Saturday, 21 October 2017
Traditional wound-healing plants used in the Balkan region (Southeast Europe)
Journal of Ethnopharmacology Volume 211, 30 January 2018, Pages 311-328 Journal of Ethnopharmacology Author links open overlay panelSnežanaJarićOlgaKostićZoranaMatarugaDraganaPavlovićMarijaPavlovićMiroslavaMitrovićPavlePavlović https://doi.org/10.1016/j.jep.2017.09.018 Get rights and content Abstract Ethnopharmacological relevance The geographical and ecological specificity of the Balkan Peninsula has resulted in the development of a distinct diversity of medicinal plants. In the traditional culture of the Balkan peoples, plants have medicinal, economic and anthropological/cultural importance, which is reflected in the sound knowledge of their diversity and use. This study analyses the traditional use of medicinal plants in the treatment of wounds and the pharmacological characteristics of the most frequently used species. Materials and methods A detailed analysis of the literature related to ethnobhe uses of medicinal plants in the Balkan region was carried out. Twenty-five studies were analysed and those plants used for the treatment of wounds were singled out. Result An ethnobotanical analysis showed that 128 plant species (105 wild, 22 cultivated and 1 wild/cultivated) are used in the treatment of wounds. Their application is external, in the form of infusions, decoctions, tinctures, syrups, oils, ointments, and balms, or direct to the skin. Among those plants recorded, the most commonly used are Plantago major, Hypericum perforatum, Plantago lanceolata, Achillea millefolium, Calendula officinalis, Sambucus nigra, Tussilago farfara and Prunus domestica. The study showed that the traditional use of plants in wound healing is confirmed by in vitro and/or in vivo studies for P. major and P. lanceolata (3 laboratory studies for P. major and 2 for P. lanceolata), H. perforatum (5 laboratory studies and 3 clinical trials), A. millefolium (3 laboratory studies and one clinical trial), C. officinalis (6 laboratory studies and 1 clinical trial), S. nigra (3 laboratory studies) and T. farfara (one laboratory study). Conclusion The beneficial effects of using medicinal plants from the Balkan region to heal wounds according to traditional practices have been proven in many scientific studies. However, information on the quantitative benefits to human health of using herbal medicines to heal wounds is still scarce or fragmented, hindering a proper evaluation. Therefore, further studies should be aimed at isolating and identifying specific active substances from plant extracts, which could also reveal compounds with more valuable therapeutic properties. Furthermore, additional reliable clinical trials are needed to confirm those experiences encountered when using traditional medicines. A combination of traditional and modern knowledge could result in new wound-healing drugs with a significant reduction in unwanted side effects. Graphical abstract fx1 Download high-res image (413KB)Download full-size image Keywords Wound-healing Medicinal plants Balkan Peninsula Pharmacological characteristics 1. Introduction The existence of traditional medicine depends fundamentally on plant species diversity and the related knowledge of their use as herbal drugs. Out of an estimated 250,000 flowering plant species globally, between 50,000 and 70,000 are known to be used in traditional and modern medicine across the world (Leaman, 2006). Of all the plant species worldwide, 15% have been evaluated phytochemically and only 6% have been screened for biological activity (Verpoorte, 2000). In the Balkan region, no data is available on the total number of medicinal plant species; however, there is data for particular countries: Serbian ethnomedicine today has knowledge of approximately 700 species, 420 of which are officially registered, and about 270 are available to buy (Kišgeci and Sekulović, 2000); in Bulgarian flora there are 768 medicinal plants and 764 are of indigenous or adventive origin (Gussev, 2005); in Romania, out of more than 3600 species of higher plants, over 700 are medicinal plants (Parvu, 2002; Tudor and Minoiu, 2004); in Montenegro there are around 700 medicinal plants, approximately 300 of which are used in traditional medicine as well as in the pharmaceutical industry (Pulević, 1965; Pulević, 1980); in Bosnia and Herzegovina there are 221 medicinal plants used for ethnopharmacological purposes (Redžić et al., 2007). For other countries in the region no complete data is available. Medicinal plants are important sources of chemical substances that have beneficial therapeutic effects on human health, and plant-based systems continue to play an essential role in the primary healthcare of almost 65% of the world's population (Farnsworth et al., 1985) and 80% of the people in the world's underdeveloped and developing countries (Maver et al., 2015). In less wealthy rural areas or during times of economic crises, medicinal plants are relied upon as home remedies for health problems (Leonti, 2011). The ethnomedicinal use of plants in the treatment of wounds (in the form of teas, decoctions, tinctures, syrups, oils, ointments, poultices, and infusions) is not only cheap and accessible, but provides a reliable natural resource of medicinal substances. Studies on medicinal plants have confirmed that herbal drugs exhibit fewer side effects in comparison to chemical agents, and are more cost-effective (Kumar et al., 2007; Rhoads et al., 2012). As medicinal plants provide this important resource of substances with beneficial therapeutic effects, they have been the subject of extensive research in the area of wound healing management (Nagori and Solanki, 2011, Kumar et al., 2013). Just 1–3% of chemicals listed in Western pharmacopoeia are indicated for the treatment of wounds and skin disease, while more than 30% of herbal medicaments are considered beneficial (Kumar et al., 2007; Rhoads et al., 2012). In recent times, pharmacological reports justify the traditional use of certain species of medicinal plants in the treatment of wounds (Gupta and Jain, 2010; Nagori and Solanki, 2011; Raina et al., 2008; Ajose, 2007). Many phytopharmaceutical laboratories are now concentrating their efforts on identifying the active constituents and models of action of various medicinal plants (Hwang et al., 2000) and a number of herbal products are being investigated at present to this effect, too. While current therapeutic agents have generally inadequate efficacy and a number of serious adverse effects, medicinal plants have been used in medicine since ancient times and are well known for their ability to promote wound healing and prevent infection without any grave side effects. Thus, herbal therapy may be an alternative strategy for the treatment of numerous health issues including wounds (Budovsky et al., 2015). Therefore, more recently scientists have been increasingly relying on modern scientific methods and evidence-based medicine to prove the efficacy of herbal medicines and focusing on a better understanding of the mechanisms of their actions. However, information concerning the quantitative human health benefits of herbal medicines is still rare or fragmented, hindering a proper evaluation. In this regard, this study provides an overview of ethnobotanical research into the use of wild and cultivated medicinal plants in the treatment of wounds in rural areas of the Balkan Peninsula. The plant parts used, as well as their preparation and administration, are noted. Special attention is given to the most commonly used species and the key laboratory experiments as well as clinical trials proving the efficacy of using herbal medicines in the healing of wounds. 2. The Balkan Peninsula as a centre of diversity of medicinal plants The Balkan Peninsula (the Balkans) lies in the south-eastern part of Europe between 35°46′53″N and 13°23′30″E and is surrounded by the Adriatic, Ionian, Aegean, Marmara and Black Seas. Its area is approximately 505,578 km2 and geopolitically it comprises the countries: Albania, Bosnia and Herzegovina, Bulgaria, Macedonia, Montenegro, Greece, Serbia, the European part of Turkey, Croatia, Slovenia and Romania (Fig. 1). Fig. 1 Download high-res image (1MB)Download full-size image Fig. 1. Map of the Balkan Peninsula. It is inhabited by around 50 million people (Grčić et al., 2013). Historically, it represents the crossroads between ancient European and Asian cultures, which has resulted in the presence of different ethnic and religious communities. Due to political turmoil in the past, many areas of the Balkan Peninsula have been subjected to political and economic changes that have heavily influenced local lifestyles, economies, food, connection to nature, and consequently, the passing on of traditional knowledge of health and local complementary and alternative medical practices. The Balkan Peninsula is one of 25 ‘hot spots’ of plant biodiversity and is home to between 7000 and 8000 species of vascular plants (Stevanović et al., 1995), around 30% of which are endemic. The extraordinary diversity and endemism of the flora has mostly been shaped by the age of the Balkan landmass and its specific geographical position, as well as the diversity of climatic influences, geological composition, and orographic factors, which brought about the genetic isolation of populations and prompted their speciation. The existing ecological distinctiveness of the different parts of the Balkans has resulted in the development of specific genetic potential in certain plant species to produce active ingredients, making the area a centre of diversity of medicinal flora found in different ecosystems and on different geological substrates and soils. Phytogeographical and ecological characteristics, as well as the demographic and ethnic structure of the Balkans, certainly had a role in the development and knowledge of ethnobotany and ethnomedicine, especially in rural areas. Traditional knowledge of plants for medicinal uses in rural areas has significant potential and demonstrates the links between plants and local people. With this in mind, ethnobotanical research into medicinal plants was carried out in some rural regions of the Balkans, with descriptions of their use and importance to the local population. There are many reasons for this type of study: 1) this mountainous region is a hotspot for both bio- and cultural/ethnic diversities; 2) historically, the area has provided botanical materials to the western European herbal market (especially in the last few centuries); 3) most dried medicinal plants and an impressive number of locally gathered plants are still widely used in local healthcare; 4) many economic initiatives and programmes devoted to rural development are based on medicinal plants (Quave et al., 2012). For most of the peoples living in the Balkans, medicinal plants have therapeutic, commercial and anthropological cultural significance and are a symbol of good health. The reasons for the specific uses of plants for numerous health problems and diseases have gradually come to light over time, so their use has gradually emerged from an empirical framework to being based on explainable facts (Parojčić and Stupar, 2003; Jarić et al., 2014). 3. Background to wound healing Wounds are any disruption to the normal anatomic structure of tissue which leads to the loss of epithelial continuity with or without a loss of underlying connective tissue, as well as the anatomic and functional integrity of the living tissue (Lazarus et al., 1994; Ramzi et al., 1994; Strodtbeck, 2001). There are various types of wounds, including incised wounds, lacerated wounds, abrasions, contusions, ulcers, and burn wounds (Leaper and Gottrup, 1998). Wound healing is a complex process which comprises three phases: inflammation, proliferation and maturation, and involves the well-organised and highly complex interaction of different tissues and cells with successive stages overlapping (Sidhu et al., 1999). The inflammatory phase starts as soon as injury occurs, with initial vasoconstriction allowing homeostasis and then inflammation mediators are released. Proliferation follows with the wound being rebuilt with new granulation tissue formed mostly by fibroblast and a new network of blood cells develop through the process of angiogenesis. Maturation involves remodelling and an improvement in collagen fibre components, leading to an increase in tensile strength (Mandelbaum et al., 2003). Parallel to this, scar formation occurs along with the accumulation of fibrous tissue at the edges of the wound, which eventually merges with surrounding tissue. However, there are numerous factors that lead to a delay in the healing of wounds, such as contaminated infective microorganisms, nutritional deficiency, interrupted blood supply and the improper movement of the disturbed body parts (Jyoti and Sharma, 2006). Synthetic agents and natural wound healing agents act to accelerate and achieve the healing of wounds (Sairam et al., 2001). Research into bio-active substances from plants has shown that they exhibit exceptional advantages in terms of fast healing (Rao et al., 2000). These bioactive phytochemical constituents include various chemical families, such as alkaloids, essential oils, flavonoids, tannins, terpenoids, saponins and phenolic compounds (Edeoga et al., 2005), which demonstrate a wide range of activities: anti-inflammatory, antibacterial, antimicrobial, and anti-oxidative. Antioxidants play a determining role in the progression of wound healing (Martin, 1996; Süntar et al., 2012), while anti-inflammatory agents also have a key role in the wound healing process and prevent the exacerbation of the severity of the wound (Sen and Roy, 2008). Antimicrobial agents are also useful in the management of microbial infection, which may concomitantly occur in severe and chronic wounds (Rhoads et al., 2012). A wide variety of bioactive constituents of different structures lies behind the therapeutic activity of medicinal plants: polyphenols (flavonoids, phenolic acids, lignans, tannins, stilbenes, and coumarins), terpenes, sulphur-containing compounds (sulphides and glucosinolates), carotenoids, saponins, furils, alkaloids, polyines, thiophenes, different sugars, fatty oils, resins, phytosterols, proteins, peptides, etc. (Sharma et al., 1990; Rostugno and Prado, 2013). In particular, the review by Ghosh and Gaba (2013) analysed the wound healing properties of several plant compounds, including flavonoids, quinones, phenolic acids, phenyl propanoids, terpenoids, tannins, and sugars, showing that the main effects of these active plant compounds were related to their anti-microbial activity, antioxidant properties and their ability to enhance cell proliferation, collagen production, and DNA synthesis. Tannins, for example, promote wound healing through several cellular mechanisms, including scavenging of free radicals and reactive oxygen species, promoting the contraction of the wound and angiogenesis (Fleischner, 1985; Fernandez et al., 2002; Deters et al., 2001; Soni and Singhai, 2012). Thanks to their astringent and antibacterial properties, tannins can be used as a medicament in the treatment of skin ulcers and wounds (Aelenei et al., 2009, de Sousa Leal et al., 2015). Similarly, tannic acids demonstrate antimicrobial activity against pathogens, as has been shown in previous research (Chung et al., 1998; Scalbert, 1991). Terpenoids, triterpenoids and flavonoids are also known to promote the wound-healing process (Tsuchiya et al., 1996). Terpenoids encourage this process, mainly due to their astringent and antimicrobial activity, which seems to be responsible for wound contraction and an increased rate of epithelialisation (Scortichini and Rossi, 1991). Flavonoids also possess potent antioxidant and free radical-scavenging properties and increase levels of antioxidant enzymes in granuloma tissue (Shenoy et al., 2009; Thakur et al., 2011). Their role in the healing of wounds is based on their ability to reduce lipid peroxidation not only by preventing or slowing the onset of cell necrosis, but also by improving vascularity (Getie et al., 2002; Manjunatha et al., 2005). Namely, any drug that inhibits lipid peroxidation is believed to increase the viability of collagen fibres by increasing their strength, increasing circulation, preventing cell damage and by promoting DNA synthesis (Shobha and Gurumadhva, 1999). Similarly, sterols and polyphenols are also responsible for wound healing for similar reasons (Baravkar et al., 2008; Soni and Singhai, 2012; Fleischner, 1985; Padmaja et al., 1994). According to Budovsky et al. (2015), in terms of plant phytochemicals, the activity of alkaloids, flavonoids, terpenes, and glycosides in promoting wound healing has been better researched than other bioactive plant constituents. The goals of wound care include reducing risk factors that inhibit wound healing, enhancing the healing process, and lowering the incidence of infection. 4. The use of medicinal plants in traditional wound healing in the Balkan region The tradition of using medicinal plants in treating people in the Balkan region dates back many centuries and has continued uninterrupted ever since. The pharmacological manuscripts of the Chilandar Medical Codex (CMC), one of the oldest written document in the Balkans, dating from the 15th and 16th centuries, testifies to this (Jarić et al., 2011). Of the 135 plant species mentioned in the CMC, 12 were used for treating wounds, with Aristolochia sp., Artemisia absinthium, Juglans regia, Malus communis, Olea europaea, Rosa canina and Salvia officinalis still used today, mainly in rural areas of the Balkans (Table 1). Table 1. Traditional uses of medicinal plants in wound healing on the Balkan Peninsula. Botanical taxa Family Common name CS/WS Used plant part (s) Form of preparation Country References Abies alba Mill. Pinaceae Silver fir w Re Balm; topically applied to wounds, sometimes together with tobacco (as a hemostatic) or on warts; Albania, Bosnia and Herzegovina, Macedonia; 1; 2; 3; Achillea collina s.l. Becker ex Rchb.pl Asteraceae Mountain yarrow W Ap, Le Decoction for cervical wounds and for cicatrizing on wounds; Bosnia and Herzegovina,Albania; 4; 5; Achillea collina s.l. Becker ex Rchb. × Achillea nobilis L. Asteraceae Yarrow W Ap, Le Decoction for cervical wounds; Bosnia and Herzegovina; 4; Achillea miollefolium L. Asteraceae Yarrow w Ap (fresh or dried), Le (fresh) Tincture; tea; cataplasm from the leaves; directly to wound as a hemostyptic powder for haemorrhoids; Kosovo, Serbia, Macedonia, Bosnia and Herzegovina; 2; 6; 7; 8; 9; 10; 11; Agrimonia eupatoria L. Rosaceae Church steeples w Ap, Le Leaf directly on wounds and cuts; infusion; Bosnia and Herzegovina, Serbia; 4; 10; Ajuga reptans L. Lamiaceae Bugle w Ap Infusion for rinsing; Bosnia and Herzegovina, 2; Alchemilla vulgaris L. Rosaceae Lady's mantle w Ap, WhPl Tea; Bosnia and Herzegovina, Serbia; 4; 11; Allium cepa L. Amaryllidaceae Onion c B Heated and externally applied as a poultice; Albania, Kosovo, Romania (south-east); 12; 13; 14; Alnus glutinosa (L.) Gaertn. Betulaceae Black alder w Le Leaves (extracted with cold water) - disinfectant on wounds; Kosovo 7: Aloe vera (L.) Burm. f. Aloeaceae Aloe c LeGl Directly on wounds; Romania (south-east); 13; Anagallis arvensis L. Primulaceae Scarlet pimpernel w Ap Decoction (for inflamed wounds); Bulgaria; 15; Angelica archangelica L. Apiaceae Garden angelica W Ro Infusion; Bosnia and Herzegovina; 4; Anthyllis vulneraria L. Fabaceae Kidney vetch w Fl Tea; for rinsing; Montenegro, Bosnia and Herzegovina; 2; 16; Arctium lappa L. Asteraceae Greater burdock W Le Boiled in milk; directly on wounds (powder); Bosnia and Herzegovina, Serbia, Kosovo; 4; 7; 10; Arctium tomentosum Mill. Asteraceae Woolly burdock W Le The same as A. lappa; Bosnia and Herzegovina; 4; 17; Aristolochia clematitis L. Aristolochiaceae Birthwort w Ap, Ro Decoction (infected wounds and ulcers; inflamed wounds (vulnerary)); tea (for rinsing and poultice); Serbia, Bulgaria, Kosovo; 7; 10; 15; Arnica montana L. Asteraceae Mountain arnica w Fl Tea; tincture; Bosnia and Herzegovina; 4; Artemisia absinthium L. Asteraceae Wormwood w Ap Decoction (mixed with honey) for wound healing); tea (washes - wound disinfectant); Romania (south-east), Albania; 12; 13; Astrantia major L. Apiaceae Great masterwort w Ap Infusion; Montenegro; 16; Bellis perennisL. Asteraceae Lawn daisy w Ap Infusion (vulnerary); Bulgaria, Montenegro; 15; 16; Calamintha officinalis L. Lamiaceae Calamint w Ap Infusion (poultice); Montenegro; 16; Calendula arvensis L. Asteraceae Field marigold w Fl, Le Infusion; oil; ointment; Bosnia and Herzegovina; 4; Calendula officinalis L. Asteraceae Pot marigold c Ap, Fl Oil; ointment; Bulgaria, Serbia, Bosnia and Herzegovina; Kosovo; 4; 10; 14; 15; 18; Capsella bursa-pastoris (L.) Medik. Brassicaceae Shepherd's purse w Ap Tincture; hemostatic compress; Bosnia and Herzegovina; Bulgaria, Serbia, Montenegro; 4; 10; 16; 18; Carlina acaulis L. Asteraceae Carline thistle w Ro Gruel made from the powdered root directly on wounds; infusion for rinsing wounds and ulcers; Serbia, Montenegro; 10; 16; Chamomilla recutita (L.) Rauschert Asteraceae Chamomile w Fl Infusion; Kosovo; 14; Chelidonium majus L. Papaveraceae Celandine w La Latex together with plum rakiafor treating wounds; Macedonia, Croatia; 9; 19; Chenopodium bonus-henricus L. Chenopodiaceae Good king henry w Ro Infusion (as a cicatrizing agent); Bulgaria; 15; Chenopodium urbicum L. Chenopodiaceae City goosefoot w Le Directly to wounds (used to heal external haemorrhoids); Macedonia; 9; Clematis vitalba L. Ranunculaceae Evergreen clematis w Le Directly to wounds; Macedonia; 9; Cotinus coggygria Scop. Anacardiaceae Smoketree w Le Compress of fresh leaves or decoction (for wounds with pus that wouldn't skin over); Bulgaria; 18; Cydonia oblonga L. Rosaceae Quince c Fr Compress (fermented and distilled fruits); Romania (south-east); 13; Equisetum arvensis L. Equisetaceae Common horsetail W Ap (fresh or dried) Infusion (rinsing the wound and as a compress); aerial part (dried)directly to wounds as a hemostatic; Bosnia and Herzegovina, Macedonia, Montenegro; 4; 9; 16; Equisetum telmateia Ehrh. Equisetaceae Great horsetail W Ap Infusion; Bosnia and Herzegovina; 4; Frangula alnus Mill. Rhamnaceae Glossy buckthorn w Bk Tea (for rinsing cervical wounds); Bosnia and Herzegovina; 17; Fraxinus angustifolia Vahl Oleaceae Narrowleaf ash w Le Directly to wounds; Macedonia; 9; Galium verum L. Rubiaceae Ladies’ bedstraw w Ap Tea (as an astringent and for poorly healing wounds); Serbia, Montenegro; 10; 16; Geranium robertianum L. Geraniaceae Robert geranium w Ap Tea (for poorly healing wounds); Montenegro; 16; Hedera helix L. Araliaceae Common ivy W Le Juice from fresh leaves directly onto wounds or as a compress; Bosnia and Herzegovina; Serbia; 4; 10; Helianthus tuberosus L. Asteraceae Jerusalem artichoke c Tb Compress (boiled in milk); Kosovo; 6; Hieracium pilosella L. Asteraceae Mouse-ear hawkweed w Ap Tea (for rinsing); Montenegro; 16; Hypericum maculatum Crantz. Hypericaceae Dotted St. John's-wort w Ap, Fl Dried and ground, and applied with salt and tobacco leaves to heal wounds; oil; Montenegro, Albania; 16; 20; Hypericum montanum L. Hypericaceae Pale St John's wort W Ap, Fl Oil; Bosnia and Herzegovina; Serbia; 4; 21; Hypericum perforatum L. Hypericaceae St John's wort W Ap, Fl Oil; infusion; Bosnia and Herzegovina; Albania, Serbia, Macedonia, Montenegro; Greece (north-western), Kosovo; 1; 3; 4; 7; 8; 9;10; 11; 14; 16; 22; 23; Hypericum tetrapterum Fr. Hypericaceae St. Peter's wort W Ap, Fl Oil (for cervical wounds); Bosnia and Herzegovina; 4; Juglans regia L. Juglandaceae Walnut c/w Fr, Le Tea (for rinsing); directly application of leaf on wounds; Macedonia, Serbia; 9; 11; Larix decidua Mill. Pinaceae European larch W Ne, Bk Compress; Bosnia and Herzegovina; 4; Lycopersicon esculentum Mill. Solanaceae Tomato c Fr Beaked fruits mixed with sugar topically applied on infected wounds; Kosovo; 7; Malus domestica Borkh. Rosaceae Apple tree c Fr Fermented and distilled “rakia” (for rinsing; compress); Romania (south-east) 13; Malus sylvestris Mill. Rosaceae Wild apple w Le Compress (applied topically on infected wounds); Kosovo, Croatia; 7; 19; Malva sylvestris L. Malvaceae Mallow w Ap Balm (extracted with fat); Albania, Kosovo, Serbia; 1; 11; 14; Matricaria chamomilla L. Asteraceae Chamomile w Fl Tea (for rinsing; compress); Montenegro; 16; Matricaria discoidea DC. Asteraceae Pineappleweed W Fl Tea (for rinsing; compress); Bosnia and Herzegovina; 4; Matricaria recutita L. Asteraceae German chamomile w Ap (dried) Decoction (applied directly: ulcers of the skin and soft tissues); Macedonia; 9; Melissa officinalis L. Lamiaceae Lemon balm w Ap (fresh) Directly applied (for suppurative wounds); Albania; 1; Momordica charantia L. Cucurbitaceae Bitter melon c Fr Mixed with oil (vulnerary for burn wounds); Kosovo; 14; Nepeta nuda L. Lamiaceae Hairless catmint w Ap Decoction; Bulgaria; 18; Nicotiana tabacum L. Solanaceae Tobacco c Le (dried) External application (hemostatic; cicatrizing); Albania, Romania (south-east); 1; 5; 13; Olea europea L. Oleaceae Olive c Fr Oil (cervical wounds); Bosnia and Herzegovina; 4; Orchis morio L. Orchidaceae Green-winged orchid w Tu Infusion (cleaning wounds); Montenegro, Kosovo; 14; 16; Phaseolus vulgaris L. Fabaceae String bean c Se Used as a compress with boiled bran (to treat bruises); half-beans are applied on the skin affected by a dog bite; when the beans fall off the wound has healed; Albania; 5; 24; Picea abies (L.) H. Karst. Pinaceae Norway spruce w Re, Wo (for immobilization) Balm; wood or four small pieces of wood, externally applied in splints; Serbia, Macedonia; 3; 21; Pinus heldreichii Christ Pinaceae Bosnian pine w Re Traditional balm; Bosnia and Herzegovina; 2; Pinus mugo Turra Pinaceae Creeping pine w Re Traditional balm; Bosnia and Herzegovina; 2; Pinus nigra J.F.Arnold Pinaceae Black pine w Re Traditional balm; Bosnia and Herzegovina; 2; Pinus silvestrisL. Pinaceae Scotch pine w Re Traditional balm; Bosnia and Herzegovina; 2; Pinus sp. Pinaceae Pine w Re Warmed resin is applied directly; Albania 1; Plantago lanceolata L. Plantaginaceae Ribwort plantain w Le, Ap (dried) Directly to the wound; Bosnia and Herzegovina, Kosovo, Macedonia, Serbia, Albania, Greece (north-western); 2; 4; 5; 7; 9; 10; 11; 23; Plantago major L. Plantaginaceae Common plantain w Le, Ap (dried) Fresh leaves (compress) or infusion directly on wounds; Bosnia and Herzegovina, Kosovo, Albania, Serbia, Bulgaria, Macedonia, Romania (south-east); 1; 2; 4; 7; 8; 9; 10; 13; 14; 18; 20; 21; 22; Plantago media L. Plantaginaceae Hoary plantain w Le The same as P. major; Bosnia and Herzegovina, Serbia; 2; 4; 10; 22; Populus alba L. Salicaceae White poplar w Ap, Lb Ointment; Kosovo; 14; Primula veris L. Primulaceae w Ap Infusium (for rinsing); Montenegro; 16; Polygonatum officinale All. Liliaceae Sweet-scented Solomon's Seal w Rh Ointment: for joint inflammation, festering wounds and ulcers, ingrown toenails; ointment (fresh ground rhizome used for ointment preparation, applied to sore area; Serbia; 10; Polygonum bistorta L. Polygonaceae Bistort w Rh Tea prepared and applied as a compress for festering wounds; Serbia; 10; Potentilla erecta (L.) Raeusch. Rosaceae Tormentil w Rh Tea (for rinsing and poorly healing wounds); Serbia, Montenegro, Bosnia and Herzegovina; 2; 10; 16; Prunella vulgaris L. Lamiaceae Common selfheal W Ap, Le Tea; Bosnia and Herzegovina; 4; Prunus armeniaca L. Rosaceae Apricot c Fr Rakia (fermented and distilled fruits - for rinsing and as a compress) Romania (south-east); 13; Prunus cerasifera Ehrh. Rosaceae Cherry-plums w Fr The same as P. armeniaca; Albania, Romania (south-east); 13; 20; Prunus cerasus L. Rosaceae Sour cherry c Re Balm (resin mixed with butter or cream; compress) Serbia; 21; Prunus domestica L. Rosaceae Plum and mirabelle c Fr (unripe fruit) The same as P. armeniaca; Albania, Serbia, Macedonia, Romania (south-east); 1; 3; 5; 13; 21; Prunus persica (L.) Batsch Rosaceae Peach tree c Fr The same as P. armeniaca; Romania (south-east); 13; Pteridium aquilinum (L.) Kuhn. Dennstaedtiaceae Brake w Le Extracted with oil (compress); Kosovo; 14; Pulmonaria officinalis L. Boraginaceae Lungwort w Le, Ap Infusion, decoction; Bosnia and Herzegovina; 2; Pyrus communis L. Rosaceae Pear tree c Fr The same as P. armeniaca; Serbia, Romania (south-east); 13; 21; Quercus cerris L. Fagaceae Turkey oak w Bk Ointment; Bosnia and Herzegovina; 17; Quercus petraea (Mattuschka) Liebl. Fagaceae Sessile oak w Bk The same as Q. cerris; Bosnia and Herzegovina; 17; Quercus pubescens Willd. Fagaceae Downy oak w Bk The same as Q. cerris; Bosnia and Herzegovina; 17; Quercus robur L. Fagaceae English oak w Bk The same as Q. cerris; Bosnia and Herzegovina; 17; Rhamnus cathartica L. Rhamnaceae Buckthorn w Fr Infusion (antiseptic for wounds); Bulgaria; 25; Rhamnus fallax L. Rhamnaceae w Le, Bk Infusion (for rinsing wounds); Montenegro; 16; Rosa canina L. Rosaceae Brier hip w Fl, Fr Tea (to heal wounds; direct application); Macedonia; 9; Rubus fruticosus L. Rosaceae Blackberry w Ap, Le, Ro Fresh leaves applied topically to wounds; infusion (rinsing for open wounds); Montenegro, Kosovo; 7; 14; 16; Rubus idaeus L. Rosaceae Red raspberry w Ro, Fl, Infusion (for rinsing); oil (extracted flowers with olive oil - to treat skin wounds caused by insects and snakes); Kosovo; 14; Rubus ulmifolius Schott Rosaceae Elmleaf blackberry w Le Crushed leaf and mixed with clarified butter, topically applied to skin infections and wounds; Albania; 12; Rumex patientia L. Polygonaceae Herb patience w Le Crushed leaf and mixed with animal fat; Albania; 12; Salvia grandiflora L. Lamiaceae Sage C Le Tea (rinsing of cervical wounds); Bosnia and Herzegovina; 4; 17; Salvia officinalis L. Lamiaceae Common sage C Le The same as S. grandiflora; Bosnia and Herzegovina; 4; 17; Salvia pratensis L. Lamiaceae Meadow sage W Le The same as S. grandiflora; Bosnia and Herzegovina; 4; 17; Salvia verticillata L. Lamiaceae Lilac sage w Le (fresh) Cataplasm; Bulgaria, Albania, Serbia; 11; 12; 18; Sambucus ebulus L. Caprifoliaceae Dwarf elder w Le Crushed and applied: bruises and wounds in animals and humans; Albania; 12; Sambucus nigra L. Caprifoliaceae Elderberry w Bk, Fl (fresh), Re Bark extracted with olive oil (sunburns); bark boiled with butter milk (thermal burns); balm – fresh flowers mixed with butter or cream, resin – in poultices (balm, melem); Serbia, Albania, Kosovo; 1; 7; 11; 12; 21; Sanicula europaea L. Apiaceae Sanicle w Ap Infusion; Montenegro; Bosnia and Herzegovina; 2; 16; Saponaria officinalis L. Caryophyllaceae Soapwort w Ro Decoction, infusion; Bosnia and Herzegovina; 2; Sedum spectabile Boreau. Crassulaceae Ice plant w Le Epithelialization of wounds, draining pus from wounds (cataplasm); *the epidermis should first be removed from the leaves Serbia; 11; Sedum telephium L. subsp. maximum (L.) Krock. Crassulaceae Orpine w Le The same as S. spectabile Montenegro, Serbia; 11; 16; Sempervivum tectorum L. Crassulaceae Houseleek w Le Ointment ( extracted with cow or pig fat and topically applied); Kosovo; 14; Solidago gigantea L. Asteraceae Giant goldenrod W Ap Tea; Bosnia and Herzegovina; 4; Solidago virgaurea L. Asteraceae Goldenrod W Ap, Le Tincture; ointment; crushed fresh leaves directly on wounds; Bosnia and Herzegovina, Montenegro; 4; 16; Stachys germanica L. Lamiaceae Downy woundwort w Le (fresh) Compress (pure wounds); Bulgaria; 18; Stachys officinalis (L.) Trev. Lamiaceae Wood betony w WhPl, Le Tea; infusion; fresh leaves are topically applied (antiseptic for inflamed wounds); Kosovo, Bulgaria, Serbia; 6; 10; 15; Symphytum officinale L. Boragniceae Common comfrey W Ro Ointment (for inflammed wounds, bone fractures and external ulcers); Bosnia and Herzegovina; Bulgaria, Kosovo; 4; 14;15; 17; Taraxacum officinale F.H. Wigg. Asteraceae Common dandelion w Fl (fresh), Ro topically applied (flower fresh); infusion (root; pure); decoction; compress; Bulgaria, Serbia; 18; 21; 22; Teucrium chamaedrys L. Lamiaceae Wall germander w Le Decoction (pure); Bulgaria; 18; Thalictrum minus L. Ranunculaceae Lesser meadow-rue w Le Decoction (pure); Bulgaria; 18; Tilia × euchlora K.Koch Tiliaceae Crimean lime W Fl Tea (compress); Bosnia and Herzegovina; 4; Tilia-hybrids Tiliaceae Lime C Fl Tea (compress); Bosnia and Herzegovina; 4; Trifolium pannonicum Jacq. Fabaceae Hungarian clover w Ap Tea; Montenegro; 16; Trifolium pratense L. Fabaceae Red clover w Ap, Fl Tea (for rinsing cervical wounds); Bosnia and Herzegovina; 17; Trifolium repens L. Fabaceae White clover w Ap, fl Tea (for rinsing cervical wounds) Bosnia and Herzegovina; 17; Triticum aestivum L. Poaceae Wheat C Fr Tea; Bosnia and Herzegovina; 4; Tussilago farfara L. Asteraceae Coltsfoot w Le (fresh) Compress - wounds are to be bandaged with fresh leaves; for festering wounds and ulcers; Bulgaria, Serbia, Montenegro, Albania; 11; 10; 16; 18; 24; Ulmus sp. Ulmaceae Elm w Bk Decoction; Albania; 1; Vaccinium vitis-idaea L. Ericaceae Lingonberry w Fr, Le Infusion; Kosovo; 14; Verbascum sp. L. Scrophulariaceae Mullein w Fl Oil; Bosnia and Herzegovina; 4; Veronica officinalis L. Scrophulariaceae Speedwell w Le Infusion; Bosnia and Herzegovina, Kosovo; 4; 14; Vitis labrusca L. Vitaceae Fox grape c Fr The same as P. armeniaca; Albania; 1; 12; Vitis vinifera L. Vitaceae Grapevine c Le The same as P. armeniaca; Croatia, Romania (south-east); 13; 19; Diverse tree species w Wo Burned, cold ashes, externally applied on wounds (hemostatic, cicatrizing) Romania (south-east); 13; CS- cultivated species; WS – wild species; Ap – aerial part; Bk – bark; Fl– flower; Fr –fruit; La – latex; Lb- leaf buds; Le – leaf; LeGl– leaf gel; Ne – needles; Re – resin; Rh –rhizome; Ro – root; Se – seeds; Tu – tuber; Wo – wood; WhPl – whole plant. References  Pieroni et al. (2015a);  Redžić (2007);  Pieroni et al. (2013);  Šarić-Kundalić et al. (2011);  Pieroni et al. (2014a);  Mustafa et al. (2012a);  Mustafa et al. (2012b);  Zlatković et al. (2014);  Rexhepi et al. (2013);  Jarić et al. (2007);  Jarić et al. (2015);  Pieroni et al. (2014b);  Pieroni et al. (2015b);  Mustafa et al. (2015);  Leporatti and Ivancheva (2003);  Menković et al. (2011);  Šarić-Kundalić et al. (2010);  Kozuharova et al. (2013);  Pieroni and Giusti (2008);  Pieroni (2008);  Pieroni et al. (2011);  Šavikin et al. (2013);  Malamas and Marselos (1992);  Pieroni et al. (2005);  Ivancheva and Stantcheva (2000). Ethnobotanical research in the Balkan region has established that there are 128 plant species used in wound treatment (Table 1). Of the total recorded species, 105 can be found in the wild and 22 are cultivated, while both wild and cultivated Juglans regia is found. In terms of the diversity of species used in the treatment of wounds in the Balkans, one (Lycopodium clavatum) belongs to the division Lycopodiophyta, two to the division Equisetophyta (Equisetum arvensis and E. telmateia), one to the division Polypodiophyta (Pteridium aquilinum), eight to the division Pinophyta (Abies alba, Larix decidua, Picea abies, Pinus heldreichii, P. mugo, P. nigra, P. sylvestris, Pinus sp. (gymnosperms)) and the rest to the division Magnoliophyta (angiosperms). These plant species are classified into 45 families, the richest being Asteraceae (21), Rosaceae (16), Lamiaceae (12) and Pinaceae (8) (Table 1). Similarly, it has been established that in Russia and Central Asia, as many as 338 plants are used for the treatment of skin wounds, skin irritations, allergic rashes and dermatitis (Mamedov et al., 2005). Of these, 31 species (approximately 10%) are the same as those used in the Balkans for the treatment of wounds. By comparing data on the use of plant species in wound healing contained in the State Pharmacopeia of the USSR (11th edition, Shikov et al., 2014) with the results of research into plant species used in the Balkans for the same purpose, it was found that 14 species (Achillea millefolium, Alnus glutinosa, Calendula officinalis, Capsella bursa-pastoris, Chamomilla recutita, Chelidonium majus, Hypericum maculatum, H. perforatum, Picea abies, Polygonum bistorta, Quercus petraea, Q. robur, Salvia officinalis and Vaccinium vitis-idaea) possess hemostatic, astringent or anti-inflammatory properties. A wide variety of plant parts are used in the treatment of wounds in the Balkans: rhizomes, bulbs, roots, stems, flowers, fruits, seeds, aboveground plant parts or the whole plant, as well as plant products (resin). Preparation methods vary. Fresh plant parts can be used (usually with the direct application of fresh leaves to the wound), in the form of fresh juice (directly squeezed onto the wound) or in the form of infusions, tinctures, decoctions, poultices, ointments, oils, and unguents, or in a dried state (often as a powder). A detailed analysis of literature related to ethnobotanical studies of the uses of medicinal plants in the Balkan region was carried out. Twenty-five studies were analysed and plants used for the treatment of wounds were singled out. Table 1 contains data on plant parts or products that are used specifically for this purpose, the methods of preparation and application, as well as the literature data related to the geographic area/region/district where the use of plants to treat wounds was recorded. The analysis showed that the most frequently used plants for wound healing in the Balkans are Plantago major (mentioned in 13 works), Hypericum perforatum (12), Plantago lanceolata (8), Achillea millefolium (7), Calendula officinalis (5), Sambucus nigra (5), Tussilago farfara (5) and Prunus domestica (5) (Fig. 2). It is interesting to note that 79 plant species are recorded in only one locality/area for the treatment of wounds, which is most likely due to the phytogeographical, cultural and traditional characteristics of the area in question. Fig. 2 Download high-res image (2MB)Download full-size image Fig. 2. The most commonly used plant species in the treatment of wounds in the region of the Balkan Peninsula: a) Plantago major; b) Plantago lanceolata; c) Achillea millefolium; d) Sambucus nigra; e) Tussilago farfara; f) Hypericum perforatum; g) Calendula officinalis; h) Prunus domestica. 5. Ethnobotanical and pharmacological characteristics of the most commonly used plants 5.1. Plantago major and Plantago lanceolata Plantago major (plantain) and Plantago lanceolata (ribwort plantain) are species of the Plantago genus, which includes 275 species worldwide. Due to their medicinal properties, these plants play a major role in traditional medicine in different parts of the world, where they have been used for centuries to treat diseases relating to skin, digestive organs and blood circulation, as well as wounds, inflammation and hypertension. Ethnobotanical research in the Balkans has revealed that P. lanceolata is used in the same way as P. major. Greek physicians described the traditional use of P. major in wound healing as early as the first century A.D. (Samuelsen et al., 1999). Whole or crushed leaves are used to treat burns and other kinds of wounds, to stop bleeding, and to treat wounds caused by dog bites (Roca-Garcia, 1972). In ‘Flora Danica’ by Simon Paulli in 1648, P. major is mentioned as a highly effective medicine for treating superficial wounds, with it being sufficient just to put some of the juice from the leaves of this plant on the wound (Brøndegaard, 1987). The use of P. major and P. lanceolata (leaves) also has a long tradition in Russia, where it is used to treat wounds, and also as an expectorant, antiphlogistic and pain-relieving herb (Turova and Sapozhnikova, 1989; Shikov et al., 2014). In central Italy, the fresh leaves of P. major are applied to wounds as a vulnerary and to reabsorb pus (Idolo et al., 2010), while in the coastal region of north-western Italy (Liguria), the leaves of P. major and P. lanceolata are applied to wounds and ulcers as an antiseptic and rubbed onto bee stings (Cornara et al., 2009). In Scandinavian countries, P. major is well-known for its wound healing properties. Norwegians and Swedes call this plant ‘groblad’, which can be translated as ‘healing leaves’ (Samuelsen, 2000). In the Indian state of Arunachal Pradesh, a paste and the juice of the leaves of P. major are applied directly to wounds and inflammations (Namsa et al., 2011), and P. lanceolata is used in a similar way in the regions of the Lesser Himalayas in Pakistan (Abbasi et al., 2013), Kurdistan (Iraq) (Ahmed, 2016) and Seharti Samre District (southern Tigray, Ethiopia) (Araya et al., 2015). In the ethnomedicine of the Balkans, three species of the genus Plantago (P. lanceolata, P. major and P. media) are used in wound healing. Of these, the most popular is P. major, the use of which is most widespread in Bosnia and Herzegovina, Serbia (Mts. Rtanj, Kopaonik, Zlatibor, and Suva Planina, and the Pešterska Visoravan plateau), the western and southern parts of Kosovo (the Albanian Alps), Albania (Rraicë and Mokra areas – eastern Albania, the Theth area – a village in the northern Albanian Alps), Macedonia (Sharr Mountains) and the Balkan part of Romania (Dobruja, southeast Romania). P. major is the most frequently used species throughout the Balkans, due to its wide distribution and that it is easy to come by. In the treatment of wounds, the leaves are used externally as a poultice (directly on the skin) or else a poultice is made from infusions or fresh juice. To treat superficial wounds it is sufficient to apply the juice from the leaves. Extract from Plantago major leaves exhibited weak antibacterial activity in vitro, but it has an effect on infected wounds in vivo. It was found that treatment with P. major extract removed infections and healed wounds more effectively than using antibiotics on the infected wounds (Samuelsen, 2000). The leaves of species of the Plantago genus are used externally to wash wounds and to treat skin infections, while crushed leaves have hemostatic (De Feo and Senatore, 1993), antifungal (McCutcheon et al., 1994), antibacterial (Moskalenko, 1986), analgesic, anti-inflammatory (Núñez Guillén et al., 1997; Beara et al., 2012; Hussan et al., 2015), antiviral (Chiang et al., 2003), immunomodulatory (Chiang et al., 2003), and antioxidant properties (Fons et al., 1998; Mahmood et al., 2011; Harput et al., 2012; Beara et al., 2012), as well as cytotoxic effect (Chiang et al., 2003; Beara et al., 2012). Plantago sp. contains several compounds, including iridoid glycosides (aucubin, catalpol, gardoside, geniposidic acid, mayoroside, and melittoside), terpenoids (loliolid, ursolic acid, and oleanolic acid), caffeic acid derivatives (caffeic acid, chlorogenic acid, plantamajoside R, and aceteoside R), polysaccharides (plantaglucide, glucomannan, PMII, and PMIa), alkaloids (indicain and plantagonin), polyholozide, flavonoids and flavone glucosides (luteolin-7 glucoside, hispidulin 7-glucuronide, apigenin, baicalein, scutellarin, and plantagonin) (Kuhn and Winston, 2000). The curative effect of P. major is the result of the activity of several compounds, whose effects can be individual or synergistic, but can also be a consequence of the mutual impact of the compounds that are present on one another (Samuelsen, 2000). According to the findings of Nazarizadeh et al. (2013), the leaves have the highest levels of phenols (ferulic acid), flavonoids and tannins. Tannin and aucubin are two important components with antimicrobial and anti-inflammatory effects, which are beneficial in wound healing (Tarle et al., 1981; Mantle et al., 2001). Polyphenols are also considered useful for wound healing and display antimicrobial and anti-inflammatory properties. Together with polysaccharides, they may have a synergistic effect on wound healing and other biological activities. The polysaccharides galactoarabinan and galactan were isolated from P. major. These substances are sometimes referred to as ‘plantaglucid’ and have been used to treat ulcers at 1.5–3 g/day (Gorin et al., 1966). Given in a dose of 1 mg/kg, plantaglucid reduced the ulceration index in rats’ stomachs 20 times over (Obolentseva and Khadzhai, 1966). A highly esterified pectin polysaccharide with Mw 46–48 kDa, PMII was isolated from a 50 °C water extract (Samuelsen et al., 1995, 1996). The extract of P. major contains a mixture of antioxidants; these may constitute one of the mechanisms that contribute to its wound healing properties (Yokozawa et al., 1997). Tea made from the green leaves of P. major has antioxidant properties, but the antioxidant capacity is higher in fresh green leaves (Campos and Lissi, 1995). According to Samuelsen (2000), the caffeic acid derivatives plantamajoside and acetoside have antibacterial properties and they also engage in anti-oxidative and free radical-scavenging activities, along with some flavonoids, while pectic polysaccharides have been reported as being effective against ulcers and exhibiting immunostimulatory activities. According to the findings of the same author, the treatment of superficial wounds is aided by the long-chained saturated primary alcohols that are present in the leaf wax. However, the leaves also contain compounds with anti-inflammatory properties, namely plantamajoside, baicalein, hispidulin, aucubin, ursolic acid and oleanolic acid. Since the inflammatory stage is part of the wound-healing process, anti-inflammatory activity may be undesirable. On the other hand, the activity of these substances, when acting together with other compounds present in the leaves, is not known at present. Thus, the full picture of P. major as a wound-healing remedy may be rather complex. The exceptionally long tradition of using P. major for treating wounds and what is known today about its chemical constituents and biological activities merit the further exploration of this plant. The wound healing properties of Plantago major L. were evaluated using an ex-vivo porcine wound-healing model. Ethanol- and water-based extracts stimulated wound healing in porcine skin, but the ethanol-based extracts had a somewhat stronger effect. A concentration of 1.0 mg/mL produced the best results for both types of extracts (Zubair et al., 2015). The effect of P. major on healing burn wounds in rats was also tested, with 20% and 50% water extracts, and revealed the best results in the group receiving the 50% solution, concluding that these solutions may be a suitable substitute for silver sulfadiazine, especially when applied in 50% concentrations (Amini et al., 2010). The antibacterial properties of phenolic compounds from different fractions of P. major leaf extracts was tested, using in vitro methods. The results indicated that the ethyl acetate fraction was the most active in vitro against Gram-negative and Gram-positive bacteria strains. A high inhibition zone of 16.7±1 mm and 14.3±0.6 was exhibited against Staphylococcus aureus and Bacillus cereus, a moderate one of 13.3±0.6 and 11.3±0.6 mm against Pseudomonas aeroginosa and Acinetobacter bowie, and the lowest antibacterial activity was found against Klebsiella pneumonia, Proteus mirabilis and Salmonella typhimurium (Karima et al., 2015). Ferrazzano et al. (2015) investigated the in vitro and in vivo antimicrobial effects of P. lanceolata herbal tea (from flowers and leaves) on cariogenic bacteria (Streptococcus bovis, S. mutans, S. mitis, S. parasanguinis, S. viridans, S. sobrinus and Lactobacillus casei), where they identified the main components as being: flavonoids, coumarins, lipids, cinnamic acids, lignans, and phenolic compounds. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of infused P. lanceolata was between 250μg/mL and 2.0 mg/mL. The antimicrobial activities of crude extracts of P. lanceolata leaves in water, methanol and acetone on Gram-negative (Klebsiella pneumoniae, Shigella boydii, and Escherichia coli) and Gram-positive (Staphylococcus aureus and Streptococcus pneumoniae) bacteria was investigated by Abate et al. (2017). The results revealed the leaf extracts had a high degree of antimicrobial activity with a mean zone of inhibition ranging from zero to 26 mm. It was also established that all bacteria were susceptible to all extracts because each different solvent of P. lanceolata leaf extracts showed a significant inhibition zone against each bacterium species. However, in most cases, the methanol extract exhibited better activity against most of the tested pathogens than the acetone and water extracts. MIC and MBC values ranged from 6.25% to 25% for all P. lanceolata leaf extracts (Brantner and Grein, 1994). 5.2. Hypericum perforatum Hypericum perforatum (St. John's wort) is widely distributed in Europe, Asia and Africa, and naturalised in America (Bombardelli and Morazzoni, 1995) and has a long history of use in traditional European herbal medicine. The medicinal properties of this species were known even back in Hippocrates’ time due to its anti-inflammatory and wound/burn healing properties (Kotsiou et al., 2016). Dioscorides, the leading physician in ancient Greece, as well as Pliny and Hippocrates, recommended the use of this herb for a host of ailments, including sciatica and poisonous bites (Culpeper, 1652). A collection of prescriptions from a monastery in Cyprus, the ‘latrosophikon’ from the Ottoman period (1571–1878), notes the use of H. perforatum for treating cuts (Lardos, 2006). In the monograph Herba hyperici, in the Pharmacopoeia of the USSR, the astringent and antiseptic properties of the aboveground parts of H. perforatum and H. maculatum are mentioned (Shikov et al., 2014). Preparations of H. perforatum, such as oils or tinctures, are used for the treatment of minor wounds and burns, sunburn, abrasions, bruises, contusions, ulcers, myalgia, and many other ailments. Pharmacological research supports its use in these fields (Wölfle et al., 2014). In today's traditional medicine, H. perforatum is used in the healing of wounds and various skin problems, as well as in the treatment of problems in the gastrointestinal, respiratory and nervous systems (depression) (Tucakov, 1997). The species is very popular in Turkey for wound healing, primarily in the form of an oil (Sezik et al., 2001; Süntar et al., 2010). In central Italy, latex is used on wounds as a vulnerary and a decoction of leaves is used to rinse wounds and accelerate healing (Idolo et al., 2010); in north-western Italy (Liguria), an oil extract is used for the same purpose (Cornara et al., 2009), and the species has a similar application on the Iberian Peninsula (northern Navarra) to treat wounds, cure burns and infections and to moisturise (Cavero et al., 2011). St John's wort is also popular in the Balkans, which can be seen in the frequency of its application. This study shows that four species of the genus Hypericum (H. perforatum, H. maculatum, H. montanum and H. tetrapterum) are used in wound healing, of which H. perforatum is the most common. The curative properties of this species (mainly the aboveground parts) is best known by the peoples of the east, north and north-east of Bosnia and Herzegovina, Serbia (Mts. Rtanj, Kopaonik, Zlatibor, and Suva Planina), western and southern Kosovo, eastern Albania (the areas of Rraicë and Mokra), Montenegro (Prokletije), Macedonia (the Sharr Mountains, the upper Reka valley, and Mt. Korab) and north-western Greece (Zagori and Epirus). An infusion, or an oil extract, is prepared from the aerial parts of St. John's wort when in bloom or else the dried aboveground parts (when in bloom) are directly applied to wounds. However, the most commonly used form is St. John's wort oil, which is made by macerating the fresh herb in sunlight, usually in sunflower or olive oil, for a period of 40 days. Studies conducted in rural areas of the Balkan Peninsula show that St. John's wort oil is primarily used in the healing of burns, lacerations, hematomas, and skin ulcers and to relieve the symptoms of haemorrhoids (Malamas and Marselos, 1992; Jarić et al., 2007, 2015; Šarić-Kundalić et al., 2011; Menković et al., 2011; Mustafa et al., 2012b, 2015; Pieroni et al., 2013, 2015a; Rexhepi et al., 2013; Šavikin et al., 2013; Zlatković et al., 2014). Pharmacological research has shown that the curative properties of H. perforatum are a result of several types of biologically active compounds, including naphtodianthrones (hypericin and pseudohypericin), prenylated acylphloroglucinols (hyperforin and adhyperforin), flavonoids (quercetin, hyperoside, rutin, and quercitrin), xanthones (1,3,6,7-tetrahydroxyxanthone), and essential oil, rich in sesquiterpenes (Nahrstedt and Butterweck, 2010). Due to the wide range of pharmacological effects of its active substances, which include anti-inflammatory (Sosa et al., 2007), antiseptic (Saddiqe et al., 2010), antiviral (Jacobson et al., 2001), antioxidant (Silva et al., 2008), analgesic and astringent properties, Hypericum extracts have high potential for healing wounds (Süntar et al., 2010). The main constituents of this extract to which the majority of these effects are attributed include naphthodianthrones (e.g. hypericin) and phloroglucinols (e.g. hyperforin) (Wölfle et al., 2014). It is thought that it is the active substances of H. perforatum that reduce the inflammation period and contribute to resistance against infections, probably providing a barrier against microbial contamination at the beginning of the wound-healing process. Hypericum species have compounds with antibacterial properties, such as hyperforin and flavonoids, which probably contribute to faster and improved healing (Herrera et al., 1996; Cecchini et al., 2007). Studies have shown that H. perforatum has an exceptionally high potential for treating wounds in the form of oil, particularly if the extract is made in olive oil. Olive oil itself as a vehicle for the preparation was also shown to possess remarkable wound-healing properties, which, however, were significantly increased by the addition of H. perforatum. Like the oil, a tincture of H. perforatum enhanced the epithelialisation phase, with an increase in the wound contraction rate (Öztürk et al., 2007). Further studies are warranted to elucidate the exact mechanism of the wound-healing effects of the plant. Recently, Yousuf et al. (2012) studied in vitro antibacterial activity and performed a phytochemical analysis of the methanol extract of the aboveground parts of H. perforatum. The extract showed pronounced activity against all the bacterial strains tested (standard laboratory isolates: Bacillus subtilus, Staphylococcus epidermidis, Proteus vulgaris and three clinical isolates: Staphylococcus aureus, Salmonella typhi, and Escherichia coli). B. subtilus and S. aureus showed maximum sensitivity to the methanol extract of H. perforatum with a mean zone of inhibition of 19.33 mm and 18.00 mm respectively at a test concentration of 50 mg/mL. The minimum inhibitory concentration (MIC) ranged from 0.78 to 3.12 mg/mL. Furthermore, a quantitative estimation of bioactive phytoconstituents showed that the plant contains alkaloids (19.10±0.4 mg/g plant sample), phenolics (21.90±0.9 mg/g sample), flavonoids (17.10±0.02 mg/g sample), tannins (1.60±0.08 mg/g sample) and carbohydrates (4.0 mg/g sample). The photodynamic antimicrobial effects of hypericin on clinically isolated S. aureus and E. coli cells were studied by Yow et al. (2012). Bacterial cells (108 cells per mL) were incubated with hypericin (0–40 μM) for 30 min and light irradiation of 600–800 nm followed at 5–30 J cm−2. It was found that a combination of hypericin and light irradiation could induce the killing of Gram-positive methicillin-sensitive and –resistant S. aureus cells at significant levels (>6 log reduction), but it was not effective against Gram-negative E. coli cells (<0.2 log reduction). They concluded that this difference was down to the different cell wall/membrane structures, which directly affected cellular uptake of hypericin. In a study by Samadi et al. (2010), the effects of H. perforatum ointment on the healing of wounds and scars resulting from Caesarean sections were researched. The sample comprised 144 women who had undergone a surgical childbirth procedure and who were randomly divided into three groups. The treatment and placebo groups applied H. perforatum or placebo ointment 3 times a day for 16 days, while the control group had no post-operative treatment. The results of the clinical study demonstrated that there were significant differences in wound healing (p<0.005) and scar formation (p<0.0001) between the treatment group and the placebo and control groups, while there were no differences in terms of wound healing (p ¼ 0.93) and scar formation (p ¼ 0.11) between the placebo and control groups. In addition, significantly lower pain and pruritus were reported by the treatment group when compared with the placebo and control groups on the 40th day postpartum. This study shows that H. perforatum ointment can effectively facilitate Caesarean wound healing and minimise scar formation, pain and pruritus without any notable side-effects. Hajhashemi et al. (2017) assessed the efficacy of Achillea millefolium and Hypericum perforatum ointments on episiotomy wound healing in 140 primiparous women, who were randomly divided into four groups – 2 control groups either undergoing no intervention or using placebo ointment and 2 case groups using H. perforatum ointment and Achillea millefolium ointment. It was established that pain levels, redness, oedema and ecchymosis in those groups using H. perforatum and A. millefolium ointments were less than in the control groups (p<0.05), which suggests that their application is useful for episiotomy treatment. In a study by Yadollah-Damavandi et al. (2015), the healing effects of H. perforatum on full-thickness diabetic skin wounds were investigated by using stereological methods. The sample, comprising forty-eight female diabetic rats, were randomly divided into four groups: a gel base treated group, an H. perforatum 5% gel treated group, an H. perforatum 10% gel treated group, and the control group, which received no treatment. Initial circular 1 cm2 full-thickness wounds, created on the necks of the test animals, were measured every three days to track the healing process. The results revealed that the group treated with H. perforatum exhibited a faster wound closure rate in comparison with the control and vehicle groups (p<0.05). In addition, the numerical density of fibroblasts, the volume density of collagen bundles, and the mean diameter and volume densities of the vessels in the H. perforatum group were significantly higher than in the control (e.g. the volume densities of the collagen bundles were 51.97% and 54.46% higher, respectively). The results of this study show that H. perforatum has the ability to improve tissue regeneration by enhancing fibroblast proliferation, collagen bundle synthesis, and revascularisation. In their study, Kıyan et al. (2015) analyse the use of H. perforatum gel in the treatment of experimental second-degree thermal burns in rats compared to silver sulfadiazine treatment. It was found that administering H. perforatum gel four times a day within the first 24 h is clearly effective in wound healing in comparison to silver sulfadiazine treatment. Similar research was carried out by Peksen et al. (2014), who compared the healing effects of silver sulfadiazine cream 1% with extract of H. perforatum on scald burn wounds in a rat model. They found that together the extract of H. perforatum and silver sulfadiazine cream 1% had a synergistic effect on the healing of burn wounds, which proved much more effective than their individual application. 5.3. Achillea millefolium Achillea millefolium (yarrow) is a widely distributed medicinal plant (Eurasian Boreo-temperate element, but naturalised in North America so that distribution is now Circumpolar Boreo-temperate (Online Atlas of British and Irish Flora)) and has been used for over 3000 years (Mitich, 1990; Blumenthal, 2000). This species is used in traditional medicine in many regions of the world. In Chinese and Persian ethnomedicine, as well as in Spanish-speaking New Mexico and southern Colorado, yarrow has been used to stop bleeding and to treat sores, snakebites, wounds, haemorrhoids, varicose veins, and as an anti-inflammatory and antispasmodic (Duke and Ayensu, 1985; Zargari, 1996; Dodson and Dunmire, 2007), while in the central part of Italy, dried and crushed apical parts are used as a cicatrizant (Idolo et al., 2010). Infusions of the leaves, stems and flowers accelerate the healing of rashes, haemorrhoids and skin ulcers (Gale, 2006). It is typically used in the treatment of skin disorders, especially inflammation of the skin and mucous membranes, and as a trophic protective agent (Bruneton, 1995). In the Balkans, A. millefolium is a popular plant in the treatment of wounds, especially in Bosnia and Herzegovina, eastern Albania (Gollobordo), eastern (Golak) and western (the Albanian Alps) Kosovo, Serbia (Mts. Rtanj, Kopaonik, and Suva Planina) and the Republic of Macedonia (the Sharr Mountains). Depending on the locality, the aerial parts (most often), leaves and flowers (fresh or dried) are used. From these plant organs, fresh juice is extracted, or an infusion, poultice or tincture is applied topically. The application of the preparations is external and used to treat purulent wounds, ulcers, and cervical wounds, or as an astringent to stop bleeding. The pharmacological activity of A. millefolium is attributed to some of its constituents, especially the essential oil, proazulenes and other sesquiterpene lactones, dicaffeoylquinic acids and flavonoids, the properties of which (antimicrobial, antiphlogistic, choleretic and antispasmodic, respectively) mean it is often used in traditional medicine (Benedek et al., 2007, 2008). The essential oil contains no chamazulene, or up to 50% (produced during the distillation of proazulene), the amount of which depends on its geographic origin. The presence of prochamazulene is linked to the chromosome number in the plant. The most common oil compounds are camphor, sabinene, 1,8-cineole, and some classes of sesquiterpene lactones: guaianolides, germacranolides and dihydroparthenolides. These substances have been proven to play a role in the antiseptic and antiphlogistic activities of yarrow. Despite its medicinal properties, the herb A. millefolium can, in some instances, provoke allergic contact dermatitis, thus limiting its use (Bisset and Wichtl, 2001; Blumenthal, 1999). Guaianolide peroxides and sesquiterpene lactones, together with azulenes in the essential oil, are believed to be responsible for itching and inflammatory skin changes with the formation of vesicles (Bisset and Wichtl, 2001). Kastner et al. (1993) believe that the topical anti-inflammatory activity of the sesquiterpenes is caused by the inhibition of the arachidonic acid metabolism. Although sesquiterpenes with an exocyclic methylene group can produce an unwanted allergic reaction after topical application, some of them, besides anti-inflammatory properties, also exhibit anti-oedematous activity. Sosa et al. (2001) investigated the anti-inflammatory activity of the sesquiterpene, 1,4-dihydroxy-germacra-5E-10(14)-diene (DHGD) (described for the first time within the A. millefolium group), which was isolated from the flower heads of Achillea pannonica Scheele. In the study, its topical anti-inflammatory activity was investigated more thoroughly, evaluating its effects on a model of skin acute inflammation - the Croton oil-induced dermatitis in the mouse ear. As references, hydrocortisone and the non-steroidal anti-inflammatory drug indomethacin were used. The sesquiterpene, 1,4-dihydroxy-germacra-5E-10(14)-diene, inhibited ear oedema in a dose-dependant manner, with an ID50 of 0.40 mmol/cm2. DHGD (0.75 mmol/cm2) provoked the global inhibition of the oedematous response (61%), higher than that induced by an equimolar dose of indomethacin (43%) within 24 h. The reduction induced by hydrocortisone (0.10 mmol/cm2) was 68%. The effect of DHGD (61% inhibition) was also greater than that of the equimolar dose of indomethacin (51% inhibition) on granulocyte recruitment at the site of inflammation. Hydrocortisone (0.10 mmol/cm2) reduced the cellular infiltrate by 44%. Hemmati et al. (2002) evaluated the effects of the hydroalcoholic extract of A. millefolium on wound healing in rabbits. Animal wounds were treated topically with eucerin containing 1% phenytoin as a standard healing agent, or eucerin containing 0%, 2%, 5% and 10% yarrow extract. Five percent yarrow extract cream exhibited a better healing profile and the rate of healing was significantly (p>0.01) more effective than that of other groups, indicating the considerable potential of yarrow cream for wound healing, possibly as it accelerates collagenation and the proliferation phase of wound healing. Temamogullari et al. (2009) compared the effects of yarrow extract on wound healing to 10% povidone iodine and 0.9% sodium chloride treatments. Three full-thickness skin defects, 3.14 cm in diameter, were created on dorsal aspects of 12 rabbits. The thickness of scar tissue changed significantly during treatment with yarrow extract and 0.9% sodium chloride (p<0.05), while wound treatment with 10% povidone iodine and 0.9% sodium chloride yielded similar results (p>0.05). The density of vascular proliferation in the study groups was significantly different only on postoperative days 4 and 16 (p<0.05). The degree of inflammatory cell infiltration was significantly different on days 8–12 for the yarrow extract group, while such a relation was not found on postoperative days 4, 12 and 16 (p>0.05). The topical application of yarrow extract on a daily basis to full-thickness skin defects in rabbits accelerated wound healing. Matić et al. (2009) tested the effects of yarrow on the epithelisation of lower leg venous ulcers. Thirty-nine patients were divided into two groups: the first (experimental) group of patients were treated with an ointment containing 7.5% yarrow extract. In the second (control) group, saline solution dressings were applied to ulcers over a period of three weeks. After three weeks, the total surface area of all the ulcers in the experimental group had decreased by 39.64%, whereas in the control group, the decrease was 15.1%. They concluded that such preparations are suitable for use in the treatment of venous ulcers, but their efficiency in wound healing is still to be investigated. 5.4. Calendula officinalis Calendula officinalis (pot marigold) is an annual plant species of Mediterranean origin, popularly used in wound healing and as an anti-inflammatory agent (Parente et al., 2012). The earliest use of calendula as a herbal remedy was recorded in the Middle Ages (12th century), when it was used to treat digestive problems, menstrual pain and various skin lesions (Leach, 2008; Ehrlich, 2013). It was introduced to England during the 13th century, from where it spread to other parts, in particular due to its use in wound healing. During the American Civil War as well as in the First World War, pot marigold was used in antiseptic and anti-inflammatory balms and creams (Alonso, 2010; World Health Organization, 2002). Because of its long history of safety as a treatment for inflammations and skin wounds (Loggia et al., 1994), there are numerous reports describing its use for many ailments: in the treatment of inflammations of internal organs, gastrointestinal ulcers and dysmenorrhea, as a diuretic and diaphoretic, for convulsions and for inflammations of the oral and pharyngeal mucosa; Calendula tea was used as an eyewash, a gargle, for nappy rashes and other inflammatory conditions of the skin (Safdar et al., 2010). However, one of the most important uses of C. officinalis as a medicinal plant is in the treatment of wounds, as seen in numerous ethnopharmacological studies: in Lithuania (the Samogitia region) and northern Italy (Valfurva, Sondrio Province) the leaves are used for compresses (Petkeviciute et al., 2010; Dei Cas et al., 2015) and an oil or ointments are made from its flowers (Dei Cas et al., 2015), while in a Transylvanian Hungarian Csángó village in Romania the flowers are used to make an astringent cream (Papp et al., 2013). Ethnopharmacological surveys of medicinal plants in Peru (Nor-Yauyos, Landscape Reserve of Nor-Yauyos-Cochas) have shown that an infusion of C. officinalis flowers is used as an antifungal and antiseptic for wounds (Rehecho et al., 2011), while on the Iberian Peninsula (Basque country), petals are used to make an ointment for wounds and cuts (Menendez-Baceta et al., 2014). In the Balkans (Bulgaria, Serbia (Kopaonik), south Kosovo, and east, north and northeast Bosnia and Herzegovina), C. officinalis is a popular plant (aerial parts) – the flowers are used to make an oil or ointment, which is applied to all types of wounds, particularly inflamed wounds (Leporatti and Ivancheva, 2003) or as a vulnerary for burns and sunburn (Mustafa et al., 2015). The wound healing potential of topically applied extract of C. officinalis flowers on excision wounds in rats under laboratory conditions was investigated by Preethi and Kuttan (2009). They found that the percentage of wound closure was 90.0% in the extract-treated group on the eighth day after wounding, whereas in the control group it was only 51.1% (p<0.01). 17.7 days were needed for re-epithelisation for the control animals, while extract treatment at a dose of 20 or 100 mg/kg bwt reduced the period to 14 and 13 days, respectively. It was also noted that there was an increase in levels of hydroxyproline and hexosamine in the extract-treated group compared to the untreated animals. These results confirm the wound healing potential of C. officinalis extract. Recently, Shafeie et al. (2015) tested the effects of different concentrations of Calendula officinalis gel to examine histological and biomechanical changes to skin in seventy-five male rats after 14 and 21 days of experiment. Calendula flowers (263.7 g) were extracted with 1200 cc ethyl alcohol 70%. Animals were treated with 5 g (5% gel), 7 g (7% gel), and 10 g (10% gel) of extract, which was added to the gel base and used for all experiments. Histopathological and biomechanical restorations in the group treated with 7% gel were significantly higher than the placebo and control group. Many pharmacological studies have confirmed that C. officinalis exhibits a wide range of biological effects, such as wound-healing (Leach, 2008; Preethi and Kuttan, 2009), antimicrobial (Attard and Cuschieri, 2009; Radioza and Iurchak, 2007; Roopashree et al., 2008), anti-inflammatory (Amoian et al., 2010; Preethi et al., 2009; Ukiya et al., 2006), immunomodulatory (Attard and Cuschieri, 2009), antioxidant (Ćetković et al., 2004; Fonseca et al., 2010), antiviral (Kalvatchev, 1997) and anti-tumoural effects (Ukiya et al., 2006). The main chemical constituents of C. officinalis include steroids, terpenoids, free and esterified triterpene alcohols, phenolic acids, flavonoids (quercetin, rutin, narcissin, isorhamnetin, and kaempferol), tocopherols, carotenes and other compounds (Re et al., 2009). Flavonoids, terpenoids, and carotenoids, as active ingredients in Calendula, are associated with anti-inflammatory and antioxidant effects, which have been confirmed in laboratory and animal studies (Pintea et al., 2003; Mohammad and Kashani, 2012). For example, Bernatoniene et al. (2011) researched the antioxidant activity of different formulations of cream with Calendula extract and found that the cream with the best properties (0.9% of Calendula extract) contained 0.73±0.04 mg/100 g of total carotenoids expressed as carotene. In an in vitro study, Nicolaus et al. (2017) analysed the molecular mechanism of the wound healing effects of C. officinalis flower extracts (n-hexanic, ethanolic, and aqueous) in human immortalised keratinocytes and human dermal fibroblasts. It was found that the n-hexanic and ethanolic extracts may have an impact on the inflammatory phase and the phase involving new tissue formation, and the formation of granulation tissue. Furthermore, the same authors believe that triterpenes in the n-hexanic extract play a minor role in wound healing, while the role of carotenoids or their degradation products is significantly more important. Chandran and Kutton (2008) investigated the effects of C. officinalis flower extract (20 mg, 100 mg and 200 mg/kg rat body weight), on acute phase proteins, antioxidant defence mechanisms, and granuloma formation in thermal burns in rats. Wound healing indicators such as collagen-hydroxyproline and hexosamine levels increased significantly in the treated group of animals, indicating accelerated wound healing. For those animals treated with 200 mg/kg body weight extract, there was found to be a significant decrease in acute phase proteins - haptoglobin and orosomucoid, and an improvement in antioxidant defence mechanisms. Moreover, lipid peroxidation and tissue damage marker enzymes decreased significantly in the treated groups in a dose dependant manner. The potential of C. officinalis extract for wound healing was also confirmed by histopathological analyses of rats’ skin tissue in this experiment. Wound-healing promotion through anti-inflammatory and antibacterial effects and the stimulation of angiogenesis and fibroblast activity has been demonstrated in animal studies. Khalid and da Silva (2012) found that methanol extracted from Calendula demonstrates antibacterial and antifungal activity against Gram-positive and Gram-negative organisms. According to Alonso (2010), the antibacterial activity of C. officinalis extract is due to the presence of flavonoids and essential oils. A study by Parente et al. (2012) investigated wound healing and the anti-inflammatory effects of C. officinalis flowers. The angiogenic activity of the ethanolic extract and its fractions (dichloromethane and hexanic fractions) was evaluated through the chorioallantoic membrane and cutaneous wounds in rat models. The healing activity of the extract was evaluated by the same cutaneous wound model through macroscopic, morphometric, histopathologic, and immunohistochemical analysis, as was antibacterial activity. The lowest concentrations that inhibit the growth of microorganisms for the ethanolic extract were 0.39 mg/mL against Staphylococcus aureus and Bacillus stearothermophylus. For the dichloromethane fractions, these concentrations were 4.37 mg/mL against S. aureus, 1.08 mg/mL against B. stearothermophylus and B. cereus, and 0.5 mg/mL against M. roseus, while for the hexanic fractions the MIC was 0.19 mg/mL against S. aureus. This research confirmed the anti-inflammatory and antibacterial activities of C. officinalis, but also its angiogenic and fibroblastic properties, which have a positive effect on the inflammatory and proliferative phases of the wound healing process. The antimicrobial activity of C. officinalis petal extracts in methanol and ethanol was also investigated by Efstratiou et al. (2012). They found that both extracts displayed excellent antifungal activity against the tested strains of fungi, in comparison with a standard antibiotic, Fluconazole, while the methanol extract exhibited better antibacterial activity than the ethanol extract against most of the bacteria tested (apart from Staphylococcus aureus and Enterococcus faecalis). A clinical study by Duran et al. (2005) is one of only a few to investigate the role of C. officinalis on wound healing. This study looked at the therapeutic efficacy of marigold extract on the epithelialization of lower leg venous ulcers in 34 patients. After three weeks, a decrease of 41.71% in the total surface area of the ulcers was noted in the group of patients treated with an ointment containing marigold extract, while saline solution dressings used in the control group of patients contributed to a reduction in the surface area of the ulcers of 14.52%. These results point to the positive effects of ointment with marigold extract on venous ulcer epithelialisation. However, the small number of clinical studies related to the role of C. officinalis in wound healing means that there is a need for further research to confirm the validity for using this species in traditional medicine. 5.5. Sambucus nigra Sambucus nigra (Black elder) is native to most of Europe, northwest Africa and southwest Asia, growing in wet and dry fertile soils, in sunny locations, forests, and along riversides (Atkinson and Atkinson, 2002). The medicinal properties of this species were well-known even in ancient times. Hippocrates (460–370 BCE) recommended S. nigra for constipation, dropsy and menstrual pain, while Pliny the Elder (23–79 CE), in his work ‘Naturalis historia’, attributes diuretic properties to this plant. The most well-known, classical pharmacologist, Dioscorides (c. 40–90 CE), in his work ‘De Materia Medica’, mentions the use of the root of this species as a remedy for dropsy and its fresh leaves as a topical treatment of boils (Bäumler, 2012; Frohn, 2007; Liebert, 2009). Later, during the Middle Ages, S. nigra was used as a laxative, emetic, diuretic, and antipyretic, in the treatment of gout and vertigo, as a blood purifying agent, and for respiratory diseases (Bäumler, 2012; Frohn, 2007; Liebert, 2009; Pilaske, 2002). However, scant data is found in literature regarding the traditional use of this plant in the treatment of wounds. There is mention of the use of the aerial parts, leaves or fruits of black elder to treat haemorrhoids, rheumatic pain, the common cold, a high fever, snake bites and wounds in Turkish folk medicine (Fujita et al., 1995; Yesilada et al., 1995; Sezik et al., 1997) and the use of its fruits and flowers is mentioned in traditional Austrian medicine (Dawidowicz et al., 2006; Veberic et al., 2009; Zakay-Rones et al., 1995). In Romanian ethnopharmacology, elder leaves are used externally in their fresh state or in infusions for the treatment of abscesses and furunculosis (Butură, 1979). Studies have shown that oils or balsams from the plant are used externally for treating wounds in Bulgaria, Serbia (Pešterska Visoravan plateau and Mt. Suva Planina), western Kosovo (the Albanian Alps) and Macedonia (the Sharr Mountains). The bark and fresh flowers are used in the Western Balkans to make balsam or oil. Thanks to the presence of active chemical compounds (anthocyanins (sambucin and sambucyanin), flavonoids (rutin and hyperoside), tannins (chlorogenic acid), and triterpenes (botulin, ursolic-, oleanolic acid, α-, and β-amyrin)), the extracts of different parts of S. nigra have anti-inflammatory, antioxidant, antibacterial, antiviral and astringent properties (Schneider and Hiller, 1999; Pilaske, 2002; Schilcher et al., 2010). Mogoşanu et al. (2014) studied the astringent, anti-inflammatory, antiseptic and cicatrizing activities of cold cream containing Sambuci folium soft extract in an experimental model of thermal skin burns in Wistar rats compared to a reference group treated with 1% silver sulfadiazine cream and a control group treated with cold-cream base. After 21 days, the damaged tissue was found to be completely epithelised only among those animals treated with cold-cream containing 10% vegetal extract. The authors of this study concluded that accelerated wound healing was mostly due to the flavonoids and tannins contained in the Sambuci folium soft extract. Similar research was carried out on the related species S. ebulus, from whose leaves four different solvent extracts were prepared, in order to investigate wound healing activity in vivo and to isolate the active component(s) (Süntar et al., 2010a). Linear incision and circular excision wound models on rats and mice were employed. According to the results, crude methanol extract of S. ebulus was found to display more effective activity regarding wound healing than the other extracts and fractions. The flavonoid derivative ‘quercetin 3-O-glucoside’ was also isolated as one of the active components impacting on wound healing. However, the role played by methanol extract in wound healing is probably the result of the synergistic effects of the constituents it contains. However, Mohammadsadeghi et al. (2013) found that the methanol extract of S. nigra berries displays strong antimicrobial activity. The minimum inhibitory concentration (MIC) of the extract ranged from 0.625 to 5 μg mL-1. The highest inhibitory concentration was found for C. albicans, somewhat less for Pseudomonas aeruginosa, Salmonella typhi and Escherichia coli, and the lowest for B. subtilis and S. aureus. In addition, a phytochemical analysis of the active fractions in the S. nigra extract revealed the presence of anthocyanin, vitamins A, C and B6, calcium, iron, sterols and tannins. The results of this study show that methanol extract of S. nigra berries can be used to treat various health problems, including the healing of wounds caused by the tested microorganisms. Hearst et al. (2010) reported findings on the major constituents, including terpenes, identified in S. nigra fresh flower and berry extracts and their concomitant strong antimicrobial effects exhibited on various nosocomial pathogens, notably upon methicillin-resistant Staphylococcus aureus, recognised globally as a clinically significant pathogen, associated with skin and soft tissue infections. Fresh flowers or berries were used to obtain aqueous or ethanol extract for testing. In this study, it was found that the extract of flowers and berries of elder contains numerous pentacyclic triterpenes, which are of great pharmacological relevance due to their ‘multi-target’ properties, such as wound (infection) healing, and anti-inflammatory, anti-bacterial, antiviral, hepatoprotective and anti-tumoural effects while interestingly exerting the least mammalian cytotoxicity. As far as we know, there have been no clinical studies which could prove/disprove the medicinal properties of S. nigra in wound healing. 5.6. Tussilago farfara Tussilago farfara (coltsfoot) is widespread and native to Europe, western and northern Asia and North Africa, and was introduced to North America (Hegi, 1987). It is one of the oldest herbs in traditional medicine, mainly used as a cough suppressant or in the treatment of obstructive lung diseases (asthma, bronchitis and emphysema). Additionally, it is used in China and Russia to improve digestion, to treat diarrhoea, applied topically to treat skin diseases, wounds, furunculosis and pimples, and also as an analgesic (Vereschagin et al., 1959; Chanaj-Kaczmarek et al., 2013). In Turkey, T. farfara is used as an antitussive, an expectorant, for wound healing and burns (Keklik-Koçoğlu et al., 1996; Tuzlacı and Aymaz, 2001; Koçyíğít and Özhatay, 2006), while in the Ukraine and Poland, compresses from the leaves of this species are used to treat wounds and ulcers (Kujawska et al., 2015). In general, data is scarce on the use of this species in wound healing and it could be the subject of future research. In the Balkans, there is information on its use in south and west Bosnia and Herzegovina, Bulgaria, Serbia (Mts. Kopaonik and Suva Planina) and Albania (Lëpushë, the northern Albanian Alps). Phytochemical and pharmacological research has revealed that the curative properties of this species are associated with the presence of its main components: polysaccharides with anti-inflammatory and immunostimulating properties (mucopolysaccharides, pectin, and inulin), flavonoids with anti-inflammatory and antispasmodic action (quercetin, kaempferol and their glycosides, hyperoside), terpenes (tussilagone, a- and b-amyrin, faradiol, and bisabolene epoxide), sterols and phenolic acids (Didry et al., 1980, 1982; Ryu et al., 1999; Xue et al., 2012). Due to the presence of pyrrolizidine alkaloids (PAs), including senkirkine, senecionine, seneciphylline, integerrimine, tussilagine and isotussilagine, T. farfara could have potentially adverse effects (Xue et al., 2012). When ingested with foods or herbal medicines, PAs could cause toxic reactions in humans, primarily veno-occlusive liver disease. Several PAs have been regarded as both hepatotoxic and carcinogenic (European Medicines Agency, 2013–2015; Joint FAO/WHO Codex Alimentarius Commission, 2011; Wiedenfeld, 2010). However, these compounds are found in the plant in varying amounts, usually at very low levels, depending on the source (Xue et al., 2012). For example, Jiang et al. (2009) stated that the content of senkirkine in samples of T. farfara flowers ranged from 19.5 ppm to 46.6 ppm, while in leaf samples it amounted to between 2.5 and 11.2 ppm, depending on the method of extraction used. Depending on the detection method employed (gas chromatography or capillary electrophoresis), the content of senecionine in leaves was below the level of detection or less than 0.9 ppm (Lebada et al., 2000). The leaves of T. farfara are used in Russian traditional medicine, with data in the 8th Pharmacopoeia of the USSR from 1952 to support this, and since that time, no adverse effects or toxicity have been reported in Russian publications. Considering the long history of the application of this plant in traditional Russian medicine, Sokolov (2000) claims that infusions of T. farfara leaves (5 g in 300 mL of water) are safe to use as an expectorant at the recommended therapeutic dose of 1/2-1/3 of a glass, 2–3 times per day. According to Lebada et al. (2000), in order to avoid any risks to those using preparations, German public health authorities limited the daily intake of toxic PAs to 1 mg. When used as a herbal tea, the concentration of these compounds in coltsfoot is limited to 10 mg/day and hence, calculated on the usual dosage, the drug must not contain more than 2 ppm of PAs. However, in the traditional medicine of some Balkan countries, the external application of whole leaves of T. farfara in the form of a compress for healing wounds is commonplace. After carefully analysing studies which investigated the toxic properties of the compounds contained in this species, we found no data to suggest that it being used externally as above can be harmful to human health. Publications reporting the chemistry and pharmacological effects of this plant remain fragmentary. One such study though is by Hleba et al. (2014). They tested the antimicrobial activity of the methanol extracts of T. farfara and S. nigra against Enterococcus raffinosus, Escherichia coli, Lactobacillus rhamnosus, Pseudomonas aeruginosa, Serratia rubidaea, Saccharomyces cerevisiae and Staphylococcus epidermis. Their results revealed that the extracts displayed significant antimicrobial activity against one or more species of the examined microorganisms. The most active antimicrobial plant extract was gathered from T. farfara and contained the flavonoids quercetin and kaempferol, as well as several phenolic acids. The methanolic plant extract of T. farfara displayed the strongest antimicrobial activity against Saccharomyces cerevisiae, as well as the other tested microorganisms, suggesting that this plant could be used in wound healing. At the same time, the S. nigra extract was found to have no antimicrobial effects with respect to the growth of Pseudomonas aeruginosa, Enterococcus raffinosus and Saccharomyces cerevisiae. For a more comprehensive overview of the pharmacological potential of T. farfara, further research is required so as to confirm the validity of its use for healing wounds in traditional medicine. 5.7. Prunus domestica Prunus domestica (European plum) originated from southern Europe or western Asia (Das et al., 2011). The European plum is highly valued in traditional medical practices for its nutritive, laxative and digestive properties and is used for the treatment of hypertension, diabetes, jaundice and fever. Recent studies have shown that it displays antioxidant, anticancer, antihyperglycemic, antihyperlipidemic, antihypertensive, anti-osteoporosis, laxative and hepatoprotective activities. Prunes contain dietary fibre, carbohydrates, amino acids, vitamins, minerals and antioxidant polyphenolic phytochemicals (Jabeen and Aslam, 2011). Accordingly, the most frequent use of the fruit of the plum in the traditional medicine of many countries is internal. This is confirmed by ethnopharmacological data from different parts of Italy, showing the use of P. domestica fruits mainly as a laxative (eaten raw, decoction) and for treating respiratory diseases, but also in the external treatment of wounds (Menale et al., 2016). In general, there is little information in literature on the use of this species for wound healing. However, in the Balkan region, it is used considerably for the treatment of wounds, especially burns (Pieroni et al., 2011, 2013, 2014a, 2015a, 2015b). In addition to P. domestica, other species of Prunus (P. armeniaca, P. cerasifera and P. persica, Prunus mahaleb, etc.) are used for the same purpose. In some rural Balkan regions, a homemade brandy, ‘rakia’, is produced from the fruits of these species, with 40–70% alcohol strength, by a process of fermentation and distillation. Rakia is mostly used for rinsing wounds and cuts. The same process is used to make rakia from Pyrus communis, Malus domestica, Cydonia oblonga and Vitis labrusca, which in addition to being used for the rinsing of wounds, is applied as a compress. Data is exceedingly scarce on studies concerned with testing the wound healing properties and antimicrobial activity of rakia. In a study by Seyyednejad et al. (2008), the antibacterial activity of the ethanolic seed extract (concentrations 0.1, 0.2, 0.3 and 0.4 g mL−1) of the related species, Prunus mahaleb, against bacteria (Bacillus anthracis, B. subtilis, B. pumilus, B. licheniformis, Staphylococcus aureus, Brucella melitensis, Escherichia coli, Salmonella typhi, Proteus mirabilis, Bordetella bronshiseptica, and Pseudomonas aeruginosa) was investigated using the agar disc diffusion method. P. mahaleb ethanolic extract had an inhibitory effect against P. mirabilis, B. anthracis and S. aureus when applied in the highest concentrations, and against Br. melitensis, E. coli and B. licheniforms in lower concentrations, whereas there was no such activity against S. typhi, B. bronshiseptica, P. aeruginosa, B. subtilis and B. pumilis. Based on the results of this study, this plant could be considered a disinfectant or antiseptic against P. mirabilis, B. anthracis, and S. aureus, thus confirming its use in folk medicine. Similar research was also undertaken on another related species, P. avium, where the antimicrobial activity of its extract on the differential growth of Gram-positive and Gram-negative bacteria was confirmed (Hanbali et al., 2012). Following an analysis of the available literature, we did not find any clinical studies to confirm the validity of using this species for healing wounds in traditional medicine. 6. Conclusions The beneficial effects of healing wounds with medicinal plants from the Balkan region according to traditional practices has been proven in many scientific studies. Our findings suggest that plants from the Balkans are an important natural source of medicinal substances that can be recommended for clinical trials which would provide reliable assessments of their efficacy and safety as herbal remedies. In this region, 128 species of plants are used by the local population for treating wounds. The considerable popularity of medicinal plants for treating wounds in the ethnomedicine of rural areas of the Balkans is the result of positive experiences dating back many centuries and passed down from generation to generation, their efficacy, simplicity of application, and relative accessibility, as well as being an alternative to costly drugs. Many of these plants promote the skin's natural repair mechanisms and therefore have huge potential for therapeutic use in wound management. Various plant parts (rhizomes, roots, tubers, bulbs, leaves, buds, flowers, fruits, seeds, bark, aerial parts or the whole plant) or plant products (resins) are used externally in the form of teas, decoctions, tinctures, syrups, oils, ointments, and salves, or by being directly applied to the skin. Traditionally, P. major, H. perforatum, P. lanceolata A. millefolium, C. officinalis. S. nigra, T. farfara and P. domestica are the most commonly used plants for wound healing. The therapeutic value of these plants is based on the relationship that exists between the chemical structures of the active substances and their pharmacodynamic effects on the wound. In this regard, the pharmacologically active compounds that play a key role in wound healing belong to different groups of chemical compounds (terpenes, flavonoids, tannins, sterols, polyphenols, etc.) and display a wide range of activities (astringent, anti-inflammatory, antimicrobial, antioxidant, etc.). However, information concerning the quantitative benefits to human health of herbal medicines in wound healing is still scarce or fragmented, hindering a proper evaluation. The results of this study show that the traditional use of plants in wound healing is confirmed by in vitro and/or in vivo studies for P. major and P. lanceolata (3 laboratory studies for P. major and 2 for P. lanceolata), H. perforatum (5 laboratory studies and 3 clinical trials), A. millefolium (3 laboratory studies and one clinical trial), C. officinalis (6 laboratory studies and 1 clinical trial), S. nigra (3 laboratory studies) and T. farfara (one laboratory study). No clinical trials are available for P. domestica although there are a few on related species such as P. machaleb and P. avium, which points to the need to obtain this missing information. Therefore, further studies should be aimed at isolating and identifying specific active substances from plant extracts, which could also reveal compounds with more valuable therapeutic properties. Furthermore, additional reliable clinical trials are needed to confirm those experiences encountered when using traditional medicines. A combination of traditional and modern knowledge could result in new wound-healing drugs with a significant reduction in unwanted side effects. Author's contributions Snežana Jarić participated in the design of this study, data collection, data interpretation and manuscript preparation. Olga Kostić participated in the design of this study and data collection. Zorana Mataruga, Dragana Pavlović and Marija Pavlović contributed to literature research. Miroslava Mitrović and Pavle Pavlović participated in data interpretation, and helped in drafting and writing the manuscript, including a critical revision of the manuscript. All the authors have read and approved the final version of manuscript. Declaration of interest The authors declare that they have no competing interests. Acknowledgements This work was supported by the Ministry of Education, Science and Technological Development of Serbia, Grants 173018. References Abate et al., 2017 L. Abate, A. Abebe, A. 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