key: cord-307607-8xn9jtmh
authors: Sargin, Seyid Ahmet
title: Potential anti-influenza effective plants used in Turkish folk medicine: A review
date: 2020-08-31
journal: J Ethnopharmacol
DOI: 10.1016/j.jep.2020.113319
sha: 
doc_id: 307607
cord_uid: 8xn9jtmh

ETHNOPHARMACOLOGICAL RELEVANCE: Due to the outbreaks such as SARS, bird flu and swine flu, which we frequently encounter in our century, we need fast solutions with no side effects today more than ever. Due to having vast ethnomedical experience and the richest flora (34% endemic) of Europe and the Middle East, Turkey has a high potential for research on this topic. Plants that locals have been using for centuries for the prevention and treatment of influenza can offer effective alternatives to combat this problem. In this context, 224 herbal taxa belonging to 45 families were identified among the selected 81 studies conducted in the seven regions of Turkey. However, only 35 (15.6%) of them were found to be subjected to worldwide in vitro and in vivo research conducted on anti-influenza activity. Quercetin and chlorogenic acid, the effectiveness of which has been proven many times in this context, have been recorded as the most common (7.1%) active ingredients among the other 56 active substances identified. AIM OF THE STUDY: This study has been carried out to reveal the inventory of plant species that have been used in flu treatment for centuries in Turkish folk medicine, which could be used in the treatment of flu or flu-like pandemics, such as COVID 19, that humanity has been suffering with, and also compare them with experimental studies in the literature. MATERIALS AND METHODS: The investigation was conducted in two stages on the subject above by using electronic databases, such as Web of Science, Scopus, ScienceDirect, ProQuest, Medline, Cochrane Library, EBSCO, HighWire Press, PubMed and Google Scholar. The results of both scans are presented in separate tables, together with their regional comparative analysis. RESULTS: Data obtained on taxa are presented in a table, including anti-influenza mechanism of actions and the active substances. Rosa canina (58.7%) and Mentha x piperita (22.2%) were identified as the most common plants used in Turkey. Also, Sambucus nigra (11.6%), Olea europaea (9.3%), Eucalyptus spp., Melissa officinalis, and Origanum vulgare (7.0%) emerged as the most investigated taxa. CONCLUSION: This is the first nationwide ethnomedical screening work conducted on flu treatment with plants in Turkey. Thirty-nine plants have been confirmed in the recent experimental anti-influenza research, which strongly shows that these plants are a rich pharmacological source. Also, with 189 (84.4%) taxa, detections that have not been investigated yet, they are an essential resource for both national and international pharmacological researchers in terms of new natural medicine searches. Considering that the production of antimalarial drugs and their successful use against COVID-19 has begun, this correlation was actually a positive and remarkable piece of data, since there are 15 plants, including Centaurea drabifolia subsp. Phlocosa (an endemic taxon), that were found to be used in the treatment of both flu and malaria.

Plants have always been the primary choice for preventing and treating various diseases faced by human beings, and contain specific or broad-spectrum active compounds for almost any type of disease (Alaoui-Jamali, 2010) . People living in Turkey have also benefited from plants in the prevention and treatment of various diseases for centuries. People living in rural areas still have an especially rich medicinal plant repertoire (Ertuğ, 2004) . Although herbal cures such as rosehip tea, peppermint-lemon tea and garlic-lemon tea, which are used to prevent and treat flu outbreaks, are well known by the local people, the vast majority of them and their antiinfluenza effects have not yet been adequately investigated in vitro by the related industries (Bekut et al., 2018) .

In virus classification, influenza viruses are RNA viruses that comprise 4 of the 7 genera of the family Orthomyxoviridae (Kawaoka, 2006) , while Human Rhinoviruses (HRVs) are within the genus Enterovirus and Only English and Turkish words were used in the search engines. If they exist, their English translations were reviewed for the studies conducted in different languages, such as Chinese, Korean and French. In this context, approximately 700 articles conducted between January 1977 and February 2020 throughout Turkey were excluded since they did not meet the inclusion criteria and a consensus has been provided among the 81 works on the determination of medicinal plants used by local people for centuries. The list of selected plants from these studies is presented in Table 1 .

The studies determined to be within the scope of plant screening were reviewed, compared and carefully selected according to the following criteria. Accordingly, a study should:

• be carried out in an area within the borders of Turkey. • performed on ethnobotanical or ethnopharmacological concept layout.

• include scientific names and local names of the plants used.

In addition, the criterion for choosing the book sources was either the writer having an academic title or the work having been cited. If neither of these were in case, the work was not taken into consideration.

The screening of the resulting plants in the world literature was carried out considering the following criteria. Accordingly, a study should be:

• an experimental (in vitro or in vivo) study, not a review.

• included the scientific name of the plant in its title. In case of writing only the English name of the plant, it is obligatory to include the scientific name in the text. • carried out under the headings of "anti-flu, anti-influenza or antiviral activities against influenza".

If it contains the active compound(s), it becomes preferable and the mechanism of action is recorded. Table 1 contains the scientific names of plants, their families, local names, English common names, parts used, forms used, and references. The validation of the scientific names of the specified plant taxa was provided by the book Turkey Plant List (Vascular Plants) (Güner et al., 2012) , the International Plant Names Index (IPNI: http://www.ipni.org) and the Plant List (http://www.theplantlist.org). English common names of the taxa are placed in the table using the following databases or search engines: EPPO Global Database J o u r n a l P r e -p r o o f , Lebanon Flora (http://www.lebanon-flora.org), Springer Link (https://link.springer.com/article), Flora of Israel Online (http://flora.org.il), Altervista Flora Italiana (http://luirig.altervista.org/flora), and Plants of the World online (http://www.plantsoftheworldonline.org). Taxa for which common English names could not be found have been noted as endemic to Turkey, or containing Irano-Turanian elements.

Finally, the plants were arranged in alphabetical order according to family names. In order to prove the scientific validity of the ethnobotanical data obtained, the research data of the experimental studies regarding the taxa in the list, as found in the world literature, are shown in a separate table (Table 4 ). In this table, the mechanism of action, active compounds and used parts are also included, in addition to the researched taxa and their references. Great care has been taken to ensure that the findings obtained in these screening studies belong to experimental studies (in vitro or in vivo), not a review.

After obtaining the total list of plants with anti-influenza potential in Turkish folk medicine, a comparison was made to determine the similarity percentages in similar studies conducted in neighboring and nearby countries (Table 2) . To avoid distraction from the subject integrity, not all studies in those countries were included in our comparison. Therefore, only the study with the richest content and the highest percentage of similarity from each country was included in the comparison list. Studies with a similarity percentage >10% were eliminated in the primary elections. Ozturk et al. (2017a) 13 5.8 Southeastern Anatolia Sargin and Büyükcengiz (2019) 13 5.8 Mediterranean Tuzlacı and Doğan (2010) 13 5.8 Eastern Anatolia Tuzlacı and Erol (1999) 13 5.8 Mediterranean Ertuğ (2004) 11 4.9 Aegean Güneş and Özhatay (2011) 11 4.9 Eastern Anatolia Kılıç (2016) 11 4.9 Eastern Anatolia Kilic and Bagci (2013) 11 4.9 Eastern Anatolia Guzel and Guzelsemme (2018) 10 4.5 Mediterranean Ozturk et al. (2017b) 10 4.5 Mediterranean Saraç (2005) 10 4.5 All Regions Tetik et al. (2013) 10 4.5 Eastern Anatolia Yeşilyurt et al. (2017b) 10 4.5 Marmara Akgül et al. (2016) Nacakcı and Dutkuner (2015) 9 4.0 Mediterranean Özçelik (2016) 9 4.0 Mediterranean Akan and Bakır Sade (2015) 8 3.6 Southeastern Anatolia AkBulut et al. (2019) 8 3.6 Aegean Kurt and Karaoğul (2018) 8 3.6 Black sea Paksoy et al. (2016) 8 3.6 Central Anatolia Sargin et al. (2013a) 8 3.6 Aegean Yılmaz (2019) 8 3.6 Aegean Demirci and Özhatay (2012) 7 3.1 Southeastern Anatolia Kaval et al. (2014) 7 3.1 Eastern Anatolia Kocabaş and Gedik (2016) 7 3.1 Mediterranean Maranki and Maranki (2016) 7 3.1 All Regions Tuzlacı and Eryaşar-Aymaz (2001) 7 3.1 Marmara Ugulu et al. (2009) 7 3.1 Aegean Tanker et al. (1998) 

The demand for new antimicrobial agents, especially antivirals, is constantly increasing. This demand arises from the lack of antiviral agents in the market and the emergence of resistant mutants to existing drugs (Vijanyan et al., 2004) . Throughout our existence, human beings have always been in search of healing from plants in the fight against winter diseases, but clinical studies have to this point been limited. Although the following work is relatively new in Turkey, they are promising for future study: Duman et al. (2018) elicited in vitro antiviral activity of Ribes uva-crispa L and Ribes multiflorum Kit ex Schult, which are naturally grown in Turkey, use the methanol and aqueous extracts of the leaves and fruits; Dogan et al. (2020) revealed anti-RSV effects of Ribes uva-crispa juicy fruit and leaf methanol extracts against the respiratory syncytial virus (RSV) (the cause of a worldwide viral infection), and emphasized their advantages to synthetic drugs; finally, Adem et al. (2020) found that natural polyphenols, such as hesperidin, routine, diosmin and apiin were more effective than nelfinavir in treating COVID-19. The plants (Table 3) , which have been used by locals in Turkey for centuries for the prevention and treatment of influenza and its adverse effects -from colds to sudden deaths from respiratory failure -need to be investigated in this way. Today, much more research is needed, as outbreaks such as SARS, avian influenza, swine influenza and COVID-19 threaten the existence of human beings every year.

Distribution of 81 studies by region was performed as follows: 13 in the Mediterranean (16.0%), 11 in Eastern Anatolia (13.6%), 10 in the Marmara and Aegean region (12.3%), 8 in the Black Sea (12%), 7 in Central and Southeastern Anatolia (11.1%), and 15 general studies across all regions (18.5%). The regional distribution of 921 total citations received was as follows: Mediterranean: 150 (16.3%), Eastern Anatolia: 141 (15.3%), Aegean: 109 (11.8%), Marmara: 98 (10.6%), Central and Southeastern Anatolia: 82 (8.9%), Black Sea: 75 (8.1%), and general studies covering all regions: 184 (20.0%). The reason why the studies conducted in the Mediterranean and Eastern Anatolia regions were highly cited may be due to the fact that there are more plant options, which is the result of having a higher rate of biodiversity and endemism in these regions (Güner et al., 2012) compared to others, that the locals can use in the treatment of influenza. In addition, the topographic structure of the region, and the fact that the region is isolated from city centers in winter conditions (Doğanay and Orhan, 2016) may have been a factor for the people living in these rural areas to choose mostly natural treatment methods.

It has been determined that 224 plants, selected from 81 studies composing of 57 articles, 13 books, seven theses, three chapters and one congress report in total, belonging to 43 families. These plant taxa most commonly belong to the Lamiaceae (88 taxa, 39.3%), Compositae (32 taxa, 14.3%), Rosaceae (21 taxa, 9.4%), Malvaceae (13 taxa, 5.8%), and other families (70 taxa, 31.3%). The most preferred outcome of the Lamiaceae family may be due to the Turkish people's preference for flu treatment, as it is the family that contains the highest dosage of essential oils (Askun et al., 2012) . The second family, Compositae, is known as Turkey's most common family (Guner et al., 2012) . Infusions prepared from taxa with capitula flower structures such as its representative Chamomile are widely used by local people. Therefore, this was an expected result.

According to studies conducted in different regions of Turkey ( Fig. 1) , the most common genera are Sideritis (16 taxa, 7.1%), Salvia (12 taxa, 5.4%), Thymus (12 taxa, 5.4%), and Origanum (10 taxa, 4.5%). This finding may indicate that these genus members are more effective in anti-influenza treatment than other genera. In addition, they are the most favored medicinal tea for the locals of Turkey, and even without natural nationwide distribution, it is possible to find these products in almost every public market, herbal and spice shop (Ertug 2004; Dogan 2012) . Some species, such as thyme (Thymus spp.), melissa (Melissa officinalis), lavender (Lavandula angustifolia), cassidony (Lavandula stoechas) and sage (Salvia officinalis), are today being grown in home gardens, balconies or on small farms by rural people for folk medicine use, or for trade and household income (Güneş, 2017; Ekşi et al., 2020) . like thyme, melissa, lavender, and sage, Among the identified plants, 145 were wild (64.7%), 49 were wild and cultivated (21.9%), 27 were endemic (12.1%) and 3 (Allium cepa, Allium sativa and Malus domestica) were cultivated (1.3%). These parameters are shown in a column in Table 3 ; wild taxa as "W", cultivated "C", cultivated & wild "CW" and endemic "E". Most of the plant pieces used are aerial parts (41.1%), flowers/flowering branches/petals (30.8%), leaves (25.0%), fruits (17.4%), seeds/cones (8.5%), roots/bulbs/tubers (6.7%), and other parts (stems, buds, barks, whole parts, resins, tars, cupula, bracts, fruit stalks, essential oils and fixed oils) (14.3%). Those parts were mostly used as infusions (78.6%), decoction/boiling (19.2%), raw eating/swallowing/salad (12.9%), molasses/jam/syrup/juice (7.6%), lotion/drop/cataplasm/vapor compression (6.3%) and other consumption types (roasting, mouthwash, tincture, mixture and pastes) (5.4%) and powdered for spice use (3.1%). The taxa having with the most usage types are Citrus spp (7 types, 3.1%), Rosa canina and Rubus sanctus (5 types, 2.2%) and Vitis vinifera (4 types, 1.8%), while the taxa with the maximum number of consumption parts belong to Rosa canina and Tilia tomentosa (6 parts, 2.7%), and Juniperus oxycedrus (5 parts, 2.2%). Additionally, Rosa canina (with 5 different types of use and 6 different parts) have appeared as the most efficient plants in terms of the total of both part and usage type (Table 3) .

16 taxa, such as Rosa canina (with 46 references and 56.8%) and Mentha x piperita (with 17 references and 21.0%) (Fig. 2 , red color), have been identified as the most frequently cited plants. The reason why these herbs are highly cited may be a reflection of their stronger protective and therapeutic effects against flu; this may be the result of the experience gained in Turkish folk medicine for centuries. We would obviously see this when comparing similar studies between 17 geographically close countries (Fig. 2 , blue color). The emergence of the data presented in Table 2 in a similar manner as in Figure 2 confirms the superior efficacy of these plants, with 76.7% similarity.

As a matter of fact, similar results were obtained from studies conducted in 17 neighboring countries, comparing with the taxon list presented in the study, including especially Rosa canina (11 countries with 64.7%), Sambucus nigra (8 countires with 47.1%) and Mentha x piperita (6 countries with 35.3%). While the similarity was seen mostly in Iraq (75.0%), Bosnia and Herzegovina (73.3%), and Cyprus (73.1%), the least similarity was seen in Montenegro (31.8%) and Israel (38.1%). This may due to the fact that, besides the resemblance of landforms, climate and vegetation, we lived together with the cultures of those countries during the Ottoman period for about 500 years. The reason for the low similarity in Israel and Montenegro may be due to the geographical distance as well as the difference of social-cultural habits, religious rituals, topography and flora (Table 2) . It was not very surprising that Matricaria chamomilla emerged as the plant used most in influenza treatment in 12 countries (70.6%) since the spreading area of this plant is very wide and it is very easy for the public to access and use (Fig. 2) . (2020) Lamiaceae

Boiss. (2006) Tuzlacı (2006) 

Experimental research studies carried out in the world in terms of anti-influenza activities have been determined only for 35 out of 224 taxa (15.6%). Still, among these studies, the active substances were detected for only 18 taxa (8.0%); for the remaining 17 taxa (7.6%), it was observed that they had not been specified (Table 4 ). In Table 4 , only "the parts used in research" were given as an idea for these taxa for which active gradients had been "not specified". It is noteworthy that no investigation has been conducted for 189 (84.4%) taxa yet (they are highlighted in bold in Table 3 ). Among these 35 taxa, the most common active chemicals are quercetin and chlorogenic acid (7.1%), mentofin (5.4%) and 1,8-cineole (3.6%). The most preferred mechanisms in research are inhibition of viral replication by inhibiting viral nucleoprotein synthesis or polymerase and neuraminidase activity (40.4% out of the 47 mechanisms in total), blocking the receptor site of the viruses by inhibition of neuraminidase, reducing the hemagglutination, or blocking hemadsorption (31.9%), inhibition of the virus-induced cytopathic effect by blocking hemadsorption (21.3%), and stimulating and boosting of the immunity (6.4%). The reason that the six taxa at the end of the list are shown as a line separated from the alphabetical sequence is that there was no significant result for virus inactivation in the experimental studies conducted for them (Table 4) .

According to screening results found in the global literature, the most preferred plants in experimental antiinfluenza studies are Sambucus nigra (14.3%, out of 35 taxa), Olea europaea (11.4%), followed by Eucalyptus camaldulensis, E. globules, Melissa officinalis and Origanum vulgare (8.6%). The reason for this may be that these plants are easily accessible in nature or from the virtual market environment, and can be obtained for less money. Additionally, eucalyptus trees in Turkey are also known as "malaria trees", as the infusion prepared from its leaves is used against malaria in traditional medicine (Baytop, 1999; Ertuğ, 2004) . Although its effectiveness against COVID-19 has not been fully proven by clinical trials, the widespread use and mass production of chloroquine and similar malaria drugs are permitted in many countries, and positive results continue to be achieved (Millán-Oñate et al., 2020; Touret and de Lamballerie, 2020) . This correlation of data has been positive and unexpected because there are fourteen more plants, including Centaurea drabifolia subsp floccosa (an endemic taxon), which have been detected in this study to be used in the treatment of malaria. These fifteen plants are presented in Table 3 by adding the "*" sign to the end of their scientific names.

The percentage of compatibility of the plant parts belonging to these 35 (15.6%) taxa found between the investigation results in the world literature and ethnobotanical results of the study was found to be 92.9%. This result may prove the fact that for centuries, the locals have been equally justified in their preferences of plant usage.

Taxa containing quercetin, which has a typical polyphenol structure with anti-influenza activity, are Hypericum perforatum, Morus alba and Papaver rhoeas (Kim et al., 2010; Liu et al., 2016; Kim and Chung, 2018) (Table 4) . It is not accidental that we detected quercetin and chlorogenic acid as the most common active gradients in our screening records, because these compounds are found to be the most effective compounds used in the treatment of influenza. Supporting these findings, Kumar et al. (2003) stated in a study of mice that quercetin ( Fig. 2A) may be useful as a drug to reduce oxidative stress caused by influenza virus infection in the lungs, and to protect them from the toxic effects of free radicals. In another study, Wu et al. (2016) stated that quercetin, which shows inhibitory activity in the early stage of influenza infection, offers a future therapeutic option for developing effective, safe and affordable natural products for the treatment and prophylaxis of influenza virus infections. Moreover, Nile et al. (2020) , in an investigation of the antiviral and cytotoxic effects of quercetin 3-glucoside (Q3G) from Dianthus superbus, Q3G (Fig. 2B) found that this substance showed strong antiviral activity against influenza A and B viruses. Therefore, they emphasized that it could be developed and used as a natural anti-influenza drug. On the other hand, chlorogenic acid (CHA) is a caffeoylquinic acid constituent (Fig. 2C) found in many vegetables and fruits traditionally used in Turkish folk medicine, such as Cydonia oblonga, Crataegus monogyna, Morus alba, Hypericum perforatum, Eucalyptus globules (Baytop, 1999; Ding et al., 2017; Kim and Chung, 2018) . Indeed, many researchers including Ding et al. (2017) and Ren et al. (2019) have pointed out that CHA acts as a neuraminidase blocker to inhibit influenza A virus at both in vitro and in vivo levels, thus they stated that CHA is potentially beneficial in the treatment of influenza.

Among the researches, the taxa containing the most active compounds in terms of anti-influenza activity were Glycyrrhiza glabra (11 chemicals with 31.4% out of the 35), Papaver rhoeas (7; 20.0%), Morus alba (5; 14.3%) and Punica granatum (4; 11.4%) ( Table 4 ). Glycyrrhiza glabra (licorice) is among the oldest and most popular traditional herbal medicines worldwide (Grienke et al., 2014) . Also, its roots are one of the most frequently used parts for treating respiratory tract infections in Turkish folk medicine (Baytop, 1999; Ertuğ, 2004) . Hence, the roots may have appeared to have the greatest number of active ingredients in the screening. This result overlaps with the findings of Grienke et al. (2014) because they had emphasized that the accumulation of the plant components exhibits 3D similarities to known flu Neuraminidase inhibitors (which are key enzymes in viral replication and the first-line drug target to fight influenza) according to their basis of a shape-focused virtual screening. Therefore, this finding may be pointing out that this plant is more effective and specific than other taxa in terms of anti-influenza activity.

Active compounds identified (and used parts)

Alcea Olea europaea L. Carvacrol (Essential oil) Shows significant antiviral activity. Olive oil was included in formulations to ameliorate its potential cytotoxic effects. Vimalanathan and Hudson (2012) J o u r n a l P r e -p r o o f 24 Olea europaea L. Not specified (Fruits-essential oil)

Both in influenza A/H1N1 and HRV14, replication cycle and progeny virus production were significantly decreased after the treatment with CAPeo (An essential oil combination based on three aromatic plants (Thymbra capitata, Origanum dictamnus and Salvia fruticosa in extra-virgin olive oil)

Origanum vulgare L β-carotene and Linoleic acid (Aerial parts) Decrease influenza virus activation by inhibiting the hemagglutination Mancini et al. (2009) Origanum vulgare L. Carvacrol (Essential oil) Shows significant antiviral activity. Olive oil was included in formulations to ameliorate its potential cytotoxic effects. Vimalanathan and Hudson (2012) Origanum vulgare L. Not specified (Essential oil) Linalool (Essential oil) Linalool (Essential oil)

Reduce visible cytopathic effects of influenza A/WS/33 virus activity by > 52.8%. Choi (2018) Papaver rhoeas L. Kaempferol-3-sophoroside, Kaempferol-3neohesperidoside, Kaempferol-3-sambubioside, Kaempferol-3-glucoside, Quercetin-3-sophoroside, Luteolin, Chelianthifoline Sambucus nigra L. Not specified (Fruits) Exhibit a specific neuraminidase-inhibiting effect Krawitz et al. (2011) Silybum marianum (L.) Gaertn.

Silymarin (Seeds) Reduces cytopathic effect (CPE) and inhibits viral mRNA synthesis with no cytotoxicity Song and Choi (2011) Thymbra capitata (L.) Cav. Carvacrol (Essential oil) Shows significant antiviral activity. Olive oil was included in formulations to ameliorate its potential cytotoxic effects.

Thymbra capitata (L.) Cav. Apigenin, Thymol (Aerial parts-Essential oil)

Both in influenza A/H1N1 and HRV14, replication cycle and progeny virus production were significantly decreased after the treatment with CAPeo (An essential oil combination based on three aromatic plants ( The results indicated that the prepared emulsions could elicit a little degree of immunity, but they could not inhibit the anamnestic response and infection. Najjari et al. (2015) Olea europaea L. * Not specified (Fruits) The results indicated that the prepared emulsions could elicit a little degree of immunity, but they could not inhibit the anamnestic response and infection. Najjari et al. (2015) Origanum acutidens (Hand.-Mazz.) Ietsw. *

None of the extracts inhibited the reproduction of influenza A/Aichi virus in MDCK cells Sökmen et al. (2004) Rosmarinus officinalis L. * Carnosic acid (Aerial parts) Inhibit both A-and B-type hRSV, while it does not affect the replication of influenza A virus Shin et al. (2013) Teucrium polium L.* Not specified (Aerial parts) No significant effects on influenza virus infectivity Derakhshan (2015) * The taxa that have no significant result for virus inactivation.

J o u r n a l P r e -p r o o f

In addition, 9 medicinal exotic herbs were detected to have been traditionally used in the treatment of influenza and sold in herbal and public markets. Zingiber officinale (ginger), Curcuma longa (turmeric), Syzygium aromaticum (cloves), Piper nigrum (black pepper) and Cinnamomum verum (cinnamon) are examples of these plants. Information on which parts, methods, and how often these plants are used in flu treatment is given in Table 5 . The citrus species presented in Table 3 are actually exotic species. For several centuries, they have mainly exhibited a distribution in the Aegean and Mediterranean coasts in Turkey's flora. Citrus limon (lemon), C. sinensis (orange), C. reticulata (tangerine), C. paradisi (grapefruit) and C. x aurantium (citrus) are among these types. Eucalyptus camaldulensis and E. globulus (Eucalyptus trees), another plant that has settled in the flora, are of Australian origin and have been used in forestry, roadside landscaping, drying of the marshes and folk medicine practices, such as combating malaria, since the Ottoman era (Özgün, 2013) .

The point we should especially emphasize here is that, while herbal products to be released for the treatment of influenza are determined by World Health Organisation (WHO) and the European Phytotherapy Scientific Cooperative (ESCOP), and controlled by the Turkish government, these standard practices are not yet available for fresh or dried plant taxa that are traditionally consumed and sold in public markets and herbalist shops in Turkey. Besides, it can never be ignored that medicinal plants are very successful in preventing and treating influenza if used according to the prescriptions specified in their pharmacopoeia. Thus, it is necessary to record traditional-empirical practices with proven trial-and-error methods urgently, to demonstrate their activities and active ingredients in vitro or in vivo studies, and to enlighten the public by adding optimal tariffs to their pharmacopoeia by the relevant official standard institutions.

In our study, it was also determined that 27 endemic plants were used effectively in influenza treatment and collected from nature. The unconscious collection of endemic and endangered species in the red list of the International Association for Nature Conservation (IUCN) should be more carefully monitored using laws, media and educational tools and methods, and the necessary precautions should be urgently taken. J o u r n a l P r e -p r o o f

Although the first choice for influenza control and reducing the effects of epidemics is a vaccine, it is also known that it is not the fastest and most effective option since modifications in viral proteins require annual adaptation of the influenza vaccine formulation, as noted by Nachbagauer and Palese (2020) . Considering the side effects and complications of antiviral medicines, the search for more effective remedies for fast-spreading pandemic influenza strains continues intensively all over the world today.

Due to their easy production, low cost, water-solubility, low toxicity and selective effects, medicinal plants, especially herbal essential oils and antiviral compounds found in their aqueous extracts are the most studied natural ingredients in recent times (Grienke et al., 2009) . Therefore, natural products such as traditional herbs show great promise in the development of potentially effective new antiviral drugs. Particularly, recent studies on phytochemicals, such as quercetin, chlorogenic acid, mentofin, and linalool abundantly found in many plants and vegetables, eliminate the efforts and huge costs of finding lots of antiviral vaccines that need to be renewed every year and allow us to be more optimistic about the successful management of the next influenza outbreaks. Turkey has remarkable potential for serious research on this topic due to having vast ethnomedicinal experience and the richest flora of Europe and the Middle East. This study, conducted in this regard, is the first nationwide ethnomedical screening study conducted on flu treatment with plants in Turkey. In particular, we would like to emphasize that the most common detected genus members, such as Sideritis (16 taxa; 7.1%), Salvia (12; 5.4%), Thymus (12; 5.4%), and Origanum (10; 4.5%) may be more efficient in terms of the anti-influenza targeting than other genera for the interest of the sectors that are researching new natural drug sources.

Through this study, we strongly recommend these 35 (15.6%) plants, which have proved their high antiinfluenza activities and inhibition potentials in the experimental studies, to be subject to clinical research and for widespread use in the near future. Also, with 189 (84.4%) taxa detections that have not been investigated yet, it is an important resource for both national and international pharmacological researchers. Clinical research and evaluation studies required for standard compliance for human use, starting especially with the fifteen plant taxa whose use records against both malaria and influenza were presented in this study, can be begun. With a possible mass production of one or more malaria-like drugs, a significant contribution can be provided to the indigenous people living in that region and to the national economy. Therefore, more experimental studies are urgently needed to understand the true value of these plants. Based on the data to be obtained, we believe that the future extension of anti-influenza studies, including plant taxa that are frequently used in Turkish folk medicine, would be a more effective option.

Adem, S., Eyupoglu, V., Sarfraz, I., Rasul, A., Ali, M., 2020. J o u r n a l P r e -p r o o f (2010) (2010) 

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Antiviral activity of chlorogenic acid against influenza A (H1N1/H3N2) virus and its inhibition of neuraminidase

Antiviral activity of Ribes uva-crispa L. extracts in vitro

Traditionally used wild edible greens in the Aegean Region of Turkey

Türkiye Beşeri Coğrafyası. Pegem Akademi Yayıncılık

Cytotoxic and antiviral activity of Ribes uva crispa Linn. and Ribes multiflorum Kit. ex Romer and Schultes extracts

Garlic and onions: An eastern tale

The Aromatic-Medicinal Plant Taxa of pure Scots pine stands in Sürmene-Camburnu (Trabzon)

Wild edible plants of the Bodrum Area

Buldan (Denizli) etnobotanik alan araştırması

Tıbbi ve Aromatik Bitkilerin Kullanım Alanları ve Etiği

Doğanın mucizesi şifalı bitkiler

Antiviral potential and molecular insight into neuraminidase inhibiting diarylheptanoids from Alpinia katsumadae

Influenza neuraminidase: A druggable target for natural products

Computer-guided approach to access the anti-influenza activity of licorice constituents

The current status of ethnopharmacobotanical knowledge in Çamlıdere (Ankara, Turkey)

Türkiye Bitkileri Listesi (Damarlı Bitkiler) (s. 47-83. Nezahat Gökyiğit Botanical Garden and Flora Research Association Publication

Wild medicinal plants sold in Balıkesir/Turkey herbal markets and their using properties

Medicinal plants used in the Uzunköprü district of Edirne

Survey of wild food plants for human consumption in Karaisalı (Adana-Turkey)

Folk medicine in Düzce Province (Turkey)

Wild plants used as medicinal purpose in Yalova (northwest Turkey). Turk

Descriptive study of contemporary status of the traditional knowledge on medicinal plants in Bulgaria

Ethnobotanical features of Güneysu (Rize) district

Inhibitory activity of a standardized elderberry liquid extract against clinically-relevant human respiratory bacterial pathogens and influenza A and B viruses

Antiviral substances in plants of the mint family (labiatae. I. Tannin of Melissa officinalis

Effect of quercetin on lipid peroxidation and changes in lung morphology in experimental influenza virus infection

Bartın'da Aktarlarda Satılan Tıbbi Aromatik Bitkiler ve Ülkemizdeki Pazar Payları

Influenza virology: current topics

Characterization of neuraminidase inhibitors in Korean Papaver rhoeas bee pollen contributing to anti-influenza activities in vitro

Ethnopharmacological survey of traditional drugs sold in Israel at the end of the 20th century

Intranasal co-administration of 1, 8-cineole with influenza vaccine provide cross-protection against influenza virus infection

Antiviral activity of Portulaca oleracea L. against influenza A viruses

Computational screen and experimental validation of anti-influenza effects of quercetin and chlorogenic acid from traditional Chinese medicine

Evaluation of compounds from oregano (Origanum vulgare) that inactivate the influenza virus in host animals

Kozmik Bilim Işığında Şifalı Bitkiler

In Vivo Anti-Viral Effect of Melaleuca alternifolia (Tea Tree Oil) and Olea europaea (Olive Leaf Extract) on Vero Cell Adapted Avian Influenza Virus

Ethnobotanical study on traditional uses of wild medicinal plants in Prokletije Mountains (Montenegro)

Successful recovery of COVID-19 pneumonia in a patient from Colombia after receiving chloroquine and clarithromycin

In vitro anti influenza virus activity, antioxidant potential and total phenolic content of twelve Iranian medicinal plants

Pomegranate peel extract inhibits internalization and replication of the influenza virus: An in vitro study

Medical ethnobotany of the Albanian Alps in Kosovo

A cross-cultural comparison of folk plant uses among Albanians, Bosniaks, Gorani and Turks living in south Kosovo

Kumluca (Antalya)'da etnobotanik bir çalışma

Is a universal influenza virus vaccine possible?

The effect of the hexanic extracts of fig (Ficus carica) and olive (Olea europaea) fruit and nanoparticles of selenium on the immunogenicity of the inactivated avian influenza virus subtype H9N2

Ethnobotanical study of medicinal plants of Sirjan in Kerman Province

Probing the effect of quercetin 3-glucoside from Dianthus superbus L against influenza virus infection-In vitro and in silico biochemical and toxicological screening

Ethnobotanical characteristics of Arıcak (Elazığ)

Antiviral activity and cytotoxicity of the lipophilic extracts of various edible plants and their fatty acids

Chapter 5: Plant diversity of the Drylands in Southeast Anatolia-Turkey: role in human health and food security

Centre for Science Technology of the Non-aligned and other Developing Countries

Determination of antiviral activity and cytotoxicity of selected sage (Salvia L.) species

Burdur ili bitki envanteri (ekonomik, nadir ve endemik bitkileri). Sistem Ofset

Sağlıklı bir yaşamdır yabancı otlar: Türk mutfak kültürü üzerine araştırmalar

Osmanlı Ağaç Kültüründe Yeni Ve Egzotik Bir Tür: Okaliptüs. Çağdaş Türkiye Tarihi Araştırmaları Dergisi

Ethnomedicinal uses of the wild vascular plants from European Turkey (Turkish Thrace)

Ethnopharmacological survey of medicinal plants in Ulukışla (Niğde-Turkey)

Local knowledge of medicinal plants and wild food plants among Tatars and Romanians in Dobruja

Traditional uses of medicinal plants in Solhan (Bingöl-Turkey)

Ethnobotanical study on medicinal plants in Bingöl (City center) (Turkey)

Antiviral activity of the oseltamivir and Melissa officinalis L. essential oil against avian influenza A virus (H9N2

Anti-influenza A virus effect of Hypericum perforatum L. extract

Identification of Traditional Medicinal Plant Extracts with Novel Anti-Influenza Activity

Docking and molecular dynamics: simulation of the inhibition of H5N1 influenza virus

Traditional medicinal plant knowledge among Albanians, Macedonians and Gorani in the Sharr Mountains (Republic of Macedonia)

Study on the effect of anti-influenza virus of the volatile oil of Schizonepetae, menthone and pulegone

Oil-in-water emulsion formulated with eucalyptus leaves extract inhibit influenza virus binding and replication in vitro

An ethnobotanical survey from Yahyalı (Kayseri) and Tarsus (Mersin)

Doğanın şifalı eli

Tıbbi bitkiler ve bitkisel sağlık rehberi. Gün Ofset

An ethnobotanical study of medicinal plants used by the local people of Alaşehir (Manisa) in Turkey

Ethnobotanical survey of medicinal plants in Bozyazı district of Mersin

Ethnomedicinal plants of Sarigöl district (Manisa), Turkey

Ethnomedicinal plants of Aydıncık District of Mersin

Plants used in ethnomedicinal practices in Gulnar district of Mersin

Medical ethnobotany on the Javor Mountain (Bosnia and Herzegovina)

Interfering with lipid raft association: A mechanism to control influenza virus infection by Sambucus nigra

Antiviral activity of carnosic acid against respiratory syncytial virus

Synthesis and in vitro study of novel borneol derivatives as potent inhibitors of the influenza A virus

Silymarin efficacy against influenza A virus replication

In vitro antioxidant, antimicrobial, and antiviral activities of the essential oil and various extracts from herbal parts and callus cultures of Origanum acutidens

Ethnobotanical Researches in the Southern Districts of Nevşehir

Farmasötik botanik

Traditional uses of some medicinal plants in Malatya (Turkey)

Of chloroquine and COVID-19

Antiviral effect of an essential oil combination derived from three aromatic plants (Coridothymus capitatus (L.) Rchb. f., Origanum dictamnus L. and Salvia fruticosa Mill.) against viruses causing infections of the upper respiratory tract

Turkish folk medicinal plants. Part II: Eğirdir (Isparta)

Turkish folk medicinal plants, IX: Ovacık (Tunceli)

The investigation and quantitative ethnobotanical evaluation of medicinal plants used around Izmir province, Turkey

Protective and antiviral activities of Nigella sativa against avian influenza (H9N2) in turkeys

Ethnobotanical research of medicinal plants in Mihalgazi (Eskişehir)

The carbohydrate-binding plant lectins and the non-peptidic antibiotic pradimicin A target the glycans of the coronavirus envelope glycoproteins

The first contribution to the ethnobotany of inland Dalmatia: medicinal and wild food plants of the Knin area

The COVID-19 epidemic

Antiviral activity of medicinal plants of Nilgiris

Anti-Influenza virus activities of commercial oregano oils and their carriers

Anti-influenza virus activity of essential oils and vapors

Anti-influenza agents from plants and traditional Chinese medicine

Influenza virus-host interactomes as a basis for antiviral drug development

Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry

İyileştiren bitkiler

An ethnobotanical survey in selected districts of the Black Sea region (Turkey)

Plants used as folk medicine in some settlements of the Marmara Region

Ethnobotanical features of Datça Peninsula (Muğla)

Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama

Eaten raw, Infusion, Decoction, Jam, Marmalate Tuzlacı and Erol (1999) , Saraç (2005) , Koçyiğit and Özhatay (2006) , Özhatay et al. (2009 Özhatay et al. ( ), Ugulu et al. (2009 

J o u r n a l P r e -p r o o f (2017) 13 5.8 Black sea Ozturk et al. (2017a) 13 5.8 Southeastern Anatolia Sargin and Büyükcengiz (2019) 13 5.8 Mediterranean Tuzlacı and Doğan (2010) 13 5.8 Eastern Anatolia Tuzlacı and Erol (1999) 13 5.8 Mediterranean Ertuğ (2004) 11 4.9 Aegean Güneş and Özhatay (2011) 11 4.9 Eastern Anatolia Kılıç (2016) 11 4.9 Eastern Anatolia Kilic and Bagci (2013) 11 4.9 Eastern Anatolia Guzel and Guzelsemme (2018) 10 4.5 Mediterranean Ozturk et al. (2017b) 10 4.5 Mediterranean Saraç (2005) 10 4.5 All Regions Tetik et al. (2013) 10 4.5 Eastern Anatolia Yeşilyurt et al. (2017b) 10 4.5 Marmara Akgül et al. (2016) 9 4.0 Central Anatolia Bulut et al. (2017a) 9 4.0 Aegean Cansaran and Kaya (2010) 9 4.0 Black sea Güner and Selvi (2016) 9 4.0 Marmara Nacakcı and Dutkuner (2015) 9 4.0 Mediterranean Özçelik ( (2010), Güneş and Özhatay (2011) , İşler (2017) Lamiaceae (2010) 

Alcea rosea L. Not specified ( Kim and Chung (2018) Nigella sativa L. Not specified (Seeds) Enhance immune responsiveness and suppress pathogenicity of influenza viruses in turkeys Umar et al. (2016) Olea europaea L. Not specified (Leaves) Blokes the receptor site of the viruses Mehmood et al. (2018) Olea europaea L. Carvacrol (Essential oil) Shows significant antiviral activity. Olive oil was included in formulations to ameliorate its potential cytotoxic effects. Vimalanathan and Hudson (2012) J o u r n a l P r e -p r o o f Sambucus nigra L. Not specified (Fruits) Exhibit a specific neuraminidase-inhibiting effect Krawitz et al. (2011) Silybum marianum (L.) Gaertn.Silymarin (Seeds) Reduces cytopathic effect (CPE) and inhibits viral mRNA synthesis with no cytotoxicity Song and Choi (2011) Thymbra capitata (L.) Cav. Carvacrol (Essential oil) Shows significant antiviral activity. Olive oil was included in formulations to ameliorate its potential cytotoxic effects. Vimalanathan and Hudson (2012) Thymbra capitata (L.) Cav. Apigenin, Thymol (Aerial parts-Essential oil)Both in influenza A/H1N1 and HRV14, replication cycle and progeny virus production were significantly decreased after the treatment with CAPeo (An essential oil combination based on three aromatic plants ( Cota tinctoria (L.) J.Gay* Not specified (Aerial parts) No correlation was found between antiviral activity and fatty acid contents of the extracts. Orhan et al. (2009) Ficus carica L.* Not specified (Fruits) The results indicated that the prepared emulsions could elicit a little degree of immunity, but they could not inhibit the anamnestic response and infection. Najjari et al. (2015) Olea europaea L. * Not specified (Fruits) The results indicated that the prepared emulsions could elicit a little degree of immunity, but they could not inhibit the anamnestic response and infection. Najjari et al. (2015) Origanum acutidens (Hand.-Mazz.) Ietsw. *

None of the extracts inhibited the reproduction of influenza A/Aichi virus in MDCK cells Sökmen et al. (2004) Rosmarinus officinalis L. * Carnosic acid (Aerial parts) Inhibit both A-and B-type hRSV, while it does not affect the replication of influenza A virus Shin et al. (2013) Teucrium polium L.* Not specified (Aerial parts) No significant effects on influenza virus infectivity Derakhshan (2015) * The taxa that have no significant result for virus inactivation.J o u r n a l P r e -p r o o f