Salvia spp. plants-from farm to food applications and phytopharmacotherapy

Dr. Bahare Salehi

Salvia is one of the largest genera of the family Lamiaceae. It is widely distributed in the temperate, subtropical, and tropical regions all over the world. Besides its ethnobotanical importance, some species such as S. officinalis (sage, common sage), S. sclarea (clary sage), S. lavandulifolia (Spanish sage), S. miltiorrhiza (danshen), and S. hispanica (chia) are traded on the market as a food and because of the interest in their essential oils and/or popularity in traditional medicine. The high diversity of the Salvia genus and phytochemical richness generate great interest for discovering new biological active compounds, including those found in essential oils. Salvia plant essential oils exhibit broad-spectrum pharmacological activities and represent great interest for food preservation as potential natural products. Thus, this review describes the phytochemical composition of essential oils from different Salvia spp. according to the geographic regions, plant organ, and phenological stage. Moreover, the cultivation and growing conditions of Salvia plants have been also revised. Finally, the interest on Salvia plants for food and pharmaceutical applications has been covered, through reporting their biological properties, including as antioxidant, antimicrobial, anti-alzheimer, hy-potensive, anti-hyperglycemia, anti-hyperlipidemia, anti-cancer, and skin curative agents.

Trends in Food Science & Technology 80 (2018) 242–263 Contents lists available at ScienceDirect Trends in Food Science & Technology journal homepage: www.elsevier.com/locate/tifs Review Salvia spp. plants-from farm to food applications and phytopharmacotherapy T Mehdi Shariﬁ-Rada, Beraat Ozcelikb,c, Gökçe Altınb, Ceren Daşkaya-Dikmenb, Miquel Martorelld, Karina Ramírez-Alarcónd, Pedro Alarcón-Zapatae, Maria Flaviana B. Morais-Bragaf, Joara N.P. Carneirof, Antonio Linkoln Alves Borges Lealf, Henrique Douglas Melo Coutinhof, Rabin Gyawalig, Reza Tahergorabig, Salam A. Ibrahimg, Razieh Sahriﬁ-Radh, Farukh Sharopovi, Bahare Salehij,k,∗, María del Mar Contrerasl,∗∗, Antonio Segura-Carreterom,n, Surjit Seno,p, Krishnendu Acharyao, Javad Shariﬁ-Radq,r,∗∗∗ a Department of Medical Parasitology, Zabol University of Medical Sciences, Zabol 61663335, Iran Istanbul Technical University, Chemical and Metallurgical Engineering Faculty, Food Engineering Department, Ayazağa Campus 34469 Maslak Istanbul Turkey c Bioactive Research & Innovation Food Manufac. Indust. Trade Ltd., Katar Street, Teknokent ARI-3, B110, Sarıyer, 34467, Istanbul, Turkey d Nutrition and Dietetics Department, School of Pharmacy, University of Concepción, 4070386 Concepción, VIII – Bio Bio Region, Chile e Clinical Biochemistry and Immunology Department, School of Pharmacy, University of Concepción, 4070386 Concepción, VIII – Bio Bio Region, Chile f Laboratory of Microbiology and Molecular Biology, Regional University of Cariri, Crato(CE), Brazil g Food and Nutritional Sciences, North Carolina A&T State University, Greensboro NC 27411, USA h Zabol Medicinal Plants Research Center, Zabol University of Medical Sciences, Zabol, Iran i Department of Pharmaceutical Technology, Avicenna Tajik State Medical University, Rudaki 139, 734003, Dushanbe, Tajikistan j Medical Ethics and Law Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran k Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran l Departamento de Ingeniería Química, Ambiental y de los Materiales, Universidad de Jaén, Spain m Department of Analytical Chemistry, Faculty of Sciences, University of Granada, Avda. Fuentenueva s/n, 18071 Granada, Spain n Research and Development Functional Food Centre (CIDAF), Bioregión Building, Health Science Technological Park, Avenida del Conocimiento s/n, Granada, Spain o Molecular and Applied Mycology and Plant Pathology Laboratory, Department of Botany, University of Calcutta, Kolkata 700019, India p Department of Botany, Fakir Chand College, Diamond Harbour, West Bengal, 743331, India q Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran r Department of Chemistry, Richardson College for the Environmental Science Complex, The University of Winnipeg, 599 Portage Avenue, Winnipeg, MB R3B 2G3, Canada b A R T I C LE I N FO A B S T R A C T Keywords: Chia Danshen Essential oil Natural food preservative Sage Salvia Salvia is one of the largest genera of the family Lamiaceae. It is widely distributed in the temperate, subtropical, and tropical regions all over the world. Besides its ethnobotanical importance, some species such as S. oﬃcinalis (sage, common sage), S. sclarea (clary sage), S. lavandulifolia (Spanish sage), S. miltiorrhiza (danshen), and S. hispanica (chia) are traded on the market as a food and because of the interest in their essential oils and/or popularity in traditional medicine. The high diversity of the Salvia genus and phytochemical richness generate great interest for discovering new biological active compounds, including those found in essential oils. Salvia plant essential oils exhibit broadspectrum pharmacological activities and represent great interest for food preservation as potential natural products. Thus, this review describes the phytochemical composition of essential oils from diﬀerent Salvia spp. according to the geographic regions, plant organ, and phenological stage. Moreover, the cultivation and growing conditions of Salvia plants have been also revised. Finally, the interest on Salvia plants for food and pharmaceutical applications has been covered, through reporting their biological properties, including as antioxidant, antimicrobial, anti-alzheimer, hypotensive, anti-hyperglycemia, anti-hyperlipidemia, anti-cancer, and skin curative agents. Corresponding author. Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Corresponding author. Departamento de Química Analítica, Instituto Universitario de Investigación en Química Fina y Nanoquímica IUIQFN, Universidad de Córdoba, Campus de Rabanales, Ediﬁcio Marie Curie, E-14071 Córdoba, Spain. ∗∗∗ Corresponding author. Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail addresses: bahar.salehi007@gmail.com (B. Salehi), mmcontreras@ugr.es (M. del Mar Contreras), javad.shariﬁrad@gmail.com, javad.shariﬁrad@sbmu.ac.ir (J. Shariﬁ-Rad). URL: http://mar.contreras.gamez@gmail.com (M. del Mar Contreras). ∗ ∗∗ https://doi.org/10.1016/j.tifs.2018.08.008 Received 18 February 2018; Received in revised form 1 July 2018; Accepted 15 August 2018 Available online 21 August 2018 0924-2244/ © 2018 Elsevier Ltd. All rights reserved. Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. and nervous conditions (Dweck, 2005). In Europe, sage leaves have been used in traditional medicinal for symptomatic treatment of mild dyspeptic complaints such as heartburn and bloating, relief of excessive sweating, and symptomatic treatment of inﬂammations in the mouth or the throat as well as minor skin inﬂammations (European Medicines Agency, 2016a,b). In addition, this plant has been traditionally used for treating gastrointestinal problems, colds, coughs, and toothache (Craft, P., and Setzer, 2017). Today, the analysis of literature data evidenced that Salvia plants have a wide range of pharmacological activities, including anticancer, anti-inﬂammatory, antinociceptive, antioxidant, antimicrobial, hypoglycemic, hypolipidemic, memory enhancing effects, etc. (Baricevic & Bartol, 2005; Ghorbani and Esmaeilizadeh, 2017). Antimicrobial activity is one of the most cited bioactivities of Salvia essential oils, including against bacteria and fungi; e.g., S. amplexicaulis (Alimpić et al., 2017), S. chloroleuca (Yousefzadi et al., 2008), S. oﬃcinalis (Hayouni et al., 2008a), etc. Salvia genus plants represent valuable sources of biological active compounds. Probably, the main bioactive components of Salvia species are the terpene derivatives terpenoids (mono-, di-, and tri-terpenoids) (Ulubelen, 2005). Other chemical groups are phenolic acids, ﬂavanoids, tannins, and others (Dweck, 2005). Phenolic compounds, monoterpenoids and triterpenoids are usually present in aerial parts and diterpenoids are the main compounds in roots of Salvia plants (Baricevic & Bartol, 2005). Jash and co-workers reviewed about 214 triterpenoids isolated and characterized from 113 Salvia species (Jash, Gorai, and Roy, 2016). Ulubelen discussed structure-related bioactive properties of a total 111 various terpenoids in Salvia species, including diterpenoids, triterpenoids, sesquiterpenoids, and sesterterpenoids (Ulubelen, 2005). The name of many compounds comes from the term Salvia, such as salvin (triterpenoid), salvinorin (diterpenoid), salvihispin (diterpenoid), salvianolic acid (phenolic acid derivative), salvigenin (ﬂavone), sclareol (diterpenoid), and others. This high diversity of the Salvia genus and phytochemical richness generates great interest for discovering new biological active compounds. As an example, galdosol, an abietane diterpene, was isolated from the aerial parts of S. canariensis L. It has antibacterial properties against Bacillus subtilis, Micrococcus luteus and Staphylococcus aureus (Gonzalez et al., 1989). Other abietane diterpenes, sugiol and 15-hydroxy-7-oxo-abiet-8,11,13-triene, were isolated from S. albocaerulea Lindl., while forskalinone was isolated from the roots of S. forskahlei L. Five phenanthrene quinone derivatives have been identiﬁed in S. miltiorrhiza: cryptotanshinone, dihydrotanshinone I, hydroxytanshinone II-A, methyltanshionate and tanshinone II-B (Baricevic & Bartol, 2005). Three antituberculous potent diterpenoids (tested on Mycobacterium tuberculosis H 37 Rv) were isolated from S. multicaulis: 12-demethylmulticaulin, 12-demethylmultiorthoquinone, and 12-methyl-5-dehydroacetylhorminone (Ulubelen, Topcu, and Johansson, 1997). Recently, salvihispin A and its glycoside, two neoclerodane diterpenoids, were isolated from the aerial parts of Salvia hispanica (Fan et al., 2018). Salvihispin A and its glycoside exhibited high neurotrophic activities at a concentration of 10 μM (Fan et al., 2018). Regarding the essential oil of Salvia plants, their chemical composition and their various biological properties have been extensively investigated. Linalool, linalool acetate, E-caryophyllene, germacrene D, spathulenol and caryophyllene-oxide were the main constituents of the following nine Salvia species: S. nemorosa, S. sclarea (clary sage), S. macrosiphon, S. verticillata, S. eremophilsamia, S. aethiopis, S.virgata, S.reuterana, and S. limbata (Rajabi et al., 2014). In this context, due to the potential applications of Salvia plants and their essential oils in the food, cosmetics, and pharmaceutical industries, this review summarizes the phytochemical composition of the essential oils of Salvia plants, and the factors aﬀecting this composition. Moreover, it also covers the habitat and cultivation conditions of Salvia plants and revises their main bioactivities reported until present. 1. Introduction Medicinal plants can be a promising alternative for numerous diseases and conditions (Salehi, Kumar, et al., 2018; Shariﬁ-Rad, Salehi, Stojanović-Radić et al., 2017; Bagheri, Mirzaei, Mehrabi, & Shariﬁ-Rad, 2016; Stojanović-Radić et al., 2016; Setzer, Shariﬁ-Rad, and Setzer, 2016). The genus Salvia is presumably the largest genus in the family Lamiaceae consisting of more than 900 species. Salvia species are widely distributed in the temperate, subtropical, and tropical regions all over the world, from both the Old and New World: Central and South America (above 500 species), Central Asia and Mediterranean (above 250 species) and Eastern Asia (above 90 species) (Walker et al., 2004). Some of the species are cultivated all over the world, but some of them grow as endemisms in speciﬁc locations. For example, S. fruticosa Mill. is an endemism of the Eastern Mediterranean basin and S. canariensis L. is a endemic plant of the Canary Islands (Karousou, Hanlidou, and Kokkini, 2005). Fifty-eight Salvia species exist in Iran, seventeen of them are endemic of this region (Rajabi et al., 2014). In the case of S. fruticosa, its oil is produced from wild plants. Alternatively, S. oﬃcinalis L. (sage, common sage) is cultivated as an aromatic and ornamental herb worldwide, and S. sclarea in Europe and North America (Baser, 2005). Chia (S. hispanica L.) seeds have special signiﬁcance in Latin America, which has been consumed since ancient times by Mesoamerican people (Valdivia-López and Tecante, 2015), and S. miltiorrhiza (danshen) in China. Many Salvia species are cultivated for their secondary metabolites, they are used for the production of specialty materials such as essential oils, pharmaceuticals, colorants, dyes, cosmetics, and biocides (Lubbea and Verpoorte, 2011). The most economically important Salvia species are S. oﬃcinalis, S. fruticosa Miller, S. lavandulifolia Vahl. (Spanish sage), S. verbenaca L., S. sclarea L. (clary sage), and S. tomentosa Miller. Among them, S. sclarea, S. oﬃcinalis, and S. lavandulifolia were traded on the global market of essential oils with an estimated volume production ranged between 50 and 100 tonnes of essential oil per year (Lubbea and Verpoorte, 2011). S. miltiorrhiza dripping pill is the most popular Chinese medicinal product for treating coronary heart disease. It ranked topmost levels in the Chinese medicinal market among all over-the-counter drugs. In 2008, the global market for S. miltiorrhiza (danshen) dripping pill was about 205 million USD (Jia, Huang, et al., 2012). Annually, Turkey produced 600 tonnes of sage leaves (Baser, 2005). The yield of essential oil from Salvia species ranges from 0.07 to 6% (Karousou, Hanlidou, and Kokkini, 2005; Rajabi et al., 2014; Sharopov et al., 2015). However, it is diﬃcult to predict the essential oil yields. The high essential oil yield is usually associated with balsams and similar resinous plant exudations (Schmidt, 2010). Moreover, the numbers of research reported that genetic and environmental factors are highly inﬂuenced in the yield of essential oil of Salvia species (Fattahi et al., 2016; Rajabi et al., 2014). It should be noted that the essential oils, oleoresins (solvent-free), and natural extractives (including distillates) of S. oﬃcinalis, S. fruticosa, S. lavandulaefolia, and S. sclarea are generally recognized as safe for the Food and Drug Administration (USA). Franz and Novak noted that near 400 Salvia species are used in traditional and modern medicine, as aromatic herbs or ornamentals worldwide (Franz and Novak, 2010). Salvia is prominently described as oﬃcial drugs in pharmacopoeias of many countries throughout the world (Dweck, 2005). Since earliest times, sage has been an important herb with beneﬁcial healing properties in the ancient Egypt, and by Romans, Greeks, Anglo-Saxons (Dweck, 2005). In the traditional medicine, the herb has been used as a carminative, a spasmolytic, an astringent, an antiseptic, a gargle or mouthwash against the inﬂammation of the mouth, tongue and throat, a wound-healing agent, in skin and hair care, and against rheumatism and sexual debility in treating mental 243 Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. 2. Habitat and cultivation of Salvia spp. plants 2.4. Optimum growing parameters 2.1. Habitat Salvia can be easily grown indoors in any climate. Growing Salvia outdoor needs appropriate climatic conditions. The genus Salvia is a polyphyletic group and the largest genus in the family Lamiaceae. Up till now ca. 980 species have been documented. Most of the species are located in the new world where as ca. 350 species are restricted to the old world (Celep, Dirmenci, and Güner, 2015; Fernández-Alonso, 2014; Hu et al., 2014; Lara-Cabrera, BedollaGarcía, and Zamudio, 2014; Takano, Sera, and Kurosaki, 2014; Turner, 2011; Will and Claßen-Bockhoﬀ, 2017; Zhu, Min, and Wang, 2011). Since Salvia plants grows in diﬀerent geo-climatic regions around the globe, their habitat range from deserts to dry shrub-lands, deciduous woodlands, pine-oak woodlands, and submontane ever wet forest (Zona, 2017). Most species love to grow in sunny to semi-shade conditions and only some species are tolerant to cold temperature and frost. The most common habitat is black soil along stream banks, where small trees and bushes provide an environment of low light and high humidity (Clebsch, 2003). 2.5. Soil Salvia species grows well in loose rich potting soil or leaf mold, with good drainage. Using slightly aged (i.e., brown) grass clippings and a little aged steer manure mixed with rich, dark potting soil, compost and coarse sand gives better result. Whatever the soil mixture is used, soil pH should be between 6.1 and 6.6. If soil is too alkaline (above 7.0) then small amount of powdered sulfur or chelated iron can be mixed. 2.6. Temperature The ideal temperature range for the plant is about 15–27 °C. Salvia plants tolerate temperatures about 10 °C above, but below this range the plants tend to grow slowly (Beifuss, 1997). 2.2. Cultivation Salvia species are characterized by weak stems that tend to fall over if not given support. When a bent-over stem come in contact with moist soil it forms new roots and eventually put out new stems from the new location. This is the main way that the plant spreads in the wild. 2.7. Humidity Salvia prefers a humid semi-tropical climate and well-drained rich soil. When the relative humidity is above 50%, they grow well. Nevertheless, they can be grown successfully in a low humidity environment (Beifuss, 1997). The plant doesn't tolerate frost or drought. 2.3. Propagation Salvia species are propagated either asexually (stem cutting) or by sexually (seed). Plants propagated from seeds should be planted 2–3 mm deep in a good quality potting mix in moist soil (Siebert, 2010). The physiological sequence of seed germination is directly inﬂuenced by dormancy, physiological immaturity and genotype (intrinsic factors) as well as light, temperature, water availability and substrate (extrinsic factors) (Kleczewski, Herms, and Bonello, 2010). Temperature is one of the important factors aﬀecting the seed germination rate and time for germination as it controls the metabolism involved in the germination process (Marcos Filho, 2005). S. hispanica seeds germinate well at 25 °C with an alternating 8 h light and 16 h dark period (Liu et al., 2006; Paiva et al., 2016). De Paiva et al. (2016) observed that light plays a crucial role for better seedling growth and accumulation of dry matter. Aud and Ferraz (2012) reported that quality, intensity and time of light irradiation have direct role on seed germination. Diﬀerent species of Salvia requires various time intervals for seed germination but it has been found in most cases it takes approximately 6 days (Mossi et al., 2011). Hashemi and Estilai (1994) have shown that the uniform seed germination was observed when seeds were shocked with the phytohormone gibberellin. Small cuttings having 2–8 inches roots size are the best choice for propagation from cutting. It should be cut oﬀ just below the node of the mother plant. Fresh cuttings are kept indoors for about 2–3 weeks, so that they can establish a good root system in the pots. Cutting techniques and application of rooting product in Salvia species plays an important role in root system development both in terms of root number and length (Nicola, Fontana, and Hoeberechts, 2002; Nicola et al., 2003; Parađiković et al., 2013). In wet season top cutting with 9 cm–12 cm size and in dry season bottom cutting with 12 cm–15 cm are recommended for propagation (Damtew Zigene and Mengesha Kassahun, 2016). When the cuttings have several roots of 1–2 cm long, they should be planted in pots of loose potting soil and watered well, so that the soil is completely moist. In a high humid environment, roots formation takes place on the stem even before plant has fallen over. These root formations make cuttings an easy method of cultivation (Beifuss, 1997). 2.8. Misting, watering and feeding Quality of water can markedly aﬀect the growth of Salvia. Hard water (i.e. above 150 ppm hardness), or water with sodium levels above 50 ppm should be avoided because it had a deleterious eﬀect on an experimentally used Salvia species (Sociedad para la Preservatiòn de las Plantas del Misterio, 1998). Drip watering systems with misting nozzles are suitable for the plants that are grown outdoors or in a humidity tent. Fertilizers like ﬁsh emulation are used by many growers, but the ﬁshy odor attracts insect pest. To avoid this problem fertilizer that contains chelated iron, magnesium and zinc are the choice of many growers as this helps to keep soil slightly acidic. The soil should never be allowed to become dry. Watering once every 7–10 days, and misting every day, maintain proper soil moisture level, encourages aeration and protect against root rot (Sociedad para la Preservatiòn de las Plantas del Misterio, 1998). 2.9. Pest and diseases There are a number of insects that commonly feast on Salvia and which if not controlled, can severely stress the plant, or in extreme cases prove fatal. Whiteﬂies (Trialeurodes vaporariorum), spider mites (Tetrancychidae spp.), aphids (Aphididae spp.) and snails are the common pests of Salvia. All the common pests of S. divinorum are relatively easy to control, and an attentive gardener should notice their appearance before any infestation becomes critical. The most important infectious diseases of sage in European countries are antracnosis caused by Colletotrichum dematium, ascochitosis caused by Ascochyta sclarea and root rot caused by Rhizoctonia solani (Subbiah et al., 1996). Economically important pathogens in Italy and Spain include Phomopsis sclarea, Phodosphaera inequalis, Erysiphae polygoni and Sclerotinia sclerotiorum (Subbiah et al., 1996). Altenaria alternata was commonly isolated from the leaves with necrotic symptoms (Zimowska, 2008). It has also been reported that Salvia plants exhibited virus like symptoms of chlorotic line patterns and ringspot (Holcomb and Valverde, 1998). 244 Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. 3. Phytochemical composition of Salvia spp. plants essential oils 3.1. Phytochemical classes Essential oils of plants contain terpenoids that have positive eﬀects on the health (Shariﬁ-Rad, Ayatollahi, et al., 2017; Shariﬁ-Rad, Varoni, et al., 2017; Shariﬁ-Rad et al., b, c, d, e, f, 2017a; Salehi et al., 2017; Shariﬁ-Rad, Salehi, Schnitzler, et al., 2017; Salehi, Mishra, et al., 2018; Shariﬁ-Rad, Varoni, et al., 2018; Shariﬁ-Rad, Mnayer, et al., 2018). The phytochemical composition of essential oils is very diverse, but generally hydrocarbons and oxygenated species are found to contribute to the main antioxidant properties (Shariﬁ-Rad, Sureda, et al., 2017; Miguel, 2010). As an example, more than 120 components have been characterized in the essential oil obtained from aerial parts of S. oﬃcinalis (Ghorbani and Esmaeilizadeh, 2017). In general, the essential oil composition of Salvia spp. are comprising of monoterpene hydrocarbones, oxygenated monoterpenes, sesquiterpene hydrocarbones, oxygenated sesquiterpenes and other cycloaliphatic compounds (nonterpenoid compounds structurally related to the cyclic terpenes) and aromatic compounds (Georgiev et al., 2013). The classiﬁcation of major phytochemicals of essential oils of Salvia species is shown in Table 1. S. oﬃcinalis may content α-thujone, β-thujone, 1,8-cineole, αpinene, camphor, caryophyllene, germacrene D, viridiﬂorol, elemene, α-humulene, linalool, borneol, and ledene (Ghorbani and Esmaeilizadeh, 2017), whose relative amounts depends on several factors, e.g., phenological state, agricultural practices, pedoclimatic conditions, etc. Gurjunene, β-elemene, germacrene D, spathulenol and n-hexyl acetate were identiﬁed as major components in the essential oils of S. reuterana Boiss. collected from seven wild-growing populations (Fattahi et al., 2016). A cluster analysis of the compositions of 39 essential oils of S. sclarea from the published literature has shown that most of the essential oils belong to the chemotype rich in linalyl acetate and linalool (Sharopov and Setzer, 2012; Sharopov et al., 2015). In addition, geraniol/geranyl acetate-rich chemotype (Elnir et al., 1991), a methyl chavicol-rich chemotype (Moretti, Peana, and Satta, 1997), a germacrene-D-rich chemotype (Carrubba et al., 2002), and α-thujone, thujene, and manool oxide/phytol chemotypes (Taarit et al., 2011) of S. sclarea have been identiﬁed. Based on their main volatile compounds, it has been described in European species three chemotypes for S. oﬃcinalis: 1, α-pinene, camphor and β-thujone, 2, α-thujone, camphor and 1,8-cineole, as well as 3, β-thujone and camphor; two chemotypes for S. lavandulifolia: 1, β-pinene, 1,8-cineole and caryophyllene, as well as 2, limonene; two chemotypes for S. fruticosa: 1, 1,8-cineole and camphor, as well as 2, β-thujone and 1,8-cineole (Franz and Novak, 2010). In another context, from a chemotaxonomical point of view, some groups of substances are more common in the biosynthetic pathway for certain taxa. As an example, eucalyptol (1,8-cineole) is present in several Salvia spp. (S. oﬃcinalis, S. lavandulifolia and S. fruticosa) (Franz and Novak, 2010). However, no phenylpropenes were detected in these species (Franz and Novak, 2010). In other cases, some compounds can be Fig. 1. Chemical structures of some active terpenoids from essential oils of Salvia spp.: (1) caryophyllene, (2) caryophyllene oxide, (3) germacrene D, (4) camphor, (5) 1,8-cineole, (6) borneol, (7) α- and (8) β-thujone. chemotaxonomic markers of Salvia spp. For instance, thujenone was mentioned to be as chemotaxonomic marker in S. staminea (Rzepa et al., 2009). These phytochemicals have diﬀerent biological activities. For instance, caryophyllene and its oxide (Fig. 1) are eﬀective anti-inﬂammatory, antioxidant and antimicrobial agents (Liang et al., 2009), while the germacrene D (Fig. 1) is an eﬀective larvicidal crop protector (Teles et al., 2013). Moreover, bioactive compounds in the essential oils can show synergistic eﬀect. This was the case of camphor and thujone (Fig. 1) in S. oﬃcinalis, which were demonstrated to exert a potentially synergistic anticancer eﬀect (Russo et al., 2013). The extracts of Salvia spp. are used in food, pharmaceutical and cosmetic industry, hence determination of their toxicity and quality parametries are crucial (Özcelik et al., 2009). The International Organization for Standardization (ISO) regulates the percentages of the eleven constituents, which are α-pinene, camphene, limonene, 1,8-cineole, linalool and its esters, cis-thujone (β-thujone), trans-thujone (α-thujone), camphor, bornyl acetate and α-humulene in the essential oils of S. oﬃcinalis for its medicinal uses (International Organization for Standardization, 1997). According to the ISO (1997), high-quality sage oil should contain 3–8.5% trans-thujone and 18–43% cis-thujone, whereas a high content Table 1 Classiﬁcation of major phytochemicals in essential oil of Salvia species. Monoterpene hydrocarbons • α-Pinene • β-Pinene • Myrcene • Camphene • Limonene • β-Ocimene • α-Thujone • β-Thujone • β-Phellandrene Oxygenated monoterpenes acetate • Bornyl • Camphor • Linalool • 1,8-Cineole • Borneol • α-Terpineol • Eugenol • Linalool Sesquiterpene hydrocarbons • Aristolone • Aromadendrene • α-Humulene • α-Cadinol • α-Copaene • β-Caryophyllene -Guaiene • βγ-Muurolene • Bicyclogermacrene • Germacrene D • β-Caryophyllene • δ-Cadinene 245 Oxygenated sesquiterpenes • α-Amorphene oxide • Caryophyllene • Elemenone • β-Eudesmol • τ-Cadinol • Viridiﬂorol • Spathulenol 0thers • (E)-caryophyllene acetate • linalyl • labdadiene-8-ol • sclareoloxide acetate • sabinyl • 1-octen-3-ol M. Shariﬁ-Rad et al. Table 2 The main phytochemical composition of diﬀerent Salvia species according to the geographic regions, phenological stage and plant organ. 246 Salvia species Geographic regions Phenological stage Part Essential oil composition (main phytochemicals) Reference S. adenophylla S. aristata Turkey Iran Aerial parts Aerial parts α-pinene (16.2%), β-pinene (14.4%) Benzene,1,3-bis(m-pheoxypheoxy) (95.42%) (Kaya et al., 2017) (Farshid, Rashid, and Reza, 2015) S. aurea Lebanon Flowering stage Beginning stage of ﬂowering Flowering stage Arial parts (Russo et al., 2016) Salvia chudaei Algeria Flowering stage Aerial parts S. S. S. S. China China Spain Iran Flowering Flowering Flowering Flowering Leaves Flowers Aerial parts Aerial parts S. hypoleuca Iran Flowering stage S. S. S. S. S. Cyprus Spain Spain Spain Iran Vegetative stage Vegetative stage Full ﬂowering stage Vegetative stage Flowering stage Aerial parts Aerial Aerial Aerial Aerial Aerial S. miltiorrhiza China Flowering stage Leaves S. oﬃcinalis Montenegro Flowering phase Arial parts S. S. S. S. oﬃcinalis oﬃcinalis oﬃcinalis oﬃcinalis China China Albania Spain Flowering Flowering Flowering Flowering stage stage stage stage Leaves Flowers Leaves Aerial parts Caryophyllene oxide (12.5%), α-amorphene (12.0%), aristolone (11.4%), aromadendrene (10.7%), elemenone (6.0%), camphor (2.4%), bornyl acetate (2.0%) Bornyl acetate (20.5%), β-eudesmol (13.6%), β-caryophyllene (10.6%), valencene (9.3%), τ-cadinol (9.3%), α-pinene (6.9%), γ-cadinene (5.8%) Ledol (8.36%), caryophyllene oxide (5.99%), 1-octen-3-ol (4.98%) β-phellandrene (29.74%), 4-terpineol (10.91%), ledol (6.98%) β-pinene (20.24%), γ-muurolene (11.48%), 1,8-cineole (11.00%), guaiol (6.15%) Bicyclogermacrene (1.5–37.3%), β-pinene (2.1–29.8%), α-pinene (1.4–29.3%), (E)-caryophyllene (2.1–21.7%) Bicyclogermacrene (1.5–37.3%), (E)-caryophyllene (2.1–21.7%), β-pinene (2.1–29.8%), α-pinene (1.4–29.3%) Thymol (12.1%), hexadecanoic acid (6.0%), carvacrol, α-thujone (5.7%), β-thujone (3.8%), 1,8-Cineole (25.20%), camphor (10.99%), β-pinene (9.77%), α-pinene (10.90%), camphene (6.87%) 1,8-Cineole (31.30%), camphor (15.59%), β-pinene, (11.83%), α-pinene (7.52%), camphene (6.27%) 1,8-Cineole (13.5–31.9%), camphor (14.4–23.9%) Camphor (12.0–39.9%), 1,8-cineole (3.6–21.8%), β-pinene (8.7–18.1%), α-pinene (4.4–10.0%), borneol (2.4–9.2%), Δ-cadinene (3.5–6.5%) β-Caryophyllene (11.05%), aromadendrene oxide (8.3%), caryophyllene oxide (7.93%), α-cadinol (7.31%), germacrene D (6.82%), 1-octen-3-ol (6.43%) cis-Thujone (16.98–40.35%), camphor (12.75–35.37%), 1,8-cineole (6.40–12.06%), trans-thujone (1.5–10.35%), camphene (2.26–9.97%), borneol (0.97–8.81%), viridiﬂorol (3.46–7.8%), limonene (1.8–6.47%), α-pinene (1.59–5.46%), α-humulene (1.77–5.02%) β-thujone (14.86%), eucalyptol (14.82%), camphor (12.7%) α-thujone (19.63%), β-pinene (15.15%), eucalyptol (14.91%) Camphor (26.6 %–43.8%), α-thujone (15.9%–30.7%), 1,8-cineole (8.4 %–14.7%) α-Thujone (22.8–41.7%), camphor (10.7–19.8%), 1,8-cineole (4.7–15.6%), β-thujone (6.1–15.6%) S. S. S. S. S. pilifera przewalskii przewalskii reuterana ringens Turkey China China Iran Bulgaria Flowering Flowering Flowering Flowering Flowering stage stage stage stage stage Aerial parts Leaves Flowers Aerial parts Leaves S. ringens Bulgaria Flowering stage Flowers S. shariﬁi Iran Beginig of ﬂowering stage Aerial parts S. staminea Turkey Full ﬂowering stage Aerial parts S. syriaca Iran Aerial parts S. uliginosa Spain Beginning of the ﬂowering stage Full ﬂowering stage S. viscosa Turkey Flowering stage Aerial parts deserta deserta greggii hypoleuca lanigera lavandulifolia lavandulifolia lavandulifolia leriifolia stage stage stage stage ﬂowering parts parts parts parts parts (Li et al., 2015) (Li et al., 2015) (Giuliani, Ascrizzi, Corrà, et al., 2017) (Sonboli, Salehi, and Gharehnaghadeh, 2016) (Sonboli, Salehi, and Gharehnaghadeh, 2016) (Tenore et al., 2011) (Porres-Martínez et al., 2014) (Porres-Martínez et al., 2014) (Porres-Martínez et al., 2014) (Youseﬁ, Nazeri, and Mirza, 2012) (Li et al., 2015) (Stešević et al., 2014) (Li et al., 2015) (Li et al., 2015) (Tosun et al., 2014) (Cutillas, Carrasco, Martinez-Gutierrez et al., 2017a,b) (Kaya et al., 2017) (Li et al., 2015) (Li et al., 2015) (Fattahi et al., 2016). (Georgiev et al., 2013) (Georgiev et al., 2013) (Asgarpanah, Oveyli, & Alidoust, 2017) Linalyl acetate (23.30%), linalool (22.05%), spathulenol (10.02%), caryophyllene oxide (5.45%), αterpineol (4.89%), sclareol (4.85%), sclareoloxide (2.89%) 1,8-Cineole (46.45%), camphor (27.58%), bornyl acetate (4.66%), sabinyl acetate (3.18%) (Çolak et al., 2017) Bicyclogermacrene (16.30%), germacrene D (14.81%) β-caryophyllene (8.57%), δ-Cadinene (8.47%), spathulenol (12.66%) α-copaene (13.0%), β-caryophyllene (10.8%), γ-muurolene (9.8%), δ-cadinene caryophyllene oxide (8.0%) (Giuliani, Ascrizzi, Tani, et al., 2017) (Farshid, Rashid, and Reza, 2015) (Kaya et al., 2017) Trends in Food Science & Technology 80 (2018) 242–263 Aerial parts β-pinene (24.9%), myrcene (9.0%), α-humulene (7.9%) Limonene (20.5%), α-terpineol (4.66%), α-eudesmol (4.08%) Limonene (3.65%) Gurjunene, β-elemene, germacrene D, spathulenol and n-hexyl acetate Camphor (17.2%), borneol (7.2%), β -pinene (6.0%), β-trans-o-cimene (4.0%), germacrene D (3.5%), α -limonene (3.3%), α -pinene (3.1%), o-cymene (3.1%), eucalyptol (3.1%) Camphor (18.8%), borneol (8.7%), camphene (5.0%), β-pinene (4.0%), α-caryophyllene (3.4%), eucalyptol (3.4%), o-cymene (3.3%), α-pinene (3.2%), α -limonene (3.1%) Germacrene D (30.3%), bicyclogermacrene (15.7%), trans-β-caryophyllene (12.3%), labdadiene-8-ol (10.1%) (Krimat et al., 2015) Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. key factors to control crop growth and productivity (Bernstein et al., 2009; Marschner, 2011). Indeed, these factors could be eﬀective on the essential oil content and/or composition of the plants (Omer et al., 2014; Ramezani, Rezaei, and Sotoudehnia, 2009; Sharma and Kumar 2012; Zheljazkov, Astatkie, and Hristov, 2012). In addition to mineral availability in the soil, the water status of the plant is crucial factor on the yield of the essential oil which may have function on the essential oil composition (Letchamo and Gosselin, 1995; Petropoulos et al., 2008; Vahidipour et al., 2013). Studies have shown that the eﬀect of water status and nutrition on the essential oil composition of S. oﬃcinalis could be diﬀerent. Corell et al. (2007) reported a reduction in total essential oil production under reduced irrigation. However, Bettaieb et al. (2009) showed that both moderate and severe water deﬁcit improved the yield of Salvia spp. From the perspective of essential oil composition, Rioba et al. (2015) have highlighted increasing nitrogen levels lead to increase of the percentage of β-pinene and reducing irrigation frequency caused to decrease of the β-pinene level. Interactive eﬀects between N and P treatments were reported for contents of both α- and β-thujones, and α-thujone accumulation was aﬀected also by the interaction between irrigation frequency and phosphorus application. Recently, the function of arbuscular mycorrhizal (AM) fungus, which is beneﬁcial for plant by making the absorption of the nutritive minerals more eﬃcient (Schnepf, Jones, and Roose, 2011) have been investigated as an agricultural practice. They have reported that the AM fungi caused to plant terpenoid variability since an enzymatic and phytohormone balance is up-regulated by this fungi symbiosis (Tarraf et al., 2017). of neurotoxic thujone limits the internal application of its products, as commented before. Among them, the β-diastereomer (Fig. 1) is generally of lower toxicity (Höld et al., 2000). Since the genus Salvia includes nearly 1000 species, the essential oil composition of Salvia spp. could be diﬀerent depending on their origins (Dizkirici et al., 2015). In addition, there are several extrinsic/intrinsic factors which may aﬀect the compositional characteristics of essential oil of Salvia spp. such as agricultural pratices (Govahi et al., 2015; Rioba et al., 2015; Uluata, Altuntaş; Özçelik, 2016; Tarraf et al., 2017), light intensity (Li, Craker, and Potter, 1995), organ age and organ type (Länger et al., 1993; Santos-Gomes & Fernandes-Ferreira, 2001), the growth and developmental stage (Lakušić et al., 2013), season of harvesting and diﬀerent plant parts processed (Verma, Padalia, and Chauhan, 2015). The main phytochemical composition of diﬀerent Salvia spp. according to the geographic regions, plant organ and phenological stage (harvesting time) are summarized in Table 2. 4. Essential oil composition of Salvia spp. from diﬀerent geographic regions The composition of phytochemicals may vary in the same Salvia species but growing in diﬀerent geographic regions (Georgiev et al., 2013). While Tosun et al. (2014) reported to that the camphor was the main phytochemical compound of essential of S. oﬃcinalis in Albenia at ﬂowering stage; β-thujone the major phytochemical in the same species at the same phenological stage but growing in China (Li et al., 2015), and α-thujone in China (Li et al., 2015) and Spain (Cutillas, Carrasco, Martinez-Gutierrez et al., 2017a,b) (Table 2). The β-Thujone was also reported to be the major constituent of the volatile oil from S. oﬃcinalis produced in Portugal, Reunion Island, Albania, and New Zealand (Mockutë et al., 2003; Perry et al., 1999; Santos-Gomes & FernandesFerreira, 2001; Vera, Chane-Ming, and Fraisse, 1999). The predominant component in the extracts of Salvia spp. from Croatia and Italy was reported as camphor (Baratta, Dorman, Deans, Biondi, & Ruberto, 1998; Giamperi, Fraternale, and Ricci, 2002; Mastelić, 2001). Indeed, viridiﬂorol and manool were reported as major components in Salvia spp. from Cuba (Lawrence, 2006). Intermedeol, 1,8-cineole, and linalyl acetate were found as the major components in the essential oils of Salvia species cultivated from Heidelberg, Germany (Sharopov et al., 2015). 7. Eﬀect of phenological stage on essential oil composition of Salvia spp. It has been demonstrated that the essential oil yield varied depending on harvesting season (phenological stage) which was highest in summer (0.43%), followed by the rainy season (0.37%), spring (0.25%) and autumn (22%), respectively. As far as phytochemical composition were considered, the predominant essential oils in the extracts of S. oﬃcinalis from India were oxygenated monoterpenes (42.1–76.3%) and were found at higher level in the summer season (76.3%), followed by rainy (74.7%), and autumn seasons (73.3%). Besides, the level of oxygenated monoterpenes were higher in the stem part (55.0%) (Verma, Padalia, and Chauhan, 2015). Since harvesting season aﬀect the essential oil composition, the antioxidant capacity of the essential oil of the plant also aﬀected from this changes. Porres-Martínez et al. (2014) reported that in full ﬂowering stage essential oil of S. lavandulifolia contained high amount of oxygenated derivatives compounds, which showed higher antioxidant capacity compared to hydrocarbons derivatives compounds in vegetative stage. The changes of essential oil composition of S. oﬃcinalis during its growing cycle were investigated by Farhat et al. (2016). They indicated that essential oil of aerial parts of S. oﬃcinalis were rich in camphor and α-thujone at the fruitining phase, whereas 1,8-cineole comprised the highest proportions at ﬂowering phase and at vegatative phase viridiﬂorol is the main compound. 5. Essential oil composition of diﬀerent organs of Salvia spp. The essential oil composition of the plant organ could be diﬀerent. Li et al. (2015) investigated diﬀerence between the essential oil proﬁles of plant organs. They selected four diﬀerent Salvia spp., S. miltiorrhiza, S. przewalskii, S. oﬃcinalis, and S. deserta (Table 2), and indicated that essential oil proﬁle of these Salvia species showed strong tissue and organ speciﬁcity. The importance of the plant part on the phytochemical composition was reported in other studies. In this sense, Velickovic et al. (2003) reported that the extracts of S. oﬃcinalis leaf, ﬂower and stem from Serbia had a diﬀerent the ratio of α-pinene and 1,8-cineole, being higher in the ﬂower extract. The other phytochemicals, camphene, limonene, cis-thujone, trans-thujone, camphor, bornyl acetate, and α-humulene, were observed to be higher in the leaf extract and the level of linalool was found highest in the stem extract. Moreover, Giuliani et al. (2017a,b) showed that the leaf of the S. uliginosa is rich in 1,8-cineole and trans-γ-cadinene, while germacrene D is the major phytochemical of essential oil in its ﬂower. 8. Food applications of Salvia spp. plants The increasing number of microorganisms that are antibiotic resistant and more tolerant to existing preservative techniques is a worldwide concern. As a result, there is a growing interest among food processors and consumers in reducing the use of synthetic preservatives in food preservation and opting instead for natural plant-derived antimicrobial preservatives (Bor et al., 2016; Gyawali, Hayek, and Ibrahim, 2015a; Gyawali and Ibrahim, 2014; Raeisi, Ojagh, Shariﬁ-Rad et al., 2017; Raeisi et al., 2016). The antimicrobial and antioxidant properties of herbs, spices, and their essential oils have been shown to exert antimicrobial activity against food spoilage and foodborne pathogens. Among several herbs, the genus Salvia has long been known for its 6. Eﬀect of agricultural practices on essential oil composition of Salvia spp. Agricultural practices are one of the important factors that inﬂuences the essential oil yield and composition of the plants. The nutritive minerals like phosphorus (P) and nitrogen (N) have been considered as 247 Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. during 30 days storage at 60 °C were investigated by Ghadermazi, Keramat, and Goli (2017). The results of this study showed that the three essential oils reduced soybean oil oxidation at 1 mg/mL, and therefore they could be used as preservatives instead of synthetic antioxidants to enhance the food safety. Tepe et al. (2005) investigated the antioxidant activities of the essential oil and various extracts of S. tomentosa (balsamic sage) and found that aqueous methanol extract was the most eﬀective antioxidant. The aqueous methanol extract showed higher free radical scavenging activity, and the inhibition of linoleic acid induced oxidation was found to be similar to that of the synthetic antioxidant butylated hydroxytoluene. Similarly, another study also showed the presence of higher phenolic content in the leaf's extract of S. oﬃcinalis which possesses strong antioxidant activities compared to that of BHT and ascorbic acid (Vitamin C) (Abdelkader, Bouznad, Rachid, & Hamoum, 2014). The extract and essential oils of S. triloba (Greek sage) and S. lanigera are free radical scavengers and have been shown to produce greater reducing power, which is considered as an indication of potential antioxidant activity (Tenore et al., 2011; Yıldırım et al., 2000). Özogul, Kuley, and Kenar (2011) investigated the eﬀect of S. oﬃcinalis tea extracts on biogenic amines (BAs) formation in vacuum packed refrigerated ﬁsh ﬁllets. Among several BAs found in ﬁsh, histamine (HIS), cadaverine (CAD), and putrescine (PUT) have been found to negatively aﬀect the ﬁsh quality. It has been found that sage tea extract signiﬁcantly reduced these BAs and trimethylamine accumulation in ﬁsh muscle during storage, whereas in the control, a 100-fold higher amount of PUT and CAD were present. These results demonstrated that sage extract can be used to improve the shelf-life of ﬁsh. Based on our literature review, it can be conﬁrmed that the majority of the Salvia spp. have some level of DPPH radical scavenging ability. Essential oils and extract from Salvia spp. rich in phenolic compounds act as free radical scavengers, being a good source of natural antioxidants. culinary and medical values, and it also has the potential to be used as a natural preservative in food applications. The antimicrobial activity of Salvia spp. is well recognized and is attributed to the presence of several active components (Delamare et al., 2007; Dorman and Deans, 2000). In general, compounds with phenolic groups are the most eﬀective against spoilage and pathogenic microorganism (Dorman and Deans, 2000). Among several species of Salvia, Salvia oﬃcinalis is the most common species that has been tested and proven to be eﬀective in several food applications. Common sage produces an extremely broad range of cyclic monoterpenes bearing diverse carbon skeletons, including members of the p-menthane (1,8-cineole), pinane (α- and βpinene), thujane (α- and β-thujone), camphane (camphene), and bornane (camphor) families. As an example, most studies have shown that 1,8-cineole (eucalyptol) and borneol (Fig. 1) are the primary and/or characteristic constituents of Salvia oils (Kelen and Tepe, 2008; Marino, Bersani, and Comi, 2001), with relatively high abundance in some species (Table 2). These components have been shown to possess antimicrobial, antioxidant and antifungal activities. As a result, Salvia spp. are particularly useful as natural preservatives to improve the microbiological quality and safety of foods (Tenore et al., 2011). In particular, the essential oils of Salvia spp. have shown bacteriostatic and bactericidal properties against several groups of food spoilage microorganisms as well as foodborne pathogens. These antimicrobials are used in foods for two main purposes: (1) in food preservation to control natural spoilage processes, and (2) for food safety to prevent or control the growth of microorganisms, including pathogenic bacteria (Tajkarimi, Ibrahim, and Cliver, 2010). The following sections discuss the eﬃcacy of Salvia spp. with regard to food preservation and food safety. 9. Food preservation In order to prolong the storage stability of foods, synthetic antioxidants are commonly used in food processing. However, synthetic antioxidants such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) have side eﬀects on human health and also have been documented as carcinogenic compounds (Tepe et al., 2005). Therefore, it is important to ﬁnd alternative agents in order to limit the contact with lipid oxidation products in foods in order to avoid the undesirable eﬀects of oxidized lipids on human health (Karpińska, Borowski, and Danowska-Oziewicz, 2001; Raeisi, Ojagh, Shariﬁ-Rad et al., 2017; Shariﬁ-Rad et al., 2016). Oxidation of lipids occurs during raw material storage, processing, heat treatment and further storage of the ﬁnal product. This process is considered to be one of the primary causes of rancidity in food products which, leads to product deterioration. Crude extracts of Salvia and essential oils are of increasing interest in the food industry because these extracts retard the oxidative degradation of lipids and thereby improve the quality and nutritional value of the food product. Research has shown that Salvia's eﬃcacy is comparable to that of synthetic preservatives and can thus be used in as a natural preservative. Consequently, several spp. of Salvia have potential to be as antioxidants and against spoilage microorganisms such as Pseudomonas aeruginosa and Bacillus cereus strains (Kelen and Tepe, 2008; Kostić et al., 2015). Sage essential oil at 3% has been shown to reduce the oxidation of raw or cooked porcine and bovine meat during refrigerated storage (1–12 days) using a thiobarbituric acid assay, a diphenylpicrylhydrazyl (DPPH) assay and a crocin assay (Fasseas et al., 2008). Mariutti et al. (2008) investigated the eﬀect of sage on pressure induced lipid oxidation in chicken breast. The results of their study showed that 0.1 g of dried sage leaves/100 g of meat, protected chicken breast processed under high hydrostatic pressure (800 MPa) for 10 min against lipid oxidation during storage at 5 °C for 2 weeks. The eﬀects of diﬀerent essential oils, including clove (Eugenia caryophyllata Thunb), oregano (Oringanum vulgare L) and sage, on the oxidation rate of soybean oil 9.1. Food safety The antimicrobial activity of Salvia plants has the potential to inﬂuence the prevalence of both susceptible and resistant foodborne microorganisms. Therefore, essential oils and extracts could be used as alternatives to the increasing use of synthetic preservatives to enhance microbial food safety. The essential oil of S. oﬃcinalis was found to be active against Escherichia coli, Salmonella enteritidis, Bacillus cereus, Bacillus subtilis, Candida albican, Staphylococcus aureus, and Aspergillus niger (Abdelkader et al., 2014; Miladinović and Miladinović, 2000). Combining S. triloba with oregano has also been shown to increase the lag phase of E. coli when compared with individual essential oils treatments. The combination of sage and thyme also had promising eﬃcacy against E. coli and Listeria monocytogenes (Gutierrez, BarryRyan, and Bourke, 2008). A study by Cui et al. (2015) has shown that essential oils of S. sclarea had inhibitory activity against the growth of E. coli, S. aureus, Bacillus pumilus, K. pneumoniae, B. subtilis, Salmonella Typhimurium, and P. aeruginosa with a minimum inhibitory concentration and minimum bactericidal concentration of 0.05 and 0.1%, respectively. Bozin et al. (2007) tested the antimicrobial activity of S. oﬃcinalis essential oil against several strains of bacteria and fungi and found that it was eﬀective against E. coli, Salmonella Typhi, S. enteritidis, and Shigella sonei. Mosafa, Yahyaabadi, and Doudi (2014) investigated the antibacterial eﬀect of ethanol extract of S. oﬃcinalis (leaves and stems) on the four species of common pathogenic bacteria (S. aureus, E. coli, P. aeruginosa and Klebsiella pneumonia) that are resistant to a variety of drugs. The results of this in vitro study indicated that sage extract can also help prevent the growth of multidrug resistant bacteria. Recently, the antimicrobial eﬃcacy of diﬀerent extracts of S. chorassanica against several Gram-positive and -negative bacteria were evaluated by Mehraban et al. (2016). The authors found that the greatest inhibitory eﬀects on tested bacteria were noted with ethanolic and hydro alcoholic extracts. They also observed that Gram-positive 248 249 Šojić et al. (2017). Selim (2011). Cui et al. (2015). Ahmed and Ismail (2010). Selim (2011). Mahdavian Mehr et al. (2010). Hayouni et al. (2008b). Total mesophilic aerobic count S. oﬃcinalis by-product extract powder 0.05, 0.075, 0.1 μL/g Pork sausage S. oﬃcinalis EO 0.5, 1%,v/w Feta cheese S. oﬃcinalis EO 0.5, 1%, v/w E. coli ATCC 25922 Aerobic & anaerobic bacteria, enterobacteriaceae, yeastmould, B. cereus and S. aureus Vancomycin resistant Enterococci (VRE) and E. coli O157:H7 Vancomycin resistant Enterococci and E. coli O157:H7 Beef slurry Minced beef mixed with soy-protein Minced beef S. sclarea EO S. oﬃcinalis EO 0.1%, v/v 0.3, 0.5% E. coli ATCC 25922 E. coli ATCC 25922 Chicken slurry Pork slurry S. sclarea EO S. sclarea EO 0.1%, v/v 0.1%, v/v Minced beef meat S. oﬃcinalis EO 1.5, 2, 3%,v/w Salmonella spp. A reduction of 0.84 and 1.29 log CFU/g for S. aureus and total viable count was observed on 45 d of storage at −12 °C Decreased of 2.1, 2.6, & 2.8 log CFU/g at 1.5, 2, and 3% respectively in 3 days Diﬀerences of ∼7.0 log CFU/mL after 48 h of incubation at 30 °C Diﬀerence of ∼7.0 log CFU/mL with control after 48 h of incubation at 30 °C Diﬀerences of ∼6.0 log CFU/mL after 48 h of incubation at 30 °C Signiﬁcantly reduced the microbial counts in the samples during the 7 days of storage at 4 °C At least 2-log cycle reduced in the VRE and E. coli O157:H7 counts in meat sample during 14 days of storage at 7 °C At least 2-log cycle reduced in the VRE and E. coli O157:H7 counts in cheese during 14 days of storage at 7 °C Reduction of 1.16 log CFU/g after 8 days of storage at 3 ± 1 °C when compared to control Total viable count & Staphylococcus aureus ATCC-29737 Hamburger S. leriifolia leaf extract 20,000 mg/L Target microorganisms Concentration applied Food types Essential oil (EO) or component Table 3 Antimicrobial activity of Salvia spp. against foodborne microorganisms in model food systems. Observations References bacteria (S. aureus, Enterococcus faecalis) are more sensitive to root extract compared to Gram-negative (E. coli, S. typhimurium) bacteria. The essential oil and the methanol extract obtained from the aerial parts of S. veneris were tested against seven Gram-negative and ﬁve Gram-positive bacteria. The strongest inhibitory eﬀect was detected in methanol extract against L. monocytogenes with a minimal inhibitory concentration (MIC) value of 60 μg/mL. The essential oil showed relatively weak antimicrobial activity compared to the methanol extract (Toplan et al., 2017). Some studies have also tested the eﬃcacy of Salvia spp. against several microorganisms in food systems (Table 3). In fact, Salvia plants are used as herbal tea and for food ﬂavouring agents. Šojić et al. (2017) investigated the eﬀect of S. oﬃcinalis herbal dust (a food industry byproduct) essential oil (0.05–0.1 μL/g) against microbial growth in fresh pork sausages to improve the safety of the meat product during storage. The addition of this essential oil reduced the microbial growth in fresh pork sausages and it had no negative eﬀect on sensory properties of this meat product at 0.05 μL/g. Among the constituents, the essential oil contained oxygenated monoterpenes, oxygenated sesquiterpenes and diterpene polyphenols (Šojić et al., 2017). Azizkhani and co-authors investigated the inhibitory activities of S. sclarea essential oil against chemical and microbial spoilage in Iranian white cheese. The minimal inhibitory and bactericidal concentrations for this essential oil were 0.015 and 0.02% against L. monocytogenes and 0.5 and 0.65% against Aspergillus ﬂavus, respectively. At 1%, the latter oil inhibited fungal growth in the cheese throughout the storage period and reduced bacterial growth [30]. In addition, Hayouni and co-workers had focused on the correlation between the chemical composition of the essential oil of S. oﬃcinalis and its eﬀectiveness as antimicrobial against Salmonella inoculated in minced beef meat. Results showed that S. oﬃcinalis essential oil exhibited stronger antimicrobial activity, probably due to its particular chemical pattern mainly the high amounts of 1,8-cineole, α/ β-thujone and borneol (Figs. 1 and 2). Foods are complex matrices, and the inhibitory action of Salvia essential oils may depend on food composition such as protein, fat, and water content (Gutierrez, Barry-Ryan, and Bourke, 2008; Shelef, Jyothi, and Bulgarellii, 1984; Tassou and Nychas, 1994). Shelef, Jyothi, and Bulgarellii (1984) reported that resistance to Salvia essential oils increased with the decrease in water content and increase in protein and fat content in foods. These authors indicated that beef, which had less water and more protein and fat, contributed a more protective action to bacteria than the rice and strained chicken. Therefore, it is expected that the antimicrobial performance of Salvia spp. against various microorganisms in food systems can vary (Table 3). The antimicrobial activity of essential oils cannot be attributable to only one speciﬁc mechanism. Essential oils can damage the microbial cell wall, disturb the phospholipid bilayer of the cytoplasmic membrane, and damage the membrane proteins, which leads to an increased permeability of the cell membrane and a loss of cellular contents. In addition, these active compounds disrupt the proton motive force, electron ﬂow and active transport, and coagulate the cell components. Essential oils and active compounds can impair a variety of enzyme systems causing inactivation or destruction of genetic material and ultimately causing cell death (Gyawali and Ibrahim, 2014; Gyawali, Hayek, and Ibrahim, 2015a, 2015b; Jayasena and Jo, 2013). Either essential oils or extracts rich in phenolic compounds of various Salvia spp. have the potential to be used in food systems. Consequently, Salvia spp. can be used to prevent food spoilage or to inhibit the proliferation of foodborne bacteria and thereby enhance food safety as well as shelf life. Future research should be carried out on various food systems, and it is also necessary to conduct the sensory evaluation of foods containing Salvia spp. as preservatives. Typically, in order to achieve a higher microbial reduction, higher concentrations of essential oils or extracts are needed, which may adversely aﬀect the organoleptic characteristics of foods. To minimize this eﬀect, it would be desirable to study the synergistic eﬀects of Salvia spp. with other natural Cui et al. (2015). Cui et al. (2015). Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. Fig. 2. Chemical structures of: (1) Salvianolic acid B and (2) A, (3) tanshinone I and (4) IIA, as well as (5) cryptotanshinone. Tanshinone I and IIA (Fig. 2) inhibit amyloid aggregation by amyloid-β peptide, disaggregate amyloid ﬁbrils, and protect SH-SY5Y neuroblastoma cells from Aβ-induced toxicity (Wang et al., 2013). Additionally, cryptotanshinone (Fig. 2), a lipophilic compound extracted of S. miltiorrhiza, also inhibits Aβ aggregation and protects damage from Aβ-induced cytotoxicity in SH-SY5Y cells (Mei et al., 2012). Aside from Aβ peptide, amyloid precursor protein can also be cleaved by γ-secretase within the Aβ sequence, thus, inhibiting Aβ generation by modulating amyloid precursor protein proteolysis is regarded as a potential target for Alzheimer disease therapy (Haass, 2004). Amyloid precursor protein metabolism is promoted by cryptotanshinione toward upregulating α-secretase by activation phosphatidylinositol 3-kinase (PI3K) pathway in human cortical neurons (Mei et al., 2010). Reactive oxygen species (ROS) have been involved in Alzheimer disease pathogenesis and the use of antioxidants is a promising strategy to suppress oxidative dependent and Aβ-mediated cytotoxicity. Salvianolic acid A protects human SH-SY5Y cells against H2O2-induced injury by increasing their stress tolerance via inhibition of the mitogenactivated protein kinase and Akt signaling pathways (Wang and Xu, 2005). Moreover, in this study salvianolic A acid presents anti-apoptotic eﬀects via regulating the expression of Bcl-2 and Bax. In a posterior study, the same authors observed that salvianolic acid A in SH-SY5Y cells presents a multifactorial activity for the treatment of Alzheimer disease: inhibited Aβ self aggregates, disaggregated pre-formed Aβ ﬁbrils, reduced metal-induced Aβ aggregation through chelating metal ions, and blocked the formation of ROS (Cao et al., 2013). Salvianolic B acid also oﬀers anti-apoptotic protection in SH-SY5Y cells treated with 6-hydroxydopamine through the inhibition of elevated concentration of intracellular ROS and Ca2+ levels, the decrease of caspase-3 activity, the increase of extracellular signal regulated kinase (ERK)1/2 phosphorylation, and the maintenance of mitochondrial membrane potential and Bcl-2 (Tian et al., 2008). Salvianic borneol ester, a compound based on the S. miltiorrhiza formula, showed signiﬁcant destabilizing eﬀect on Aβ oligomers and protect SH-SY5Y and motor neuron hybridoma cells VSC 4.1 against H2O2-induced toxicity in a dose-dependent manner (Han et al., 2011). In other study performed in SH-SY5Y cells, S. miltiorrhiza extract (0.01, 0.1 or 0.2 mg raw herb/mL) concentration-dependently protects against Aβ25-35-induced apoptosis via inhibiting oxidative stress and attenuating the mitochondria-dependent apoptotic pathway (Yu et al., 2014). Thus, S. miltiorrhiza and its active components, such salvianolic acids, tanshiones and cryptotanshinone, exhibit multiple neuroprotective eﬀects and are likely to be promising preservative techniques. Extract of essential oils of Salvia spp. can be combined with other natural antimicrobials or applied as part of a hurdle system. For example, smaller amounts of EOs or extracts can be combined with other non-thermal preservation techniques such as low acidity, salting, drying, modiﬁed atmosphere package, high hydrostatic pressure, natural preservatives (e.g. organic acids, bacteriocins, etc.) and low doses of irradiation (Jayasena and Jo, 2013; Tajkarimi, Ibrahim, and Cliver, 2010). As a result of such hurdle technology, higher antimicrobial activity can be achieved without aﬀecting the sensorial acceptability of food. 10. Biological activities of Salvia spp. plants in human (in vitro, in vivo and in humans) Several biological activities have been reported for this genus since the available traditional medicine information, ethnobotanical knowledge and science have walked together (Bahadori, Valizadeh, & Farimani, 2016; Tan et al., 2016). In this context, this review describes the anti-Alzheimer disease and cognitive-enhancing potential, eﬀects on cardiovascular health, anti-hyperglycemia/hyperlipidemia properties, hypotensive eﬀects, cytotoxicity/anticancer potential, skin curative properties and antimicrobial activity of Salvia plants. 11. Anti-Alzheimer disease and cognitive-enhancing potential Alzheimer disease is characterized by neural loss, abnormal extracellular aggregation of amyloid-β peptide (Aβ) plaques and intraneuronal accumulation of neuroﬁblillary tangles. Several components derived from S. miltiorrhiza have proposed as therapeutic target for anti-Alzheimer disease through their involvement in the inhibition of Aβ production, aggregation and clearance (Zhang et al., 2016). According to their structural characteristics, the constituents of S. miltiorrhiza have been divided into hydroxycinnamic acid derivatives such as salvianolic acids, which are water-soluble and abietane type-diterpene quinone such as tanshinone I and IIA, which are more lipophilic. These compounds have been studied as possible active compounds of this plant, while the therapeutic base of its essential oil is poorly understood. Salvianolic B acid (Fig. 2), the most abundant salvianolic acid in S. miltiorrhiza, dose dependently prevents Aβ1-40 aggregation, destabilizes preformed Aβ ﬁbrils, and reduces Aβ–induced cytotoxicity in human neuroblastoma SH-SY5Y cells (Durairajan et al., 2008). 250 Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. it is debatable if these eﬀects can be achieved by both alpha-linolenic acid and omega-3 long-chain PUFAs. A study conducted on 10 postmenopausal healthy woman supplemented with 25 g/day milled chia for 7 weeks resulted in signiﬁcant increase of alpha-linolenic and eicosapentaenoic but not docosapentaenoic and docosahexaenoic acids concentrations in serum (Jin et al., 2012). A prospective cohort study of 3277 healthy Danish women and men conclude that there is no association between alpha-linolenic intake and risk of ischemic heart disease, but a high intake of omega-3 long-chain PUFAs had a signiﬁcant cardioprotective eﬀect in women (Vedtofte et al., 2011). Nieman et al. showed no health beneﬁts from chia seed, the concentration increase of alpha-linolenic and eicosapentaenoic acids in serum had no inﬂuence in inﬂammatory markers, blood pressure or body composition in some studies (Nieman et al., 2009, 2012). One of these studies was a singleblind trial conducted on 76 obese people that showed that the group that consumed 25 g chia seeds in 250 mL water, twice a day, for 12 weeks no reduced body weight, lipid proﬁle, blood pressure, blood sugar levels or inﬂammatory markers, but increased alpha-linolenic acid in serum (Nieman et al., 2009). Another study from same authors was obtained similar results with a double-blind randomized design conducted on 62 overweight women aged 49–75 years and supplemented with 25 g/day whole or milled chia seeds for 10 weeks (Nieman et al., 2012). However, later studies demonstrated beneﬁcial eﬀects of chia intake on human health (Jin et al., 2012; Guevara-Cruz et al., 2012; Vuksan et al., 2010; Ho et al., 2013; Vuksan, Choleva, et al., 2017) such decreasing postprandial glycaemia; this diﬀerence could be due to the biochemical components of the chia used in the various studies and the diﬀerences in the treatment duration employed (Ali et al., 2012). In another context, Zhi-Xiong capsules (ZXC), a traditional Chinese medicinal formula containing Ligusticum chuanxiong, S. miltiorrhiza, Leonurus artemisia and Pueraria lobata, was applied for treating cerebral arteriosclerosis and blood-stasis in Chinese clinics. Zhou and co-authors suggested that ZXC has signiﬁcant antithrombotic activity, via the pathway of anti-coagulation, anti-platelet activation and anti-ﬁbrinolysis (Zhou et al., 2018). therapeutics for Alzheimer disease (Zhang et al., 2016). Also positive eﬀects of other plants of genus Salvia has been reported in patients with Alzheimer's disease. In a double-blind randomized study conducted for 4-month on 30 Alzheimer disease patients with average age of 72 years, the eﬃcacy of ethanolic extract of S. oﬃcinalis (60 drops/day) was evaluated (Akhondzadeh et al., 2003). In this study, people taking Salvia liquid drops experienced signiﬁcantly greater better cognitive function, as measured as measured by the Alzheimer's Disease Assessment Scale, and the Clinical Dementia Rating Scale, compared with control group (60 placebo drops/day). Another clinical study on S. oﬃcinalis suggested positive eﬀects on memory and cognitive functions. A 333 mg dose of S. oﬃcinalis extract was associated with signiﬁcant enhancement of secondary memory performance (Scholey et al., 2008). In other study, with open-label design and conducted on 11 patients with probable Alzheimer's disease aged 76–95 years, it has been administered 1–3 capsules per day, containing 50 μL of S. lavandulaefolia essential oil plus 50 μL of sunﬂower oil, over a 3-week period (Perry et al., 2003). There were statistically signiﬁcant reductions in caregiverrated neuropsychiatric symptoms and improvements in attention, although this study is limited for the open-label design, no placebo group and small sample size. Several studies, performed on healthy people, shown acute cognitive-enhancing eﬀects of diﬀerent Salvia species. Cognitive and mood positive eﬀects were reported on healthy young people from the single administration of diﬀering dosages of essential oil of S. lavandulaefolia (Kennedy et al., 2011; Tildesley et al., 2003, 2005) and S. oﬃcinalis (Kennedy et al., 2006). Also, enhancement in attention and memory were reported in a double-blind study that administrated S. oﬃcinalis extracts on 20 healthy older-age adults with a mean age of 73 years (Scholey et al., 2008). In a single-blind randomized study conducted on 135 healthy adults with a mean age of 22 years was found that the exposure to the aroma of S. oﬃcinalis and S. lavandulaefolia provoke positive cognitive and mood-enhancing eﬀects (Moss et al., 2010). These studies support the potential cognitive-enhancing and protective eﬀects of Salvia species and their potential eﬀects in dementia (Lopresti, 2017). 13. Anti-hyperglycemia/hyperlipidemia potential 12. Eﬀects on cardiovascular health The potential of plants to manage hyperglycaemia and hyperlipidemia conditions leads to be also targets for treating metabolic syndrome. In this way, the potential eﬀect of chia on reduction of postprandial glycaemia was showed in healthy subjects in various studies performed by Vuksan et al. (Ho et al., 2013; Vuksan et al., 2010; Vuksan, Choleva, et al., 2017; Vuksan, Jenkins, et al., 2017). A doubleblind randomized trial conducted on 13 healthy people evaluated the eﬀects of 50 g bread with 0, 7, 15 and 24 g chia seeds added, whole or in ground form, on postprandial glycaemia after 2 h post consumption (Ho et al., 2013). The results of this study showed that both ground and whole chia seed, added into bread, reduced glucose levels in a dosedependent manner. Similar results are showed in a similar study, conducted on 11 healthy men and women and showing a reduction in postprandial glucose excursion and prolongation of satiety (Vuksan et al., 2010), the authors proposed these as explanation of long-term eﬀect of chia on improvements in blood pressure, coagulation and inﬂammatory markers seen in other study conducted on subjects with type II diabetes (Vuksan et al., 2007). In another study conducted on 15 health adults, Vuksan and coworkers have compared the eﬀects of chia seeds and ﬂax on postprandial glycaemia, and conclude that chia reduced postprandial glycaemia and reduced the mean rating of desire to eat, prospective consumption and appetite when compared with ﬂax (Vuksan, Choleva, et al., 2017). Moreover, the authors of these studies suggest that chia aﬀects satiety through their ability to convert glucose into a slow-release carbohydrate. In a recent double-blind randomized trial conducted on 77 overweight or obese patients with type II diabetes, Vuksan and colleagues have studied the eﬀects of 6-month Metabolic syndrome is a clustering of insulin resistance, hypertension, dyslipidemia as well as obesity, and raises a health problem throughout the world. This condition has been associated with increased risk of cardiovascular disease and type 2 diabetes in adults (Rodríguez-Pérez, Segura-Carretero, & Contreras, 2017). Salvia spp. has been commonly used for hundreds of years in traditional Chinese medicine in the management of cardiovascular diseases (Chang, Lee, et al., 2016; Hung et al., 2015). Among the Salvia spp., chia (S. hispanica), which is considered by some people as a “super food” since it contributes to human nutrition, helps to increase the satiety index and exhibited several biological properties (Valdivia-López and Tecante, 2015). In this context, a double-blind randomized trial was conducted on 67 men and women aged 20–60 years to evaluate the eﬀects of a dietary pattern on the biochemical variables of metabolic syndrome (GuevaraCruz et al., 2012). The dietary pattern included 4 g of chia seeds mixed with palm, oats and soy powder diluted in 250 mL of water, twice a day, and a reduction diet for 2 months. The results of this study showed a decrease of concentration of triacylglycerol, C-reactive protein, and insulin resistance in group with chia-based diet (Guevara-Cruz et al., 2012). Other study conducted on 26 men and woman aged 45–55 years concluded that 35 g chia ﬂour/day for 12 weeks decreased total cholesterol level and increased low density lipoprotein (LDL) cholesterol and induced discrete weight loss (Toscano et al., 2015). Omega-3 polyinsatturated fatty acids (PUFAs) have been proposed as cardioprotectors, primarily in relation to ischemic heart disease, but 251 Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. pressure and C-reactive protein concentration in plasma. Moreover, both α-linolenic acid, and eicosapentaenoic acid PUFAs levels were double increased in serum of chia supplemented patients. Homocysteine is a by-product of methionine metabolism and an elevated homocysteine concentration in blood is a risk factor of several vascular diseases. S. miltiorrhiza aqueous extract protects human umbilical vein endothelial cells against homocysteine-induced endothelial dysfunction (Chan et al., 2004). Endothelial nitric oxide synthase (eNOS) uncoupling plays a causal role in endothelial dysfunction in many cardiovascular and metabolic diseases (Salehi, Zucca, et al., 2018). In human endothelial cell line EA.hy926, it has been reported that tanshinone IIA has a vasodilatory eﬀect through restoring eNOS coupling, induced by high glucose, leading to reduced intracellular oxidative stress and increased NO generation (Zhou et al., 2012). In addition to reducing ROS, in the same cell line tanshinone IIA reduces apoptosis induced by H2O2 decreasing the Bax/Bcl-2 ratio and inhibiting caspase-3 activation (Jia, Yang, et al., 2012). The antioxidant therapy with S. miltiorrhiza herb extract injection (200 mg/kg) has been evaluated on children (aged 2–15 years old) with mild pulmonary hypertension scheduled for operative repair of congenital ventricular or atrial septum defect (Xia et al., 2003). In this double-blind randomized study conducted on 20 children S. miltiorrhiza injection reduces myocardial damage and attenuates postoperative vasoactive mediator imbalance decreasing plasma levels of endothelin-1 and thromboxane B2. Apoptosis of vascular endothelial cells results in the loss of endothelial integrity and is a risk factor of atherosclerosis (Mishra et al., 2018). Methanol extract of S. miltiorrhiza treatment (50–500 μg/mL) for 24 h dose-dependently inhibited the tumor necrosis factor-α (TNF-α)induced migration of human aortic smooth muscle cells, suggesting a potential anti-atherosclerotic utility (Jin, Kang, et al., 2006). In another study, tanshinone IIA (1–20 μM) inhibited the adhesion of THP-1 cells to the TNF-α-stimulated human vascular endothelial cells in a dosedependent manner (Chang et al., 2014). Salvianolic acid B has the ability to change the gene expression proﬁle of endothelial cells thereby preventing vascular events. After treatment of human umbilical vein endothelial cells with this compound (12.5–500 μg/mL) for 2–12 h, a dose- and time-dependent decrease in plasminogen activator inhibitor activity, and increase in ﬁbrinolytic and anticoagulant potential was observed. These results suggest a potential eﬀect of Salvia spp. compounds against atherosclerosis and thrombosis (Shi et al., 2007). dietary incorporation of chia on weight reduction (Vuksan, Jenkins, et al., 2017). The results of this study shown that chia seeds promotes weight- and waist circumference-lost and maintain good glycemic control, suggesting that is a useful dietary addition to conventional therapy in the management of obesity in diabetes. Hyperglycemia induces oxidative stress situation that provoke endothelial dysfunction, involving micro- and macro-vascular diseases. In a randomized experimental study conducted on 54 diabetic patients with chronic heart diseases was evidenced that S. miltiorrhiza hydrophilic extract ameliorates oxidative stress by hyperglycemia, increasing antioxidant enzyme activities (Qian et al., 2012). The intervention period of this study was 60 days, placebo group received hypoglycemic therapy and treatment group received hypoglycemic therapy plus 5 g extract of S. miltiorrhiza, twice per day. In another study, the same authors investigated the eﬀect of S. miltiorrhiza hydrophilic extract on the expression of vascular endothelial growth factor induced by high concentration of glucose (Qian et al., 2011). In this study performed on HMEC-1 cells the results shown that S. miltiorrhiza hydrophilic extract reversed the induction of vascular endothelial growth factor by hyperglycemia via ameliorating mitochondrial oxidative stress. The hypoglycemic eﬀect of S. oﬃcinalis was investigated in 12week, double-blind placebo-controlled study conducted on 80 type II diabetic patients with a mean age of 52 years. The results of this study revealed that one tablet of 150 mg S. oﬃcinalis, three times a day reduce blood sugar and cholesterol (Behradmanesh, Derees, and RaﬁeianKopaei, 2013). In another randomized double-blind placebo-controlled clinical trial with 67 patients aged 20–60 years, with newly diagnosed primary hyperlipidaemia, was observed that S. oﬃcinalis leaf extract (one 500 mg capsule every 8 h for 2 months) signiﬁcantly lowered the blood levels of total cholesterol, triglyceride, LDL and VLDL, and increased blood HDL levels (Kianbakht et al., 2011). In another doubleblind, placebo-controlled study, performed for the same authors, S. oﬃcinalis leaf extract was evaluated as add-on to statin therapy in hypercholesterolemic type II diabetic patients (Kianbakht, Nabati, and Abasi, 2016). This study was conducted on 100 participants for 2 month and its results shown that the extract intake (500 mg capsule three times a day) as add-on to therapy signiﬁcantly lowered fasting glucose, 2 h postprandial glucose, glycosylated hemoglobin, total cholesterol and LDL levels and increased blood HDL levels. Magnesium tanshinoate B is an active compound puriﬁed from S. miltiorhiza. This aqueous compound inhibits oxidative modiﬁcation of LDL and hence prevents the uptake of LDL by THP-1 derived macrophages (Karmin et al., 2001). Moreover, magnesium tanshinoate B protects human endothelial cells against oxidized lipoprotein-induced apoptosis (Au-Yeung, K, Choy, Zhu, & Siow, 2007). These results suggest a therapeutically eﬀect protecting cells from lipid peroxidation in vascular disorders. 15. Cytotoxicity/anticancer potential The plant kingdom is an unlimited source of phytotherapeutics with promising potential as anticancer agents or as adjuvants in conventional anticancer therapies (Salehi, Anil Kumar et al., 2018). In line with this, several Salvia extracts have been tested in vitro against cancer cells. As an example, the aqueous extract of S. miltiorrhiza (doses higher to 1.5 mg/mL) showed clear cytotoxic eﬀects, and strongly inhibited the proliferation of HepG2 human hepatoma cells, changing their morphology and inducing cell death by apoptosis (Liu, Shen, and Ong, 2000). Also, the ethanol extract of Salvia miltiorrhiza (5 μg/mL for 3 h) exert similar eﬀect inhibiting proliferation of MCF-7 breast cancer cells through inhibition of Akt activity and up-regulation of p27 (Yang et al., 2010). The S. miltiorrhiza polysaccharides promote the proliferation and enhance cytotoxicity of T lymphocytes in peripheral blood of cancer patients through the activation of Toll-like receptors, mitogen activated protein kinase and NF-κB signaling pathways (Chen et al., 2017). In human rhabdomyosarcoma cells, incubation with cryptotanshinone (2.5–40 μM) for 48 h inhibited cell proliferation arresting cells in G1/ G0 phase of the cell cycle (Chen et al., 2010). The inhibition mechanism involved is that cryptotanshinone suppress mammalian target of rapamycin-mediated cyclin D1 expression and retinoblastoma protein phosphorylation (Chen et al., 2010). Additionally, cryptotanshinone treatment (5, 10, 20, and 40 μM), for 24 h in human myeloid leukemia KBM-5 cells, dose dependently decreases viability leukemic cells, 14. Hypotensive eﬀects of Salvia spp. Hypertension is the most readily modiﬁable risk factor for cardiovascular diseases and, in traditional Chinese medicine, S. miltiorrhiza is the most frequently prescribed single herb for hypertension (Yang et al., 2015) given to this plant the importance for “activating circulation and dispersing stasis or sludging of blood” (Chang, Chang, et al., 2016). Via the renin-angiotensin system, angiotensin I-converting enzyme (ACE-I) plays an important role in blood pressure regulation. Chia protein hydrolysates revealed a signiﬁcant inhibition of ACE-I suggesting a blood pressure potential through obstructing the powerful vasoconstrictor angiotensin II generation (Segura-Campos et al., 2013). These hydrolyzed chia proteins added into white bread and carrot cream also present the ACE inhibitory activity without signiﬁcant eﬀects on quality of these food products. A randomized study using single-blind cross-over design was performed on 11 men and 9 women aged 18–75 years with type 2 diabetes (Vuksan et al., 2007). This study found that 37 g chia seeds added to bread per day for 12 weeks reduced systolic blood 252 Salvia species Use Used part Preparations Utilization method Local Reference S. aegyptiaca S. chudaei Digestive diseases Digestive diseases (diarrhoea, ulcer), kidney diseases, and urinary tract infection Anti-cough, anti-diarrhoeic, throat ache, intestine gaseous, digestive troubles, heartburn, ﬂatulence, stomachache, wound, antiseptic, and vaginitis Treat abdominal pains Stomachache Stomach disorders Digestive disorder Seeds, aerial parts Leaves, aerial parts Infusion, decoction Decoction, powder, infusion Internal Internal, external Algeria Algeria (Ramdane et al., 2015) (Ramdane et al., 2015; Sekkoum et al., 2011) Fresh leaves, dried leaves, plant core section, shoot, ﬂowers, aerial parts Leaves Leaves, ﬂowers Herb Flowery plant; Infusion, volatile oil Internal. external Cyprus, Turkey (Dokos et al., 2009; Fakir, Korkmaz, and Güller, 2009; Gürdal and Kültür, 2013) Decoction Tea Infusion Infusion Internal Internal Internal medicine Internal Italy Bosnia and Herzegovina Turkey Spain Stomachache Skin diseases Treatment of stomach disturbances Catarrh Gastric infections Teeth pain, periodontitis, infections, heartburn, stomach ache, digestive, treat abdominal pains, colic in gastrointestinal tract, ﬂatulence, diarrhea, antibacterial, gingivitis, mouth and throat infections, skin ailments, urogenital system infections, women infections, skin rash, skin diseases, wounds, cough, treatment of sore throat, tonsillitis, and other infection of the respiratory system Treat abdominal pains, stomachache, and skin diseases Cough Leaves Root extract NI Herb Leaves Leaves, ﬂowers, aerial parts, and herb Infusion NIa Tea Decoction NI Balm, tea, decoction, infusion, syrup, infusion for drinking or gargling; fresh leaf for chewing Oral NI Internal Internal NI Internal, external. Mouth wash, vaginal path, internal (coughs with honey) Mexico India Lebanon Turkey Ecuador Bosnia and Herzegovina, Egypt, Iraq, Palestine, Lebanon, Serbia, Slovenia, Italy, Kosovo, Romania, Serbia (Idolo, Motti, and Mazzoleni, 2010) (Šarić-Kundalić et al., 2010) (Altundag & Ozturk, 2011) (Benítez, González-Tejero, and Molero-Mesa, 2010) (del Carmen Juárez-Vázquez et al., 2013) (Trak and Giri, 2017) (Arnold, Baydoun, Chalak, & Raus, 2015) (Altundag & Ozturk, 2011) (Jerves-Andrade et al., 2014) (AbouZid & Mohamed, 2011; Ahmed, 2016; Arnold et al., 2015; Cornara et al., 2014; Guarrera, 2005; Idolo, Motti, and Mazzoleni, 2010; Jaradat and Adawi, 2013; Jarić et al., 2015; Lumpert and Kreft, 2017; Maxia et al., 2008; Mustafa et al., 2015; Pieroni, Nedelcheva, and Dogan, 2015; SaricKundalic et al., 2016; Šavikin et al., 2013) Leaves, ﬂowers Decoction, tea, infusion Internal Italy, Bosnia and Herzegovina Leaves and young shoots Aerial part Shoot, ﬂowers and leaves, tranches Infusion Oral Lebanon Infusion Infusion Internal Internal Bolivia Turkey (Fernandez, Sandi, and Kokoska, 2003) (Fakir, Korkmaz, and Güller, 2009; Özdemir and Alpınar, 2015) Herb Leaves, shoot, and ﬂowers Infusion Infusion, cataplasm, mash. Oral Internal, external. Colombia Turkey (Angulo, Rosero, & Gonzales, 2012) (Fakir, Korkmaz, and Güller, 2009; Sargın, Akçicek, and Selvi, 2013) Leaves Hot beverage, decoction Internal Jordan Aerial parts, leaves, and herb Decoction tea; cataplasm, fresh leaves compress Serbia, Bulgaria, Turkey Shoot, ﬂowers and leaves Infusion Internal, external. Oral: drink one teacup two times a day for 5 days NI (Aburjai, Hudaib, Tayyem, Yousef, & Qishawi, 2007; Oran and Al-Eisawi, 2015) (Altundag & Ozturk, 2011; Jarić et al., 2015; Kozuharova et al., 2013; Kültür, 2007) S. fruticosa S. S. S. S. S. S. S. S. S. S. glutinosa grandiﬂora hydrangea lavandulifolia subsp. vellerea leucantha moorcroftiana multicaulis nemorosa ochrantha oﬃcinalis 253 S. pratensis S. rubifolia S. sagittata S. sclarea S. triloba (synonym of S. trijuga Diels) S. verticillata Sore throat, throat inﬂammation, antitussive, ulcer and intestines spasm, and gynaecological disease S. viridis a Not identiﬁed . Turkey (Idolo, Motti, and Mazzoleni, 2010; Redžić, 2007) (Arnold et al., 2015) (Fakir, Korkmaz, and Güller, 2009) Trends in Food Science & Technology 80 (2018) 242–263 S. scutellarioides S. tomentosa Tuberculosis Sore throat, throat inﬂammation, antitussive, gynaecological disease, ulcer, and intestine spasm, diarrhea Gastrointestinal diseases Respiratory tract diseases, bronchitis, asthma, sorethroat, throat inﬂammation, antitussive, tonsillitis, throatache, toothache, gastrointestinal diseases, diarrhea, ulcer, intestines, spasm, and gynaecological disease Stomach ache, abdominal pain, colic pain, and oral infection Coughs, infection of the oral cavity, catarrh, wounds, and abdominal pain M. Shariﬁ-Rad et al. Table 4 Use of Salvia genus in folk medicine against signs and symptoms related to bacterial and fungal infections. Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. 2006). The Salvia genus possesses many species considered to be medicinal in popular therapeutics. In this review, a total of 23 species were listed for the treatment of symptoms that may be associated with bacterial and fungal infections (Table 4). enhancing TNF-α induced apoptosis which appeared through ROS-dependent activation of caspase-8 and p38 (Kim et al., 2011). Moreover, cryptotanshinone suppressed inﬂammation in human U937 promonocytes, stimulated by lipopolysaccharide and phorbolmyristate acetate, inhibiting cyclooxygenase-2 enzymatic activity, and consequently reducing prostaglandin E2 synthesis (Jin, Yin, et al., 2006). Salvianolic acid B modulates growth and angiogenic potential of oral squamous carcinoma cell lines, and this could be attributed by a decreased expression of some key regulator genes, such as TNF-α, matrix metalloproteinase 9 (MMP-9), and hypoxia-inducible factor (HIF)-1 (Yang et al., 2011). The HIF is an important target in the development of anticancer drugs. Diverse abietane diterpenes isolated from S. miltiorrhiza, sibiriquinone A, sibiriquinone B, cryptotanshinone, and dihydrotanshinone I, inhibited the activation of HIF-1 with IC50 values of 0.34, 3.36, 1.58, and 2.05 μM on AGS cells (human gastric cancer cell line) and 0.28, 3.18, 1.36, and 2.29 μM on Hep3B cells (human hepatocarcinoma cell line), respectively (Dat et al., 2007). Abietane diterpenoids isolated from aerial parts of S. pachyphylla and S. clevelandii, carnosol, 20-deoxocarnosol, and 16-hydroxycarnosol, presented in vitro cytotoxic activity against human cancer cell lines (A2780 ovarian cancer, SW1573 nonsmall-cell lung cancer, WiDr colon cancer, T-47D breast cancer, and HBL-100 breast cancer cells) showing GI50 values in the range 3.6–35 μM for the ﬁve cell lines (Guerrero et al., 2006). Tanshinone IIA (10–100 μM) induced apoptosis in human hepatoma BEL-7402 cells via activation of calcium-dependent apoptosis signaling pathways, increases intracellular calcium, decreases mitochondrial membrane potential, and induces Bcl-2-associated death promoter (Bad) and metallothionein 1A (MT 1A) mRNA expression (Dai et al., 2012). In human colon carcinoma cell lines, HT29 and SW480, tanshinone IIA suppressed the NF-κB signal transduction pathway and inhibited in vitro (0.5–2.5 mg/L) and in vivo (20–80 mg/kg day) invasion and metastasis by reducing levels of urokinase plasminogen activator (uPA), matrix metalloproteinases (MMP)-2, MMP-9, and by increasing levels of tissue inhibitor of matrix metalloproteinase protein (TIMP)-1 and TIMP-2 (Shan et al., 2009). A component of S. miltiorrhiza, 15,16-dihydrotanshinone I, signiﬁcantly inhibited proliferation of human benign (SW480) and malignant (SW620) colorectal cancer cells at a concentration as 2.5 μg/mL (Suk et al., 2013). Salvileucalin B, a diterpenoid from aerial parts of S. leucantha, exerted cytotoxic activity against A549 and HT-29 cells with IC50 values of 5.23 and 1.88 μg/mL, respectively (Aoyagi et al., 2008). The cytotoxic activity of taxodione, isolated from the methanol extract of S. staminea, has evaluated in a panel of cell lines: BC1, LU1, COL2, KB, KB-VI, LNCaP, and A2780, showing signiﬁcant cytotoxicity and IC50 values of 1.2, 5.1, 0.7, 3.4, 4.1, 0.7, and 9.0 μg/mL, respectively (Topcu et al., 2003). 17.1. Antifungal activity Microbiological assays have favoured the discovery of plants that possess an eﬀect on pathogenic fungal lineages and opportunistic commensals. In this context, the Salvia genus has been also evaluated, including their essential oils. The eﬀect of the essential oil derived from the S. oﬃcinalis aerial parts on fungi of the Candida, Cryptococcus, Aspergillus, Epidermophyton, Trichophyton and Microsporum (standards and isolates) genus were evaluated by microdilution in the study by Abu-Darwish et al. (2013). Fluconazole (MIC, 16–128 μL/mL) and amphotericin B (MIC only for Aspergillus, 2–8 μL/mL) were used as controls. The MIC of the oil ranged from 0.64 μL/mL to 2.5 μL/mL. Dermatophyte strains showed a higher oil sensitivity (0.64–2.5 μL/mL) when compared to Candida (2.5–5 μL/ mL) and Aspergillus (2.5 to > 20 μL/mL). The best results were against T. rubrum, E. ﬂoccosum and C. neoformans (0.64–1.25 μL/mL). Garcia et al. (2013) carried out experiments on Candida albicans and Candida tropicalis strains using an hydroalcoholic extract (1:10) of this plant. In the well diﬀusion test, inhibition halos were veriﬁed only for C. albicans in the 100 μL (10 mm) and 200 μL (40 mm) volumes and for the control (80% ethanol) the halos measured 10 and 20 mm, respectively. In this extract the potential active compounds were saponins, tannins and ﬂavonoids instead of terpenoids. The essential oil of S. mirzayanii Rech.f. & Esfand. aerial parts (not in ﬂowering), presented MIC varying from 0.03 to 2 μL/mL and a MFC ranging from 0.5 to 8 μL/mL, when tested against diﬀerent Candida species, being shown to be more eﬀective against Candida glabrata (MIC, 0.03 μL/mL and MFC 0.5 μL/mL) and Candida dubliniensis with fungistatic eﬀect for 50% of the microbial population. The drugs ﬂuconazole and itraconazole obtained a MIC between < 0.12 and 32 μL/ mL and < 0.03–4 μL/mL, respectively (Zomorodian et al., 2017). Ethanolic extract from the root, ethanolic extract and essential oil from aerial parts of S. cilicica Boiss. (SCA), S. tomentosa Mill. (STA), S.fruticosa Mill. (SFA) and S. oﬃcinalis (SOA) were investigated against strains from the Microsporum, Trichophyton and Candida genera. The essential oils from the four tested Salvia species indicated high antifungal activity with SCA and SFA being more eﬀective against C. parapsilosis (0.2 μL/mL), M. gypseum (0.4 μL/mL) and T. mentagrophytes (0.4 μL/mL). Itraconazole (06–0.12 μg/mL) and amphotericin B (0.5–4 μg/mL) were used as controls (Tan et al., 2016). SCA contained as main compounds: spathulenol (23.8%), caryophyllene oxide (14.9%), and hexadecanoic acid (10.3%). In another study, the MIC and minimum fungicidal concentration (MFC) of the essential oil from S. tomentosa Mill. fresh leaves against C. albicans strains were considered moderate, above 4 mg/mL, for both strains (standard and isolates). The positive control was ﬂuconazole with a MIC and MFC of 0.25 μg/mL (Marchev et al., 2015). In the case of the essential oil of S. fruticosa Mill. leaves, it had a MIC value of 512 μg/mL for C. albicans and 256 μg/mL for Trichophyton rubrum (Khoury et al., 2016). In this study, the drugs itraconazole and ﬂuconazole, positive controls, had a MIC lower, 4 and < 0.003 μg/mL and 16 and 2 μg/mL for these fungi, respectively. Bahadori et al. (2015) used the essential oil and methanolic, dichloromethane as well as n-hexane extracts from the aerial parts of S. spinosa L. (in ﬂowering) against Aspergillus niger and C. albicans. In the disk diﬀusion assay, inhibition zones ranged from 12.8 mm to 23.2 mm for A. niger and from 13.8 mm to 28.5 mm for C. albicans, with the nhexane extract showing the best result against A. niger and the dichloromethane extract against C. albicans. In the MIC assay, the methanol extract stood out (100 and 50 μg/mL) followed by the essential oil (400 and 200 μg/mL), respectively. The nystatin control had 24.2 and 27.0 mm inhibition zones for the strains, with a MIC of 50 μg/mL 16. Skin curative properties The beneﬁts of topical product containing 4% chia oil and applied for 8 weeks was evaluated on ﬁve patients with pruritus aﬀected by end stage renal disease and ﬁve health volunteers having xerotic pruritus (Jeong et al., 2010). The results of this study shown that the topical application added with chia oil signiﬁcantly improved skin hydration and suggest that this product can be used as an adjuvant moisturizing agent for pruritic skin, including that of end-stage renal disease patients. Other skin protection eﬀect is reported using tanshinone I and dihydrotanshinone I as a pretreatment that causes a signiﬁcant suppression of skin cell death induced by solar simulated ultraviolet radiation (Tao et al., 2013). 17. Antimicrobial activity of Salvia plants The ethnobiological approach is an important strategy for selecting plants with pharmacological potential (de Albuquerque & Hanazaki, 254 Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. extracts from dry S. rigens Sibith & Sm. aerial parts against diﬀerent fungi genera. The oil had a MIC that ranged from 0.125 to 3 mg/mL, standing out against C. albicans, C. krusei and C. parapsilosis (MIC, 0.125 mg/mL). For MFC the predominant value among the strains was 3 mg/mL, with Trichophyton mentagrophytes presenting the lowest concentration (1.50 mg/mL). The ethanol extract had a MIC of 64 mg/mL for C. krusei and C. albicans while the aqueous extract had a MIC of 16 mg/mL for Aspergillus glaucus. In another study, Alimpić et al. (2017) used the ethanolic and aqueous extracts from the S. amplexicaulis Lam. aerial (ﬂowering) parts against Candida, Aspergillus and Trichophyton strains, verifying that only against the Candida spp. was the aqueous extract slightly eﬀective (MIC ranging from 16 mg/mL to 64 mg/mL). Generally, the aqueous extract was a stronger antifungal agent (MIC varied from 8.0 mg/mL to 64.0 mg/mL) than the ethanol extract. In both studies, ketoconazole, positive control, had a predominant MIC and MFC values, ranging from 0.0156 to 0.0078 mg/mL. In general, it seems that the activity of aqueous extracts of Salvia plants required larger dose to be active than that of extracts obtained by solvents and essential oils. As an example, Baka (2014) evaluated the antifungal activity of the aqueous extract from aerial parts of the Salvia aegyptiaca L. species against A. ﬂavus, A. niger and Fusarium moniliforme (2.5%–10%) and veriﬁed their eﬀectiveness in reducing the mycelial growth of all fungi at increasing concentrations. The inhibition halos ranged from 32.3 to 45.1 mm, with the A. ﬂavus strain standing out reaching halos with smaller measurements. Nevertheless, Rongai et al. (2015) tested the eﬀect of the aqueous extract from S. guaranitica (synonym of Salvia guadalajarensis Briq.) fresh leaves against Fusarium oxysporum f.sp. lycopersici by disc diﬀusion showing that it was one of the most active extracts compared to other 24 plant extracts. After 4 days of incubation, the extract had an inhibition halo measuring 26 mm, while the synthetic fungicide Marisan 50 PB had a halo measuring 17.8 mm. The results catalogued in this review highlight that when diﬀerent species of the Salvia genus were evaluated against diﬀerent pathogenic fungi, they presented activities against Candida, Cryptococcus, Aspergillus, Trichophyton, Microsporum, Penicillium, Fusarium, Cladosporium and Botrytis cinerea, with the best eﬀects obtained against C. albicans, followed by C. krusei, C. parapsilosis, A. ﬂavus and Trichophyton mentagrophytes. for both. The essential oil contained mainly caryophyllene oxide (63.0%), and spathulenol (23.0%). In another study, the essential oil of the aerial parts from S. santolinifolia Boiss. (in ﬂowering) was also tested against the latter fungi, by Bahadori et al. (2016) Inhibition halos were lower (400 μg/mL), 13.8 for A. niger and 15.8 mm for C. albicans, and as well the MIC, i.e. 800 μg/mL and 400 μg/mL, respectively. As a control, nystatin (halo and MIC against A. niger, 24.2 mm and 50 μg/mL; halo and MIC against C. albicans, 27.0 and 50 μg/mL) was used. The main volatiles compounds were others: α-pinene (49.3%), β-eudesmol (20.0%), camphene (7.8%) and limonene (7.7%). Ghasemi and his collaborators (2010) carried out disk diﬀusion and microdilution assays with the essential oil and ethanolic extract from S. hydrangea DC. leaves and ﬂowers against C. albicans. Amphotericin B (5 mg/mL) served as a positive control (16 mm). The antifungal activity at 100 μg/disc had halos of 11 mm and 17 mm and MICs of < 0.039 mg/mL for the ethanolic extract and essential oil, respectively. A lower activity was observed by Hristova et al. (2013) using a commercial sample of the S. sclarea essential oil and against Candida spp. strains. The C. albicans (MIC and MFC, 128 and 256 μg/mL) and C. krusei (MIC and MFC, 128 and 256 μg/mL) strains were more susceptible, followed by C. parapsilosis (MIC and MFC, 256 μg/mL), C. tropicalis (MIC and MFC, 512 μg/mL) and C. glabrata (MIC and MFC, 512 and 1024 μg/mL). Fluconazole, intraconazole and ketoconazole (controls) had MIC values ranging from 0.5 to 64 μg/mL; 0.125–0.5 μg/mL; 0.5–16 μg/mL, respectively, and MFC values ranging from 8 to 64 μg/mL for all strains. S. veneris plant has also demonstrated antifungal activity against these strains. In this sense, crude methanolic extract and essential oil from S. veneris Hedge (in ﬂowering) aerial parts were tested against Candida glabrata, C. utilis, C. parapsilosis, C. krusei, C. albicans and C. tropicalis. The oil exhibited anticandidal eﬀects between concentrations of 125–500 μg/mL while the methanolic extract reached its eﬀects between 60 and 500 μg/mL against all the tested pathogenic yeasts with Candida utilis being the most susceptible strain. As controls, the MICS for amphotericin-B and ketoconazole ranged from 0.25 to 1 μg/mL and 0.25 to 0.12 μg/mL, respectively (Toplan et al., 2017). Sepahvand et al. (2014) evaluated the essential oil from the S. sclareoides Brot. aerial parts against C. albicans, which presented both a MIC as well as a MFC of 125 μg/mL. More active was the essential oil from S. lanigera Poir. aerial parts tested by Tenore et al. (2011), which showed a fungistatic eﬀect with MICs of 50 μg/mL (C. albicans and Botrytis cinerea), and 100 μg/mL (Fusarium oxysporum and Aspergillus ﬂavus). For Cladosporium herbarum, the MIC value was higher > 100 μg/mL. Amphotericin B and econasol had MICs of 1 μg/mL and 4 μg/mL, respectively. In the antifungal assay by Salari et al. (2016) against 96 yeasts of the Candida genus, the methanolic extract from the S. rhytidoa Benth. aerial parts was higher for some of the studied species compared to the aforementioned essential oils and methanol extracts, with MICs ranging from 3.125 to > 100 μg/mL. For the MFC, the values ranged from 6.25 μg/mL to > 100 μg/mL, with C. albicans (6.25 μg/mL) standing out. For the drug nystatin the result was 0.25–16 μg/mL for the MIC and 0.5–64 μg/mL for the MFC. The potential active compounds were ﬂavonoids and tannins. When testing the hexanic extract from S. apiana Jeps. roots against Candida species at the concentrations from 3.37 to 27 μg/10 μL, Córdova-Guerrero et al. (2016) veriﬁed a signiﬁcant increase in inhibition halos against C. albicans in comparison to the control (5 mm) in a dose-dependent manner, with inhibition zones varying from 8 to 13 mm. Lee and Kim (2016) studied the eﬀect of the S. miltiorrhiza Bunge dried roots ethanolic extract against Candida spp. with the species presenting an eﬀect against C. albicans and C. krusei (39 μg/mL), C. glabrata and C. tropicalis (78 μg/mL). The researchers concluded that the oil inhibits cell wall synthesis and increased membrane permeability by performing tests with ergosterol, sorbitol and (1,3)-β-glucan synthase. The MIC of the drug amphotericin B was 1 μg/mL. Alimpić et al. (2017) investigated the essential oil, ethanolic and aqueous 17.2. Antibacterial activity Science tries to look for in plants active principles that aim to neutralize bacterial resistance and plants of the Salvia genus have been targets for antibacterial research, as can be seen in the studies reported below. The antibacterial activity of essential oils from S. oﬃcinalis has been reported by several authors. As an example, four essential oil samples from this plant were tested against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus. MIC values were of 10 μL/mL, respectively. While the MIC for S. aureus was the 1.3 μL/mL concentration for the ﬁrst three oils and 0.6 μL/mL for the latter, the MBC followed respectively the same MIC value from 1.3 to 0.6 μL/mL (Cutillas, Carrasco, Martinez-Gutierrez et al., 2017a,b). Khedher et al. (2017) tested the antimicrobial activity from the S. oﬃcinalis essential oil derived from its dried leaves. The results of the cavity diﬀusion, MIC and MBC tests were, respectively, 12–25 mm at 0.312–10 mg/mL and 0.625–10 mg/mL, respectively, against Micrococcus luteus, Agrobacterium tumefaciens, S. aureus, Bacillus subtilis, Salmonella enteritidis, E. coli and Bacillus cereus. The gentamicin control had halos of 18–24 mm. In addition, eﬀectiveness percentages of 96% in combating E. coli, 100% in Klebsiella pneumoniae, more than 83% in Proteus mirabilis, 75% in Morganella morganii, 100% in Enterobacter aerogenes and 100% in Klebsiella oxytoca were obtained when Pereira et al. (2004), tested the essential oil from leaves of this Salvia species in strains isolated from urinary tract infections. The antibacterial activity of the S. oﬃcinalis 255 Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. halos of 15.2 mm (10%) and 23.7 mm (20%). Belkhiri et al. (2017) tested ethyl acetate (EAE), chloroform (ChE), aqueous (AqE) and crude (CrE) extracts of S. verbenaca L. (6 mg/disc) against 10 standard strains. EAE showed eﬀect against nine out of the ten bacterial strains (E. coli, P. aeruginosa, S. aureus, B. cereus, Klebsiella pneumoniae, Enterococcus faecalis, Citrobacter freundii, Acenetobacter baumanii and Lysteria monocytogeness) with inhibition zones of 9–12 mm (100 mg/mL) and from 12 to 16 mm (200 mg/mL). ChE (200 mg/mL) inhibited the growth of eight strains (except Salmonella typhi and L. monocytogenes) with halos of 10–14 mm. Whereas CrE inhibited the growth of six strains with diameters of 9–12 mm (200 mg/mL). The aqueous extract had no eﬀect. Gentamicin inhibition halos (10 μg/disc) ranged from 14 to 34 mm. The hexanic extract from S. apiana roots showed inhibition halos ranging from 10 to 24 mm, 28–40 mm and 9–17 mm against S. aureus, Streptococcus pyogenes and E. faecalis, respectively, with a dose-dependent eﬀect except for S. pyogenes (Córdova-Guerrero et al., 2016). From S. tomentosa Miller aerial parts, the essential oil, hexane (HE), dichloromethane (DCM), methanolic (MeOH) and deodorized methanolic (DeMeOH) extracts were tested against bacteria. The extracts were active against S. aureus (HE 12.5 mm and DeMeOH, 11.5 mm), Streptococcus pneumoniae (HE, DCM, MeOH and DeMeOH 12–19.5 mm), Moraxella catarrhalis (HE 11 mm), B. cereus (HE, DCM and DeMeOH, 10.5–14.5 mm), Acinetobacter lwoﬃi (HE, DCM, MeOH and DeMeOH, 9.5–15 mm), Clostridium perfringens (HE, DCM, MeOH and DeMeOH, 9–14.5 mm), Mycobacterium smegmatis (HE and DeMeOH, 14 and 14.5 mm). The oil presented halos from 7.25 to 18.75 mm and a MIC from 2.25 to 72 mg/mL against the above-mentioned bacteria, as well as Enterobacter aerogenes and Klebsiella pneumoniae (7 and 6.5 mm and a MIC of 72 mg/mL) (Tepe et al., 2005). The netilmicin control was not tested against all strains (MIC 1 × 10−2 to 8 × 10−3). Gülçin et al. (2004) tested the antibacterial activity of the chloroform and acetonic extracts of the S. sclarea L. dry plant. The chloroform extract showed activity against Micrococcus luteus (8 mm) and Mycobacterium smegmatis (9 mm). The acetone extract had a 9 mm halo (B. megaterium, B. cereus, P. aeuroginosa), a 8 mm (M. luteus, B. brevis, P. vulgaris) and a 7 mm halo (M. smegmatis and K. pneumoniae). Kivrak et al. (2009) evaluated the antibacterial eﬀect of the S. potentillifoli (whole plant) oil and ethanolic extract, with the oil being the most eﬀective with inhibition halos of 28 mm and a MIC of 20 μg/mL against Micrococcus luteus, 22 mm and MIC 17 μg/mL against B. subtilis and 18 mm and MIC of 25 μg/mL for K. pneumoniae. The ethanol extract was active against S. aureus, M. luteus, B. subtilis and B. cereus (19–22 mm). The smallest MIC was against Yersinia enterecolitica (26.5 μg/mL). Ebrahimabadi et al. (2010) evaluated the antibacterial activity of the essential oil and methanolic extract from Salvia eremophila Boiss. aerial parts. The inhibition zone observed was of 9 mm (E. coli and Salmonella paratyphi-A serotype), 10 mm (B. subtilis and Proteus vulgaris) and 32 mm (S. epidermidis). Signiﬁcant MIC values for the oil were 125 μg/mL (S. epidermidis) and 7.8 μg/mL (S. aureus), the remainder were 500 μg/mL or higher. The extract was shown to be eﬀective with an inhibition halo of 17–26 mm and MIC of 125 μg/mL to 500 μg/mL, except against S. paratyphi-A serotype; and P. aeruginosa. Finally, some chemical constituents and isolates from Salvia plants has been tested to ﬁnd the active molecules. In this context, Sonboli et al. (2006) evaluated the antimicrobial activity of the essential oil from Salvia spp. aerial parts and of the isolated constituents. S. mirzayanii presented halos of 16–27 mm and MIC of 10 to 1.25 mg/mL against Bacillus subtilis, E. faecalis, S. aureus, S. epidermidis. S. hydrangea and S. santolinifolia had inhibition zones of 10–17 mm and the MIC reduced from 7.5 to 15.0 mg/mL against B. subtilis and E. faecalis. The compounds that showed the best activity were β-pinene (15.2 mm and MIC 1.87 mg/mL), limonene (18 mm and MIC 0.6 mg/mL), linalol (29 mm and MIC 0.2 mg/mL) and 1,8-cineol (25 mm and MIC 0.93 mg/ mL). Other chemical classes have been studied too. From fresh aerial essential oil has been also evaluated by Bozin et al. (2007) using 20% and 50% solutions in n-hexane and cavity diﬀusion. All E. coli strains showed sensitivity with halos of 20–25 mm, and as well Micrococcus ﬂavus ATCC 10240 and Salmonella typhi IPH-MR with halos of 50–60 mm and 40–50 mm, respectively. Other Salvia essential oils have been also tested. Cutillas et al. (2017a,b) tested the antibacterial activity of the essential oil from the S. lavandulifolia aerial parts. The S. aureus bacterium showed greater susceptibility to the essential oil than E. coli. The results for the MIC and MBC were 9.0 mg/mL against E. coli and 4.5 mg/mL against S. aureus. The control used was streptomycin sulfate (1.0 × 10−3). Moreover, the S. mirzayanii ﬂowering aerial part essential oil was evaluated against 17 strains of Staphylococcus, Enterococcus, Streptococcus, Escherichia, Pseudomonas and Salmonella genotypes showing MIC95 ranging from 0.03 to > 128 μL/mL and MBC from > 0.031 to > 128 μL/mL (Zomorodian et al., 2017). Essential oil samples from the aerial parts of two S. multicaulis Vahl chemotypes and the main constituent, nerolidol, were tested against standard and multiresistant S. aureus and P. aeruginosa strains revealing MICs ranging from 128 to 512 μg/mL, however nerolidol had no eﬀect on P. aeruginosa (Fahed et al., 2016). Thus, other volatile compounds could participate in the bactericidal action. Tepe et al. (2004) found that the S. cryptantha Montbret & Aucher ex Benth oil was eﬀective against Streptococcus pneumoniae (11 mm), Mycobacterium smegmatis (18 mm), Clostridium perfringens (11 mm) and Streptococcus pneumoniae (11 mm) with a MIC 2.25 mg/mL. Whereas the Salvia multicaulis (Vahl) oil was active against Streptococcus pneumoniae (20 mm), B. cereus and Acinetobacter lwoﬃi (10 mm), Clostridium perfringens (15 mm) and M. smegmatis (14 mm) with a MIC ranging from 2.25 to > 72 mg/mL. The S. cryptantha extract had an eﬀect only against Streptococcus pneumoniae (14 mm), while S. multicaulis was active against S. aureus, Streptococcus pneumoniae, Moraxella catarrhalis and Bacillus cereus (11–13 mm and MIC of 2.25 mg/mL). Essential oils from aerial parts of Salvia spp. were evaluated obtaining similar results. In this way, S. oﬃcinalis (1) was active against S. mutans, S. aureus, Serratia marcescens and E. faecalis (8.7–11 mm) and S. oﬃcinalis (2) for S. aureus and E. faecalis (9.5 mm and 10.5 mm). S. lavandulifolia and S. sclarea were eﬀective against all bacteria (9.0–10.2 mm and 9.0–11.7 mm, respectively) and obtained identical MICs as Salvia spp. against B. subtilis (3.42 mg/mL). The MICs of S. oﬃcinalis (1) were the same against all Gram-negative strains (6.93 mg/ mL) and S. oﬃcinalis (2) ranged from 4.62 to 6.93 mg/mL. Against S. mutans, the MICs were 4.62 mg/mL (S. oﬃcinalis 1 and 2 and S. sclarea) and 3.27 mg/mL (S. triloba) and 2.87 mg/mL for S. lavandulifolia. The MIC values against S. aureus were 2.31 mg/mL (S. lavandulifolia), 2.87 mg/mL (S. oﬃcinalis 2) and 3.42 mg/mL (S. oﬃcinalis 1, S. triloba and S. sclarea) (Pierozan et al., 2009). Extracts from S. oﬃcinalis obtained using diﬀerent solvents have also demonstrated antibacterial activity. In this sense, a S. oﬃcinalis hydroalcoholic extract was shown to be eﬀective through disc diﬀusion (30 μL) and diﬀusion in wells (50 μL) against S. aureus with inhibition zones with a mean rate of 12.6 mm and 18.6 mm, respectively. When the concentration was doubled (100 μL), the mean of the inhibition zones was 22 mm. For the positive control, the following antibiotics were used: oxacillin (1 pg) with a 13 mm halo; gentamicin (10 μg) and vancomycin (30 μg) with 15 mm halos; cefoxitin (30 μg) with 20 mm and erythromycin (15 μg) with 23 mm (Garcia et al., 2013). In another study, Haida et al. (2007) tested n-hexane (EH), chloroform (EC), acetone (EA) and ethanol (EE) 80% and aqueous (infusion) extracts from this plant against bacteria by disc diﬀusion (10 μL) in varying concentrations. Its eﬀect was veriﬁed against P. aeuroginosa, where the ethanol extract presented a halo of 11 mm (10%) and 38 mm (50%) and the hexanic (50%) extract against the same strain formed a halo of 11 mm. In the diﬀusion assay performed by Alvarenga, Schwan, Dias, Schwan-Estrada, and Bravo-Martins (2007) with the aqueous and ethanolic extracts (10 and 20%) from S. oﬃcinalis leaves against Shigella ﬂexneri (ATCC 25931), only the ethanolic extract presented inhibition 256 Trends in Food Science & Technology 80 (2018) 242–263 M. Shariﬁ-Rad et al. parts of the S. barrelieri Etl., 12 isolates were isolated and tested for their antibacterial activity against E. faecalis, S. aureus, Staphylococcus epidermidis, E. coli and P. aeruginosa (Lehbili et al., 2017), for which some were active with a MIC ranging from 62.5 to 125 (epi-germanidiol), 125–250 μg/mL (micromeric acid), 31.5–500 μg/mL (ursolic acid), 31.2–125 μg/mL (apigenin-7-O-β-d-glucuronopyranoside), and 31.2–250 μg/mL (cynaroside or luteolin7-O-glucoside). From the dichloromethane extract of the S. chamaedryoides aerial parts, three compounds being classiﬁed as furan-diterpenes were active Splenidine and galdosol were found to be eﬀective against Enterococcus faecium and E. faecales with MICs ranging from 32 to 128 μg/mL, and one of the furan-diterpenes had an eﬀect only against E. faecium (Bisio et al., 2017). Two diterpenoids isolated from S. austriaca roots, taxodone and 15-deoxy-fuerstione, when tested against S. aureus caused a signiﬁcant inhibition of microbial adhesion (68.3 and 67.9%, 71.4% and 70.5%) and bioﬁlm formation (14.5 and 67%, 90.4 and 94.5%) at ½MIC and ¼MIC, respectively. Taxodone was also able to limit S. aureus survival in human blood (Sadowska et al., 2016). In general, the antimicrobial activity of the Salvia genus was evaluated against several Gram-positive and Gram-negative strains of the Staphylococcus, Streptococcus, Bacillus, Lysteria, Shigella, Micrococcus, Acinetobacter, Enterobacter, Escherichia, Klebsiella, Proteus, Pseudomonas, Clostridium, Mycobacterium, Salmonella, Morganella, Yersinia, Enterococcus, and Citrobacter genera. The best results presented were of the oils compared to the evaluated extracts. 19. Conclusions The species of the genus Salvia have attracted the attention of many scientists in the world due to unique biological properties. Some Salvia species are intensively investigated for their pharmacological values. In fact, the use of Salvia plants is widespread in more than 20 countries in diﬀerent continents, being the infusion of leaves the predominant preparation form, followed by decoction, which are administered orally. Among the cited species, S. oﬃcinalis L. stands out for its versatility and its widespread use. Nevertheless, the interest in using Salvia plants for food and pharmaceutical applications ﬁrstly implies good practices of cultivation of Salvia. Generally, these plants grow in diﬀerent geo-climatic regions in wild. Although it seems that Salvia can be easily grown indoors in any climate, outdoor needs appropriate climatic conditions, especially temperature. Concerning the phytochemical composition of the essential oils of Salvia plants, it depends on the species, although intra-species variation has also been observed. Other important aspects that should be considered is the origin of the Salvia species, plant part, phenological stage and agronomical practices since these factors aﬀect the proﬁle of volatile compounds. In the latter case, water status, nutrition and their interactive eﬀects may inﬂuences both the composition, e.g., pinene, αand β-thujones levels, and the essential oil production. In food systems, S. oﬃcinalis essential oil has been studied as a preservative agent to avoid oxidation and reduce foodborne pathogens. In general, relative higher concentrations of essential oils are needed, which may adversely aﬀect the organoleptic characteristics of foods. To minimize this eﬀect, it would be desirable to study the synergistic effects of Salvia spp. with other preservative techniques, including other natural antimicrobials and essential oils from other plants as well as with other non-thermal preservation techniques. Moreover, the direct use of S. oﬃcinalis essential oil may be limited by the presence of α/βthujone, whose dose should be limited due to its toxicity. So, the standardization of the essential oils is mandatory. Alternatively, the use of chemotypes with low content of these monoterpenes and other Salvia plants with lower amounts of thujone is an alternative, but the phytochemical proﬁle and biological properties may vary. Thus, as available data is still limited, further studies about this topic are needed. This review also highlights that diﬀerent Salvia species inhibit the growth of pathogenic fungi, such as Candida spp., and Gram-positive as well as Gram–negative bacteria in vitro. In particular, the essential oils of S. lanigera and S. hydrangea exhibited MIC values ≤ 100 μg/mL for some fungi species. Although the MIC, MFC and MBC values are higher than those of drug controls, these essential oils are natural products that can satisfy consumers' preferences. Nevertheless, more clinical studies are required. Concerning other biological properties, S. oﬃcinalis extracts and S. lavandulaefolia essential oils seem promising for enhancing memory and cognitive functions as shown in clinical studies. S. miltiorrhiza extracts and their constituents, such as salvianolic acids, tanshinone I and IIA, as well as cryptotanshinone, could be anti-Alzheimer agents, as suggested several in vitro studies. Moreover, S. hispanica seeds may have potential cardiovascular beneﬁts, although the results from clinical trials are contradictory. Nonetheless, the consumption of S. hispanica seeds could decrease glucose levels in humans as several clinical studies have evidenced. Besides the latter plant, other interesting Salvia species are S. miltiorrhiza and S. oﬃcinalis, which exhibited potential cardiovascular and/or hypoglycemic eﬀect. The anti-cancer properties of Salvia plants and their constituents have been mainly tested in vitro. However, there are few examples in animal models and in humans, so more studies are required. Therefore, although some Salvia plants represent promising therapeutic agents, there is a need of clinical studies to support this statement for each extract and plant type, but before their safety assessment is a requirement due to the potential presence of toxic compounds. 18. Toxicity The European Medicines Agency has recently published assessment reports on S. oﬃcinalis, folium, S. oﬃcinalis, aetheroleum, and S. fruticosa, folium with an overview of available toxicological data. These reports suggested that sage leaf is safe when used in recommended dosages, while the current data supporting safety and toxicocity of S. fruticosa is still limited (European Medicines Agency, 2016a, 2016b). However, thujone (Fig. 1) is reported to be neurotoxic in high doses (European Medicines Agency, 2016b). For this reason, this agency has reported a general Public statement on the use of herbal medicinal products containing thujone, including S. oﬃcinalis oil, and other plants (such as cedar leaf, tansy, wormwood, thyme and rosemary). In this statement a recommendation is done on the basis of limit doses of 3.5 and 6.6 mg/day: the amount of thujone in a preparation needs to be speciﬁed, while for higher concentrations, a case-by-case beneﬁt/risk assessment would be necessary (European Medicines Agency, 2016b). In the case of the acute LD50 value for sage oil is 2.6 g/kg in rats for oral administration (European Medicines Agency, 2016b), being slightly toxic based on Hodge and Sterner (1949) classiﬁcation. Some Salvia representatives produce other toxic compounds. As an example, S. divinorum contains the psychotropic molecule salvinorin A. Structurally, it belongs to the terpenoids class and it produces a unique proﬁle of dissociative, hallucinogenic and memory eﬀects (MacLean et al., 2013). Red sage (S. haematodes Wall.) has anticonvulsant eﬀects and depress the central nervous system (Baricevic & Bartol, 2005). In another context, although the toxicological information on chia seeds from animal and controlled human studies is still limited, their previous uses for food applications in other countries can be regarded as supportive evidence of their safety (European Food Safety Authority, 2009). Similarly, S. miltiorrhiza is a well-known traditional Chinese herb and with no serious adverse eﬀects (Zhou, Zuo, and Chow, 2005). The LD50 of several extracts from this plant was higher than 2.5 g/kg in animal models (Zhou, Zuo, and Chow, 2005), while that for danshensu (3-(3,4-dihydroxyphenyl)lactic acid), one of its active compounds, was 2.4 g/kg in mice after a single intravenous dose (Gao et al., 2009). 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