Introduction

The family Apiaceae is considered one of the largest families in the plant kingdom, usually known as parsley, carrot or celery family, comprising 418 genera and 3257 species (http://www.theplantlist.org), predominantly aromatic plants with hollow stems. Several species are consumed as vegetables or condiments and some of them possessing medicinal properties (Tamokou et al. 2017).

Although some studies suggested that Dorema spp. should be taxonomically subsumed within genus Ferula (Shneyer et al. 1995; Panahi et al. 2015, 2018), other ones considered Dorema as a distinct genus. Anyway, the plants possess thickened storage roots and large simple umbels with male flowers on the lower branches and hermaphrodite flowers on the upper branches. They are monocarpic and can reach 3 m in height with stem diameter of 10 cm or more (Schischkin et al. 1951; Pimenov and Leonov 1993).

The genus Dorema includes 12 accepted species mostly distributed in the southern regions of central western Asia such as Caucasus, Iran, Afghanistan, and Pakistan (http://www.theplantlist.org) (Schischkin et al. 1951; Pimenov and Leonov 1993). Among them, 7 species, namely D. aitchisonii Korovin ex Pimenov, D. ammoniacum D. Don, D. aucheri Boiss., D. aureum Stocks, D. glabrum Fisch. & C.A. Mey., D. kopetdaghense Pimenov and D. hyrcanum Koso-Pol., belong to Iranian flora (Rechinger and Hedge 1987; Mozaffarian 2003, 2007). In particular, D. ammoniacum and D. kopetdaghense are endemic to Iran and their oleo gum resin is used for 4000 years (Hooper 1937; Duthie 1956; Jafari et al. 2004). D. ammoniacum (local names: Ushaq, Oshagh, Vasha, and Kandal) and D. aucheri (local name: Bilhar) are widely consumed in cuisine as food and additive. In folk medicine, the D. ammoniacum resin, commonly known as “ammoniacum” or “gum ammoniac”, is traditionally collected for several purposes including the treatment of the respiratory, digestive and urinary systems. It is also mentioned in Unani Medicine or Greco-Arab Medicine, one of the oldest traditional medicines, as a potent drug useful for various ailment and diseases (Mobeen et al. 2018) as reported by Avicenna (1930) and Al-Razi in their treatises (Razi and Kitab 1991; Baitar 1999).

Coumarin, sesquiterpene and flavonoid derivatives were identified as the major phytochemicals of the genus Dorema. Sesquiterpenes in both hydrocarbon and oxygenated forms were described as the predominant volatile oil compounds characterizing various plant parts.

In recent years, the number of papers reporting experimental data on the biological effects of Dorema species has increased. However, there is no available systematic review that summarizes current knowledge. Due to widespread traditional use of these plant species, the present work aimed to comprehensively collect the published studies on their ethnobotanical use, phytochemical and pharmacological features, for the first time. A literature search was carried out (last search: 01.03.2020) using the PubMed and Web of Science databases with “Dorema” as keyword.

Traditional uses of Dorema species

Table 1 lists the ethnomedicinal uses of the Dorema species. The most used part is the oleo gum resin which is mainly obtained from stem, root and petiole parts. In Iran, the resin from D. ammoniacum is used for its expectorant, anticonvulsant, anthelmintic, antimicrobial, anti-inflammatory, analgesic, vasodilator, carminative, mild diuretic, antispasmodic and diaphoretic properties, as well as for the treatment of chronic bronchitis, persistent coughs, respiratory and gastrointestinal disorders (Rajani et al. 2002; Mood 2008; Irvani et al. 2010; Nabavi et al. 2012; Adhami et al. 2013; Hosseini et al. 2014; Ajani et al. 2018; Ghasemi et al. 2018). According to the British Herbal Pharmacopoeia (1983, 1993), the same resin is also useful as a hepatoprotective, sudorific, sedative and sexual stimulant agent, to regulate the menstrual cycle, reduce blood fats and prevent diabetes. Otherwise, the D. ammoniacum young leaves and branches are harvested to cure digestive disorders, as well as to be preserved pickled for eating (Ajani and Bockhoff 2018). The seeds are collected to treat respiratory disorders (Abedini et al. 2014).

Table 1 Ethnobotanical uses of Dorema species
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The efficacy of D. ammoniacum in livestock was also reported. Both resin and roots are used to heal infected wounds and abscesses in sheep and goats (Amiri and Joharchi 2016).

D. aucheri is the second most used Dorema species in Iranian folk medicine. A fresh root-based paste is used locally as a remedy in the healing of burns, while the resin is administered orally against asthma, bronchitis, as an expectorant and for its antispasmodic properties. Resin roots are also applied to infected sheep wounds. On the other hand, the young aerial parts are used against disorders due to constipation and parasites in the digestive system. In cuisine, they are used in the preparation of typical soups or pickles (Amiri and Joharchi 2016; Akbarian et al. 2016; Ajani and Bockhoff 2018). For this species, the ability to reduce blood pressure and triglycerides, as well as to modulate pain, is also recorded (Mostafavi et al. 2013; Vani et al. 2019).

Diuretic and anti-diarrheal potential, along with treatment of bronchitis and catarrh, were described for D. glabrum leaves and resin (Delnavazi et al. 2015a,b).

Conversely, the use of Dorema species is rather limited in other Asian countries. In the Iraqi Hawraman area (Kurdistan), only the young aerial parts from D. aucheri (local name: Bana) are used as food (Pieroni et al. 2017), while in India, the resin is renowned for its expectorant, stimulant, and antispasmodic effects (Kumar et al. 2006).

Phytocostituents

Non-volatile components

In general, half of the accepted Dorema species (6 out of 12) were studied for their non-volatile composition. Totally, 10 phenolic acids (31–40), 7 flavonoids (10–16), 7 acetophenones (17–23), 6 coumarins (4–9), 7 sesquiterpenes (24–30), 3 chromandiones (1–3), and 2 phytosterols (41–42) were identified as the main secondary metabolites (Table 2).

Table 2 Non-volatile phytoconstituents isolated from the Dorema genus
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Coumarin and acetophenone derivatives were isolated from 4 (D. ammoniacum, D. glabrum, D. hyrcanum and D. kopetdaghense) and 3 species (D. aitchisonii, D. glabrum and D. hyrcanum), respectively. Chromandione derivatives were identified only in the resin of D. ammoniacum. Most of the coumarins were found in the roots, gum-resin and aerial parts. The flavonoid presence was exclusively reported in the aerial parts, extracted both with chloroform (CHCl3) and methanol (MeOH). Otherwise, acetophenones were only detected in the MeOH extract obtained from the roots, whereas the sesquiterpene derivatives were mostly isolated from their CHCl3 extract. Moreover, all plant parts (whole aerial parts, flowers, leaves, roots and stems) were rich in phenolic acids. The chemical structures of the identified non-volatile secondary metabolites of the Dorema species are illustrated in Fig. 1a, b.

Fig. 1
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a, b Chemical structures of the non-volatile phytochemicals isolated from Dorema species

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Prenylated chromandiones

A new prenylated chromandione (2′S,5′S)-2′-ethenyl-5′-(3-hy-droxy-6-methyl-4-oxohept-5-en-2-yl)-7-methoxy-2′-methyl-4H-spiro[chromene-3,1′-cyclopentane]-2,4-dione (1) and doremone A (2) were isolated from dichloromethane (DCM) extract of D. ammoniacum resin (Arnone et al. 1991; Adhami et al. 2013), while ammodoremin (3) was obtained from n-hexane extract. It is an epimeric mixture of prenylated chromandiones whose structures were established by spectral data and single-crystal X‐ray analysis (Appendino et al. 1991). The compound (1) was identified as an analogue of (2).

Coumarins

The coumarin 6,7,8-trihydroxycoumarin (4) was finally isolated by chromatography on a RP-18 column from the MeOH extract of D. glabrum roots (Delnazavi et al. 2015). Ammoresinol (5) was identified as a simple coumarin derivative, with a significant yield from DCM (Adhami et al. 2013) and n-hexane (Appendino et al. 1991) extracts of D. ammoniacum resin. From the same n-hexane extract, 7-hydroxyferprenin (6) was also obtained (Appendino et al. 1991).

Three other coumarin analogues were identified in two Dorema species. 3-Dihydro-7 methoxy-2S*,3R*-dimethyl-2-[4,8-dimethyl-3(E),7-nonadienyl]-furo[3,2-c] coumarin (7) was isolated from acetone fraction of D. kopetdaghense aerial parts (Iranshahi et al. 2007), as well as from D. hyrcanum MeOH extract (Naghibi et al. 2015). 2,3-Dihydro-7-methoxy-2S*,3R*-dimethyl-2-[4,8-dimethyl-3(E),7-nonadien-6-onyl]-furo[3,2-c] coumarin (8) and 2,3-dihydro-7-methoxy-2R*,3R*dimethyl-2-[4,8-dimethyl-3(E),7-nonadienyl]-furo[3,2-c] coumarin (9) were isolated from CHCl3 and MeOH extracts of D. kopetdaghense (Iranshahi et al. 2007) and D. hyrcanum (Naghibi et al. 2015) roots, respectively.

Flavonoids

The aerial parts of D. glabrum and D. aucheri were investigated and 7 flavonoid derivatives were identified. Three glycosylated flavonols including isorhamnetin-3-O-β-d-glucopyranoside (10), isoquercetin (11), and astragalin (12) were obtained from MeOH extract of D. glabrum (Delnavazi et al. 2015b). Four flavones, namely salvigenin (13), nepetin (14), cirsiliol (15) and eupatorine (16), were identified in CHCl3 extract from D. aucheri (Wollenweber et al. 1995).

Acetophenones

Seven glycosylated acetophenone derivatives were isolated from Dorema species. All the compounds were purified from root MeOH extracts. Azerosides A (17) and B (18) were obtained from D. glabrum for the first time as natural products, along with echisoside (19), pleoside (20) and hyrcanoside (21) (Delnazavi et al., 2015a; Jafari et al. 2018). 4-Methoxy-6-hydroxyacetophenone-2-O-β-d-gentiobioside (22) and 2,6-dihydroxy-4-methoxyacetophenone-2-O-β-gentiobioside (23) were also isolated from alcoholic extracts of D. hyrcanum (Naghibi et al. 2015) and D. aitchisonii (Bukreeva and Pimenov 1991), respectively.

Sesquiterpenes

Sesquiterpenes were identified as one of the predominant phytochemical classes in Dorema species. Three new sesquiterpene derivatives namely kopetdaghin A (24), kopetdaghin B (25), and kopetdaghin C (26) were isolated both from aerial (acetone extract) and root (CHCl3 extract) parts of D. kopetdaghense (Iranshahi et al. 2007). Furthermore, kopetdaghin D (27) and kopetdaghin E (28) were found in root CHCl3 extract for the first time (Iranshahi et al. 2007). Naghibione (29) was also isolated in MeOH extract of D. hyrcanum root as a novel compound (Naghibi et al. 2015). Dshamirone (30) was isolated from the purified DCM extract of D. ammoniacum resin (Adhami et al. 2013).

Phenolic acids

Some phenolic acids were characterized starting from different parts of D. aucheri and D. glabrum. In the study of Mianabadi et al. (2015), HPLC fingerprinting analysis allowed to determine their presence in MeOH extracts obtained from D. aucheri stems, flowers and leaves, both from a qualitative and quantitative point of view. The stem extract was the richest sample in gallic acid (31) and chlorogenic acid (35). Otherwise, the highest contents of p-coumaric acid (32) and caffeic acid (36) were quantified in the flowers (Mianabadi et al. 2015). Chlorogenic acid (35) was furtherly isolated from ethyl acetate (EtOAc) (Delnavazi et al. 2015b) and MeOH (Jafari et al. 2018) extracts of D. glabrum aerial parts and roots, respectively. The MeOH extract of D. glabrum roots was previously studied leading to the isolation of acid-4-O-β-d-glucopyranoside (33) and 7,8-dihydroferulic acid-4-O-β-d-glucopyranoside (34) (Delnavazi et al. 2015a). Four caffeoylquinic acid derivatives were detected in D. glabrum MeOH extracts. They are 4,5-di-O-caffeoylquinic acid (37) and 5-O-caffeoylquinic acid (39) from the roots (Delnavazi et al. 2015a; Jafari et al. 2018), 3,5-di-O-caffeoylquinic acid (38) from the aerial parts (Delnavazi et al. 2015b) and 1,5-di-O-caffeoylquinic acid (40) both from roots and aerial parts (Delnavazi et al. 2015a,b; Jafari et al. 2018).

Phytosterols

By using various chromatography methods, sitosterol 3-O-glucoside (daucosterol) (40) from acetone and EtOAc extracts of D. kopetdaghense (Iranshahi et al. 2007) and D. glabrum (Delnavazi et al. 2015b) aerial parts, in addition to stigmasterol 3-O-glucoside (41) from acetone extract of D. kopetdaghense, were isolated as the only phytosterols identified in the Dorema genus.

Volatile components

Different plant parts (whole aerial parts, fruits, leaves, roots, stems and seeds) of the three most common Dorema species—D. ammoniacum, D. aucheri and D. glabrum—were analyzed for their essential oil content (EO) (Table 3).

Table 3 Volatile compounds identified in Dorema species
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Overall, all the studies were carried out on Iranian populations and the greatest EO content was found in the leaves. In particular, the highest and lowest yields were observed for EO of D. ammoniacum leaves (0.7%) (Yousefzadi et al. 2009, 2011; Masoudi and Kakavand 2017). Hydrocarbon and oxygenated sesquiterpenes were characterized as the major volatile oil compounds. β-Caryophyllene (3.54–3.54%), caryophyllene oxide (6.3−32.45%), (E)-β-ocimene (18.1−30.94%), and α-eudesmol (31.2%) were the most significant components (Yousefzadi et al. 2009, 2011; Akbarian et al. 2016; Zandpour et al. 2016; Masoudi and Kakavand 2017).

Figure 2 depicted the chemical structures of the main EO compounds in the Dorema species.

Fig. 2
figure 2

Chemical structures of the main essential oil compounds from Dorema species

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Pharmacological activities

Bioactivities of extracts, isolated secondary metabolites, oleo gum resin and essential oils of Dorema species were assessed by several research groups (Table 4). So far, six species were subjected to different in vitro and in vivo experiments. Two species—D. ammoniacum and D. aucheri—were extensively investigated, specifically their free radical scavenging and antimicrobial activities, probably due to the plant material availability and the wide applications in traditional medicine and cuisine.

Table 4 Biological activities of Dorema species
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In vivo studies on analgesic (D. ammoniacum), anticonvulsant (D. ammoniacum), antidiabetic (D. ammoniacum, D. aucheri), anti-inflammatory (D. ammoniacum), anti-plasmodial (D. hyrcanum), antiproliferative and cytotoxic (D. aucheri), antithyroid (D. aucheri), hepatotoxic (D. aucheri), hypolipidemic (D. aucheri), neuroprotective (D. ammoniacum), and vascular toxic (D. ammoniacum) effects were carried out. Furthermore, antiradical (D. ammoniacum, D. aucheri, D. aitchisonii, D. glabrum), antimicrobial (D. ammoniacum, D. aucheri), and neuroprotective (D. ammoniacum) activities were reported. In the assays, methanolic or hydroethanolic extracts of aerial parts were mostly used, along with oleo gum resin in case of D. ammoniacum. In most cases, studies were performed using crude extracts without identifying the compounds responsible for bioactivity and determining their mechanisms of action, bioavailability, pharmacokinetics and physiological pathways. Therefore, detailed investigations are still needed regarding both the chemical characterization and the explanation of the results from preclinical experiments, including possible toxicity, as well as the standardization of formulations based on Dorema species ingredients.

Analgesic activity

Different doses (125, 250, 500 mg/kg) of aqueous solution of D. ammoniacum resin were examined for their analgesic activity in male albino mice. The sample was effective in a dose-dependent manner (P < 0.05) both in acute and chronic phase of formalin test as well as in acetic acid writing test 30 min after its injection. In particular, the dose of 500 mg/kg significantly reduced the pain (p < 0.001) (Bakhtiarian et al. 2017).

Anticonvulsant activity

The anticonvulsant potential of D. ammoniacum resin was analyzed by inducing seizures in mice with pentylenetetrazole (60 mg/kg). In comparison to Diazepam (1 mg/kg) used as a control and able of providing 100% protection, the resin (700 and 1000 mg/kg) revealed weak protection by 33% (Motevalian et al. 2017).

Antidiabetic activity

The ethanolic (EtOH) extract (30%) of D. aucheri leaves was studied for its effect on blood glucose and insulin levels in nicotinamide/streptozotocin-induced diabetic adult male Wistar rats. After a daily administartion of 100, 200 and 400 mg/kg for 4 weeks, the insulin level significantly increased (up to 30.071 ± 1.92 µLU/mL) and blood glucose concentration decreased (up to 121.429 ± 9.13 mg/dl) in treated mice compared to the diabetic control group (11.916 ± 1.21 µLU/mL and 167.5 ± 8.60, respectively). Moreover, the 200 mg/kg dose was able to remarkably lower insuline resistance (P < 0.01) (Ahangarpour et al. 2014).

D. aucheri was also investigated in a double-blind, placebo-controlled, randomized clinical trial recruiting 170 patients with type II diabetes. They took a gelatine capsule (200 or 500 mg) prepared with the powdered extract obtained from the aerial parts daily. Ater 45 days of treatment, a significant (1.1 to 2.5 folds) increase in PPAR-g expression was observed in patients treated with 500 mg of the extract, compared to the placebo-treated control group (P < 0.01). In the same group of patients, the extract also increased plasma superoxide dismutase activity (from 1313.38 to 1444.51 U/g protein) and vascular catalase gene activity (from 79.71 to 90.32 kU/g protein) (Nahvinejad et al. 2016).

Hypolipidemic activity

The study carried out by Ahangarpour et al. (2014) showed that the administration of 100 mg/kg of 30% EtOH extract of D. aucheri leaves to nicotinamide/streptozotocin-induced diabetic rats, was able, after 4 weeks, to significantly reduce total cholesterol (TC, 57 mg/dL), triglycerides (Tr, 66.71 mg/dL), very low-density lipoprotein (VLDL, 13.34 mg/dL) and leptin (0.93 ng/dL) levels, compared to diabetic control group characterized by higher values for all the parameters considered (TC, 67.87 mg/dL; Tr, 126.12 mg/dL; VLDL, 25.22 mg/dL; leptin content, 1 ng/dL).

Anti-inflammatory activity

An in vivo study using carrageenan-induced paw edema in mice showed significant dose-dependent anti-inflammatory activity of the aqueous extract of D. ammoniacum resin. At the highest dose of 500 mg/kg, less developed edema was recorded. The sample significantly reduced (up to 47%) inflammation compared to the negative control (saline) and its effect was immediately (1 h after the treatment) similar to that of indomethacin (− 33% and − 36%, respectively) used as a positive control (Bakhtiarian et al. 2017). These outcomes were confirmed by Pandpazir and colleagues (2018). Their aqueous extract also showed significant systemic anti-inflammatory activity. All tested doses (100, 200 and 300 mg/kg) were able to inhibit edema in a similar or superior way to that of mefenamic acid (30 mg/kg) used as a positive control, at various time intervals (from 54.1–65.1% vs. 62.4% at 30 min and from 76.7–98.4% vs. 62.8% at 3 h). Topical administration of the D. ammoniacum resin extract (100 mg/kg) was less effective. Nevertheless, its action was similar or higher (19.5% and 43.3% inhibition of paw edema, respectively, after 2 and 4 h of application) than that of diclofenac gel 2% (18% and 26.4%) (Pandpazir et al. 2018).

Even some pure compounds such as sesquiterpenes kopetdaghins A (24), C (26) and E (28) from D. kopetdaghense were tested for their anti-inflammatory effect showing a remarkable activity. In particular, kopetdaghins (10–100 µg/mL) significantly inhibited, in a concentration-dependent manner, the LPS-induced nitric oxide (NO) release by the activated J774A.1 macrophages. At the highest concentration, all three compounds 100% inhibited the NO production, but kopetdaghin A (24) was the most active compound with 57.3%, 77.8%, and 94.2% inhibitions at 10, 20, and 50 µg/mL, respectively (Rabe et al. 2013, 2015).

Antimicrobial activity

The ability of various extracts and EOs of two Dorema species—D. aucheri and D. ammoniacum—against a wide range of microbial strains were analyzed.

The antibacterial activity of 95% MeOH extract from D. aucheri aerial parts was assessed against various pathogenic food-altering bacteria, both Gram-negative and Gram-positive. By the disc diffusion and Microtiter broth dilution methods, the extract showed the greatest activity against the Gram-negative bacterium Salmonella enteritidis with an inhibition zone (IZ) diameter of 14.3 mm and an inhibition of the growth equal to 99.1%. The IZs of the other treated bacteria ranged from 7.76 to 12.6 mm and their growth was inhibited from 70.6–97.9% (Gheisari et al. 2016).

D. aucheri root CHCl3 extract possessed the highest antibacterial effect against Shigella flexneri, with a minimum inhibitory concentration (MIC) of 0.15 µg/mL in microbroth dilution assay. Its potential was higher than that of the reference compound ciprofloxacin (0.156 µg/mL vs. 0.313 µg/mL). However, ciprofloxacin was more effective against Staphylococcus aureus (0.156 µg/mL vs. 0.313 µg/mL), Escherichia coli (0.156 µg/mL vs. 0.625 µg/mL) and Bacillus subtilis (0.625 µg/mL vs. 2.50 µg/mL) (Khan et al. 2014). The n-hexane extract from D. aucheri roots was found even more active. Its MIC values were equal to that of the ciprofloxacin against Escherichia coli (0.156 µg/mL), Staphylococcus aureus (0.156 µg/mL) and Shigella flexneri (0.313 µg/mL), halved against Bacillus subtilis (0.313 µg/mL vs. 0.625 µg/mL) (Khan et al. 2014).

Lastly, the antibacterial activities of 80% MeOH extracts obtained from leaves, stems, and flowers of D. aucheri against 4 selected bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Salmonella enterica) were studied. None of the extracts was able to inhibit the growth of Escherichia coli, while the leaf and flower samples showed the maximum activity against Staphylococcus aureus with MIC of 10 mg/mL. In general, the stems were the least effective organs against all bacteria (MICs from 20 to 40 mg/mL) (Mianabadi et al. 2015).

As for D. ammoniacum, the agar dilution-streak was used to evaluate the antimicrobial activity of the DCM-MeOH (1:1) resin extract in two studies. In the work of Kumar et al. (2006), the extract (500 and 1000 µg/ml) completely inhibited the growth of almost all tested bacteria (Bacillus cereus var. mycoides, Bacillus pumilus, Bacillus subtilis, Bordetella bronchiseptica, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae, Streptococcus faecalis) and fungi (Candida albicans, Aspergillus niger, Saccharomyces cerevisiae), similarly to the positive controls ciprofloxacin (3 µg/mL) and amphotericin-B (3 µg/mL). Previously, Rajani and colleagues (2002) reported that the same extract had no inhibitory action against the same microorganisms at concentrations of 10 and 20 µg/mL. The complete inhibition of their growth, comparable to that due to ciprofloxacin (2 µg / mL), was recorded at higher concentrations (40, 60, 100 and 200 µg / mL). Only Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Candida albicans were not sensitive to the effect of D. ammoniacum resin at any used concentration.

In a screening study on the antimicrobial activity of 36 plant species against a broad spectrum of pathogenic and multidrug-resistant microrganisms, including 35 bacteria and 1 fungus, the MeOH extract of D. ammoniacum seeds was one of the most active. Its bactericidial activity was characterized by the lowest MIC and MBC values (78 and 312 µg/mL, respectively) against 2 Staphylococcus aureus strains, Staphylococcus epidermidis and Staphylococcus lugdunensis. Although the fungicidal activity had a MIC (0.6 µg / mL) lower than the control (amphotericin B, ≤ 1 µg / mL) in the preliminary phase of the study, it was not significant in the more refined subsequent measurement (Abedini et al. 2014).

Interestingly, the aqueous extract of D. ammoniacum aerial parts used to synthesize silver nanoparticles (SNPs) increased their antibacterial effectiveness compared to AgNO3 solution used as a positive control. SNPs showed a stronger activity against all tested bacteria, namely Bacillus cereus, Staphylococcus aureus, Escherichia coli and Salmonella typhimurium (IZs, 9.4, 9.2, 10.7, and 9.0 mm vs. 8.5, 9.0, 9.1 and 8.0 mm, respectively). The highest effect against Escherichia coli was confirmed by the MIC (0.12 µg/mL) and MBC (0.23 µg/mL) values (Zandpour et a. 2018).

In addition, also the EO extracted from fruits of D. ammoniacum was subjected to antimicrobial activity assessment using seven bacteria (Bacillus subtilis, Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and three fungi (Candida albicans, Saccharomyces cerevisiae and Aspergillus niger). The results revealed that the EO had the highest IZs (23 and 22 mm) and MIC values (3.75 mg/mL) against Bacillus subtilis and Staphylococcus epidermidis, respectively. Nevertheless, only in the case of Bacillus subtilis, EO showed greater inhibition than that of the antibiotic tetracycline (30 µg/disc, IZ = 21 mm) (Yousefzadi et al. 2009; 2011).

Antiplasmodial activity

Natural sources of potential products effective in the fight against malaria have been extensively studied, including Dorema species. EtOAc extract of D. hyrcanum roots (10 mg/kg) demonstrated a marked inhibition (by 73%) of Plasmodium berghei growth assessed by Peter′s 4-day suppressive test on mice, although lower than the effect of chloroquine (20 mg/kg) showing 100% inhibition. In addition, among the secondary metabolites isolated from the extract, naghibione (29) (10 mg/kg) inhibited the parasite growth by 68.1%, followed by 2,3-dihydro-7-methoxy-2 S *,3R*-dimethyl-2-[4,8-dimethyl-3(E),7-nonadienyl]-furo[3,2-c]coumarin (8) (29.3%), 2,3-dihydro-7-ethoxy-2R*,3R*dimethyl2-[4,8-dimethyl-3(E),7-nonadienyl]-furo[3,2-c]coumarin (9) (23.3%) and acetophenon (22) (10.1%) (Naghibi et al. 2015).

In a screening phase, via using parasite lactate dehydrogenase method, in vitro antiplasmodial activity of the MeOH extract of D. hyrcanum roots against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum reported IC50 values equal to 28.64 µg/mL and 9.79 µg/mL, respectively (Naghibi et al. 2015).

Antioxidant activity

Different soluble extracts obtained from various parts of three Dorema species including D. aitchisonii, D. aucheri, and D. glabrum were investigated for their antiradical activity. For example, EtOH extract of D. aitchisonii aerial parts was characterized by an IC50 value equal to 488.1 µg/mL indicating a weak scavenger activity against the free radical DPPH compared to reference compounds ascorbic acid, quercetin, and BHA (butylated hydroxy anisole) (IC50 = 5.05, 5.28, and 53.96 µg/mL, respectively). The low effect was confirmed by ICA (nitric oxide scavenging activity) method, where the IC50 value (778.2 µg/mL) was 40 times higher than that of EDTA (18 µg/mL) used as a positive control. NOSA (nitric oxide scavenging activity) and HPSA (hydrogen peroxide scavenging activity) results also showed a low activity of the extract (IC50 = 1300 and 210.6 µg/mL, respectively) compared to quercetin (IC50 = 20 and 52 µg/mL, respectively) (Nabavi et al. 2012).

In another experiment, the DPPH assay was used to evaluate the radical scavenging activity of crude petroleum ether (PET), CHCl3, EtOAc, and MeOH extracts obtained from D. glabrum aerial parts, together with the isolated compounds. Among the extracts, MeOH fraction was the most effective with an IC50 of 48.3 µg/mL, while the lowest IC50 (2.23 µg/mL), almost 9 times less than that of the BHT control (IC50 = 19.5 µg/mL), was found for chlorogenic acid (35) (Delnavazi et al. 2015).

In a comparitive study by Khan et al. (2014) on the roots of D. aucheri, the results of DPPH assay showed that n-hexane extract (IC50 = 104.3 µg/mL) was more active than CHCl3 extract (IC50 = 132.4 µg/mL). However, this effect was significantly less than those of the n-propyl gallate (IC50 = 40.8 µg/mL) and t-BHA (IC50 = 59.8 µg/mL) positive controls.

In the FRAP assay, the MeOH extract of D. aucheri stems and flowers was able to reduce the ferric ion (Fe3+) more effectively than the extract obtained from the leaves (4.33 Fe2+/g and 4.22 mmol Fe2+/g vs. 1.7 mmol Fe2+/g). Stems and flowers also demonstrated the highest activity in the inhibition of lipid peroxidation obtained by applying β-carotene bleaching method (Mianabadi et al. 2014).

Antiproliferative and cytotoxic activity

In an in vivo study on rats, the effect of 50% EtOH extract of D. aucheri plants on breast tumour induced by 7,12-dimethylbenz[a]anthracene (DMBA) was evaluated. The obtained results indicated that, after 12 weeks, the tumour average size in the groups that took orally 200 mg/kg or 400 mg kg of extract every day was 152.92 mm and 444.14 mm, respectively. Otherwise, in the control groups, the tumour average size was 746.2 mm (Gourabi et al. 2015).

Eftekhari et al. (2019) used the MTT test to investigate the cytotoxic activity of different extracts (PET, CHCl3, EtOAc and MeOH) obtained from the D. aucheri aerial parts against MDA-MB-231 (breast cancer), A549 (lung carcinoma), HT-29 (colon carcinoma), HeLa (cervical cancer) and normal fibroblast cell lines. Of all the samples, PET and CHCl3 extracts were the most potent cytotoxic agents (IC50 = 17.00 and 69.7 µg/mL, respectively) against normal fibroblast and MDA-MB-231 cell lines.

The MTT assay also showed that chlorogenic acid (35) isolated from D. glabrum roots significantly increased apoptosis and hindering cell cycle progression accompanied by upregulation of Bax and caspase 3 gene expression in adenocarcinoma gastric cell line (Jafari et al. 2018). In addition, both the root EtOH extract and the pure compound naghibione (29) were analyzed to assess their cytotoxic potential against Madin–Darby bovine kidney cell line. The crude extract showed better activity (IC50 = 69.67 µg/mL) than the isolated sesquiterpene (IC50 > 100 µg/mL). However, both samples were much less active than the positive control tamoxifen (IC50 = 4.76 µg/mL) (Naghibi et al. 2015).

Antithyroid activity

The 50% EtOH extract from D. aucheri aerial parts (100, 200 and 400 mg/kg) was evaluated for its activity on thyroid hormones (TSH, T3 and T4) in Wistar rats. After 3 weeks of administration, only the lowest dose (100 mg/kg) significantly increased TSH levels (11.63 ng/dL) compared to the control group (0.84 ng/dL). Differently, the concentrations of T3 and T4 hormones were similar in all studied groups regardless of the extract dosage (Azarneushan et al. 2010).

Hepatotoxic activity

Two in vivo studies investigated the hepatotoxic effect of D. aucheri leaves. Mostafavi et al. (2013) reported that the 95% EtOH extract increased the levels of liver enzymes serum glutamate pyruvate transaminase (SGPT) from 179.89 to 263.5 IU (international unit)/L, serum glutamate oxaloacetate transaminase (SGOT) from 93.60 to 131.51 IU/L, and alkaline phosphatase (ALP) from 189.09 to 295.44 IU/L, by increasing the injection dosage of the extract from 0.4 to 3.2 mL/kg, respectively. Otherwise, SGPT, SGOT, and ALP contents were lower in case of the non-injected control group (86.43, 37.81, and 181.43 IU/L, respectively). The study also analyzed liver homogenates and it was found that the injection of the plant extract altered liver function causing necrosis, inflammation of the liver tissue, cell proliferation, cholestasis and significant increase in bilirubin levels (up to 1.86 mg/dL) compared to the control groups (Mostafavi et al. 2013).

In addition, the leaves of D. aucheri were extracted with 30% EtOH and injected into the streptozotocin-induced diabetic rats. The most effective concentration of the extract on the level of hepatic enzymes SGPT (37.71 ng/dL), SGOT (86.62 ng/dL), and ALP (112 ng/dL) was 200 mg/kg. These values were similar to or lower than those of the control group (56.25, 87, and 117.12 ng/dL, respectively) and the diabetic group (67, 126.62, and 139.25 ng/dL) (Ahangarpour et al. 2014).

Neuronal activity

The intracellular recording assay was used to explore the effect of D. ammoniacum resin on the epileptiform activity of F1 neurons in Helix aspersa (Iranian garden snail) induced by pentylenetetrazole (PTZ). The results demonstrated that increasing dosage of the extract (0.01–0.3%), applied as an epileptic drug, enhanced the hyperexcitability induction and epileptiform activity by depolarizing the membrane potential from − 32.91 to − 39.16 mV, increasing the firing frequency from 3.39 to 3.47 Hz and decreasing the after hyperpolarization amplitude (AHP) from − 1.263 to − 1.122 mV. All this suggests that the sample potentiated the PTZ-induced hyperexcitation by electrophysiologically suppressing the Ca2+ and/or voltage-dependent K+ channels (Ghasemi et al. 2018).

Vascular toxicity

The vascular toxicity of D. ammoniacum resin was recently demonstrated. Fertilized chicken eggs were inoculated with 20% EtOH extract (50 or 100 mg/kg egg-weight) and the vascular network parameters were altered compared to those of the control group. In particular, after treatment with 100 mg/kg of extract, the vessel area significantly decreased from 63.3–39.2% as well as the total vessel length (from 8721.32 pixel to 722.84 pixel) and the vascular branch (from 132 to 48), while the lacunarity increased from 0.33 to 0.91 (Tavakkoli et al. 2020).

Conclusions

The species of the genus Dorema, particularly D. ammoniacum (oleo gum resin) and D. aucheri (aerial parts) are traditionally used as medicine and food in Middle East, especially in Iran. In the last years, the phytochemistry of the Dorema species were considered as a promising research field. Regarding this issue, among the 12 accepted species, only 6 and 3 species, respectively, were investigated for their non-volatile and volatile phytoconstituents.

According to the results obtained from the phytochemical analyses, phenolic acids, flavonoids, acetophenones, coumarins and sesquiterpenes are the main secondary metabolite classes of the Dorema genus. In particular, coumarin and acetophenone derivatives may be presumed as the predominant compounds of the genus. Most of the reported coumarins and flavonoids were isolated from the roots and aerial parts. The roots also provided all the acetophenones and most of the sesquiterpenes. The phenolic acids were present in almost all plant parts.

Among the identified phytochemicals, kopetdaghin A (24), kopetdaghin B (25), and kopetdaghin C (26) from D. kopetdaghense, and naghibione (29) from D. hyrcanum, along with (2′S,5′S)-2′-ethenyl-5′-(3-hy-droxy-6-methyl-4-oxohept-5-en-2-yl)-7-methoxy-2′-methyl-4H-spiro[chromene-3,1′-cyclopentane]-2,4-dione (1) and doremone A (2) from oleo gum resin of D. ammoniacum were isolated as new secondary metabolites.

The leaves were the richest organs in EO. It was mainly composed of sesquiterpenes as aromatic components, although the most abundant volatile oil constituents included also monoterpenes.

So far, the bioactivity of only 6 Dorema species, namely D. aitchisonii, D. ammoniacum, D. aucheri, D. glabrum, D. hyrcanum, and D. kopetdaghense, were studied. Among them, D. ammoniacum and D. aucheri, were the most tested species. Some of the most significant results, higher than those of the used positive controls, concern (i) the anti-inflammatory activity of the topical application of the D. ammoniacum resin extract, (ii) the antibacterial effect of the CHCl3 extract of D. aucheri roots, (iii) increasing TSH level by 50% EtOH extract of D. aucheri aerial parts, (iv) the hypolipidemic activity of EtOH extract from D. aucheri leaves.

As for the other uninvestigated 6 species, they may be assumed as promising plant material for further experiments, both in vitro and in vivo, to discover new sources of compounds potentially interesting as natural drug candidates. Moreover, since some of these species are traditionally consumed as food, the evaluation of their safety and toxicity is indispensable.