A review of the most effective medicinal plants for dermatophytosis in traditional medicine

Fungi can evade the immune system via different processes, including recombination, mitosis, and expression of genes involved in oxidative stress responses. These processes can lead to chronic fungal diseases. Despite the growth of health care facilities, the incidence rate of fungal infections is still considerably high. Dermatophytes represent the main cause of cutaneous diseases. Dermatophytes attack keratinized tissues, such as nail, hair, and stratum corneum, due of their gravitation towards keratin, which leads to dermatophytosis. Medicinal plants have long been used to treat different diseases, and in the recent years, use of plant-based products to fight fungal, bacterial, and parasitic infections have attracted extensive attention. This is because the use of medicinal plants has many advantages, such as decreased costs and fewer side effects. This review article was conducted to report medicinal plants with anti-dermatophytosis properties. Seventy-six articles were retrieved from databases Google Scholar, PubMed, ScienceDirect, and Scopus. After exclusion of duplicate and irrelevant articles, 54 articles were selected. Of the remaining articles, 23 articles were screened and included in this study. According to the findings, Azadirachta indica, Capparis spinosa, Anagallisarvensis, Juglans regia, Inula viscosa, Phagnalon rupestre, Plumbago europaea, Ruscus aculeatus, Ruta chalepensis, Salvia fruticosa, Artemisia judaica, Ballota undulate, Cleome amblyocarpa, Peganum harmala, Teucrium polium, Aegle marmelos, Artemisia sieberi, Cuminum cyminum, Foeniculum vulgare, Heracleum persicum, Mentha spicata, Nigella sativa, and Rosmarinus officinalis are the most effective plants against dermatophytes which have been identified to date. Abstract


Background
Fungal infections are divided into two types: primary and opportunistic.Opportunistic infections occur mainly in immunocompromised hosts, but primary infections may also occur in hosts with a healthy immune system.Besides that, fungal infections can be systemic or local [1].Fungi can evade immune system responses via different processes, including recombination, mitosis, and expression of genes involved in oxidative stress responses, and, therefore, can cause chronic fungal diseases.Despite the expansion of health care facilities, the incidence rate of fungal infections is still very high.For example, fungal infections are the fourth leading skin diseases worldwide.In 1984, 984 million people suffered from fungal skin infections.Secondary infection, deafness, tinea, and skin lesions are some of the complications due to fungal infections [2].
Dermatophytes represent the main cause of cutaneous diseases.Dermatophytes attack keratinized tissues, such as nail, hair, and stratum corneum, causing dermatophytosis [1].Dermatophytosis is very common and can be life-threatening for the elderly and immunocompromised people.The highest prevalence of this disease is seen in people between the ages of 20-31 years.Dermatophytes cause skin scaling, create gray loops in the skin, and cause hair loss and loosening and nail deformities [3].Dermatophytes have three genera: Microsporum, Tricophyton, and Epidermophyton, whose reservoirs are soil, animals, and humans [4].
The cloning process of dermatophytes is associated with the release of proteolytic enzymes and spontaneous stimulation of the host inflammatory responses, and causes dermatophytosis or tinea (ringworm).Inflammatory symptoms at the infection site include redness, swelling, and alopecia.Swelling causes transmission of infection to other parts of the body that causes circular lesions.The severity of infection due to dermatophytes depends on age, surrounding temperature, humidity level, and health and social conditions [5].Different genera of dermatophytes have many phenotypic and genotypic similarities that make their detection challenging.Colony testing, microscopic examination of morphology, genotypic tests, and in some cases, detection of nutritional requirements, temperature tolerance, and urease production are used to detect dermatophytes [6].Some parts of the body, such as nail subdistal region and area between the fingers, are more prone to dermatophytosis because they are exposed to the fungus in the long-term and provide certain factors, such as sugar and pH, that are required for the fungus [5].
Dermatophytes can induce increased immediate, delayed, or mediated cell susceptibility.In infected people with a normal immune system, response to increased susceptibility is induced within 30 days and is spontaneously recovered after 50 days.Dermatophyte distribution is different across the world [5].In the past half-century, Tricophyton rubrum has been the most common dermatophyte, and in poor developing countries, Mycosis is endemic and affects a large number of children.Epidermophyton floccosum was common during two decades, i.e. 1980-1990, and among the isolated dermatophytes, is the leading dermatophyte in Iran with 31.4% prevalence [7,8].In eastern and southern Europe, low quality of life has caused increased infection with animal-friendly dermatophytes.As well, urbanism, contacts, and travels have led to increased prevalence of T. rubrum [9].
Medicinal plants have long been used to treat different diseases in developed and developing countries [10][11][12][13].In recent years, medicinal plants have also attracted much attention because their uses have had many benefits, such as decreased expenses and fewer side effects [14][15][16][17].Use of plant-based products to fight fungal, bacterial, and parasitic infections has also been considered as an effective approach [7,8].Moreover, certain measures can be taken to produce drugs by identifying the active compounds of the plants [18,19].The antifungal effects of some plants, such as ginger, Narcissus tazetta, Myrtus communis, dill, cilantro, garlic, onions, henna, oak, black beans and thyme, on fungal infections have already been demonstrated.Flavonoids, alkaloids, tannins, citronellol , geraniol, thymoquinone, and phenolic compounds are some of the antifungal or other microbial active compounds found in these plants [20,21].This review article was conducted to report medicinal plants with anti-dermatophytosis properties.

Materials and Methods
We searched the keywords "Medicinal plants", "Traditional medicine" with the keyword "Dermatophytosis" in the Google Scholar, PubMed, Science Direct, and Scopus databases.
After the first search, seventy-six articles were found to be relevant.After exclusion of duplicates and irrelevant articles by checking article topics, 54 articles were selected.After reviewing abstracts of the remaining articles, 23 articles were included in this study.

Results
Fungal diseases are known as mycoses, according to the National Institute of Allergies and Infectious Diseases.Mycoses can affect various parts of the body, including body hair, lungs, nervous system, nails, and skin.The most common types of fungal infections are tinea infections and fungal infections of hair, skin or nails; these include athlete's foot, jock itch, candida, and vaginal yeast infections.Fungal skin infections usually involve itching, skin discoloration, and changes in skin texture in the affected area.
Certain herbs are known as fungicides, or agents that destroy fungi and their spores.Since fungal infections are often tenacious and difficult to eliminate, several different medicines may be necessary to provide therapeutic relief.On the other hand, the routine fungicides like azoles have several side effects.
According to findings of the study herein, Azadirachta indica, Capparis spinosa, Anagallisavensis, Juglans regia, Inula viscosa, Phagnalon rupestre, Plumbago europaea, Ruscus aculeatus, Ruta chalepensis, Salvia fruticosa, Artemisia judaica, Ballota undulate, Cleome amblyocarpa, Peganum harmala, Teucrium polium, Aegle marmelos, Artemisia sieberi, Cuminum cyminum, Foeniculum vulgare, Heracleum persicum, Mentha spicata, Nigella sativa, and Rosmarinus officinalis are the most effective plants on dermatophytes that have been identified to date.Various form of extracts and essences of these plants were found to have growth inhibition or killing effect on dermatophytosis agents and their pathogenicity.Most of the plants belong to family Lamiaceae.All the plants have very good effects against dermatophytosis agents in either minimum inhibitory concentration test (MIC) or in minimum fungicidal concentration test (MFC), and other tests.Even some clinical dermatophytosis isolates show drug resistance from these plants.Table 1 shows further information about the botanical names, studied doses, and effects of these plants.
Overall, many of the sulfuric compounds, phenolic compounds, flavonoids, tannins, and anthocyanins in the plants cause antifungal effects.Here, in this review article, we touched on the active compounds of the reported plants according to phytochemical investigations.Eugenol is the main antifungal compound of O. sanctum [45].Tetranortriterpenoid has been demonstrated to be main antifungal compound present in A. indica, while some other compounds, such as 6-deacetylnimbin, azadiradione, nimbin, salannin and epoxyazadiradione, are considered main active compounds of A. indica with antifungal activity [46].Moreover, rutin, tocopherols, carotenoids, and vitamin C have been confirmed to be the antimicrobial and antifungal compounds of C. spinosa.Glycosidic saponin is the antifungal active compound of A. arvensis [47].
A study on C. amblyocarpa demonstrated that this plant contained a number of valuable fatty acids, such as stearic acid, oleic acid, and linoleic acid.In addition, C. amblyocarpa contained some other compounds, including vitamin C, gallic acid, gallotannins and iridoid, that have many properties, namely antifungal [48].In A. judaica, certain antifungal active compounds

Rutaceae
The MIC test of A. marmelos essential oil indicated that 500 microg/ml of this essential oil exerted inhibitory effect on dermatophytes [37] .18 Artemisia sieberi

Asteraceae
The effect of A. sieberi essential oil on T. rubrum, T. verrucosum, Tricophyton schoenleinii, T. mentagrophytes, M. canis, and M. gypseum was investigated by adding 4 microL of the essential oil to disk; A. sieberi essential oil exerted the most potent inhibitory effect on T. rubrum and the lowest inhibitory effect on M. gypseum. A. sieberi essential oil MIC for these fungi was investigated and the fungi's growth was found to be inhibited fully at 1-8 microg/ml of this essential oil depending on the type of the studied fungus [38] .19

Cuminum cyminum
After 7-day treatment of the culture medium with different doses of C. cyminum essential oil, T. rubrum was eliminated by all doses, and M. gypseum growth was inhibited by 85% by the lowest dose and completely by other doses of the essential oil [39] .20 Foeniculum vulgare

Apiaceae
The inhibitory effect of F. vulgare essential oil on the growth of T. rubrum and T. mentagrophytes mycelia was investigated.F. vulgare essential oil at 0.2, 0.4, and 0.5 microg/ml exerted antifungal effects [40].21 Heracleum persicum

Lamiaceae
The antifungal effect of M. spicata essential oil on T. rubrum and M. gypseum was investigated by disk diffusion method and found to be potent.M. spicata essential oil up to 16 and 36 ml inhibited the growth of T. rubrum and M. gypseum, respectively [42].23 Nigella sativa

Ranunculaceae
The effects of N. sativa essential oil, methanolic extract, and aqueous extract on T. mentagrophytes, M. canis, and M. gypseum were investigated by disk diffusion method.The essential oil was found to have the most potent effect [43].24 Rosmarinus officinalis

Lamiaceae
The antifungal effect of R. officinalis on M. canis isolates was investigated by MIC and MFC that were derived 2.5 and 7.5 microg/ml, respectively, at which the fungi were fully inhibited.Besides that, four of seven cats treated with different combinations of plant-based extracts all of which contained R. officinalis were fully recovered.Three of the four recovered cats had negative culture and one had positive culture [44].
Due to a high prevalence of dermatophytosis and high speed of acquiring this disease around the world, especially in low-income regions and developing countries, it is necessary to investigate these drugs as well as pharmaceutical and antifungal agents with anti-dermatophytes

Table 1 . The botanical name,studied dose, and effect of medicinal plants effective on dermatophytosis
[32]ydroalcoholic A. arvensis extract, 15 microg/ml of this extract caused full inhibition of T. violaceum growth, and inhibited the growth of M. canis and T. mentagrophytes to a great extent[25].5JuglansregiaJuglandaceaeThreeand 5 microg/ml of J. regia, according to agar dilution, led to full inhibition of the growth of M. canis and T. violaceum.Moreover, 0.6 microg/ml of J. regia caused 97.6% inhibition of T.AsteraceaeThe MIC of A. judaica essential oil was derived 0.64 microg/ml for Epidermophyton floccosum,T.rubrum,M.canis,Microsporiumgypseum, Tricophyton verrucosum, and T. mentagrophytes[32].*Minimum inhibitoryconcentration; ** minimum fungicidal concentration continued to the next page to the next page