiting ACE [74].

Hypoglycemic Effect
The hypoglycaemic effects of methanol extract of the aerial parts of S. kali, S. soda, and S. oppositifolia were evaluated in vitro using an in vitro assay based on the suppression of the α-amylase digesting enzyme. The ethyl acetate fraction of the extract was the most active, with an IC 50 value of 0.022 mg/mL.
In addition, N-acetyltryptophan (121), which is a derivative of amino acid and was isolated from S. collina, showed a moderate inhibition of α-amylase activity using the Caraway iodine/potassium iodide (IKI) method [47].

Anti-Acetylcholinesterase and Anti-Butyrylcholinesterase Activity
Triterpene salsolic acid (140) was isolated from the chloroform fraction of S. baryosma, and showed inhibitory activity against the enzyme butyrylcholinesterase (BChE) [43,44]. Moreover, amino acid derivative, N-acetyltryptophan (121), which was isolated from S. grandis, displayed a marked inhibitory activity against acetylcholinesterase (AChE) (64.90 ± 1.61%) at a dose of 50 µg/mL using a microtiter assay. Moreover, molecular modelling experiments were performed. The interactions between N-acetyltryptophan (121), at the atomic level, and AChE, were established using in silico experiments. Thus, N-acetyltryptophan (121) could be a valuable preclinical molecule for AChE inhibitors, with neuroprotective potential, especially in the treatment of Alzheimer's disease (AD) [50].
Moreover, due to high catecholamine content in their S. vermiculata's roots, they could also inhibit AChE-with an IC 50 value of 0.45 ± 0.17 mg/mL, which is comparable with that of Eserine (physostigmine) [26].
Moreover, alkaloid fractions prepared from S. oppositofolia, S. soda, and S. tragus aerial parts showed promising activity against acetylcholinesterase (AChE) and BChE enzymes. The S. tragus activity was the highest against AChE and BchE (with an IC 50 of 30.2 g/mL and IC 50 of 26.5 g/mL, respectively). Meanwhile, with IC 50 values of 34.3 g/mL and 32.7 g/mL, respectively, S. soda and S. oppositifolia alkaloid fractions had a specific inhibitory action against BChE. The high activity of S. tragus against AChE and BChE enzymes could be due to its high alkaloids salsoline (110) (36.5%) and salsolidine (112) (17.7%) contents [112].
Other components in the Salsola matrix with higher specific activity may, however, perform additively or synergistically, and may eventually be relevant in the anti-acetylcholinesterase effect [26].

Neuroprotective Activity
Exogenous nerve growth factor (NGF) improves the cholinergic neuron system and has therapeutic potential for neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, and diabetic polyneuropathy. Nineteen compounds isolated from the MeOH extract of the aerial parts of S. komarovii were tested on C6 glial cells to see how they affected NGF induction. Cell viability was determined by MTT assay, and 6-Shogoal was used as a positive control. (8S,8 R,7 R)-9 -[(β-glucopyranosyl)oxy] lyoniresinol (197) was a stimulant for NGF secretion in C6 cells (127.3 ± 10.3%) but was cytotoxic at low concertations. Additionally, alangilignoside C (199), conicaoside (200) and blumenyl B β-D-glucopyranoside (206) were found to upregulate (NGF) secretion without significant cell toxicity. The most effective stimulator of NGF release, conicaoside (200), may have neuroprotective properties by stimulating NGF secretion [41].

Tyrosinase Inhibitory Activity
The three isolated phenolic compounds, N-  (101) from the whole plant of S. baryosma, were studied for their ability to inhibit mushroom tyrosinase. They exhibited pronounced tyrosinase inhibition activity, with an IC 50 of 2.61, 1.85, and 0.40 µM, respectively. As a result, S. baryosma can be utilized to treat disorders such as hyperpigmentation, caused by excessive melanocyte production [55].

Other Activities
Many species of this genus can act as an allergenic substance [119]. S. baryosma is used as a diuretic agent, vermifugal, and the ash is applied to itches [87]. Furthermore, an aqueous extract of S. collina is an effective means of cholelithiasis prophylaxis by: (i) inhibiting the development of inflammation in the mucous membrane of the gallbladder against the background of an aggressive atherogenic diet; (ii) favoring cholesterol absorption by the mucous membrane of the gallbladder; (iii) stimulating the absorption of water, thus maintaining a high concentration of bile acid in the gallbladder bile; (iv) preventing the precipitation of calcium allodeoxycholate crystals and the formation of a biliary slough [120].

As a Fodder
Salsola species, especially in the autumn and winter in deserts, can be utilized as a partial substitute for feed concentrates. The aerial parts of S. cyclophylla, which grow in marshy areas of central Saudi Arabia, are frequently used for both medicinal and feeding purposes [39], as a potential alternative food supply during food shortages and drought times [36], and as nutraceuticals. This was corroborated by the richness of phytoconstituents such as flavonoids and phenols [39]. Moreover, Salsola species are a promising camel feed in Pakistan's Cholistan desert [121]. Their development as a viable fodder species in arid regions was aided by a number of characteristics such as excellent nutritional qualities, prolific seed production, resistance to high temperatures, and long-term drought tolerance [122].

Conclusions and Future Prospective
A major driving force for drug discovery over the last century has involved utilizing natural products and their metabolites as a chemically diverse starting building block. The application of natural products, however, is not limited to the modern era, as most traditionally used crude drugs (remedies) have plant-derived extracts. Furthermore, the advancement of modern technologies and the ability to isolate and identify the natural bioactive ingredient in plants, have encouraged researchers to explore and apply them in food and nutraceuticals, as well as medicine.
The genus Salsola, known to be widespread worldwide, has a history of medicinal uses against different diseases in the folk medicine system of several civilizations. In this review, the authors rediscover the genus Salsola by highlighting the important isolated and identified chemical compounds and extracts, along with their reported biological activities. For example, salsolic acid (140), which was isolated from S. baryosma, showed inhibitory activity against (BChE). Meanwhile, N-acetyl tryptophan (121), which was isolated from S. grandis, displayed a marked inhibitory activity against (AchE). Thus, it might be a promising precursor model with neuroprotective potential. In addition, compounds (197,199,200,206), isolated from the methanol extract of the aerial parts of S. komarovii, were found to be a potent stimulant of (NGF) secretion, with potential neuroprotective activity and without significant cell toxicity. Thus, this has therapeutic potential for neurodegenerative diseases, and particularly for (AD) treatment. The three phenolic compounds (99-101) isolated from the whole plant of S. foetida exhibited pronounced tyrosinase inhibition activity, with the potential to be used for the treatment of diseases such as hyper-pigmentation, associated with the overproduction of melanocytes. These bioactive molecules could be used as a starting material in drug discovery for treatment of the aforementioned diseases.
Promising activity was also observed for some Salsola species. The alkaloid fraction of S. tragus showed promising activity against both AChE and BChE enzymes and could be a source of drug lead in AD treatment. Different fractions (n-hexane, CH 2 Cl 2 , EtOAc and diethyl ether) and isolated flavonols from the EtOAc fraction of S. oppositifolia aerial parts exhibited promising in vitro cytotoxic activity against five human tumor cell lines: ACHN, LNCaP, MCF-7, COR-L23 and C32. Moreover, the ethanol extract of S. collina showed anti-cancer activity on human colon carcinoma HT29 cells in a dose-dependent manner by cell regulation. Ulcer-protective effects such as Ranitidine's effect against aspirin-induced gastric ulceration were found in the alcoholic extract of the aerial parts of S. tetrandra. Moreover, the EtOAc fraction of aerial parts of S. oppositifolia and S. soda, together with compounds (110,112), found in S. kali, showed hypotensive activity.
Whilst most studies of the bioassays of Salsola extracts or its isolated compounds focused on in vitro cell-based assays, few have attempted to use animal models to confirm efficacy. These studies should now follow, so that the results are conclusive. Likewise, profiling halophytes of a different geographical origin can reveal how different environments can affect Salsola's chemistry and or biological effects. The application of metabolomic approaches for the large-scale profiling of the genus, to provide a holistic assessment of its metabolite chemical composition, has been little reported in the literature compared to other medicinal plants. The optimization of extraction methods that would aid in recovering the highest yield of its bioactive compounds should be attempted, considering its high salt levels, which could hinder the detection and or identification of active agents. Indeed, identification of the best extraction strategies for halophytes is much more limited than that reported for other plant phyla.
Additionally, plants in the genus Salsola have long been used in traditional medicine to treat a variety of ailments that have yet to be pharmacologically proven. Standardization of these traditionally used plants will facilitate their incorporation in nutraceuticals. Most of the published research has concentrated on the chemistry and pharmacology of the aerial parts, with only a few publications on the roots encouraging researchers to investigate them further. Since cinnamate esters have been found in a variety of Salsola species, the presence of benzoate esters in S. cyclophylla suggests the need for further studies on the biosynthetic pathways involved in the production of benzoates versus cinnamates. While rosmarinic acid (87) is common in the Lamiaceae family, its presence in S. imbricata necessitates greater research into biosynthesis pathways, which can help further agronomic and molecular approaches to improve its yield. Moreover, a detailed phytochemical profiling, in parallel with gene expression, could help to establish different biosynthetic pathways in different organs. While isoflavones are restricted to a few plant families, mostly legumes, they have been detected in the roots of S. somalensis, S. tetrandra and leaves of S. imbricata; their ecological role in Salsola has yet to be determined. Whether cardinolides only exist in S. tetragona, or if they occur in other Salsola species, needs to be confirmed by profiling many other species for comparison. Finally, few studies have been presented on the volatile composition in Salsola species; this should be compared to that reported in S. cyclophylla and S. vermiculate in the future.