Iranian Medicinal Plants: From Ethnomedicine to Actual Studies

Iran has a rich and diverse cultural heritage, consisting of a complex traditional medicine deeply rooted in the history of the territory that goes back to the Assyrian and Babylonian civilizations. The ethnomedical practices that can be identifiable nowadays derive from the experience of local people who have developed remedies against a wide range of diseases handing down the knowledge from generation to generation over the millennia. Traditional medicine practices represent an important source of inspiration in the process of the development of new drugs and therapeutic strategies. In this context, it is useful to determine the state of the art of ethnomedical studies, concerning the Iranian territory, and of scientific studies on plants used in traditional Iranian medicine. Data regarding 245 plants used in Iranian ethnomedical practices and scientific studies conducted on 89 plants collected in the Iranian territory have been reported. All of the scientific studies here reported draw inspiration from traditional medicine. The World Health Organization (WHO) has repeatedly called for an intensification of the scientific validation processes of traditional medicines intended as an important contribution to public health in various parts of the world. The process of study and validation of Iranian ethnomedical practices appears to be at an early stage.


Introduction
Traditional medicine practices represent an important and often underestimated part of healthcare around the world. Moreover, traditional knowledge is a source of inspiration for researches on biological activities of vegetal extracts and pure compounds that can be obtained from them. A great number of lifesaving therapeutic assets belonging to modern medicine and new active compounds are derived from traditional knowledge and traditional uses of plants.
The awareness of this fact led to the drawing up of the World Health Assembly (WHA) resolution on Traditional Medicine (WHA62.13) and the WHO Traditional Medicine Strategy 2002-2005 and 2014-2023. These documents aim to integrate at the international level national healthcare systems with traditional knowledge and practices through an assessment of safety, efficacy, and quality of the treatments. In order to achieve these objectives, it is necessary to properly carry out scientific researches; the biological activities of the plants used must be tested, and the effectiveness of the treatments both "in vitro" and "in vivo" must be assessed considering the risk/benefit profile. Thus, one of the main raised issues-related to the use of traditional practices in national policies and regulations-is the lack of research data [1].
WHO defines traditional medicine as follows: "Traditional medicine has a long history. It is the sum total of the knowledge, skill, and practices based on the theories, beliefs, and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness" [2].
In light of a literature search, the traditional Iranian medicine (also known as Persian medicine) results, particularly rich in information, which can justify new studies regarding the therapeutic use of plants and vegetal extracts; it consists of the totality of the knowledge passed down through the generations and of the practices based entirely on observations and practical experience used, from ancient times to nowadays, in diagnosis, prevention, and elimination of diseases in the Iranian territory [3].
In this context, it was of great interest for us to collect scientific reports/studies, deriving from traditional practices, regarding health properties: biological activities of native Iranian plants proper to the medicinal, dermo-cosmetic, and nutriceutical use, in order to provide a complete overview of the scientific knowledge and establish a starting point for further research. Particular attention was paid to works that open up research possibilities on new therapeutic assets that deserve a follow-up to determine the efficacy of the reported biological activities in vivo.

Materials and Methods
The Present Review Was Performed Adopting The Following Databases: Scifinder, Pubmed, Google Scholar Selection criteria were defined, including articles regarding ethnobotanical studies on medicinal plants traditionally used in the Iranian territory and articles reporting scientific studies on plants grown and collected in Iran, including biological activities that can be spent in the pharmaceutical, cosmetic/cosmeceutical, nutraceutical fields. Particular attention was paid to works that may open up research paths to new therapeutic assets. All the studies reported in this review draw inspiration from Iranian traditional medicine practices.
The following keywords were selected: "Iran plants", "Iranian medicinal plants", "Iranian plants biological activities". Only articles in the English language were selected, and data from patents, symposiums, and congress abstracts were excluded because not enough complete to warrant an effective comparison with full papers. Papers that did not show a clear botanical identification were rejected. The database www.theplantlist.org was used to check the correctness of the nomenclature of the reported plant species.

Medicinal Plants Traditionally Used in Iran
Iran has a history of great importance in the field of traditional medicine practices; this knowledge heritage goes back to the time of Babylonian-Assyrian civilization; every generation added his experience and new elements to this "cultural database". Nowadays, medicinal plants are still used in Iran as curatives for various types of health problems [4]. A great part of this traditional knowledge has not been considered by the scientific point of view yet, and it would be advisable to check the effectiveness of the traditional treatments, especially when there are no supporting data in the scientific literature.
A bibliographic search was performed, selecting ethnobotanical studies conducted through questionnaires and personal interviews with traditional healers and local people in the Iranian territory that include clear botanical identification of the plants, traditional uses, and type of administration. Table 1 collects reports of plants used for medicinal purposes in the Iranian territory, their local name, the part of the plant used, type of extraction/preparation, the territory where the plant use is reported.

Biological Activities of Plants Grown and Collected in Iran
A bibliographic search was conducted, focusing on biological activities of plants collected in the Iranian territory. The purpose of this section is to collect data related to scientific studies in order to evidence potential correlations between traditional treatments and proved biological activities of plants and phytocomplexes obtained from them. The results are summarized in Table 2.

Antibacterial Activity
Abedini et al. (2014) [13] tested the antimicrobic activity of forty-four methanolic extracts, obtained from plants grown and collected in the Iranian territory, against thirty-five pathogenic bacteria and one yeast. The biological activity was evaluated with Müller-Hinton agar in Petri dishes seeded by a multiple inoculator and minimal inhibition concentration (MIC) method. The authors identified four candidates that deserve further chemical characterization and biological evaluation: Dorema ammoniacum, Ferula assa-foetida, Ferulago contracta (Seeds), and Perovskia abrotanoides (Aerial parts). These plants showed broad-spectrum activity and interesting MIC values against one or several strains (MIC= 78 µg/mL). The lowest MIC value of 78 µg/mL was achieved by Dorema ammoniacum against Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdunensis. Ferula assa-foetida against Staphylococcus aureus and Staphylococcus epidermidis. Ferulago contracta against Staphylococcus epidermidis [13].
Bonjar (2004) [11] evaluated the antibacterial properties of forty-five plant species used in Iranian traditional medicine practices against eleven bacterial species. The extracts were prepared by maceration of the plant material with methanol for three days, and the result was lyophilized after filtration. The lyophilized methanol extracts were diluted to a concentration of 20 mg/mL in dimethylsulfoxide (DMSO): methanol (1/1: v/v) solvent in order to perform antimicrobial bioassay. The author declared that the following plant extracts showed broad spectra antimicrobial activity: Rhus coriaria L., Trachyspermum ammi L., Alhagi maurorum Medik., Trigonella foenum-graecum L., Lawsonia inermis L., Rheum ribes L., and Cuminum cyminum L. Further studies are needed to find out which compounds are responsible for this activity. Particular plants, such as Lawsonia inermis L., which is active against Pseudomonas fluorescens and Trachyspermum ammi L., Nymphaea alba L. active against Pseudomonas aeruginosa, are proper candidates for further studies as possible sources of active compounds [11].
Sulfur compounds obtained by methanolic extract of the roots of the plant were isolated and characterized to test their antimicrobial activity and cytotoxic activity. Six compounds were isolated: foetithiophene C, foetithiophene F, foetithiophene A, foetithiophene B, coniferaldehyde, and sinapic aldehyde.
Their antimicrobial activities and cytotoxicity were evaluated using broth microdilution method and Alamar blue assay. Antimicrobial activity was evidenced against Gram-positive bacteria, more in particular foetithiophene F, which showed interesting antimicrobial activity with MIC value 50 mg/mL against the Gram-positive Bacillus cereus. No cytotoxic activity was detected against MCF-7 and K562 cells [15]. Koochak et al. (2010) [12] conducted a preliminary study regarding the antibacterial activity of ethanolic extracts obtained by four plant species used in traditional medicinal practices in Iran. The studied plants were Beta vulgaris L., Amaranthus graecizans L., Rumex obtusifolius L., Polygonum patulum M. Bieb. The antibacterial activity was tested using the agar disc diffusion method against Gram-positive and Gram-negative bacteria. No one of the used extracts had significant antibacterial activity against Gram-negative bacteria. The highest activity was evidenced by the ethanolic extract of Polygonum patulum against Streptococcus pyogenes (inhibitory zone = 28 mm) followed by Beta vulgaris against Staphylococcus epidermidis (inhibitory zone = 23 mm) and Rumex obtusifolius against Streptococcus pyogenes. Minimum inhibitory concentration (MIC) = minimum bactericidal concentration (MBC) = 5 mg/mL. Further studies are needed to define which compounds contained in the extracts are responsible for the antimicrobial activity [12].  Lotfipour et al. (2008) [10] tested the antimicrobial activity of thirty-six extracts obtained from ten plans collected in north-west Iran against some Gram-negative strains.
Among them, the methanol extract of Thalictrum minus was the most active one with a minimum inhibitory concentration (MIC) value of 0.3125 mg/mL against Staphylococcus aureus.
Furthermore, the broad spectra of activity of some plant extracts (especially methanolic extracts) studied, obtained by the plants Thalictrum minus, Salvia sahendica, Achillea millefollum, and Echium italicum, were promising [10].
Mehdi Razavi et al. (2011) [16] tested the in vitro antimicrobial activity and cytotoxic activity of different extracts obtained by the plant Malva sylvestris L. (flowers and leaves); this plant is commonly used in traditional medicine practices in Iran. Flowers and leaves of the plant were collected from Tabriz, Iran. The flowers methanolic extract showed high antibacterial effects against some human pathogenic bacteria strains, such as Staphylococcus aureus, Streptococcus agalactiae, Enterococcus faecalis, with MIC values of 192, 200, and 256 µg/mL, respectively. Further studies are needed to identify the main active compounds [16]. Nariman et al. (2004) [18] tested the antibacterial activity of six plants collected (and endemic) in Iran, against Helicobacter pylori: Glycyrrhiza aspera, Juglans regia, Ligustrum vulgare, Thymus kotschyanus, Trachyspermum copticum, and Xanthium brasilicum. A disk susceptibility assay was used for the evaluation. All of the studied extracts showed anti-H. pylori activity; the most active were obtained from Xanthium brasilicum and Trachyspermum copticum; the solvents used to obtain the extracts were water and an equal mixture of methanol, petroleum benzene, diethyl ether. Minimum inhibitory concentrations (MIC) of the extracts obtained from the two plants range from 31.25 to 250 µg/mL [18]. Pirbalouti et al. (2010) [17] tested the antibacterial activity of essential oils and ethanolic extracts obtained by ten plants traditionally used as medicaments grown and collected in Iran. The tested vegetal extracts were investigated against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae by agar disc diffusion assay. Most of the samples showing antibacterial activity were considered as interesting by the authors against the tested bacteria with the diameter of inhibition zone ranging between 8 and 23 mm. The most interesting plants were Satureja bachtiarica and Thymus daenensis (leaves and flowers), with MIC values ranging from 0.039 to 10 mg/mL [17]. Sepahi et al. (2014) [14] tested the antibacterial activity of aqueous extracts obtained by four plants collected in Iran: Ferula gummosa, Echinophora orientalis, Nasturtium microphyllum, and Verbascum thapsus. The radial diffusion assay was performed using Staphylococcus aureus and Escherichia coli; moreover, hemolysis assay was used to test eventual toxic effects on human red blood cells. All the studied extracts showed interesting activity with MIC values lower than 750 µg/mL, and these extracts deserve further studies to identify the main active compounds [14]. Imani et al. (2015) [20] studied the essential oil obtained by hydro-distillation of aerial parts of Zhumeria majdae, which is a traditionally used medicinal plant endemic in Iran. The antifungal activity was determined using the serial dilution method. The essential oil (EO) was tested on six pathogenic fungal species and one yeast, and all of them resulted as sensitive to Z. majdae essential oil. Moreover, in particular, the essential oil was interestingly effective against Candida albicans, with a MIC (minimal inhibitory concentration) of 0.031 µL/mL. This evidence confirmed the value of Zhumeria majdae as an antifungal agent, and further studies are needed to identify the compounds responsible for this biological activity [20].

Antifungal Activity
In a study conducted by Pirbalouti et al. (2009) [19], the anti-Candida activity of essential oils and extracts of nine plants grown and collected in Iran was tested by agar disc diffusion assay. The studied plants are used in ethnomedical practices. Most of the tested samples showed diameters of inhibition zone ranging from 7 to 46 mm; moreover, in particular, the extracts of Ziziphus spinachristi and Scrophularia striata and the essential oil of Satureja bachtiarica showed the best anti-Candida activity, followed by the essential oils of Thymus daenensis and Trachyspermum ammi [19].

Antimalarial Activity
Afshar et al. (2018) [22] studied the in vitro antimalarial activity of different extracts of three Iranian endemic species belonging to the Scrophularia genus, including Scrophularia frigida, Scrophularia subaphylla, and Scrophularia atropatana. The antimalarial activity was tested by the cell-free β-hematin formation assay. Among the studied extracts, the dichloromethane one, obtained by aerial parts of Scrophularia frigida, exhibited strong antimalarial activity with inhibitory capacity (IC 50 ) value of 0.67 ± 0.11 mg/mL. Scrophularia frigida represented a deserving candidate for further studies focused on the identification of the main active compounds [22].
Feiz Haddad et al. (2017) [21] tested the in vitro and in vivo antimalarial activity of ten Iranian plants used in traditional medicine practices. All the plants' samples were collected in the Iranian territory. Methanolic extracts were tested for in vitro antimalarial activity against chloroquine-sensitive 3D7 and multi-drug resistant K1 strains of Plasmodium falciparum. The in vivo activity against Plasmodium berghei infection in mice was determined. Citrullus colocynthis fruits, Physalis alkekengi leaves and fruits, and Solanum nigrum fruits displayed potent in vitro antimalarial activity against both 3D7 and K1 strains; the in vivo studies comparisons between mice treated with the three plant extracts and untreated controls showed reduced parasitemia by 65.08%, 57.97%, and 60.68%, respectively [21]. Moreover, no toxicity was evidenced. Further studies can be designed to identify the active constituents and clarify their mechanism of action.

Antioxidant Activity
Alinezhad et al. (2012) [25] tested the antioxidant activity of ethyl acetate extracts of stems and leaves and owes of the plant Hyssopus angustifolius, collected in Iran. Antioxidant activity of extracts was evaluated with six different tests: nitric oxide, hydrogen peroxide scavenging, 2,2-diphenyl-1-picrylhydrazyl (DPPH), metal chelating, reducing power activities, and hemoglobin-induced linoleic acid system. The results confirmed the interesting antioxidant profile of this plant; it could be a natural source of active compounds. Further studies are necessary to identify the main active compounds present in the different parts of the plant [25]. Dehghan et al. (2016) [23] evaluated the antioxidant activity and α-amylase and α-glucosidase inhibition activity of n-hexane, ethyl acetate, and methanolic extracts obtained by various parts of eleven plants grown and collected in Hyrcania region, Iran. As regards the antioxidant activity, methanolic extract of Convolvulus persicus roots (IC 50 = 38.9 mg/mL), methanolic extract of Pyrus boissieriana stems (IC 50 = 39.3 mg/mL), and methanolic extract of Primula heterochroma leaves, and ethyl acetate and methanolic extracts of its roots (IC 50 = 41.7 mg/mL, 37.9mg/mL, and 30.1 mg/mL, respectively) evidenced strong activity if compared with butylated hydroxytoluene (BHT) (IC 50 = 16.7 mg/mL; used as a positive control) [23]. Dehghan et al. (2017) [24] evaluated the antioxidant and antidiabetic activity of extracts obtained by the plant Heracleum persicum. This work led to the isolation of eleven furanocoumarins. These compounds were identified as psoralen, bergapten, xanthotoxin, iso-pimpinellin, angelicin, isobergapten, sphondin, pimpinellin, heratomin, 5-methoxyheratomin, moellendorffiline, and fraxetin. As the antioxidant activity concerns, among the listed compounds, moellendorffiline exhibited strong antioxidant activity with IC 50 = 0.2 µM, a value that was interesting if compared with butylated hydroxytoluene (BHT) (IC 50 = 0.1 µM; used as a positive control) [24]. Ebrahimabadi et al. (2010) [30] tested the antioxidant activity of polar and non-polar fractions of the methanolic extract obtained by the plant Stachys inflata. Aerial parts of the plant were collected from Kashan area, Isfahan province, Iran. The biological activity was tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and β-carotene/linoleic acid assays. In the DPPH test, interesting results were shown by the methanolic extract polar subfraction with an IC 50 of 89.50 µg/ mL, indicating an antioxidant potency of about 22% of that of butylated hydroxytoluene (IC 50 = 19.72 µg/mL). In β-carotene/linoleic acid assay, the best inhibition belonged to the nonpolar subfraction, with an inhibition percentage of 77.08%. Further studies are needed to identify the main active compounds [30]. Fathiazad et al. (2011) [26] studied the ethyl acetate and n-butanol extracts obtained by aerial parts of the plant Hyssopus officinalis L., a medicinal herb collected from north of Iran. Total phenolic content and antioxidant activity were tested by Folin-Ciocalteau and DPPH tests. Apigenin 7-O-β-D-glucuronide was also isolated as the major flavon. Phenolic content of n-butanol and ethyl acetate extracts was determined and expressed as milligrams of gallic acid equivalents-246 mgGAE/g and 51 mg GAE/g, respectively. The antioxidant activity of apigenin 7-O-β-D-glucuronide, ethyl acetate extract, and the n-butanol extract was determined, obtaining IC 50 values of 116×10 −3 , 103×10 −3 , 25×10 −3 mg/mL, respectively. The purified apigenin 7-O-β-D-glucuronide showed weak activity. The extract that showed interesting antioxidant activity values, because of the highest content of total phenolic compounds, was the n-butanol one [26]. Khazaeli et al. (2009) [28] tested five traditional medicinal plants from Iran on free radicals scavenging activity and on the inhibition of mushroom tyrosinase activity. Focusing on the radical scavenging activity, methanolic extracts of Quercus infectoria and Terminalia chebula showed a strong radical scavenging effect in the 2,2 -diphenyl-1-picrylhydrazyl (DPPH) assay with values of IC 50 (concentration providing 50% inhibition of the DPPH radical) of 15.3 and 82.2 µg/mL, respectively. This study encouraged further investigations on Quercus infectoria and Terminalia chebula in the field of solar protection (due to the radical scavenging activity) and of skin depigmentation agents (due to inhibitory effects on mushroom tyrosinase) [28]. Dehshiri et al. (2013) [31] tested the antioxidant activity of laminas, stems, petioles, fruits, peduncles, and flowers in the hydro-alcoholic extracts from the plant Tetrataenium lasiopetalum. The plant samples were collected from Oshtoran Kuh, Azna, Lorestan, Iran. Antioxidant activities of the extracts were examined by different in vitro assays: 2,2 -diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, metal chelating, reducing power activities, and hemoglobin-induced linoleic acid system. All the tested extracts showed interesting antioxidant activity, confirming hypotheses based on traditional knowledge. Moreover, in particular, the hydro-alcoholic extract of the flower showed the highest activity in the DPPH test (IC 50 = 170 ± 7 µg/mL). In the metal chelating assay, lamina extract showed the best iron ion chelating activity among the other extracts (IC 50 = 230 ± 10 µg/mL).
Lamina hydro-alcoholic extract demonstrated better activity in the hemoglobin-induced linoleic acid system test than other parts of T. lasiopetalum [31]. Further studies could identify the main active compounds. Pourmorad et al. (2006) [27] worked on the antioxidant activity, phenol, and flavonoid content of five plants (Mellilotus officinalis, Equisetum maximum, Plantago major, Adiantum capillus-veneris, and Urtica dioica) collected from Northern provinces of Iran (Gilan and Mazandaran). Methanolic extraction was performed after drying at room temperature, and the result was freeze-dried. The extract of Mellilotus officinalis showed a high amount of flavonoid (57 ± 5.4 mg/g) and phenolic compounds (289.5 ± 5 mg/g) and exhibited the greatest radical scavenging activity (IC 50 = 0.018 mg/mL) in a DPPH test among the tested extracts [27]. Sonboli et al. (2010) [29] assessed antioxidant activities and total phenolic contents of methanolic extracts obtained from male inflorescences of Salix aegyptiaca L., grown and collected in Ashena Abad village, Urmia (West Azarbaijan province), Iran. 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay and Folin-Ciocalteu method were performed on the whole methanolic extract and on three fractions (water fraction, butanol fraction, and chloroform fraction) obtained from it. The butanol fraction evidenced, among the others, the best antioxidant activity and the highest phenolic content with an IC 50 value of 27.7 µg/ mL and total phenols of 313.8 ppm; the results were interesting because this extract was comparable with the synthetic antioxidant butylated hydroxytoluene (BHT) (IC 50 = 26.5 µg/mL) [29]. The detected antioxidant activity encouraged the use of this plant for its antioxidant properties in food industries and in cosmetic and pharmaceutical preparations. The results evidenced strong cytotoxicity against HT-29 and HepG-2 cell lines and interesting apoptosis induction ability; the authors suggested further studies in this field [35]. Jassbi et al. (2016) [32] tested the cytotoxic activity, against three human cancer cell lines (LS180, MCF-7, and MOLT-4), of dichloromethane and methanol extracts of Anthemis mirheydari, an endemic plant from Iran. The plant samples were collected in Jahrom in Fars province, Iran, and the whole plant was used for the extraction. The dichloromethane extract evidenced interesting IC 50 values, 30.8, 25.2, and 8.6 mg/mL for the three cell lines, respectively. Four compounds were isolated from the dichloromethane extract: taraxasterol, pseudotaraxasterol, β-sitosterol, and 7-methoxycoumarin. Taraxasterol and 7-methoxycoumarin are known in scientific literature to present anticancer properties; this fact, along with the encouraging results of the study, makes Anthemis mirheydari a new potential anticancer medicinal plant that certainly deserves further investigations [32].
Mehdi Razavi et al. 2011 [16] tested the in vitro cytotoxic activity of different extracts obtained by the plant Malva sylvestris L. (flowers and leaves); this plant is commonly used in traditional medicine practices in Iran. Flowers and leaves of the plant were collected from Tabriz, Iran. The methanolic extracts of flowers and leaves evidenced interesting cytotoxic activity against the MacCoy cell line, reducing their viability with IC 50 values of 265.3 and 311.0 µg/mL, respectively. The authors declared that Malva sylvestris L. plant extracts could be considered as an antiproliferative agent [16]. Further studies are needed to identify the main active compounds. Sahranavard et al. (2009) [34] tested the cytotoxic activity of methanolic extracts of fifteen Iranian medicinal plants against three cancer cell lines (MCF7, HepG2, WEHI164). The extract obtained by Ferula szowitsiana root showed IC 50 values lower than 100 µg/mL in all the tested cell lines, and it was chosen for further studies. Fractionation was performed, which led to the isolation of two monoterpenoids; both of them were bornyl esters that were identified as Chimganin and Chimgin. These compounds showed interesting cytotoxic effects with values of IC 50 significantly lower if compared to the whole extract; they performed a little less than tamoxifen, which was used as a positive control. These results demonstrated that the two compounds were mostly responsible for the cytotoxic activity of this plant [34].
The n-hexane extract of Heracleum persicum (aerial parts, roots), ethyl acetate and n-hexane extract of Smilax excelsa (stem and leaves), methanolic, n-hexane, ethyl acetate extract of Pyrus boissieriana (leaves and steam), ethyl acetate and methanolic extract of Parrotia persica (leaves), and methanolic and ethyl acetate extract of Primula heterochroma (leaves and roots) exhibited significant antidiabetic activities in αglucosidase and α-amylase assays, more effective than acarbose used as a positive control [23]. These plants, in conclusion, are deserving candidates for further studies in the antidiabetic field. Dehghan et al. (2017) [24] evaluated the antidiabetic activity of extracts obtained by the plant Heracleum persicum. This work led to the isolation of eleven furanocoumarins. These compounds were identified as psoralen, bergapten, xanthotoxin, iso-pimpinellin, angelicin, isobergapten, sphondin, pimpinellin, heratomin, 5-methoxyheratomin, moellendorffiline, and fraxetin. Among them, moellendorffiline showed significant inhibitory activity against α-glucosidase with an IC 50 value of 17.9 nM, and it was more active than acarbose (IC 50 = 23.5 nM; used as a positive control) [24]. Hasanein et al. (2016) [37] studied the effects of Salvia officinalis L. against learning and memory deficit induced by diabetes. This plant has been used in Iranian traditional medicine practices against diabetes. The plant samples were collected in Hamedan, Iran. The effects of the leaves' hydro-alcoholic extract on passive avoidance learning (PAL) and memory in streptozocin-induced diabetic and non-diabetic rats were evaluated. Administration for thirty days demonstrated to alleviate the negative influence of diabetes on learning and memory. Positive effects on hyperglycemia and oxidative stress were evidenced. Therefore, Salvia officinalis L. and its constituent rosmarinic acid represented a potential therapeutic option against diabetic memory impairment, and further studies are needed to clarify the mechanisms involved in this activity [37].
3.2.7. Iron chelating Activity Ebrahimzadeh et al. (2008) [38] tested the iron chelating activity, phenol, and flavonoid content of eleven medicinal plants from Iran. The extraction was performed by maceration of the vegetal dried material for three days. The solvent was evaporated under reduced pressure and then lyophilized. Epilobium hirsutum leaves and Melilotus arvensis showed the best chelating activity with IC 50 values of 0.49 ± 0.01 mg/mL and 0.08 ± 0.01 mg/mL, respectively. These plant extracts also showed high phenol and flavonoid contents. Feijoa sellowiana leaves and Pistacia lentiscus showed good chelating activity [38].
3.2.8. Anti-Platelet Aggregation Activity Lorigooini et al. (2014) [39] studied the essential oil obtained by aerial parts of Allium atroviolaceum. The plant was collected in Rig mountain, Shahr-e-kord province, Iran. In this work, the anti-platelet aggregation activity of the essential oil was examined using arachidonic acid (AA) and adenosine diphosphate (ADP) as platelet aggregation inducers.
The essential oil evidenced dose-dependent inhibitory effect against AA and ADP-induced aggregation with IC 50 values of 0.25 mg/mL and 0.47 mg/mL, respectively [39]. Further studies are required to identify the main active compounds of the essential oil.
3.2.9. Mushroom Tyrosinase Inhibition Activity Khazaeli et al. (2009) [28] tested five traditional medicinal plants from Iran on the inhibition of mushroom tyrosinase activity. Methanolic extracts obtained from Quercus infectoria galls and Terminalia chebula fruits showed inhibitory effects on mushroom tyrosinase in the hydroxylation of L-tyrosine (85.9% and 82.2% of inhibition, respectively). Furthermore, these two plants inhibited the oxidation of Levodopa (L-DOPA), performing similarly to kojic acid (used as a positive control) with values of IC 50 = 102.8 and 192.6 µg/mL, respectively [28]. This study encouraged further investigations on the two plants in the field of solar protection due to the radical scavenging activity and of skin depigmentation agents due to inhibitory effects on mushroom tyrosinase.

Acetylcholinesterase-Inhibitory Activity
Abbas-Mohammadi et al. (2018) [42] tested the acetylcholinesterase-inhibitory activity of n-hexane, ethyl acetate, and methanolic extracts obtained by aerial parts of twenty-five plants grown and collected in Iran. The evaluation was conducted by an in vitro enzymatic Ellman method and molecular docking study. The n-hexane extract obtained by the plant Prangos ferulacea showed the highest acetylcholinesterase (AChE)-inhibitory activity with 75.6% inhibition at a concentration of 50 µg/mL. The chemical characterization of the extract led to the identification of seventeen compounds. Further studies led to the identification of a subfraction (named F 10f ) that resulted as the most potent inhibitor of AChE in this extract with an IC 50 value of 25.2 µg/mL [42]. Prangos ferulacea deserves further in vivo and in vitro studies as the discovery of new acetylcholinesterase (AChE) inhibitors might lead to new tools for the treatment of Alzheimer's disease. Adhami et al. (2011) [41] tested the acetylcholinesterase-inhibitory activity of forty herbal drugs traditionally used against cognitive disorders in Iran. Eighty drugs were tested by TLC bioautography method and microplate colorimetric assay, and, due to the interesting activity, the seeds of Peganum harmala L. were investigated in detail. The alkaloids harmaline and harmine were identified as active compounds. The IC 50 values were 8.4 µg/mL for harmaline (pure compound) and 10.9 µg/mL for harmine (pure compound), 41.2 µg/mL for the methanolic extract, 95.5 µg/mL for the dichloromethane extract [41]. The two tested alkaloids were the major AChE-inhibitory compounds in Peganum harmala; this plant deserves further studies to test the biological activity in vivo. Jazayeri et al. (2014) [40] evaluated the acetylcholinesterase-inhibitory activity of eighteen aqueous-methanolic extracts (1:1 v/v) obtained by plants commonly used in Iranian traditional medicine collected in Tehran. The inhibitory activity was tested using the in vitro Ellman spectrophotometric method. According to the results, five plants evidenced interesting properties. The inhibitory activity values, expressed as IC 50 µg/mL, in fact were 5.96 µg/mL for Camellia sinensis (leaves), 19.57 µg/mL for Citrus aurantifolia (fruits), 24.37 µg/mL for Zizyphus vulgaris (fruits), 84.30 µg/mL for Brassica nigra (seeds), and 93.1 µg/mL for Rosa damascena (flowers) [40]. Further investigations regarding the identification of active components in the extracts are needed.
3.2.11. Antihyperlipidemic and Antihypertensive Activities Asgary et al. (2000) [43] studied the antihyperlipidemic and antihypertensive effects of Achillea wilhelmsii C. Koch drops, with a double-blind placebo-controlled clinical trial. The aerial parts of the plant were collected in Chatrood village in the province of Kerman, Southeast Iran. Moderate hyperlipidemic and primary hypertensive subjects were treated with a hydro-alcoholic extract twice daily for more than six months. The results showed a significant decrease in triglycerides after two months of treatment. Significant decreases in triglycerides, total cholesterol, and low-density lipoproteins (LDL)-cholesterol were observed after four months of treatment. Levels of high-density lipoproteins (HDL)-cholesterol were significantly increased after six months. A significant decrease in diastolic and systolic blood pressure was observed after two and six months, respectively [43]. Karimi et al. (2004) [44] studied the gastric antiulcerogenic activity of aqueous and ethanolic extracts obtained from the plant Portulaca oleracea L. collected in the village of Khaje-rabi, Khorasan province, Iran. Both leaves extracts, tested in vivo in mice, showed remarkable dose-dependent inhibition of gastric lesions induced by absolute ethanol or HCl [44]. This gastroprotective activity resulted in line with Iranian traditional medicine knowledge, and it deserves further studies to determine the involved mechanisms.

Gastric Antiulcerogenic Activity
3.2.13. Anti-Dyspepsia Activity Khonche et al. (2017) [45] tested the efficacy of Mentha pulegium L., collected in the Alborz province of Iran, against functional dyspepsia in a randomized double-blind placebo-controlled clinical trial. Leaves of this plant are used in Iranian traditional medicine practices to treat dyspeptic symptoms. The hydro-alcoholic leaf extract taken daily for two months was shown to be effective in the reduction of dyspeptic symptoms, improving quality of life, and contributing to eradicate Helicobacter pylori in patients affected by functional dyspepsia [45].
3.2.14. Inhibitory Effect on Gastric Acid Output Niazmand et al. (2010) [46] studied the effects of the aqueous-ethanolic extract obtained by aerial parts of the plant Achillea wilhelmsii on rat's gastric acid output in basal, vagotomized, and vagal-stimulated conditions. The plant samples were collected from South Khorasan province, Iran. Achillea wilhelmsii is a plant frequently used in Iranian traditional medicine against gastrointestinal disorders. The results of the in vivo study showed that the aqueous-ethanol extract of A. wilhelmsii exhibited an inhibitory effect on gastric acid output in basal conditions via the gastric parasympathetic nerve. The extract had no effect on vagal-stimulated conditions [46]. Further studies are needed to identify the compounds and mechanisms responsible for this activity.

Anti-Colitic Activity
Minaiyan et al. (2011) [47] tested the anti-colitic activity of hydro-alcoholic extract and the essential oil obtained by Rosmarinus officinalis leaves. The plant material was collected in the city of Isfahan, Iran. The study was performed in vivo on a model of experimental colitis induced by trinitrobenzene sulfonic acid in rats.
Both the extracts at all the tested doses demonstrated to be effective in the reduction of colon tissue lesions and of colitis indices; the higher doses tested were considerably effective in diminishing histopathologic parameters. These data supported the traditional medicine knowledge and suggested that both hydro-alcoholic extract and the essential oil obtained by Rosmarinus officinalis leaves possess consistent anti-colitic activity [47].

Conclusions
The Iranian territory possesses a great abundance of plants suitable for medicinal use and remarkable heritage of knowledge handed down from generation to generation concerning natural remedies against a wide range of diseases and disorders. Nowadays, the study of this heritage is at an early stage.
As reported in Sections 3 and 4, the bibliographic research evidenced ethnobotanical studies conducted in the Iranian territory, carrying out questionnaires and interviews with traditional healers or local people, and scientific studies inspired by traditional medicinal practices conducted on plants collected in Iran. Comparing ethnobotanical studies and traditional medicine-inspired scientific studies, it is evident that most of the Iranian traditional herbal remedies have not been considered from a scientific point of view yet. Only 34 plants are cited in both Sections 3 and 4 among the 245 of Section 3. Table 3 provides a comparison between traditional uses and tested biological activities of the plants cited both in Sections 3 and 4. The identification of a direct correspondence between the traditional uses and biological activities represents a complex issue. Some plant species mentioned in this work have already been studied in other parts of the world with different climatic characteristics and, consequently, different phytocomplexes. In our opinion, it is of interest to study plants that are not interesting from a medicinal point of view in other parts of the world if included in traditional medicinal practices in Iran, as they could be active due to a quite different phytocomplex expressed in the particular climatic characteristics and ecosystems of the Iranian territory. It should be pointed out that, considering the research works found in literature, the process of valorization and study of plant species does not often pay particular attention to the aspect of sustainability of eventual systematic exploitation. This aspect is becoming more and more important these days.
Traditional remedies are often effective due to the synergistic activity of a large number of compounds that are part of the plant phytocomplex; therefore, careful research is needed to identify the active molecules. The research work is further complicated by the fact that in some cases, natural remedies act as palliatives. In any case, the evidence that nature has always inspired medicine, constituting itself as a source of inspiration for the development of pharmacological treatments, makes the study of traditional remedies a very important component of basic research in the medicinal and pharmacological field.
A summary of the information in the scientific literature, related to documented traditional medicinal practices and plants studied from a scientific point of view in the same territory, represents a useful tool to plan new researches in order to avoid repeating work already done and to concentrate on apparently effective but not yet scientifically evaluated plants. In our opinion, there is still a large room for scientific works that could deepen the above-stated aspects, encouraging further research in the field.