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Review

Extraction Processes Affect the Composition and Bioavailability of Flavones from Lamiaceae Plants: A Comprehensive Review

1
Centro de Investigación en Alimentación y Desarrollo, A. C., Carretera a Eldorado Km 5.5 Col. Campo El Diez, Culiacán 80110, Sinaloa, Mexico
2
Cátedras CONACYT-Centro de Investigación en Alimentación y Desarrollo, A.C., Av. Sábalo Cerritos S/N, S/C, Mazatlán C.P. 82112, Sinaloa, Mexico
3
Centro de Investigación en Alimentación y Desarrollo, A.C., Av. Sábalo Cerritos S/N, Mazatlán C.P. 82112, Sinaloa, Mexico
4
Unidad Académica de Ingeniería en Energía, Maestría en Ciencias Aplicadas, Universidad Politécnica de Sinaloa, Carretera Municipal Libre Mazatlán-Higueras Km 3, Mazatlán 82199, Sinaloa, Mexico
5
Cátedras CONACYT-Centro de Investigación en Alimentación y Desarrollo, A.C., Carretera a Eldorado Km 5.5 Col. Campo El Diez, Culiacán 80110, Sinaloa, Mexico
*
Author to whom correspondence should be addressed.
Submission received: 11 August 2021 / Revised: 13 September 2021 / Accepted: 14 September 2021 / Published: 18 September 2021
(This article belongs to the Special Issue Feature Review Papers in Section "Food Processes")

Abstract

:
Lamiaceae plants are a widespread family of herbaceous plants with around 245 plant genera and nearly 22,576 species distributed in the world. Some of the most representative and widely studied Lamiaceae plants belong to the Ocimum, Origanum, Salvia, and Thymus genera. These plants are a rich source of bioactive molecules such as terpenes, flavonoids, and phenolic acids. In this sense, there is a subgroup of flavonoids classified as flavones. Flavones have antioxidant, anti-inflammatory, anti-cancer, and anti-diabetic potential; thus, efficient extraction techniques from their original plant matrixes have been developed. Currently, conventional extraction methods involving organic solvents are no longer recommended due to their environmental consequences, and new environmentally friendly techniques have been developed. Moreover, once extracted, the bioactivity of flavones is highly linked to their bioavailability, which is often neglected. This review aims to comprehensively gather recent information (2011–2021) regarding extraction techniques and their important relationship with the bioavailability of flavones from Lamiaceae plants including Salvia, Ocimum, Thymus, and Origanum.

1. Introduction

1.1. Lamiaceae

The Lamiaceae family of plants, also known as the mint family, belongs to the major group Angiosperms, which is a group of herbs and shrubs that are annual or perennial, and most of which are aromatic plants [1,2,3]. The Plant List database states that around 245 plant genera are included in the Lamiaceae family, with around 7886 species [4], representing the sixth largest family of flowering plants in the world. The Lamiaceae family is distributed around the world and is widely diverse. Moreover, some of the most evaluated plant genera are Salvia (986 species), Ocimum (66 species), Origanum (56 species), and Thymus (315 species) [4]. Plants of the Lamiaceae have square stems and opposite leaves, with zygomorphic flowers that have five united petals and five united sepals. These plant species are also known for their aromatic characteristics given by their essential oils and as a source of natural compounds such as terpenes, essential oils, phenolic acids, and flavonoids [5,6]. There is an increasing interest in plant-based natural compounds for pharmacological uses, either as prophylactic or therapeutic agents, due to their antioxidant, anti-inflammatory, anti-obesity, and anti-cancer properties. In this sense, Lamiaceae plants represent an interesting and promising source of natural compounds with bioactive properties; some of the compounds that have attracted attention are flavones, which are described in Section 2.

1.2. Phenolic Compounds

Phenolic compounds are secondary metabolites that are ubiquitously found in plants that act as plant defense metabolites against biotic and abiotic stress. Their distribution in plants depends on the plant species, plant part, place of origin, phenological stage, and environmental factors [7]. Phenolic compounds are derived from pentose phosphate, shikimate, and phenylpropanoid pathways in plants. Furthermore, strictly phenolic compounds are ‘secondary metabolites derived exclusively from the shikimate-derived phenylpropanoid and the polyketide pathways, featuring more than one phenolic ring and being devoid of any nitrogen-based functional group’ [8]. Phenolic compounds are chemically characterized by having one aromatic ring with -OH radical groups They are also chemically similar to alcohols or aliphatic molecules with -OH attached to carbon atoms. Phenolic compounds are also considered weak acids due to the hydrogen atom lability in the -OH [9,10]. Some of the most studied plants belong to the Lamiaceae genera; these plants and herbs have been used in folk medicine for many purposes. Lamiaceae are a rich source of phenolic compounds such as phenolic acids and flavonoids that are distributed in leaves, flowers, roots, stems, and aerial parts. Flavonoids have been attributed with strong antioxidant, anti-inflammatory, anti-obesity, and anti-cancer properties [5,6,11,12,13].
Phenolic compounds are classified by their biosynthetic origin and chemical characteristics. Chemically, phenolic compounds can be classified as:
  • Flavonoids
    Flavonols and flavones;
    Flavanones;
    Isoflavones;
    Anthocyanins;
    Flavan-3-ols.
  • Non-flavonoids
    Hydroxycinnamic acids;
    Hydroxybenzoic acids;
    Coumarins;
    Benzophenones and xanthones;
    Stilbenes;
    Chalcones;
    Lignans.
Flavonoids are produced from the phenylpropanoid pathway [14,15]. During flavonoid biosynthesis, the main flavonoid backbone (a chalcone with a C6-C3-C6 structure), is derived from the shikimic acid pathway and is produced through the action of the enzyme 4-coumaroyl coenzyme A; this generates the synthesis of the B and C rings, and three molecules of malonyl coenzyme A, the precursor of ring A. The resulting flavonoid backbone produces the other flavonoid subclasses, which are further synthesized by the action of reductases, isomerases, hydroxylases, and other enzymes [15,16]. Subsequently, flavones are produced from the flavanone naringenin by catalysis of two oxidoreductases, flavone synthase I and II, introducing a double bond between C2 and C3 [17]. For a more detailed description of the biosynthesis of flavones, we recommend the work by Jiang, Doseff and Grotewold [17].

1.3. Flavones

Flavones are a subtype of flavonoids that are characterized by a double bond in C2-C3 in the flavonoid structure and a ketone group at C4, and a lack of oxygenation at C3 (Figure 1) [18]. Some of the most known flavones are apigenin, cirsimaritin, luteolin, scutellarein, and their derivatives (Figure 2). Flavones can be found in nature with various substitutions, including -OH radicals, methylation, O- and C-alkylation, and glycosylation [10]. These residues may be found alone or in combination with flavones [19]. Many flavones have been reported in Lamiaceae plants, where they mostly accumulate in leaves, aerial parts, and exudates.
In plants, flavones act as plant defenses against UV radiation, favor pollination, and have an ecological interaction with the soil microbiota [20,21]. However, flavones have also attracted the attention of scientists because their consumption has been associated with beneficial health properties including the prevention of oxidative stress, the prevention of premature aging, the decreased incidence of noncommunicable diseases such as diabetes and different types of cancer, and decreased risk of cardiovascular diseases [17,22]. These noncommunicable diseases represent a global burden in health care systems and are the main cause of death worldwide [23]. The bioactive properties of flavones depend on the number, nature, and position of the substituents in the flavone skeleton, which will modulate their regioselectivity and the way flavones interact with biological targets to exert health-promoting properties [24]. Due to the importance of flavones in human health, several strategies have also been reported to produce them synthetically [24].
Moreover, some of the structural characteristics that facilitate the interaction of flavones with biological molecules to act as antioxidants and exert other bioactive properties are: (a) the presence of catechol on ring B; (b) the 2,3-olefinic bond and the keto group provides electron delocalization from ring B, which facilitates the donation of an electron to free radicals; (c) the -OH groups at C3 and C5 form hydrogen bonds with the keto group; (d) the synergy between flavones and some physiological antioxidants; and (e) the capacity of flavones to chelate metal ions attributed to the -OH at C5 and the C4 keto group [17,20].
Figure 2. Common aglycone flavones in Lamiaceae plants (a) apigenin, (b) cirsimaritin, (c) luteolin, and (d) scutellarein [25,26,27,28].
Figure 2. Common aglycone flavones in Lamiaceae plants (a) apigenin, (b) cirsimaritin, (c) luteolin, and (d) scutellarein [25,26,27,28].
Processes 09 01675 g002

2. Literature Research Strategy

To identify relevant information on Lamiaceae flavones, this review was compiled based on recent scientific literature (2011–2021) from the Scopus, Google Scholar, and Web of Science databases. The keywords used for the literature search included the terms Lamiaceae, Origanum, Ocimum, Salvia, Thymus, flavones, apigenin, luteolin, scutellarein, cirsimaritin, extraction, supercritical CO2, ultrasound-assisted extraction, and microwave-assisted extraction (Figure 3).

3. Flavones Distribution in Lamiaceae Plants

3.1. Salvia

3.1.1. Characteristics of the Salvia Genus

Salvia L. species constitute the largest genus in the family Lamiaceae with over 1000 species, organized into five subgenera (Sclarea, Audibertia, Jungia, Leonia, and Salvia); these plants grow in temperate, subtropical, arctic, and sub-arctic areas of the world and are distributed mainly in Central and South America (500 spp.), Central Asia/Mediterranean (250 spp.) and Eastern Asia (100 spp.). Mexico is the country with the largest number of species (about 300). Salvia plants are typically 30–150 cm tall. Most species are perennial or annual herbs, they are rarely biennial, although shrubs, and a few trees and vines, also exist, with attractive flowers in various colors that are typically pink, red, or purple to blue [29,30,31,32,33,34]. Some members of the Salvia genus are used as flavoring agents in perfumery and cosmetics; for example, S. sclarea and S. pratensis. Around 134 of the 1000 Salvia species were studied for different functions [29]. Recently, the Salvia genus was explored for medical purposes; as the name suggests, the term “Salvia” is derived from the Latin “salvare” meaning ‘to heal or to be safe and unharmed’, referring to the medicinal properties of some of the species [33]. In this sense, many species within the genus exhibit antibacterial, antiviral, antioxidative, antimalarial, anti-inflammatory, antidiabetic, cardiovascular, antitumor, and anti-cancer properties [35].

3.1.2. Flavones in Salvia Species

Flavones are the most representative flavonoids in Salvia species, mostly flavones of apigenin, luteolin, ladanein, and salvigenin, and their corresponding 6-hydroxylated derivatives, flavonols, and their glycosides; these could be found in aerial parts or roots [32,33,36]. The flavones luteolin and salvigenin, identified in several Salvia species, are known for their anti-inflammatory effects [33]. In addition, the 6-methoxyflavones (nepetin and hispidulin), and their glycosides, inhibited NO and PGE2 production, and the expression of the iNOS and COX-2 proteins, through heme oxygenase-1 (HO-1) induction, via the activation of nuclear factor erythroid 2-related factor2 (Nrf2), which suggests in vitro and in vivo anti-inflammatory activities [10]. Other flavones with anti-inflammatory activities are genkwanin, luteolin, cirsimaritin, and salvigenin, isolated from S. lavandulifolia [33].
Methoxyflavones isolated from S. mirzayanii Rech. f. & Esfand presented chemopreventive activity; these results were better than the hydroxylated ones. They reduced the invasion of tumors and suppressed cancer cell proliferations through proapoptotic properties, thanks to such chemical structures as 5,7-dihydroxy, 5,6,7-trihydroxy, and 5,7-dihydroxy-6-mehoxy at ring A, and 3′, 4′-dihydroxy at ring B [33].
Among Salvia bioactivities, the amoebicidal and giardicidal effects and the anti-diarrheal properties of S. divinorum Epling & Jativa, S. gesneriiflora Lindl. & Paxton, S. herbacea Benth., S. microphylla Kunth, and S. shannonii Donn. Sm. have been studied, and it was found that the antiprotozoal activity of flavonoids, such as flavones, appears to be related to the phenolic and hydroxy groups at C-3, C-5, and C-7 of the flavonoid backbone. The change of a hydroxy to a methoxy group or a monosaccharide moiety at C-3 decreases the activity. Especially about flavones, a methoxy group at C-6 was favorable, and when the degree of oxygenation in the B-ring increased, the antiprotozoal activity decreased significantly; it was also observed that the 2,3-double bond was not essential for high antiprotozoal activity, but the stereochemistry could play an important role [37]. In this sense, Bautista, Calzada, Yépez-Mulia, Bedolla-García, Fragoso-Serrano, Pastor-Palacios and González-Juárez [37] determined the antiprotozoal activity of S. connivens Epling, against Entamoeba histolytica (IC50 0.072 ± 0.006 μM) and Giardia lamblia (IC50 0.118 ± 0.006 μM), which was comparable to the drug metronidazole; these results were related to the presence of three flavones: eupatorin, cirsiliol, and nuchensin.
One of the major active compounds in S. plebeia is hispidulin, which demonstrated antifungal, anti-inflammatory, antioxidant, antithrombotic, antiepileptic, neuroprotective, and anti-osteoporotic activities [33]. While S. sharifii Rech. f. and Esfan. possess two flavones, ladanein and 6-hydroxy-5,7,4′-trimethoxyflavone, both compounds have presented antimicrobial activity, especially in Gram-negative bacteria such as E. coli; additionally, these flavones showed antioxidant and cytotoxic activity [32].
There is a large variability of flavonoid structures among the Salvia genus, such as flavones; their chemical differentiation might be correlated to the geographical and ecological conditions under which they grow [31]. Researchers often find new structures in Salvia species; for example, two new flavone glycosides, with an unusual interglycosidic linkage, were isolated from the petals of S. uliginosa [29].

3.2. Ocimum

3.2.1. Characteristics of the Ocimum Genus

The genus Ocimum comprises more than 300 species of annual and perennial herbs and shrubs, and it is considered as one of the largest genera of the Lamiaceae family; this genus comprises many distinct species and varieties [38,39,40]. The typical characteristics of this genus, as with other members from the same family, are a square stem, and opposite and decussate leaves with many gland dots. The flowers (white, pink, violet) are strongly zygomorphic with two distinct lips; the stamens lie over the lower (anterior) lip of the corolla rather than ascending under the upper (posterior) lip [41]. The genus Ocimum is widely distributed in tropical and warm temperate regions over Asia, Africa, and Central and Southern America; this genus requires warmth for growth and should be protected from frost [41]. The name “Ocimum” is derived from the Greek meaning ‘‘to be fragrant’’; therefore, plants of this genus are aromatic and rich in secondary metabolites, which humans have learned to use since antiquity for food preservation, flavoring, and as medicine [1,40].

3.2.2. Flavones in Ocimum Species

The flavones apigenin, luteolin, chrysoeriol, 6-hydroxy, and hydroxyl-flavones in glycosidic combination, and lipophilic flavones, such as 5,6,4-trihydroxy-7,3-dimethoxy-flavone, were detected in Ocimum species [42]. In addition, two unusual flavones from O. canum were reported. The identified flavones were navadensin (5,7-dihydroxy-6,8,4′-trimethoxy flavone) and salvigenin (5-hydroxy-6,7,4′-trimethoxyflavone); the amount of these flavones was 0.1% of the dry weight of the material [41]. The flavone xanthomicrol (5,4′-dihydroxy-6,7,8-trimethoxyflavone) was isolated from the leaves of a Nigerian O. basilicum; three flavones, eriodictyol, eriodictyol-7-glucoside, and vicenin-2 (apigenin di-C-glycoside), were identified from the leaves of O. basilicum grown in Greece; three flavones were also isolated from the leaves of O. sanctum, these being vicenin (apigenin-6, 8-Cglycoside), galuteolin (luteolin-5-O-glycoside) and cirsilineol (5,4′-dihydroxy-6,7,3′-trimethoxyflavone) [41].
Due to large variation in the morphological characteristics of species, in addition to human intervention, it has become difficult to identify some species. Therefore, it has been concluded that identification can be conducted in an auxiliary manner through molecular markers, such as the tetrahydroxyflavone luteolin 5-O-glucoside, considered as a chemosystematic element in O. americanum, O. basilicum, O. gratissimum, O. kilimandscharicum, O. lamiifolium, O. minimum, O. selloi, O. gratissimum, and O. citriodorum [38,39].
Ocimum species have been related to many different bioactivities, and most of them have been correlated to essential oils and their components. Nonetheless, a recent study showed that the polymethoxylated flavones 5-demethyl nobiletin and 5-demethyl sinensetin, together with luteolin, isolated from O. campechianum, decreased blood glucose in in vivo model; furthermore, it was proposed that these two polymethoxylated flavones can be considered as chemotaxonomical markers for the genus [18]. In addition, luteolin, and luteolin glycosides from O. sanctum leaves presented leishmanicidal properties against L. major, antituberculosis, and cytotoxic cells of prostate carcinoma in mice, and showed anti-inflammatory and antiproliferative activities [1].

3.3. Origanum

3.3.1. Characteristics of Origanum

Origanum is an important plant genus that belongs to the Lamiaceae family. Its foremost characteristic species is Origanum vulgare L., commonly known as European oregano. The genus Origanum comprises 49 taxa and more of 42 species and 18 hybrids [43]. Origanum were divided into ten sections: (i) Amaracus Bentham, (ii) Anatolicon Bentham, (iii) Brevifilamentum Ietswaar, (iv) Longitubus Ietswaart, (v) Chilocalys Ietswaart, (vi) Majorana Bentham, (vii) Campanula ticalix Ietswaart, (viii) Elongatispica Ietswaart, (ix) Origanum Ietswaart, and (x) Prolaticorolla Ietswaart [44]. The majority of the Origanum species are located within the Mediterranean, occurring mainly in Greece and Turkey [43]. This plant grows at altitudes between the 400 and 1800 m, and in sunny areas [45]. Origanum species are annual, perennial herbs with oval to small circular leaves, with sometimes toothed margins and obtuse to pointed tips. The flowers might present white, pink or purple colors and are clustered in spikes [46].

3.3.2. Flavones in Origanum Species

Much attention has been given to the chemical constituents of essential oils from Origanum species. Nevertheless, it was recently reported that polyphenolic components in extracts from these plants might exert beneficial effects [18]. The main phenolic components in Origanum species are phenolic acids and flavonoids [47]. Regarding the focus of this review, several studies have been carried out to identify flavones present in plants belonging to the genus Origanum. For instance, Gird et al. [48] performed a preliminary study to determine the total flavone content in ethanolic extracts of indigenous O. vulgare L. aerial parts and showed 4.21 ± 0.127 g of rutin equivalents/100 g dry extract. In a more profound study, Martins et al. [49] identified and quantified several flavones present in the infusion, decoction, and hydroalcoholic extracts from O. vulgare L. flowering aerial parts. The flavones detected were apigenin-6,8-di-C-glucuronide (0.52 ± 0.06–0.98 ± 0.00 mg/g extract), luteolin-O-glucuronide (12.48 ± 0.09–28.27 ± 0.24 mg/g extract), luteolin-7-O-glucoside (20.88 ± 0.00–25.26 ± 0.44 mg/g extract), apigenin-7-O-rutinoside (0.74 ± 0.00–1.53 ± 0.06 mg/g extract), apigenin-7-O-glucuronide (5.78 ± 0.03–8.63 ± 0.02 mg/g extract), and methylapigenin-O-glucuronide (0.61 ± 0.02–1.26 ± 0.13 mg/g extract). Additionally, Milevskaya et al. [50] identified the flavones present in O. vulgare extracts using HPLC-ESI-MS. In this case, the flavones detected were apigenin, luteolin, apigenin-7-glucuronide, and luteolin-7-O-β-D-glucuronide. Moreover, Tuttolomondo et al. [51] identified and quantified seven flavones, using HPLC-PDA-ESI/MS, in the ethyl acetate extracts from dried aerial parts of 57 biotypes of O. vulgare subsp hirtum (wild Sicilian oregano). The flavones detected were luteolin (0.15–1.16 mg/kg dry weight), sorbifolin (0.04–2.90 mg/kg dry weight), cirsiliol (0.02–4.61 mg/kg dry weight), apigenin (0.26–2.34 mg/kg dry weight), cirsilineol (0.13–4.08 mg/kg dry weight), cirsimaritin (0.55–8.69 mg/kg dry weight), and xanthomicrol (0.03–9.09 mg/kg dry weight).
Furthermore, Maietta et al. [52] obtained an aqueous infusion from O. dictaminus dried herb and identified its flavone components using RP-HPLC-DAD-ESI/MS. The extract presented several flavones, such as 6,8-di-C-hexosylapigenin, apigenin-7-O-triglucuronide, luteolin-7-O-diglucuronide, apigenin-O-triglucuronide, apigenin-7-O-diglucuronide, apigenin-7-O-glucuronide, luteolin-7-O-rutinoside, and xanthomicrol (5,4′-dihidroxy-6,7,8-trimethoxyflavone). Table 1 shows other flavones identified in several plants belonging to the genus Origanum.
From these studies, the most frequently identified flavones in the different polyphenolic extracts from Origanum species are luteolin and apigenin derivatives, which have shown antioxidant [53,54], anti-cancer [55], and anti-inflammatory properties [56]. Other flavones, such as didymin, isolated from O. vulgare, presented biological properties, such as anti-inflammatory activity and a reduction in the hepatic damage induced by CCl4, in male mice [57].
Table 1. Flavones identified in several Origanum species.
Table 1. Flavones identified in several Origanum species.
Plant SpeciesPlant PartType of ExtractMethod of IdentificationFlavonesReference
O. vulgare subsp. hirtum (Greek oregano)Aerial partsAqueous, afterward extraction using ethyl-acetateLC-DAD-MSApigenin 7-O-glucoside
Apigenin
Apigenin 7-O-glucuronide
Luteolin 7-O-glucuronide
Luteolin
Cirsimaritin
[58]
O. vulgare subsp. viridulumFlower buds (without stem)Water:methanol (6:4)HPLC-PDALuteolin glycosides
Apigenin glycosides
[59]
O. vulgareUnspecifiedPressurized liquid extractionLC-MS/MSLuteolin-7-O-glucuronide
Luteolin
Apigenin
[60]
O. dictamnusAerial partsAqueous, afterward extraction using ethyl-acetateLC-DAD-MSApigenin-7-O-glucuronide
Cirsiliol
Cirsilineol
Luteolin-7-O-glucuronide
[58]
O. glandulosumAerial partsMicrowave-assisted solvent extractionLC-DAD-ESI-MS/MSLuteolin-O-hexoside
Luteolin-6,8-di-C-glucoside
Luteolin-7-O-glucuronide
Other luteolin derivatives
[61]
O. majorana L.Aerial partsMethanolUPLC-ESI-QTOF-MS/MSLuteolin-6,8-C-dihexose
Apigenin-6,8-di-C-hexoside
Isoorientin
Orientin
Vitexin/Isovitexin
Luteolin-O-glycoside
Diosmin
Apigenin-O-glucuronide
Acacetin rutinoside
Luteolin
Apigenin
[62]
O. mycrophillumAerial partsAqueous, afterward extraction using ethyl-acetateLC-DAD-MSApigenin-7-O-glucoside
Apigenin
Genkwanin
[58]

3.4. Thymus

3.4.1. Characteristics of Thymus

The genus Thymus, belonging to the Lamiaceae family, consists of over 336 species [63]. Thymus vulgaris L., known as common thyme, is the most significant species of this genus [64]. Plants from the Thymus genera are native to the Eurasian and the Mediterranean region and are also distributed over North Africa, Australia, and South America [64,65]. Thymus species are small perennial shrubs that possess grey to green leaves that might be arranged oppositely or clustered. The flowers present light violet, purple or white coloring [64].

3.4.2. Flavones and Their Significance in Thymus Species

As in Origanum species, plants belonging to Thymus genus are well recognized for their essential oil content. Nevertheless, polyphenolic extracts from this genus were recently studied due to their health-beneficial potential [66]. In this context, Desta et al. [67] used LC-ESI-MS/MS to identify the individual components of polyphenolic extracts from T. schimperi. It was determined that the extracts were rich in flavone content; luteolin derivatives were the main constituents (21.83%), and the extracts contained apigenin and chrysoeriol glycosides and other poly-methoxyflavones (unidentified). Afonso et al. [68] determined the total flavone content and the individual constituents of decoction extracts from three Thymus species (T. fragrantissimus, T. pulegioides, and T. zygis). Thymus pulegioides showed the highest flavone content (55.62 ± 1.05 µg/mg extract), followed by T. fragrantissimus (21.67 ± 0.59 µg/mg extract) and T. zygis (16.01 ± 0.27 µg/mg extract). The flavone luteolin-O-glucuronide was the main component found in the three species of Thymus evaluated. In T. pulegioides, the main flavones were luteolin-O-glucuronide (26.14 ± 0.78 µg/mg extract), chrysoeriol-O-hexoside (12.00 ± 0.15 µg/mg extract), apigenin-O-glucuronide (9.20 ± 0.21 µg/mg extract), and luteolin-C-glucoside (8.27 ± 0.13 µg/mg extract). In T. fragrantissimus, the major flavone components were luteolin-O-glucuronide (16.86 ± 0.21 µg/mg extract), apigenin-di-C-glucoside (2.69 ± 0.50 µg/mg extract), and luteolin-C-glucoside (2.00 ± 0.0.02 µg/mg extract), while, in T. zygis, luteolin-O-glucuronide (7.57 ± 0.05 µg/mg extract), luteolin-C-glucoside (4.86 ± 0.03 µg/mg extract), and apigenin-di-C-glucoside (1.60 ± 0.32 µg/mg extract) were the predominant flavones. It is clear from this study that the flavone content and composition are affected by the Thymus species evaluated. Additionally, it was reported that flavone content varies in Thymus species according to the phenological phases. For instance, they determined the effect of the phenological phases on the flavone content in several Thymus species (T. austriacus, T. x citriodorus, T. longicaulis, T. x oblongifolius, T. praecox ssp. arcticus, T. pulegioides, T. serpyllum, and T. sibtorpii). The authors analyzed the extracts from Thymus species using HPLC-UV and found luteolin-7-rutinoside, luteolin-7-glucoside, and apigenin-7-glucoside to be present. The highest flavones content was described during the flowering phase and a significant diminution was observed throughout the fruit maturation and the end of vegetation. The flavone luteolin-7-glucoside was identified in all species studied, except in T. austriacus, while apigenin-7-glucoside was only detected in samples of T. serpyllum, T. sibthorpii, and T. praecox ssp. arcticus. Luteolin-7-rutinoside was identified in all Thymus species under study [69].
Recently, Kindl et al. [70] analyzed, using LC-DAD-ESI-MS/MS, the polyphenolic composition of extracts from T. longicaulis C. Presl, T. praecox Opiz subsp. polytrichus (A.Kern. ex Borbás) Jalas, T. pulegioides L., T. serpyllum L. subsp. serpyllum, T. striatus Vahl, and T. vulgaris. These authors found that glycosides of luteolin and scutellarein were the most abundant polyphenolic constituents in the extracts of the Thymus spp mentioned. Furthermore, luteolin-7-O-hexuronide (4.56 ± 0.03–14.43 ± 0.29 mg/g of dry extract) was the flavone found in all Thymus species under study. In contrast, the apigenin derivatives, apigenin-7-O-hexuronide (6.86 ± 0.03 mg/g of dry extract) and apigenin-hexoside-hexuronide (1.44 ± 0.01), were only found either in T. pulegioides or T. striatus, respectively. Other flavones identified in several Thymus species are shown in Table 2.
Polyphenolic extracts containing flavones from several Thymus species have been evaluated to determine their biological properties. For instance, it was demonstrated that decoction extracts containing glucosides of luteolin and apigenin from T. herba-barona, T. pseudolanuginosus, and T. caespititius possess antioxidant, anti-inflammatory, and antibacterial activities [71].
Table 2. Flavones identified in several Thymus species.
Table 2. Flavones identified in several Thymus species.
Plant SpeciesPlant PartType of ExtractMethod of IdentificationFlavonesReference
T. vulgaris (common thyme) LeavesUltrasound-assisted maceration with methanol; afterward, liquid–liquid extraction using ethyl acetateRP-HPLC-ESI-MS/MSLuteolin-O-hexosideLuteolinEupatorinePoly-methoxyflavones[72]
Aerial partsMethanolRP-HPLC–DADLuteolin-hexosideLuteolin-7-O-glucosideLuteolin-7-O-hexuronide[70]
Deodorized leavesPressurized hot water extractionHPLC-ESI-Q-TOFApigenin-6,8-di-C-glucosideLuteolinLuteolin-7-O-glucosideLuteolin-7-O-glucuronideApigenin-7-O-glucuronideCirsimaritinCirsilineol5,6-Dihydroxy-7,8,3′,4′-tetramethoxyflavone[73]
T. algeriensisAerial partsInfusion, decoction or ethanol:water (80:20)LC-DAD-ESI/MSApigenin-6,8-C-dihexosideApigenin-8-C-glucosideLuteolin-7-O-glucuronideApigenin-7-O-glucuronide[74]
T. capitatusLeavesMethanolUHPLC-DAD-ESI-MSApigenin-C-di-hexoside[75]
T. x citriodorusAerial parts80% ethanolHPLC–DAD-ESI–MSLuteolin-5-β-O-glucosideLuteolin-7-α-O-glucuronideLuteolin-7-O-glucosideChrysoeriol-7-β-O-glucosideApigenin-7-β-O-glucuronide[76]
T. lotocephalusAerial partsWater, water:ethanol (1:1) or ethanolHPLC-DADLuteolinApigenin[77]
T. pseudolanuginosusAerial partsDecoction extracts (water)UHPLC-DAD-ESI-MSLuteolin-C-glucosideLuteolin-O-glucuronideApigenin-O-glucosideApigenin-O-glucuronide[71]
T. puligioidesAerial partsDecoction extracts (water)UHPLC-DAD-ESI-MSLuteolin-C-glucosideScutellarein-O-glucuronideLuteolin-O-glucuronideChrysoeriol-O-hexosideApigenin-O-glucuronide[68]
Aerial parts70% ethanolHPLC-UVLuteolin-7-rutinosideLuteolin-7-glucoside[69]
T. serpyllumObtained as herbal tea95% ethanolHPLC-DADLuteolin-7-O-glucosideLuteolinApigenin[78]
Whole plantAqueous extractHPLC-DADLuteolinApigenin[79]
UnspecifiedPressurized liquid extractionLC-MS/MSLuteolin-7-O-glucosideLuteolin-7-O-glucuronideApigenin-7-O-glucuronideLuteolinApigeninCirsimaritin[60]

4. Extraction Methods of Flavones from Lamiaceae Plants

4.1. Conventional Methods

Flavones are usually extracted by conventional techniques, including maceration, Soxhlet extraction, hydrodistillation, and boiling, among others [80]. In almost all extraction, it is necessary to decrease particle size to help the process [81]; the plant is dried and pulverized to obtain a powder used for the extraction. Table 3 summarizes the conventional extraction techniques used to obtain flavones in Lamiaceae species; we encourage the reading of each specific research paper to obtain detailed information about the extraction process, identification technique, and compound identification. In general, apigenin, luteolin, and their glucosides are widely distributed in the genera analyzed and can be extracted by various conventional methods. Moreover, the aerial parts (leaves, stems, and flowers) are the most used in these extractions; separately, however, leaves, roots, flowers, and residues from previous processes can also be used to obtain flavones.
In Salvia species, hydrophilic solvents are widely used to extract flavones. For instance, methanolic, ethanolic, and aqueous mixtures have been used to extract various compounds, mostly luteolin and apigenin derivatives, including glucoside and glucuronides, along with hydroxylated and methylated derivatives [36,82,83,84,85,86,87,88,89,90,91,92]. In contrast, other polar solvents such as acetone and ethyl acetate are less used to extract these compounds [32,37,93,94,95], while dichloromethane is even less common [96,97]. Furthermore, the use of hot water to extract flavones is generally used to simulate the usual way in which these plants are consumed (infusion or decoction), with good results found when obtaining apigenin and luteolin derivatives [90], and other flavones such as cirsimaritin [98]. To improve the separation of desired compounds, it is necessary to fractionate the extracts by subsequent extractions using solvents with different polarity or by column chromatography, as seen in the hot water extract of Salvia absconditiflora, which was sequentially fractionated with ethyl acetate and n-butanol, and was found to be rich in flavones in the ethyl acetate fraction [98]. Similarly, the n-hexane extract of Salvia chloroleuca fractionated with ethyl acetate and methanol showed the first fraction as the best one to obtain these compounds. Moreover, flavones such as salpleflavone were found in the ethyl acetate fraction of the ethanolic extract of Salvia plebeian [92]. In addition, further fractionation of the ethanolic extract was useful to isolate the flavones neocafhispidulin and 6″-O-acetylhomoplantaginin, among others [86]. Similarly, the fractionation of the acetone extract of Salvia connivens was useful to isolate three bioactive flavones [37]. Meanwhile, fractionation was also used for less polar solvents such as the dichloromethane extract of Salvia circinata [97].
Polar solvents such as methanol, ethanol, and aqueous mixtures have been used to obtain extracts from species including O. basilicum, O. gratissimum, O. sanctum, and O. tenuiflorum with good results [84,99,100,101,102,103,104]. Less used, but also effective in the extraction of flavones, are solvents such as diethyl ether, which is useful to extract such flavones as nevadensin and salvigenin in O. basilicum [105]. Fewer studies were observed with other solvents such as hot water extract that showed similar results to hydromethanolic and hydroethanolic extractions in the same plant [106]. On the other hand, some studies further fractionated the extract to isolate the compounds, as seen in the infusion of O. campechianum [107] and the methanolic extract of O. gratissimum and O. sanctum [100,101].
Water extracts are effective in the extraction of flavones of Origanum species; numerous studies show the presence of mostly apigenin and its derivatives in the aqueous extracts of O. acutidens, O. majorana, O. minutiflorum, and O. vulgare [108,109,110,111,112]; while methanolic and hydroethanolic extracts can also extract luteolin derivatives in O. vulgare and O. majorana [112,113,114,115]. Furthermore, fractionation with diverse solvents, in addition to chromatography, is effective in isolating some flavones, such as cirsiliol and cirsilineol, that were only found in O. dictamnus after fractionation [58,116].
For Thymus species, multiple studies have been conducted using mostly ethanol, methanol, water, and their mixture as solvents, in which not much variety was observed in the flavones extraction of such species as T. alternans, T. caespititius, T. fragrantissimus, T. mastichina, T. pulegioides, T. serpyllum, and T. vulgaris, among others [68,71,117,118,119,120,121]. However, using fractionation techniques, it is possible to obtain flavones that have not been identified in crude extracts such as 7-methoxyapigenin (genkwanin) [122] and nobiletin [123,124], while, by using dichloromethane, hydroxyluteolin and hydroxyapigenin derivatives can be extracted from T. mastichina [125]. Furthermore, the water residue from hydrodistillation from T. vulgaris process has shown to be a valuable source of flavones such as luteolin and apigenin glucuronide derivatives [126].
Table 3. Conventional solvent extraction methods of flavones from Salvia, Ocimum, Origanum, and Thymus species.
Table 3. Conventional solvent extraction methods of flavones from Salvia, Ocimum, Origanum, and Thymus species.
SourcePartExtraction MethodIdentification MethodFlavone/Flavone DerivativeReference
Salvia absconditifloraAerial partsHot water, subsequent fractionation1H NMR, 13C NMR, HPLC-TOF/MSCirismaritin
Apigenin-7-O-β-glucoside
Luteolin
Luteolin-7-O-β-glucoside
[98]
Salvia apianaAerial partsEthanolic extract (95%)1H NMR, 13C NMR, HRMSCirismaritin
Salvigenin
[127]
Salvia chloroleucaAerial partsSequentially extracted with n-hexane, ethyl acetate, and
methanol
1H NMR, 13C NMR, HPLC-PDASalvigenin
Luteolin
Cirsiliol
[95]
Salvia chrysophyllaAerial parts Dichloromethane extract1H NMR, 13C NMR, HRESIMS, FT-IR, UV-VisSalvigenin[96]
Salvia circinataAerial partsAcetone extract, subsequent fractionation1H NMR, 13C NMRApigenin
6-Dihydroxy-7,3′,4′-trimethoxyflavone
[93]
Aerial partsDichloromethane-methanol extract, subsequent fractionation1H NMR, 13C NMR, IR, HRESIMS, ECDPedalitin
Apigenin-7-O-β-D-glucoside
2-(3,4-Dimethoxyphenyl)-5,6-dihydroxy-
7-methoxy-4H-chromen-4-one
[97]
Salvia connivensLeavesAcetone extract, subsequent fractionation1H NMR, 13C NMR, HMBC, ESIMSEupatorin
Cirsiliol
Nuchensin
[37]
Salvia elegansAerial partsDecoctionUHPLC-DAD-ESI-MSnHydroxyluteolin-glucuronide
Scutellarein-O-glucuronide
Luteolin-7-O-glucuronide
Apigenin-glucuronide
[90]
Salvia fruticosaNot specifiedEthyl acetate extractHPLC-SPE-NMRHispidulin
Cirsimaritin
Salvigenin
[128]
Aerial partsMethanolic extractHPLC-ESI-QTOF-MSNepetin
Luteolin
Apigenin
Hispidulin
Cirsimaritin
Genkwanin
Luteolin-O-glucuronide
Luteolin-O-glucoside
Apigenin-O-glucuronide
[87]
Salvia greggiiAerial partsDecoctionUHPLC-DAD-ESI-MSnLuteolin-C-hexoside
Luteolin-7-O-glucoside
Apigenin-C-hexoside
Apigenin-hexoside
[90]
Salvia judaicaAerial partsEthanolic extract 1H NMR, 13C NMR, UV-Vis, FT-IRLuteolin-3′-methyl ether
Apigenin
Salvigenin
Cirsilineol
[82]
Salvia macrosiphonAerial partsEthyl acetate and methanolic extracts1H NMR, 13C NMR, MSApigenin-7, 4′-dimethyl
ether
Apigenin-7-O-glucoside
Luteolin-7-O-glucoside
Salvigenin
[36]
Salvia officinalisLeaves Ethanolic (30–70%) and acetone (30–70%) extractsHPLC-UV/PDA6-Hydroxyluteolin-7-glucoside
Luteolin-7-glucuronide
Luteolin-7-glucoside
Apigenin-7-glucunoride
Apigenin-7-glucoside
Luteolin-3-glucuronide
[94]
Aerial partsDecoctionUHPLC-DAD-ESI-MSnApigenin-6-C-glucoside-7-O-glucoside
Apigenin-glucuronide
Apigenin-diglucuronide
Luteolin-7-O-glucuronide
Scutellarein-O-glucuronide
Apigenin-rutinoside
[90]
Aerial partsMethanolic extract1H NMR, UPLC -QTOF-MSCirsiliol
Luteolin
[91]
Salvia plebeiaAerial partsMethanol:
water: formic acid (50:45:5, v/v/v)
UPLC-DAD-QTOF-MSApigenin
Apigenin-7-O-glucoside
Hispidulin
Hispidulin-7-O-glucoside
Luteolin
Luteolin-5-O-glucoside
Luteolin-7-O-glucoside
6-Hydroxyluteolin 7-O-glucoside
Nepetin
Nepetin-7-O-glucoside
[88]
Whole plantsEthanolic (95%) extract, subsequent fractionationHR-DART-MS, 1H NMR, 13C NMR, HMBCNeocafhispidulin
6″-O-Acetylhomoplantaginin
Sorbifolin
Jaceosidin
Nepetin
Pectolinarigenin
Hispidulin
(2S)-5,7,4′-Trihydroxy-6-methoxy-flavanone-7-O-β-D-glucopyranoside
Galuteolin
Nepitrin
Homoplantaginin
[86]
Aerial partsEthanolic extract (95%), subsequent fractionation1H NMR, 13C NMR, 1H–1H COSY, HMQC, HMBC, NOESY, HR-ESI-MS, IRSalpleflavone
6-O-Methyl-scutellarein
[92]
Salvia pomiferaAerial partsMethanolic extractHPLC-ESI-QTOF-MSLuteolin
Apigenin
Hispidulin
Cirsimaritin
Genkwanin
Luteolin-O-hexoside
[87]
Salvia rosmarinusLeavesMethanolic extractHPLC-ESI-MSHispidulin
Cirsimaritin
[83]
Not specifiedAcidified water extractHPLC-DAD, HPLC-ESI-QTOF-MSLuteolin 3′-(3″-acetylglucuronide)[109]
Salvia sharifiiAerial partsEthyl acetate-methanol extract1H, 13C NMR, EI-MS, UVLadanein
6-Hydroxy-5,7,4′-trimethoxyflavone
[32]
Salvia splendensLeavesMethanolic extract (80%), subsequent fractionation1H NMR, 13C NMR, ESI-MS, UVLuteolin
Luteolin 7-O-(4″, 6″-di-O-α-L-rhamnopyranosyl)-
β-D-glucopyranoside
Apigenin
Apigenin-7-O-β-D-rutinoside
Cosmosiin
Cinaroside
Pedalitin
Crisiliol
[89]
Salvia trichocladaAerial partsMethanolic extract1H NMR, 13C NMRApigenin-7-O-rhamnoside[84]
Ocimum basilicumLeavesEthanolic extract (80%)1H NMR, 13C NMR, ESI-MSApigenin
Luteolin
Vitexin
Isovitexin
3″-O-Acetylvitexin
[99]
Leaves and flowersDiethyl ether extractHPLC-PDANevadensin
Salvigenin
[105]
LeavesHot water extractUPLC-ESI-MS/MSApigenin
Apigenin-O-glucoside
Apigenin-O-glucuronide
Luteolin
Luteolin-7-O-glucuronide
Luteolin acetylglucuronide
[106]
LeavesMethanolic extractHPLC-UV/VisLuteolin
Apigenin
[103]
Aerial partsEthanolic extract (70%)HPLC-MSLuteolin[104]
Ocimum campechianumLeavesInfusion, subsequent fractionation1H NMR, 13C NMR, COSY, HSQC, HMBC5-Demethyl nobiletin
5-Demethyl sinensetin
Luteolin
[107]
Ocimum gratissimumLeavesMethanol extract, subsequent fractionationHPLC-DADLuteolin[101]
Ocimum sanctumLeavesMethanolic extract (50%), subsequent fractionationLC-QTOF-MSVicenin 2
Luteolin-7-O-glucuronide
Isorientin
Orientin
Galuteolin
Apigenin-7-O-glucuronide
Isovitexin
Luteolin
Apigenin
Cirsimaritin
[100]
LeavesMethanolic extractHPLC-UV/VisLuteolin
Apigenin
[103]
Ocimum tenuiflorumLeavesMethanolic extractHPLC-MSLuteolin
Diosmetin
Nevadensin
Xanthomicrol
[102]
Origanum acutidensAerial partsHot water, subsequent fractionationHPLC-TOF-MSApigenin-7-glucoside[112]
Origanum dictamnusAerial partsFractionation with various solventsLC-DAD-MSCirsiliol
Cirsilineol
[58]
Origanum majoranaLeavesMethanolic extract, subsequent fractionationUPLC-ESI-MS/MSLuteolin-7-O-glucoside[113]
Aerial partsHot water extraction, subsequent fractionationHPLC-TOF-MS, UV, 1H NMR, 13C NMR5,6,3′-Trihydroxy-7,8,4′-trimethoxyflavone[111]
LeavesMethanolic extractHPLC-UVApigenin
Luteolin-7-O-rutinose
[115]
Origanum microphyllumAerial partsFractionation with various solventsLC-DAD-MSApigenin
Apigenin-7-O-glucoside
Genkwanin
[58]
Origanum minutiflorumAerial partsHot water extraction, subsequent fractionation1H NMR, 13C NMR, LC-TOF-MSApigenin
Apigenin-7-O-glucuronide
Vicenin-2
Luteolin
[110]
Origanum rotundifoliumAerial partsFractionation with various solventsLC-TOF-MS, UV, 1H NMR, 13C NMRApigenin
Vitexin
[116]
Origanum vulgareShootsWater extractUPLC-MS/MSApigenin[108]
Not specifiedAcidified water extractHPLC-DAD, HPLC-ESI-QTOF-MS, FT-IRApigenin-7-O-glucuronide[109]
Aerial partsEthanolic extract (50%)HPLC-DADLuteolin glycosides
Apigenin glycoside
[114]
Aerial partsHot water, ethyl acetate, methanolic, hexane extractHPLC-TOF-MSApigenin-7-glucoside[112]
Aerial partsFractionation with various solventsLC-DAD-MSApigenin
Apigenin glucosides
Apigenin glucuronides
Luteolin
Luteolin glucosides
Luteolin glucuronides
Cirsimaritin
[58]
Thymus algeriensisAerial partsInfusion, decoction or ethanolic extract (80%)UPLC-DAD-ESI-MSnApigenin-6,8-C-dihexoside
Apigenin-8-C-glucoside
Apigenin-7-O-glucuronide
Luteolin-7-O-glucuronide
[74]
Thymus alternansAerial partsMethanolic extractHPLC-MSn, 1H NMR COSY, HSQC-DEPT, HMBC, TOCSY, NOESYLuteolin-3-O-glucopyranoside
Luteolin-7-O-glucopyranoside
Luteolin-7-O-rutinoside
Chrysoeriol-hexoside
Methoxy luteolin-hexoside
Chrysoeriol-7-O-hexosyl-deoxyhexoside
Apigenin-7-O-glucopyranoside
[117]
Thymus austriacusAerial partsEthanolic extract (70%)HPLC-UVLuteolin-7-rutinoside[69]
Thymus caespititiusAerial partsDecoctionUHPLC-DAD-ESI-MSnApigenin di-C-glucoside
Luteolin-O-rutinoside
Luteolin-O-glucuronide
Chrysoeriol-O-rutinoside
Apigenin-O-glucuronide
[71]
Thymus caramanicusAerial partsMethanolic extract (80%)HPLC-UVLuteolin[129]
Aerial partsMethanolic extractHPLC-UVApigenin
Luteolin-7-O-glucoside
[130]
Thymus capitatusLeavesMethanolic extractUHPLC-DAD-ESI/MSnApigenin-C-di-hexoside[75]
Thymus daenensisAerial partsMethanolic extractHPLC-UVApigenin
Luteolin-7-O-glucoside
[130]
Thymus fallaxAerial partsMethanolic extractHPLC-UVApigenin
Luteolin-7-O-glucoside
[130]
Thymus fedtschenkoiAerial partsMethanolic extractHPLC-UVApigenin
Luteolin-7-O-glucoside
[130]
Thymus fragrantissimusAerial partsDecoctionUHPLC-DAD-ESI-MSnApigenin-di-C-glucoside
Luteolin-C-glucoside
Luteolin-O-di-glucoside
Luteolin-O-glucuronide
Apigenin-O-glucuronide
[68]
Thymus herba-baronaAerial partsDecoctionUHPLC-DAD-ESI-MSnLuteolin-C- glucoside
Luteolin-O-rutinoside
Luteolin-O-glucuronide
Chrysoeriol-O-glucoside
Apigenin-di-C-glucoside
Apigenin-O-glucoside
Apigenin-O-glucuronide
[71]
Thymus kotschyanusAerial partsMethanolic extractHPLC-UVApigenin
Luteolin-7-O-glucoside
[130]
Thymus marschallianusAerial partsEthanolic extract (70%)HPLC-DAD-ESI-MSLuteolin
Luteolin-7-O-glucuronide
Apigenin
Apigenin-7-O-glucuronide
[131]
Thymus mastichinaAerial partsMethanolic extractHPLC-DADApigenin
Luteolin
[118]
Aerial partsDichloromethane, ethanolic extract1H NMR, 13C NMR, FT-IR, MS, [α]Dt values6-Hydroxyluteolin-7-O-β-glucopyranoside
6-Hydroxyapigenin-7-O-β-glucopyranoside
[125]
Leaves and flowersMethanolic extract (50%)HPLC-DADLuteolin
Luteolin glucoside
[132]
Thymus migricusLeavesWater, methanolic extractRP-UHPLC-ESI-MS/MSAcacetin
Amentoflavone
Apigenin
Cynaroside
Luteolin
[133]
Aerial partsMethanolic extractHPLC-UVApigenin
Luteolin-7-O-glucoside
[130]
Thymus longicaulisAerial partsMethanolic extractLC-DAD-ESI-MS/MS6-Hydroxyluteolin-hexoside
Scutellarein-7-O-hexoside
Luteolin-7-O-glucoside
Luteolin-7-O-hexuronide
[70]
Aerial partsEthanolic extract (70%)HPLC-UVLuteolin-7-rutinoside
Luteolin-7-glucoside
[69]
Thymus lotocephalusAerial partsWater, ethanolic or mixture extractHPLC-DADLuteolin
Apigenin
[77]
Thymus pallescensAerial partsInfusionHPLC-DAD-ESI/MSApigenin-6,8-C-dihexoside
Apigenin-O-glucuronide
Luteolin-O-diglucuronide
Luteolin-O-diglucuronide
Luteolin-7-O-rutinoside
Luteolin-7-O-glucuronide
[134]
Thymus praecoxAerial partsMethanolic extractLC-DAD-ESI-MS/MSScutellarin
Scutellarein-7-O-hexoside
Luteolin-7-O-hexuronide
[70]
Aerial partsEthanolic extract (70%)HPLC-UVLuteolin-7-rutinoside
Luteolin-7-glucoside
Apigenin-7-glucoside
[69]
Aerial partsMethanolic extract, subsequent fractionation1H NMR, 13C NMR, HPLC-DADLuteolin-5-O-β-D-glucopyranoside[135]
Aerial partsFractionation with various solventsHPLC-DAD, LC-ESI-QTOF-MS/
MS
Luteolin-7-O-glucoside
Apigenin 7-O-glucuronide
[136]
Thymus pseudolanuginosusAerial partsDecoctionUHPLC-DAD-ESI-MSnApigenin-di-C- glucoside
Luteolin-C- glucoside
Luteolin-O-glucuronide
Apigenin-O-glucoside
Chrysoeriol-O-glucoside
Apigenin-O-glucuronide
[71]
Thymus pubesenceAerial partsMethanolic extractHPLC-UVApigenin
Luteolin-7-O-glucoside
[130]
Thymus pulegioidesAerial partsMethanolic extractLC-DAD-ESI–MS/MSLuteolin-hexoside
Luteolin-7-O-hexuronide
Apigenin-7-O-hexuronide
[70]
Aerial partsDecoctionUHPLC-DAD-ESI-MSnApigenin-di-C-glucoside
Luteolin-C-glucoside
Scutellarein-O-glucuronide
Luteolin-O-glucuronide
Chrysoeriol-O-hexoside
Apigenin-O-glucuronide
[68]
Aerial partsEthanolic extract (70%)HPLC-UVLuteolin-7-rutinoside
Luteolin-7-glucoside
[69]
Aerial partsDecoction, ethanolic extract (80%)HPLC-DAD, HPLC-ESI-MSnLuteolin-7-O-glucoside (only in ethanolic extract)
Luteolin-O-hexuronide
Luteolin-O-hexuronide
Apigenin-glucuronide
[121]
Thymus saturoidesLeavesAcetone extract (80%), subsequent fractionationHRESI-MS, UV/Vis, 1H NMR, 13C NMR, IR8-Methoxycirsilineol
Nobiletin
Luteolin
Chrysin
[124]
Thymus schimperiNot specifiedMethanolic extract, subsequent fractionationHPLC-ESI-MS/MSLuteolin
Luteolin-7-O-glucoside
Luteolin-4′-O-(rhamnosyl)glucoside
Luteolin-6-C-pentoside-8-C-hexoside
Luteolin-6-C-glucoside
Chryseoriol-7-O-glucoside
Luteolin-7-O-(2″-apiosyl-acetyl)glucoside
Luteolin-6-C-pentoside
Luteolin-7-O-(acetyl-apiosyl)xyloside
Luteolin-7-O-(dipentosyl)glucuronide
Luteolin-7-O-glucuronide-3′-O-glucoside
Luteolin-7-O-glucoronide
Dihydroxytrimethoxy flavone
Apigenin-7-O-(acetyl-apiosyl)glucoside
Hispidulin
Trihydroxy-dimethoxyflavone
Hydroxy-trimethoxyflavone
Trihydroxy-trimethoxyflavone
[67]
Thymus serpyllumCommercial herbal teaEthanolic extract (95%)RP-HPLC-DADLuteolin
Luteolin-7-O-glucoside
Apigenin
[78]
Aerial partsMethanolic extractLC-DAD-ESI-MS/MS6-Hydroxyluteolin-hexuronide
Scutellarin
Luteolin-7-O-hexuronide
[70]
Aerial partsEthanolic extract (70%)HPLC-UVLuteolin-7-rutinoside
Luteolin-7-glucoside
Apigenin-7-glucoside
[69]
Aerial partsMethanolic extractHPLC-UVApigenin
Luteolin-7-O-glucoside
[130]
Whole plantMethanolic extract (75%)HPLC-ESI-MS/MSApigenin 6,8-di-C-glucoside
Apigenin O-glucuronide
Luteolin
Luteolin-O-diglucuronide
Luteolin 7-O-glucuronide
Luteolin 7-O-glucoside
[137]
Thymus sibthorpiiAerial partsFractionation with various solventsUV-Vis, 1H NMR, 13C NMRApigenin
7-Methoxyapigenin
[122]
Aerial partsEthanolic extract (70%)HPLC-UVLuteolin-7-rutinoside
Luteolin-7-glucoside
Apigenin-7-glucoside
[69]
Thymus sipyleusAerial partsMethanolic extractRP-HPLC-DADApigenin[138]
Aerial partsInfusion, decoctionHPLC-UVLuteolin-7-O-glucoside[139]
Thymus striatusAerial partsMethanolic extractLC-DAD-ESI-MS/MS6-Hydroxyluteolin-hexoside
Luteolin-7-O-hexoside-hexuronide
Apigenin-hexoside-hexuronide
Luteolin-7-O-glucoside
Luteolin-7-O-hexuronide
Luteolin-3′(4′)-O-hexuronide
[70]
Thymus transcaspicusAerial partsMethanolic extractHPLC-UVApigenin
Luteolin-7-O-glucoside
[130]
Thymus trautvetteriAerial partsMethanolic extractHPLC-UVApigenin
Luteolin-7-O-glucoside
[130]
Thymus vulgarisAerial partsMethanolic extract, subsequent fractionationHPLC-ESI/MSApigenin
Nobiletin
[123]
Aerial partsMethanolic extractLC-DAD-ESI-MS/MSLuteolin-hexoside
Luteolin-7-O-glucoside
Luteolin-7-O-hexuronide
[70]
LeavesMethanolic extractHPLC-DADLuteolin-7-O-glucoside[140]
Aerial partsEthanolic extract (45%)HPLC-PDA-ESI-MSLuteolin-7-O-glucuronide
Apigenin-7-O-glucuronide
[126]
Post-distillation waste-
LeavesMethanolic extractHPLC-UVApigenin
Luteolin-7-O-rutinose
[115]
LeavesWater extractHPLC-PDA-ESI-MSLuteolin
Luteolin-7-O-glucoside
Apigenin
Apigenin-7-O-glucoside
Acacetin
[119]
Aerial partsMethanolic extractHPLC-UVApigenin
Luteolin-7-O-glucoside
[119]
LeavesInfusionHPLC-PDA-ESI-MSApigenin 6,8-di-C-glucoside
Luteolin-7-O glucoside
Luteolin-O-diglucuronide
Luteolin-diglucuronide-glucuronide
Luteolin-7-O-glucuronide
Apigenin-O-glucuronide
Luteolin
[120]
Thymus zygisAerial partsDecoctionUHPLC-DAD-ESI-MSnLuteolin-C-glucoside
Luteolin-di-C-glucoside
Scutellarein-O-glucuronide
Luteolin-O-glucuronide
Chrysoeriol-O-hexoside
Apigenin-O-glucuronide
[68]
Aerial partsDecoction, ethanolic extractRP-HPLC-DAD, HPLC-ESI-MSnApigenin-(6,8)-C-diglucoside
Luteolin-O-hexoside
Luteolin-O-hexoside
Luteolin-O-hexorunide
[141]

4.2. Alternative Methods (Environmentally Friendly)

Alternative extraction methods aim to limit the use of organic solvents, thereby reducing environmental damage and improving extraction efficiency. The most common alternative extraction techniques include ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE), pressurized liquid extraction (PLE, also known as accelerated solvent extraction), and supercritical fluid extraction (SFE), among others [142]. These technologies have been shown to be effective for extracting flavones from Lamiaceae, mostly apigenin and luteolin derivatives; the aerial parts are the most used for this. However, other parts, such as roots and even residues from previous processes, are rich in flavones. A summary of these extraction methods to obtain flavones in Lamiaceae species is shown in Table 4.
PLE has been widely used to obtain flavones from diverse Salvia species using water or ethanol as a solvent, obtaining similar compounds in them [143]. Although MAE can obtain a good variety of flavones [144], UAE was demonstrated to be more effective than MAE in some cases, because it is less time consuming [145]. On the other hand, SFE with ethanol as cosolvent was proven to be a more selective technique for the extraction of flavones such as cirsimaritin, genkwanin and salvigenin from Salvia rosmarinus leaves, compared to PLE, which obtained a greater variety of flavones [146]. Similarly, more flavone diversity was observed in the extract of roots from Salvia viridis obtained from UAE and MAE than from SFE [144]. For Origanum species, O. glandulosum (leaves and flowers) and O. majorana (leaves) have been extracted by MAE and UAE, respectively, with apigenin and luteolin derivatives in the former, but only luteolin derivatives in the latter [61,147]. However, in O. vulgare aerial parts, the same flavones profile was found using UAE, PLE, and MAE [148], while fewer flavones were found in another extract obtained by PLE [60,149]. With regard to Thymus genus, UAE is a popular extraction method to extract flavones from species such as T. marschallianus, T. seravschanicus, and T. serpyllum, and T. vulgaris [150,151,152]. Nevertheless, PLE is also effective in the extraction of flavones from Thymus species [149], including cirismaritin from T. serpyllum [60], which was also detected in T. Vulgaris after a combination of alternative extraction methods, namely pulsed electric field followed by ultrasound-assisted extraction [153]. A study by Palmieri et al. [154], with different conventional methods involving PLE and rapid solid–liquid dynamic extraction, showed that the aforementioned methods obtain better extract yield from T. vulgaris leaves and stems [154]. Subsequently, the extraction of flavones from Thymus residues using these technologies was studied, as seen in the extracts that were rich in flavones derived from steam distillation residues from T. mastichina [155], and the herbal dust and hydrodistillation residue from T. serpyllum and T. vulgaris obtained by PLE, respectively [73,156]. Finally, not many studies have been recently conducted regarding the extraction of flavones from Ocimum species using alternative methods. In this regard, the extract, obtained by UAE, of O. tenuiflorum leaves showed higher quantities of apigenin and luteolin, compared with a conventional ethanolic extract [157]; this demonstrates the high potential of these kinds of techniques in the extraction of flavones from Ocimum species.
Table 4. Alternative extraction methods of flavones from Salvia, Ocimum, Origanum, and Thymus species.
Table 4. Alternative extraction methods of flavones from Salvia, Ocimum, Origanum, and Thymus species.
SourcePartExtraction MethodIdentification MethodFlavone/Flavone DerivativeReference
Salvia amplexicaulisNot specifiedPressurized liquid extraction with ethanol or waterUPLC-QTOF-MSApigenin-7-O-β-D-glucuronide[143]
Salvia austriacaNot specifiedPressurized liquid extraction with ethanol or waterUPLC-QTOF-MSApigenin-7-O-β-D-glucuronide[143]
Salvia sclareaNot specifiedPressurized liquid extraction with ethanol or waterUPLC-QTOF-MSApigenin-7-O-β-D-glucuronide
Luteolin-7-O-β-D-glucuronide
[143]
Salvia forsskaoliiNot specifiedPressurized liquid extraction with ethanol or waterUPLC-QTOF-MSApigenin-7-O-β-D-glucuronide
Luteolin-7-O-β-D-glucuronide
[143]
Salvia fruticosaNot specifiedUltrasound-assisted extraction with various solventsHPLC-DAD-ESI-MSnLuteolin-7-O-rutinoside
Apigenin-6-C-glucoside-7-O-glucoside
Luteolin-diglucuronide
[145]
Aerial partsDeep eutectic solvent extraction with lactic acid and sodium citrate dibasicLC-DAD-MS/MSLuteolin-7-O-glucuronide[158]
Salvia glutinosaNot specifiedPressurized liquid extraction with ethanol or waterUPLC-QTOF-MSApigenin-7-O-β-D-glucuronide[143]
Salvia nemorosaNot specifiedPressurized liquid extraction with ethanol or waterUPLC-QTOF-MSApigenin-7-O-β-D-glucuronide
Luteolin-7-O-β-D-glucuronide
[143]
Salvia officinalisNot specifiedUltrasound-assisted extraction with various solventsHPLC-DAD-ESI-MSnLuteolin-7-O-rutinoside
Apigenin-6-C-glucoside-7-O-glucoside
Luteolin-diglucuronide
[145]
LeavesMicrowave-assisted extraction with various solventsHPLC-UV/PDA6-Hydroxyluteolin-7-glucoside
Luteolin-7-glucuronide
Luteolin-7-glucoside
Luteolin-3′-glucuronide
Apigenin-7-glucuronide
Apigenin-7-glucoside
[159]
LeavesUltrasound-assisted extraction with ethanol (30%)HPLC-UV/PDA6-Hydroxyluteolin-7-glucoside
Luteolin-7-glucuronide
Luteolin-7-glucoside
Luteolin-3-glucuronide
Apigenin-7-glucuronide
Apigenin-7-glucoside
[85]
Not specifiedPressurized liquid extraction with ethanol or waterUPLC-QTOF-MSApigenin-7-O-β-D-glucuronide
Luteolin-7-O-β-D-glucuronide
[143]
Salvia
pomifera
Not specifiedUltrasound-assisted extraction with various solventsHPLC-DAD-ESI-MSnLuteolin-7-O-rutinoside
Apigenin-6-C-glucoside-7-O-glucoside
Luteolin-diglucuronide
[145]
Salvia pratensisNot specifiedPressurized liquid extraction with ethanol or waterUPLC-QTOF-MSApigenin-7-O-β-D-glucuronide[143]
Salvia rosmarinusLeavesSupercritical CO2 extraction with ethanol as cosolventHPLC–DAD-MSCirismaritin
Genkwanin
Salvigenin
[146]
Pressurized liquid extraction with water or ethanolLuteolin
Luteolin-3′-O-(O-acetyl)-β-
D-glucuronide
Scutellarein
Scutellarein-7-O-β-glucuronide
Nepitrin
Apigenin
Apigenin-7-O-glucoside
Homoplantaginin
Cirsimaritin-4′-glucoside
Hispidulin
Cirsimaritin
Genkwanin
Hydrodistillation residueUltrasound-assisted extraction with ethanolLC-PDA-ESI-MSScutellarein
Apigenin
Cirismaritin
Acacetin
Genkwanin
[160]
Salvia stepposaNot specifiedPressurized liquid extraction with ethanol or waterUPLC-QTOF-MSApigenin-7-O-β-D-glucuronide[143]
Salvia verticillataNot specifiedPressurized liquid extraction with ethanol or waterUPLC-QTOF-MSApigenin-7-O-β-D-glucuronide
Luteolin-7-O-β-D-glucuronide
[143]
Salvia viridisRootsMicrowave-assisted extraction with ethanol (96%)UHPLC-ESI-MS/MSLuteolin-C-hexoside-C-pentoside
Luteolin-C-hexoside-O-pentoside
Apigenin-C-hexoside-O-pentoside
Luteolin-O-(pentosyl)hexoside
Luteolin-O-glucuronide
Luteolin-7-O-glucoside (Cynaroside)
Luteolin-O-(deoxyhexosyl)hexoside
Apigenin-O-(deoxyhexosyl)hexoside
Cosmosiin (Apigetrin, Apigenin-7-O-glucoside)
Apigenin-O-glucuronide
Luteolin
Luteolin-O-(coumaroyl)hexoside
Apigenin
Chrysoeriol
Genkwanin
[144]
RootsUltrasound-assisted extractionUHPLC-ESI-MS/MSLuteolin-C-hexoside-C-pentoside
Luteolin-C-hexoside-O-pentoside
Apigenin-C-hexoside-O-pentoside
Luteolin-O-(pentosyl)hexoside
Luteolin-O-glucuronide
Luteolin-7-O-glucoside (Cynaroside)
Apigenin-C-hexoside-O-deoxyhexoside
Apigenin-O-(deoxyhexosyl)hexoside
Apigenin-O-(deoxyhexosyl)hexoside
Apigenin-O-glucuronide
Luteolin
Luteolin-O-(coumaroyl)hexoside
Apigenin (4′,5,7-trihydroxyflavone)
Chrysoeriol
Genkwanin
Apigenin-4′,7-dimethyl ether
[144]
RootsSupercritical CO2 extractionUHPLC-ESI-MS/MSGenkwanin
Apigenin-4′,7-dimethyl ether
[144]
Ocimum tenuiflorumLeavesUltrasound-assisted extraction with ethanol (55.34%)HPLC-UV/VisLuteolin
Apigenin
[157]
Origanum glandulosumLeaves and flowerMicrowave-assisted extraction with waterHPLC-DAD-ESI-MS/MSLuteolin-O-hexoside
Luteolin-6,8-di-C-glucoside
Luteolin-7-O-glucuronide
[61]
Origanum majoranaLeavesUltrasound-assisted extraction with waterRP-HPLC-DADLuteolin-7-
O-glucoside
Apigenin-7-O-glucoside
[147]
Origanum vulgareNot specifiedPressurized liquid extraction with water, ethanol or mixtureHPLC-DAD-ESI-MS/MSApigenin
Luteolin
Luteolin-7-O-glucuronide
[60]
Not specifiedPressurized liquid extraction with methanolHPLC-ESI-MS/MSApigenin
Luteolin
[149]
Aerial partsUltrasound-assisted extraction with ethanolUHPLC-LTQ OrbiTrap MSLuteolin
Luteolin-7-O-hexosyl-hexoside
Luteolin-7-O-pentosyl-hexoside
Luteolin-7-O-pentosyl-acetyl-hexoside
Luteolin-7-O-acetyl-hexosyl-acetylhexoside
Apigenin
Apigenin-7-O-hexosyl-acetyl-hexoside
Apigenin-7-O-hexuronide
Apigenin-7-O-pentosyl-acetyl-hexoside
Acacetin
Acacetin-7-O-hexosyl-acetyl-hexoside
Acacetin-7-O-pentosyl-hexoside
Acacetin-7-O-hexuronide
Acacetin-7-O-pentosyl-acetyl-hexoside
Diosmetin-7-O-pentosyl-acetyl-pentoside
[148]
Microwave-assisted extraction with ethanol
Pressurized liquid extraction with ethanol
Thymus fontanesiiAerial partsMicrowave-assisted extraction with ethanolHPLC-DAD-ESI-MS/MSLuteolin-O-hexoside
Luteolin-6,8-di-C-glucoside
Luteolin-7-O-glucuronide
[61]
Thymus
marschallianus
Aerial partsUltrasound-assisted extraction with ethanolRP-HPLC-PDA, HPLC-ESI-QTOF-MSLuteolin
Luteolin-7-O-rutinoside
Luteolin-7-O-glucoside
Luteolin-7-O-glucuronide
Luteolin-7-O-dipentoside
Luteolin-7-O-(6″-3-hydroxy-3-methyl-glutaryl)-glucoside
Apigenin
Apigenin-7-O-glucoside
Apigenin-7-O-glucuronide
Apigenin-7-O-rhamnoglucuronide
Diosmetin-glucuronide
[151]
Thymus mastichinaSteam distillation residuesUltrasound-assisted extraction with ethanolLC-DAD-ESI-MSLuteolin
Luteolin-glucoside
Apigenin
Apigenin-7-O-glucoside
[155]
Thymus seravschanicusAerial partsUltrasound-assisted extraction with ethanolRP-HPLC-PDA, HPLC-ESI-QTOF-MSLuteolin-7-O-rutinoside
Luteolin-7-O-glucoside
Luteolin-7-O-glucuronide
Luteolin-7-O-(6″-3-hydroxy-3-methyl-glutaryl)-glucoside
Apigenin-7-O-glucuronide
Diosmetin glucuronide
[151]
Thymus serpyllumAerial partsUltrasound-assisted extraction with ethanolRP-HPLC-DAD, HPLC-MS6-Hydroxyluteolin-7-O-glucoside
Luteolin-7-O-glucuronide
Apigenin-glucuronide
[150]
Not specifiedPressurized liquid extraction with waterHPLC-DAD-ESI-MS/MSLuteolin
Luteolin-7-O-glucoside
Luteolin-7-O-glucuronide
Apigenin
Apigenin-7-O-glucuronide
Cirsimaritin
[60]
Herbal dust (industrial waste from filter-tea production)Pressurized liquid extraction with ethanolHPLC-Orbitrap-ESI-MS/MSLuteolin[156]
Thymus vulgarisNot specifiedUltrasound-assisted extraction with waterUPLC-TOF-MS/MSLuteolin-7-O-glucuronide
Luteolin-7-O-malonyl-glucoside
Apigenin
Apigenin-7-O-glucuronide
Chrysoeriol-7-O-(6-malonyl-apiosyl-glucoside)
[152]
Leaves and stemsRapid solid–liquid dynamic extraction with ethanolHPLC-UVLuteolin
Apigenin
[154]
Ultrasound-assisted extraction with ethanolHPLC-UVLuteolin
Apigenin
[154]
Not specifiedPressurized liquid extraction with methanolHPLC-ESI/MS/MSApigenin
Luteolin
[149]
Leaves and stemsPulsed electric field followed by ultrasound-assisted extraction with ethanolUPLC-ESI-MS/MSLuteolin
Luteolin-7-O-glucuronide
Luteolin-rutinoside
Luteolin-7-O-glucoside
Cirsimaritin
[153]
Leaves residue from hydrodistillationPressurized hot water extractionHPLC-ESI-QTOF-MSApigenin-6,8-di-C-glucoside
Apigenin-7-O-glucuronide
Luteolin
Luteolin-7-O-glucoside
Luteolin-7-O-glucuronide
Cirsimaritin
[73]

5. Bioavailability and Bioactivity Relationship of Flavones in Lamiaceae

As previously mentioned, the chemical structure of flavones determines their bioactivity since it establishes the way in which they interact with biological molecules through different mechanisms of action [17,20,24]. Thus, any changes in the structures of flavones can affect (positively or negatively) their antioxidant, anti-inflammatory, anti-obesity, and anti-cancer properties. Once consumed, flavones enter the body and travel through the gastrointestinal tract. Here, flavones can be affected by physiological and biochemical conditions such as changes in pH, and interaction with other food constituents and digestive enzymes. These physiological conditions can alter the chemical structures of flavones by partial hydrolysis from the food matrix, by deprotonation of the -OH radicals of the flavone molecule, or through interaction with digestive enzymes, which will affect their bioactive properties [161,162].
Thus, it is important to evaluate the bioaccessibility and bioavailability of flavones to improve our understanding of their mechanisms of action and bioactive effects, and to develop strategies to enhance their bioavailability. Bioaccessibility is the amount of a food constituent that is released during gastrointestinal digestion and is accessible to be absorbed or pass through the enterocytes. Additionally, bioavailability is defined as the amount of the food constituent or molecule that is absorbed through the enterocytes into the bloodstream, distributed, metabolized, and excreted [161]. Bioaccessibility is assessed using simulated gastrointestinal protocols coupled with cell-based assays (Caco-2, HepG2), and bioavailability is assessed using in vivo assays that measure pharmacokinetic parameters [163,164,165,166,167].
In this sense, once consumed, flavones pass by the mouth where the saliva is present, and mastication occurs. Saliva is mainly constituted by water, electrolytes, proteins, and digestive enzymes. After that, the compounds are transported to the stomach, where pH drops to 2–4, facilitating the partial hydrolysis of these molecules from the matrix. Then, the chyme is transported from the stomach to the small intestine, passing through the duodenum, where the pH stabilizes to 7. Additionally, the small intestine is the major site of absorption for nutrients and phenolic compounds such as flavones [161,168]. The enterocytes in the small intestine are also a site of metabolism attributed to the phase I and phase II xenobiotic metabolic enzymes [169]. Generally, phenolic compounds have low bioaccessibility and bioavailability; most are degraded, metabolized, and excreted. Several factors can affect the bioavailability of flavones and phenolic compounds in general; these factors are related to the molecule and the food matrix, and others are related to the host, such as intestinal and systemic factors [170].
It was reported that aglycone flavones are more rapidly absorbed than their glycosylated derivatives due to their lower molecular weight; however, cell metabolism and transporters can mediate their active absorption [171]. In this sense, Caco-2 cell assays showed that apigenin is more permeable than apigenin-7-O-glucoside; furthermore, in vivo rat studies reported higher absorption of apigenin. Moreover, due to the xenobiotic metabolism in the body, most flavones in plasma are reported in their conjugated form by sulfation, glucuronidation, or methylation.
Few reports assess the bioaccessibility of flavones from plants of the Salvia, Thymus, Origanum, and Ocimum genus. These reports are summarized in Table 5. All reports use an in vitro gastrointestinal digestion process that simulates the digestion in the mouth, stomach, and small intestine, mimicking their physiological and enzymatic conditions; only two reports that coupled the simulated digestion to cell-based assays were found. In this sense, Chohan et al. [172] evaluated the effect of cooking and an in vitro digestion process on the total phenolic content and bioactive properties of Salvia officinalis and Thymus vulgaris. The cooking process increased the bioaccessible phenolic compounds, which might be related to the improvement of the release of phenolics from the vacuoles due to the cell wall rupture during cooking. In addition, following this, the anti-inflammatory potential of these extracts increased after the cooking and digestion process, indicating a correlation between bioaccessibility and bioactivity. Gayoso et al. [173] evaluated the bioaccessibility, through an in vitro digestion, of Origanum vulgare where an HPLC analysis showed the presence of a luteolin glycoside derivative. After digestion, luteolin glycoside had a bioaccessibility of 41%; moreover, the antioxidant activity of O. vulgare remained stable with no significant changes after the digestion process, indicating that digested phenolics are potentially bioactive. Recently, de Torre et al. [114] also evaluated the bioaccessibility of O. vulgare in an improved oral pharmaceutical form; the authors encapsulated O. vulgare and subjected it to gastrointestinal digestion. Three flavones were identified in the samples, namely two luteolin glycosides and one apigenin glycoside. The encapsulation enhanced the bioaccessibility of Origanum flavones, based on initial values with a bioaccessibility of 82.52, 85.31, and 89.28%, for the two luteolin glycosides and the apigenin glycoside, respectively. The high bioaccessibility of the flavones in the encapsulated samples is related to a higher stability as they were protected from the gastrointestinal environment.
Rubió et al. [174] showed that a mixture of olive oil and Thymus vulgaris extracts increased the bioaccessibility of luteolin as compared to thyme extract alone, with values of 16.7% and 14.6%, respectively. Moreover, a Caco-2 and Caco-2/HepG2 co-cultured assay showed that luteolin was one of the flavonoids detected after the incubation and that luteolin conjugated with sulfate and glucuronide were the main metabolites identified in the apical and basolateral sides of the cell cultures. On the other hand, incubation with HepG-2 cells only showed the presence of luteolin glucuronide.
Similarly, Villalva et al. [175] evaluated ethanol extracts of O. majorana subjected to a combination of simulated gastrointestinal digestion and a Caco-2 permeability assay. The authors identified several apigenin and luteolin derivates in the samples. The in vitro digestion process showed that the flavones with higher bioaccessibility were diosmin, luteolin-7-O-glucuronide, and luteolin-7-O-glucoside, with high stability values of nearly 99.7, 94.55, and 94.19% of the initial content. Furthermore, the contents of apigenin-7-O-glucoside and apigenin-7-glucuronide increased by 31.42 and 57.7%. The Caco-2 assay showed that luteolin and apigenin derivatives have low bioaccessibility, showing poor permeability capacity through the enterocytes. The increased levels of apigenin-7-O-glucoside and apigenin-7-glucuronide suggested cellular reflux of metabolized flavones, which are usually excreted at a physiological level. Additionally, the authors showed that rosmarinic acid enrichment of O. majorana extracts increases the content of its phenolic acids and flavonoids by 1.5–1.8 times, with luteolin and its glycosides being the main flavones detected in the enriched sample. In addition, it was suggested that the flavones luteolin and apigenin showed a synergistic effect with rosmarinic acid, protecting it from degradation during the digestion process. Furthermore, the aglycone forms of luteolin and apigenin were the main metabolites detected in the apical side of the Caco-2 monolayer culture, which might be attributed to the action of the metabolic enzyme lactase-phlorizin hydrolase. Due to the overall low bioaccessibility of phenolic compounds, it is sometimes suggested that after ingestion, their health-promoting properties could decrease. Nonetheless, in this study, the authors found that digested extracts displayed anti-inflammatory activity through inhibition of the secretion of the cytokines TNF-α, IL-1β, and IL-6 in a THP-1 cell line.
Our literature search found two recent studies that included an in vivo evaluation of the bioavailability of flavones from the Ocimum, Origanum, Salvia, and Thymus genus. Briefly, Rubió et al. [176] evaluated the effect of the combination of olive oil and Thymus vulgaris on the bioavailability and antioxidant capacity of the mixture using Wistar rats administered a dose of 1.5 mg/kg BW. The study showed that this type of extract modulated plasmatic antioxidant activity. Thyme extract and an olive oil/thyme mixture decreased the levels of the antioxidant enzymes superoxide dismutase and glutathione peroxidase, but catalase activity was increased. In addition, the pharmacokinetic data showed that the presence of thyme extracts enhances olive oil phenolics; for instance, luteolin and apigenin were the main flavones identified in the sample, and the metabolites found in plasma were hydroxyphenylpropionic acid sulfate and dihydroxyphenylpropionic acid sulfate. The other study was reported by Zhang et al. [177], who evaluated the pharmacokinetics of danshen and huangquin (dried root of Scutellaria baicalensis Georgi), administered to Sprague-Dawley rats, which were prepared using a 1:1 ratio of weight in the mixture. Four main flavones were identified in the administered samples: baicalein, baicalin, wogonin, and wogonoside; these were found at concentrations of 13.606, 447.983 8.901, and 122.236 mg/kg, respectively. In plasma, the content of aglycone and glycoside flavones decreased significantly. Moreover, the Tmax values ranged from 1 to 8 h, and the Cmax values were 306.92, 2465.0, 373.17, and 1779.17 mg/L for baicalein, baicalin, wogonin, and wogonoside, respectively.
Table 5. Bioaccessibility and bioavailability studies of flavones from Lamiaceae species.
Table 5. Bioaccessibility and bioavailability studies of flavones from Lamiaceae species.
Plant SpeciesDescription of SampleBioaccessibility MethodFlavones in SampleResultsReference
Salvia officinalis1 g of sage was infused in water (25 mL, 37 °C, 10 min). Cooking treatment consisted of heating sage in a frying pan for 10 min.Static simulated digestion (mouth, stomach, small intestine)Not identifiedCooked and digested sage had higher levels of phenolic compounds. Cooked and digested sage inhibited IL-8 [172]
Thymus vulgaris1 g of thyme was infused in water (25 mL, 37 °C, 10 min). The cooking treatment consisted of heating thyme in a frying pan for 10 min.Static simulated digestion (mouth, stomach, small intestine)Not identifiedCooked and digested thyme had higher levels of phenolic compounds, and inhibited IL-8 [172]
Origanum vulgareMethanol extracts (10 g/250 mL) were boiled by refluxing for 30 min. Static simulated digestion (stomach, small intestine)Luteolin glycosideLuteolin glycoside had a bioaccessibility of 41%. The simulated digestion did not affect the antioxidant capacity of the O. vulgare extract by chemical methods (ABTS, DPPH, TPC, FRAP)[173]
Origanum vulgareHydroalcoholic extracts were obtained (10 g sample, 250 mL ethanol 50%). The extracts were used lyophilized in oral pharmaceutical forms.Static simulated digestion (stomach, small intestine)Luteolin glycosides
Apigenin glycoside
Two luteolin glycosides with higher bioaccessibility, of around 83%, were identified in encapsulated form, and the apigenin glycoside was identified, with nearly 90% bioaccessibility[114]
Thymus vulgarisFreeze-dried olive cake and dried thyme were used for extracts by means of an accelerated solvent extractor. Static simulated digestion (stomach, small intestine) coupled to a Caco-2 permeability assay and Caco-2 cells co-cultured with HepG-2 cells.LuteolinThe bioaccessibility of luteolin from thyme and in thyme and olive oil during the simulated digestion was 14.6% and 16.7%, respectively. Luteolin and its sulfate and glucuronide metabolites were detected after the incubation of Caco-2 cells. The flavone luteolin and its metabolites were the most bioaccessible.[174]
Origanum majorana100 mg of oregano dissolved in 50% ethanol were used Static simulated digestion (stomach, small intestine) coupled to a Caco-2 permeability assay6-Hydroxyluteolin-7-O-glucoside
Luteolin-O-glucoside
Luteolin-7-Oglucoside
Luteolin-7-O-glucuronide
Diosmin
Apigenin-7-O-glucoside
Apigenin-7-O-glucuronide
Luteolin
Apigenin
The highest bioaccessibility was shown for diosmin, luteolin-7-O-glucuronide, and luteolin-7-O-glucoside, with 99.70, 94.55 and 94.19%, respectively. The process decreased the content of the flavones and their derivatives. Luteolin-7-O-glucoside and luteolin-7-O-glucuronide were the most stable. Luteolin and apigenin derivatives had low permeability in the Caco-2 assay. [175]
Plant SpeciesDescription of SampleAnimal Model UsedFlavones in SampleBioavailability Assay ResultsReference
Thymus vulgarisPhenolic extracts were obtained using 80% ethanol. After that, thyme extracts and a combination of freeze-dried olive cake and dried thyme extract (1:1) were usedMale Wistar rats were treated intragastrically and gavaged with 1.5 g/kg BW in water of the extractsApigenin
Luteolin
Sulfate conjugated forms of phenolics were the main identified metabolites after dosing. The Cmax in thyme extracts showed a two-phase mode kinetic pattern. The identified metabolites in rat plasma were hydroxyphenylpropionic acid sulphate, dihydroxyphenylpropionic acid sulfate, and caffeic acid sulfate. [176]
Danshen (dried roots and rhizomes of Salvia miltiorrhiza Bunge)Danshen and huangquin (dried root of Scutellaria baicalensis Georgi) were used to obtain water extracts. Pure extract of danshen and a combination with huangqin was used at a 1:1 ratioSprague-Dawley rats (12 weeks old, 200–220 g). Rats were orally administered with a single dose of danshen and the combination of danshen and huangqin at concentrations of 12.5 g/kgBaicalein (5,6,7-trihydroxyflavone)
Baicalin (Baicalein-7-O-glucuronide)
Wogonin (5,7-dihydroxy-8-methoxyflavone)
Wogonoside (Wogonin-7-O-β-D-glucuronide)
The pharmacokinetic parameters of baicalein, baicalin, wogonin, and wogonoside in the combined extracts of Danshen and Huangqin were Cmax values of 306.92, 2465, 373.17, and 1779.17, respectively. [177]
Furthermore, some chemical characteristics can aid in predicting the bioavailability of flavones and other phenolics, and these characteristics are known as the rule of five (or Lipinski’s rule of five) [178]. These rules predict the drug-likeness of the passive absorption of a molecule. For instance, a molecule can permeate cells by passive absorption if the following conditions are met:
  • Molecular weight ≤500;
  • The molecule has no more than 5 hydrogen bond donors;
  • The molecule has no more than 10 hydrogen bond acceptors;
  • The partition coefficient (Log p) is ≤5.
Following these characteristics, conjugated flavones will often have lower cell permeability due to their higher molecular weight and numbers of H bond donors and acceptors. Nonetheless, cell transporters can metabolize these molecules via active means of absorption. The predicted passive absorption of some flavones mentioned in this study is shown in Table 6.

6. Conclusions

Plants of the Lamiaceae family, such as Ocimum, Origanum, Salvia, and Thymus, are rich sources of flavones. Flavones are flavonoids with antioxidant, anti-inflammatory, anti-cancer, and anti-diabetic potential. Some of the most abundant flavones in these species are apigenin and luteolin (and their derivates), cirsimaritin, and scutellarein. Thus, the development of methods to enhance their extraction is of interest to human health. For this, conventional techniques involving maceration, Soxhlet extraction, hydrodistillation, and boiling have been used for many years. It has been reported that the bioactive properties of flavones are highly dependent on their chemical structure, which is in turn highly dependent on the method of extraction and its further metabolism after ingestion. The factors mentioned above, plus an effort to diminish the environmental impact of conventional techniques, have led to the development of more environmentally friendly techniques such as ultrasound-assisted extraction, microwave-assisted extraction, pressurized liquid extraction, and supercritical fluid extraction. These techniques usually involve a higher initial investment expense but offer a higher yield, purity, and bioactivity of flavones. Moreover, after ingestion, flavones are highly metabolized in the gastrointestinal system by pH changes, digestive enzymes, and xenobiotic metabolic enzymes in the enterocytes and liver. In this sense, most flavones identified in plasma are conjugated derivatives rather than parental molecules. This can affect their bioactive effect and prevent their delivery at target sites in the body. Moreover, we suggest a systematic approach when evaluating the properties of flavones, including the appropriate extraction methods coupled with bioaccessibility/bioavailability studies concomitant to the evaluation of their bioactive properties.

Author Contributions

Conceptualization, E.P.G.-G., M.A.P.-S. and J.B.H.; writing, M.A.P.-S., N.L.-L., D.L.A.-P. and E.P.G.-G.; Review and editing, J.B.H. and E.P.G.-G. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by CONACYT (Project 316498).

Data Availability Statement

Not applicable.

Acknowledgments

Manuel Adrian Picos-Salas thanks CONACYT for the doctoral scholarship. Erick P. Gutiérrez-Grijalva would like to thank Cátedras CONACYT for the support via project 397.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Zahran, E.M.; Abdelmohsen, U.R.; Khalil, H.E.; Desoukey, S.Y.; Fouad, M.A.; Kamel, M.S. Diversity, phytochemical and medicinal potential of the genus Ocimum L. (Lamiaceae). Phytochem. Rev. 2020, 19, 907–953. [Google Scholar] [CrossRef]
  2. Sitarek, P.; Merecz-Sadowska, A.; Śliwiński, T.; Zajdel, R.; Kowalczyk, T. An In Vitro Evaluation of the Molecular Mechanisms of Action of Medical Plants from the Lamiaceae Family as Effective Sources of Active Compounds against Human Cancer Cell Lines. Cancers 2020, 12, 2957. [Google Scholar] [CrossRef] [PubMed]
  3. World Flora Online. Lamiaceae Martinov. Available online: http://www.worldfloraonline.org/taxon/wfo-7000000318 (accessed on 21 July 2021).
  4. The Plant List. The Plant List. Available online: http://www.theplantlist.org/1.1/browse/A/Lamiaceae/ (accessed on 19 July 2021).
  5. Trivellini, A.; Lucchesini, M.; Maggini, R.; Mosadegh, H.; Villamarin, T.S.S.; Vernieri, P.; Mensuali-Sodi, A.; Pardossi, A. Lamiaceae phenols as multifaceted compounds: Bioactivity, industrial prospects and role of “positive-stress”. Ind. Crops Prod. 2016, 83, 241–254. [Google Scholar] [CrossRef]
  6. Carović-Stanko, K.; Petek, M.; Grdiša, M.; Pintar, J.; Bedeković, D.; Ćustić, M.H.; Satovic, Z. Medicinal plants of the family lamiaceae as functional foods—A review. Czech. J. Food Sci. 2016, 34, 377–390. [Google Scholar] [CrossRef] [Green Version]
  7. Mesquita, L.S.S.D.; Luz, T.R.S.A.; Mesquita, J.W.C.D.; Coutinho, D.F.; Amaral, F.M.M.D.; Ribeiro, M.N.D.S.; Malik, S. Exploring the anticancer properties of essential oils from family Lamiaceae. Food Rev. Int. 2019, 35, 105–131. [Google Scholar] [CrossRef]
  8. Quideau, S.; Deffieux, D.; Douat-Casassus, C.; Pouységu, L. Plant Polyphenols: Chemical Properties, Biological Activities, and Synthesis. Angew. Chem. Int. Ed. 2011, 50, 586–621. [Google Scholar] [CrossRef] [PubMed]
  9. Vermerris, W.; Nicholson, R. Families of Phenolic Compounds and Means of Classification. In Phenolic Compound Biochemistry; Vermerris, W., Nicholson, R., Eds.; Springer: Dordrecht, The Netherlands, 2006; pp. 1–34. [Google Scholar]
  10. Crozier, A.; Jaganath, I.B.; Clifford, M.N. Phenols, Polyphenols and Tannins: An Overview. In Plant Secondary Metabolites: Occurrence, Structure and Role in the Human Diet; Crozier, A., Clifford, M.N., Ashihara, H., Eds.; Blackwell Publishing Ltd.: Hoboken, NJ, USA, 2006. [Google Scholar]
  11. Boniface, P.K.; Elizabeth, F.I. Flavones as a privileged scaffold in drug discovery: Current developments. Curr. Org. Synth. 2019, 16, 968–1001. [Google Scholar] [CrossRef] [PubMed]
  12. Hostetler, G.L.; Ralston, R.A.; Schwartz, S.J. Flavones: Food sources, bioavailability, metabolism, and bioactivity. Adv. Nutr. 2017, 8, 423–435. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Tzima, K.; Brunton, N.P.; Rai, D.K. Qualitative and quantitative analysis of polyphenols in lamiaceae plants—A review. Plants 2018, 7, 25. [Google Scholar] [CrossRef] [Green Version]
  14. Croteau, R.; Kutchan, T.M.; Lewis, N.G. Natural Products (Secondary Metabolites). In Biochemistry & Molecular Biology of Plants; Buchanan, B., Gruissem, W., Jones, R., Eds.; American Society of Plants: Rockville, MD, USA, 2015; pp. 1250–1318. [Google Scholar]
  15. Vuolo, M.M.; Lima, V.S.; Maróstica Junior, M.R. Chapter 2—Phenolic Compounds: Structure, Classification, and Antioxidant Power. In Bioactive Compounds; Campos, M.R.S., Ed.; Woodhead Publishing: Cambridge, UK, 2019; pp. 33–50. [Google Scholar]
  16. Talapatra, S.K.; Talapatra, B. Polyketide Pathway. Biosynthesis of Diverse Classes of Aromatic Compounds. In Chemistry of Plant Natural Products: Stereochemistry, Conformation, Synthesis, Biology, and Medicine; Talapatra, S.K., Talapatra, B., Eds.; Springer: Berlin/Heidelberg, Germany, 2015; pp. 679–715. [Google Scholar]
  17. Jiang, N.; Doseff, A.I.; Grotewold, E. Flavones: From biosynthesis to health benefits. Plants 2016, 5, 27. [Google Scholar] [CrossRef]
  18. Gutiérrez-Grijalva, E.P.; Picos-Salas, M.A.; Leyva-López, N.; Criollo-Mendoza, M.S.; Vazquez-Olivo, G.; Heredia, J.B. Flavonoids and phenolic acids from Oregano: Occurrence, biological activity and health benefits. Plants 2018, 7, 2. [Google Scholar] [CrossRef] [Green Version]
  19. Valant-Vetschera, K.M.; Wollenweber, E. Flavones and Flavonols. In Flavonoids: Chemistry, Biochemistry and Applications; Andersen, Ø.M., Markham, K.R., Eds.; CRC Press: Boca Raton, FL, USA, 2006. [Google Scholar]
  20. Verma, A.K.; Pratap, R. The biological potential of flavones. Nat. Prod. Rep. 2010, 27, 1571–1593. [Google Scholar] [CrossRef]
  21. León-Chan, R.G.; López-Meyer, M.; Osuna-Enciso, T.; Sañudo-Barajas, J.A.; Heredia, J.B.; León-Félix, J. Low temperature and ultraviolet-B radiation affect chlorophyll content and induce the accumulation of UV-B-absorbing and antioxidant compounds in bell pepper (Capsicum annuum) plants. Environ. Exp. Bot. 2017, 139, 143–151. [Google Scholar] [CrossRef]
  22. Siddiqui, A.; Badruddeen; Akhtar, J.; Uddin, S.; Khan, M.I.; Khalid, M.; Ahmad, M. A Naturally Occurring Flavone (Chrysin): Chemistry, Occurrence, Pharmacokinetic, Toxicity, Molecular Targets and Medicinal Properties. J. Biol. Act. Prod. Nat. 2018, 8, 208–227. [Google Scholar] [CrossRef]
  23. World Health Organization. Global Health Observatory Data. Available online: http://www.who.int/gho/en/ (accessed on 21 July 2021).
  24. Verma, A.K.; Pratap, R. Chemistry of biologically important flavones. Tetrahedron 2012, 68, 8523–8538. [Google Scholar] [CrossRef]
  25. National Center for Biotechnology Information. PubChem Compound Summary for CID 5280443, Apigenin. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Apigenin (accessed on 30 July 2021).
  26. National Center for Biotechnology Information. PubChem Compound Summary for CID 188323, Cirsimaritin. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Cirsimaritin (accessed on 30 July 2021).
  27. National Center for Biotechnology Information. PubChem Compound Summary for CID 5280445, Luteolin. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Luteolin (accessed on 30 July 2021).
  28. National Center for Biotechnology Information. PubChem Compound Summary for CID 5281697, Scutellarein. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Scutellarein (accessed on 30 July 2021).
  29. Wu, Y.B.; Ni, Z.Y.; Shi, Q.W.; Dong, M.; Kiyota, H.; Gu, Y.G.; Cong, B. Constituents from Salvia species and their biological activities. Chem. Rev. 2012, 112, 5967–6026. [Google Scholar] [CrossRef] [PubMed]
  30. Li, M.; Li, Q.; Zhang, C.; Zhang, N.; Cui, Z.; Huang, L.; Xiao, P. An ethnopharmacological investigation of medicinal Salvia plants (Lamiaceae) in China. Acta Pharm. Sin. B 2013, 3, 273–280. [Google Scholar] [CrossRef] [Green Version]
  31. Kharazian, N. Identification of flavonoids in leaves of seven wild growing Salvia L. (Lamiaceae) species from Iran. Prog. Biol. Sci. 2013, 3, 81–98. [Google Scholar] [CrossRef]
  32. Farjam, M.H.; Rustaiyan, A.; Ezzatzadeh, E.; Jassbi, A.R. Labdane-Type Diterpene and Two Flavones from Salvia Sharifii Rech. f. and Esfan. and their Biological Activities. Iran. J. Pharm. Sci. 2013, 12, 395–399. [Google Scholar]
  33. Bonesi, M.; Loizzo, M.R.; Acquaviva, R.; Malfa, G.A.; Aiello, F.; Tundis, R. Anti-inflammatory and Antioxidant Agents from Salvia Genus (Lamiaceae): An Assessment of the Current State of Knowledge. Antiinflamm. Antiallergy Agents Med. Chem. 2017, 16, 70–86. [Google Scholar] [CrossRef] [PubMed]
  34. Jash, S.K.; Gorai, D.; Roy, R. Salvia genus and triterpenoids. Int. J. Pharm. Sci. Res. 2016, 7, 4710–4732. [Google Scholar] [CrossRef]
  35. Coisin, M.; Necula, R.; Grigoraş, V.; Gille, E.; Rosenhech, E.; Zamfirache, M.M. Phytochemical evaluation of some Salvia species from romanian flora. Analele Stiint. Universitatii Al. I. Cuza Iasi 2012, 58, 35–44. [Google Scholar]
  36. Gohari, A.R.; Ebrahimi, H.; Saeidnia, S.; Foruzani, M.; Ebrahimi, P.; Ajani, Y. Flavones and Flavone Glycosides from Salvia macrosiphon Boiss. Iran. J. Pharm. Sci. 2011, 10, 247–251. [Google Scholar]
  37. Bautista, E.; Calzada, F.; Yépez-Mulia, L.; Bedolla-García, B.Y.; Fragoso-Serrano, M.; Pastor-Palacios, G.; González-Juárez, D.E. Salvia connivens, a Source of Bioactive Flavones with Amoebicidal and Giardicidal Activity. Rev. Bras. Farmacogn. 2020, 30, 729–732. [Google Scholar] [CrossRef]
  38. Kashyap, C.P.; Ranjeet, K.; Vikrant, A.; Vipin, K. Therapeutic Potency of Ocimum KilimandscharicumGuerke—A Review. Glob. J. Pharmacol. 2011, 5, 191–200. [Google Scholar]
  39. Mahajan, V.; Rather, I.A.; Awasthi, P.; Anand, R.; Gairola, S.; Meena, S.R.; Bedi, Y.S.; Gandhi, S.G. Development of chemical and EST-SSR markers for Ocimum genus. Ind. Crops Prod. 2015, 63, 65–70. [Google Scholar] [CrossRef]
  40. Avetisyan, A.; Markosian, A.; Petrosyan, M.; Sahakyan, N.; Babayan, A.; Aloyan, S.; Trchounian, A. Chemical composition and some biological activities of the essential oils from basil Ocimum different cultivars. BMC Complement. Altern. Med. 2017, 17, 60. [Google Scholar] [CrossRef] [Green Version]
  41. Nahak, G.; Mishra, R.C.; Sahu, R.K. Taxonomic Distribution, Medicinal Properties and Drug Development Potentiality of Ocimum (Tulsi). Drug Invent. Today 2011, 3, 95–113. [Google Scholar]
  42. Rubab, S.; Irshad, H.; Barkat, A.K.; Ayaz, A.U.; Khawaja, A.A.; Zawar, H.K.; Mour, K.; Shazea, K.; Khalil, U.R.; Haroon, K. Biomedical Description of Ocimum basilicum L. J. Islam. Int. Med. Coll. 2017, 12, 59–67. [Google Scholar]
  43. Kintzios, S.E. 21—Oregano. In Handbook of Herbs and Spices, 2nd ed.; Peter, K.V., Ed.; Woodhead Publishing Limited: Cambridge, UK, 2012; Volume 2, pp. 417–436. [Google Scholar]
  44. Kintzios, S.E. 1—Profile of the multifaceted prince of the herbs. In Oregano: The Genera Origanum and Lippia, 1st ed.; Kintzios, S.E., Ed.; CRC Press: London, UK, 2004; p. 296. [Google Scholar]
  45. Marrelli, M.; Statti, G.A.; Conforti, F. Origanum spp.: An update of their chemical and biological profiles. Phytochem. Rev. 2018, 17, 873–888. [Google Scholar] [CrossRef]
  46. Stefanaki, A.; van Andel, T. Chapter 3—Mediterranean aromatic herbs and their culinary use. In Aromatic Herbs in Food; Galanakis, C.M., Ed.; Academic Press: Cambridge, MA, USA, 2021; pp. 93–121. [Google Scholar]
  47. Milevskaya, V.V.; Prasad, S.; Temerdashev, Z.A. Extraction and chromatographic determination of phenolic compounds from medicinal herbs in the Lamiaceae and Hypericaceae families: A review. Microchem. J. 2019, 145, 1036–1049. [Google Scholar] [CrossRef]
  48. Gird, C.E.; Duţu, L.E.; Costea, T.; Nencu, I.; Popescu, M.L.; Olaru, O. Preliminary research concerning the obtaining of herbal extracts with potential neuroprotective activity note I. Obtaining and characterization of a selective Origanum vulgare L. dry extract. Farmacia 2016, 64, 680–687. [Google Scholar]
  49. Martins, N.; Barros, L.; Santos-Buelga, C.; Henriques, M.; Silva, S.; Ferreira, I.C.F.R. Decoction, infusion and hydroalcoholic extract of Origanum vulgare L.: Different performances regarding bioactivity and phenolic compounds. Food Chem. 2014, 158, 73–80. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Milevskaya, V.V.; Temerdashev, Z.A.; Butyl’skaya, T.S.; Kiseleva, N.V. Determination of phenolic compounds in medicinal plants from the Lamiaceae family. J. Anal. Chem. 2017, 72, 342–348. [Google Scholar] [CrossRef]
  51. Tuttolomondo, T.; La Bella, S.; Licata, M.; Virga, G.; Leto, C.; Saija, A.; Trombetta, D.; Tomaino, A.; Speciale, A.; Napoli, E.M.; et al. Biomolecular characterization of wild sicilian oregano: Phytochemical screening of essential oils and extracts, and evaluation of their antioxidant activities. Chem. Biodivers. 2013, 10, 411–433. [Google Scholar] [CrossRef]
  52. Maietta, M.; Colombo, R.; Corana, F.; Papetti, A. Cretan tea (Origanum dictamnus L.) as a functional beverage: An investigation on antiglycative and carbonyl trapping activities. Food Funct. 2018, 9, 1545–1556. [Google Scholar] [CrossRef]
  53. Özer, Z.; Gören, A.C.; Kılıç, T.; Öncü, M.; Çarıkçı, S.; Dirmenci, T. The phenolic contents, antioxidant and anticholinesterase activity of section Amaracus (Gled.) Vogel and Anatolicon Ietsw. of Origanum L. species. Arab. J. Chem. 2020, 13, 5027–5039. [Google Scholar] [CrossRef]
  54. Tian, C.; Liu, X.; Chang, Y.; Wang, R.; Lv, T.; Cui, C.; Liu, M. Investigation of the anti-inflammatory and antioxidant activities of luteolin, kaempferol, apigenin and quercetin. S. Afr. J. Bot. 2021, 137, 257–264. [Google Scholar] [CrossRef]
  55. Shankar, E.; Goel, A.; Gupta, K.; Gupta, S. Plant flavone apigenin: An emerging anticancer agent. Curr. Pharmacol. Rep. 2017, 3, 423–446. [Google Scholar] [CrossRef] [PubMed]
  56. Funakoshi-Tago, M.; Nakamura, K.; Tago, K.; Mashino, T.; Kasahara, T. Anti-inflammatory activity of structurally related flavonoids, apigenin, luteolin and fisetin. Int. Immunopharmacol. 2011, 11, 1150–1159. [Google Scholar] [CrossRef]
  57. Huang, Q.; Bai, F.; Nie, J.; Lu, S.; Lu, C.; Zhu, X.; Zhuo, L.; Lin, X. Didymin ameliorates hepatic injury through inhibition of MAPK and NF-κB pathways by up-regulating RKIP expression. Int. Immunopharmacol. 2017, 42, 130–138. [Google Scholar] [CrossRef]
  58. Tair, A.; Weiss, E.-K.; Palade, L.M.; Loupassaki, S.; Makris, D.P.; Ioannou, E.; Roussis, V.; Kefalas, P. Origanum species native to the island of Crete: In vitro antioxidant characteristics and liquid chromatography–mass spectrometry identification of major polyphenolic components. Nat. Prod. Res. 2014, 28, 1284–1287. [Google Scholar] [CrossRef] [PubMed]
  59. González, M.; Luis, C.; Lanzelotti, P. Polyphenolic profile of Origanum vulgare L. ssp. viridulum from Argentina. Phyton 2014, 83, 179–184. [Google Scholar]
  60. Miron, T.L.; Plaza, M.; Bahrim, G.; Ibáñez, E.; Herrero, M. Chemical composition of bioactive pressurized extracts of Romanian aromatic plants. J. Chromatogr. A 2011, 1218, 4918–4927. [Google Scholar] [CrossRef] [Green Version]
  61. Nabet, N.; Gilbert-López, B.; Madani, K.; Herrero, M.; Ibáñez, E.; Mendiola, J.A. Optimization of microwave-assisted extraction recovery of bioactive compounds from Origanum glandulosum and Thymus fontanesii. Ind. Crops Prod. 2019, 129, 395–404. [Google Scholar] [CrossRef]
  62. Taamalli, A.; Arráez-Román, D.; Abaza, L.; Iswaldi, I.; Fernández-Gutiérrez, A.; Zarrouk, M.; Segura-Carretero, A. LC-MS-based metabolite profiling of methanolic extracts from the medicinal and aromatic species Mentha pulegium and Origanum majorana. Phytochem. Anal. 2015, 26, 320–330. [Google Scholar] [CrossRef]
  63. Soorni, A.; Borna, T.; Alemardan, A.; Chakrabarti, M.; Hunt, A.G.; Bombarely, A. Transcriptome landscape variation in the genus Thymus. Genes 2019, 10, 620. [Google Scholar] [CrossRef] [Green Version]
  64. Stahl-Biskup, E.; Venskutonis, R.P. 27—Thyme. In Handbook of Herbs and Spices, 2nd ed.; Peter, K.V., Ed.; Woodhead Publishing Limited: Cambridge, UK, 2012; Volume 2, pp. 499–525. [Google Scholar]
  65. Nabavi, S.M.; Marchese, A.; Izadi, M.; Curti, V.; Daglia, M.; Nabavi, S.F. Plants belonging to the genus Thymus as antibacterial agents: From farm to pharmacy. Food Chem. 2015, 173, 339–347. [Google Scholar] [CrossRef]
  66. Li, X.; He, T.; Wang, X.; Shen, M.; Yan, X.; Fan, S.; Wang, L.; Wang, X.; Xu, X.; Sui, H.; et al. Traditional uses, chemical constituents and biological activities of plants from the genus Thymus. Chem. Biodivers. 2019, 16, e1900254. [Google Scholar] [CrossRef] [PubMed]
  67. Desta, K.T.; Kim, G.S.; El-Aty, A.M.A.; Raha, S.; Kim, M.-B.; Jeong, J.H.; Warda, M.; Hacımüftüoğlu, A.; Shin, H.-C.; Shim, J.-H.; et al. Flavone polyphenols dominate in Thymus schimperi Ronniger: LC–ESI–MS/MS characterization and study of anti-proliferative effects of plant extract on AGS and HepG2 cancer cells. J. Chromatogr. B 2017, 1053, 1–8. [Google Scholar] [CrossRef]
  68. Afonso, A.F.; Pereira, O.R.; Válega, M.; Silva, A.M.S.; Cardoso, S.M. Metabolites and biological activities of Thymus zygis, Thymus pulegioides, and Thymus fragrantissimus grown under organic cultivation. Molecules 2018, 23, 1514. [Google Scholar] [CrossRef] [Green Version]
  69. Raudone, L.; Zymone, K.; Raudonis, R.; Vainoriene, R.; Motiekaityte, V.; Janulis, V. Phenological changes in triterpenic and phenolic composition of Thymus L. species. Ind. Crop. Prod. 2017, 109, 445–451. [Google Scholar] [CrossRef]
  70. Kindl, M.; Bucar, F.; Jelić, D.; Brajša, K.; Blažeković, B.; Vladimir-Knežević, S. Comparative study of polyphenolic composition and anti-inflammatory activity of Thymus species. Eur. Food Res. Technol. 2019, 245, 1951–1962. [Google Scholar] [CrossRef]
  71. Afonso, A.F.; Pereira, O.R.; Neto, R.T.; Silva, A.M.S.; Cardoso, S.M. Health-promoting effects of Thymus herba-barona, Thymus pseudolanuginosus, and Thymus caespititius decoctions. Int. J. Mol. Sci. 2017, 18, 1879. [Google Scholar] [CrossRef]
  72. Pacifico, S.; Piccolella, S.; Papale, F.; Nocera, P.; Lettieri, A.; Catauro, M. A polyphenol complex from Thymus vulgaris L. plants cultivated in the Campania Region (Italy): New perspectives against neuroblastoma. J. Funct. Foods 2016, 20, 253–266. [Google Scholar] [CrossRef]
  73. Vergara-Salinas, J.R.; Perez-Jimenez, J.; Lluis Torres, J.; Agosin, E.; Perez-Correa, J.R. Effects of Temperature and Time on Polyphenolic Content and Antioxidant Activity in the Pressurized Hot Water Extraction of Deodorized Thyme (Thymus vulgaris). J. Agric. Food Chem. 2012, 60, 10920–10929. [Google Scholar] [CrossRef] [PubMed]
  74. Ziani, B.E.C.; Heleno, S.A.; Bachari, K.; Dias, M.I.; Alves, M.J.; Barros, L.; Ferreira, I.C.F.R. Phenolic compounds characterization by LC-DAD- ESI/MSn and bioactive properties of Thymus algeriensis Boiss. & Reut. and Ephedra alata Decne. Food Res. Int. 2019, 116, 312–319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Jaouadi, R.; Cardoso, S.M.; Silva, A.M.S.; Ben Hadj Yahia, I.; Boussaid, M.; Zaouali, Y. Variation of phenolic constituents of Tunisian Thymus capitatus (L.) Hoff. et Link. populations. Biochem. Syst. Ecol. 2018, 77, 10–15. [Google Scholar] [CrossRef]
  76. Pereira, O.R.; Peres, A.M.; Silva, A.M.S.; Domingues, M.R.M.; Cardoso, S.M. Simultaneous characterization and quantification of phenolic compounds in Thymus x citriodorus using a validated HPLC–UV and ESI–MS combined method. Food Res. Int. 2013, 54, 1773–1780. [Google Scholar] [CrossRef]
  77. Costa, P.; Gonçalves, S.; Valentão, P.; Andrade, P.B.; Coelho, N.; Romano, A. Thymus lotocephalus wild plants and in vitro cultures produce different profiles of phenolic compounds with antioxidant activity. Food Chem. 2012, 135, 1253–1260. [Google Scholar] [CrossRef]
  78. Janiak, M.A.; Slavova-Kazakova, A.; Kancheva, V.D.; Ivanova, M.; Tsrunchev, T.; Karamać, M. Effects of γ-irradiation of wild thyme (Thymus serpyllum L.) on the phenolic compounds profile of its ethanolic extract. Polish J. Food Nutr. Sci. 2017, 67, 309–315. [Google Scholar] [CrossRef] [Green Version]
  79. Çakmakçi, E.; Deveoglu, O.; Muhammed, A.; Fouad, A.; Torgan, E.; Karadag, R. HPLC-DAD analysis of Thymus serpyllum based natural pigments and investigation of their antimicrobial properties. Pigment. Resin Technol. 2014, 43, 19–25. [Google Scholar] [CrossRef] [Green Version]
  80. Chávez-González, M.L.; Sepúlveda, L.; Verma, D.K.; Luna-García, H.A.; Rodríguez-Durán, L.V.; Ilina, A.; Aguilar, C.N. Conventional and Emerging Extraction Processes of Flavonoids. Processes 2020, 8, 434. [Google Scholar] [CrossRef] [Green Version]
  81. Makanjuola, S.A. Influence of particle size and extraction solvent on antioxidant properties of extracts of tea, ginger, and tea-ginger blend. Food Sci. Nutr. 2017, 5, 1179–1185. [Google Scholar] [CrossRef]
  82. Al-Qudah, M.A.; Tashtoush, H.I.; Khlaifat, E.F.; Ibrahim, S.O.; Saleh, A.M.; Al-Jaber, H.I.; Abu Zarga, M.H.; Abu Orabi, S.T. Chemical constituents of the aerial parts of Salvia judaica Boiss. from Jordan. Nat. Prod. Res. 2020, 34, 2981–2985. [Google Scholar] [CrossRef]
  83. Bower, A.M.; Hernandez, L.M.R.; Berhow, M.A.; de Mejia, E.G. Bioactive Compounds from Culinary Herbs Inhibit a Molecular Target for Type 2 Diabetes Management, Dipeptidyl Peptidase IV. J. Agric. Food Chem. 2014, 62, 6147–6158. [Google Scholar] [CrossRef]
  84. Çulhaoğlu, B.; Hatipoğlu, S.D.; Dönmez, A.A.; Topçu, G. Antioxidant and anticholinesterase activities of lupane triterpenoids and other constituents of Salvia trichoclada. Med. Chem. Res. 2015, 24, 3831–3837. [Google Scholar] [CrossRef]
  85. Dent, M. Comparison of Conventional and Ultrasound-assisted Extraction Techniques on Mass Fraction of Phenolic Compounds from Sage (Salvia officinalis L.). Chem. Biochem. Eng. Q. 2015, 29, 475–484. [Google Scholar] [CrossRef]
  86. Jin, M.R.; Xu, H.; Duan, C.H.; Chou, G.X. Two new flavones from Salvia plebeia. Nat. Prod. Res. 2015, 29, 1315–1322. [Google Scholar] [CrossRef] [PubMed]
  87. Koutsoulas, A.; Čarnecká, M.; Slanina, J.; Tóth, J.; Slaninová, I. Characterization of Phenolic Compounds and Antiproliferative Effects of Salvia pomifera and Salvia fruticosa Extracts. Molecules 2019, 24, 2921. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Lee, S.-H.; Kim, H.-W.; Lee, M.-K.; Kim, Y.J.; Asamenew, G.; Cha, Y.-S.; Kim, J.-B. Phenolic profiling and quantitative determination of common sage (Salvia plebeia R. Br.) by UPLC-DAD-QTOF/MS. Eur. Food Res. Technol. 2018, 244, 1637–1646. [Google Scholar] [CrossRef] [Green Version]
  89. Moharram, F.A.-E.; Marzouk, M.S.; El-Shenawy, S.M.; Gaara, A.H.; El Kady, W.M. Polyphenolic profile and biological activity of Salvia splendens leaves. J. Pharm. Pharmacol. 2012, 64, 1678–1687. [Google Scholar] [CrossRef]
  90. Pereira, O.; Catarino, M.; Afonso, A.; Silva, A.; Cardoso, S. Salvia elegans, Salvia greggii and Salvia officinalis Decoctions: Antioxidant Activities and Inhibition of Carbohydrate and Lipid Metabolic Enzymes. Molecules 2018, 23, 3169. [Google Scholar] [CrossRef] [Green Version]
  91. Yanagimichi, M.; Nishino, K.; Sakamoto, A.; Kurodai, R.; Kojima, K.; Eto, N.; Isoda, H.; Ksouri, R.; Irie, K.; Kambe, T.; et al. Analyses of putative anti-cancer potential of three STAT3 signaling inhibitory compounds derived from Salvia officinalis. Biochem. Biophys. Rep. 2021, 25, 100882. [Google Scholar] [CrossRef]
  92. Yu, H.-F.; Zhao, H.; Liu, R.-X.; Ma, L.-F.; Zhan, Z.-J. Salpleflavone, a new flavone glucoside from Salvia plebeia. J. Chem. Res. 2018, 42, 294–296. [Google Scholar] [CrossRef]
  93. Calzada, F.; Bautista, E.; Barbosa, E.; Salazar-Olivo, L.A.; Alvidrez-Armendáriz, E.; Yepez-Mulia, L. Antiprotozoal Activity of Secondary Metabolites from Salvia circinata. Rev. Bras. Farmacogn. 2020, 30, 593–596. [Google Scholar] [CrossRef]
  94. Dent, M.; Dragovic-Uzelac, V.; Penic, M.; Brncic, M.; Bosiljkov, T.; Levaj, B. The Effect of Extraction Solvents, Temperature and Time on the Composition and Mass Fraction of Polyphenols in Dalmatian Wild Sage (Salvia officinalis L.) Extracts. Food Technol. Biotechnol. 2013, 51, 84–91. [Google Scholar]
  95. Salimikia, I.; Reza Monsef-Esfahani, H.; Gohari, A.R.; Salek, M. Phytochemical Analysis and Antioxidant Activity of Salvia chloroleuca Aerial Extracts. Iran. Red Crescent Med. J. 2016, 18, e24836. [Google Scholar] [CrossRef] [Green Version]
  96. Çulhaoğlu, B.; Yapar, G.; Dirmenci, T.; Topçu, G. Bioactive constituents of Salvia chrysophylla Stapf. Nat. Prod. Res. 2013, 27, 438–447. [Google Scholar] [CrossRef] [PubMed]
  97. Flores-Bocanegra, L.; Gonzalez-Andrade, M.; Bye, R.; Linares, E.; Mata, R. α-Glucosidase Inhibitors from Salvia circinata. J. Nat. Prod. 2017, 80, 1584–1593. [Google Scholar] [CrossRef] [PubMed]
  98. Koysu, P.; Genc, N.; Elmastas, M.; Aksit, H.; Erenler, R. Isolation, identification of secondary metabolites from Salvia absconditiflora and evaluation of their antioxidative properties. Nat. Prod. Res. 2019, 33, 3592–3595. [Google Scholar] [CrossRef]
  99. Abdelhady, M.I.S.; Motaal, A.A. A cytotoxic C-glycosylated derivative of apigenin from the leaves of Ocimum basilicium var. thyrsiflorum. Rev. Bras. Farmacogn. Braz. J. Pharmacogn. 2016, 26, 763–766. [Google Scholar] [CrossRef] [Green Version]
  100. Chaudhary, A.; Sharma, S.; Mittal, A.; Gupta, S.; Dua, A. Phytochemical and antioxidant profiling of Ocimum sanctum. Food Sci. Technol. 2020, 57, 3852–3863. [Google Scholar] [CrossRef] [PubMed]
  101. Irondi, E.A.; Agboola, S.O.; Oboh, G.; Boligon, A.A. Inhibitory effect of leaves extracts of Ocimum basilicum and Ocimum gratissimum on two key enzymes involved in obesity and hypertension in vitro. J. Intercult. Ethnopharmacol. 2016, 5, 396–402. [Google Scholar] [CrossRef]
  102. Mousavi, L.; Salleh, R.M.; Murugaiyah, V. Phytochemical and bioactive compounds identification of Ocimum tenuiflorum leaves of methanol extract and its fraction with an anti-diabetic potential. Int. J. Food Prop. 2018, 21, 2390–2399. [Google Scholar] [CrossRef]
  103. Ullah, S.; Rahman, K.U.; Rauf, A.; Hussain, A.; Ullah, A.; Ramadan, M.F. Phenolic acids, flavonoids and antiradical activity of Ocimum sanctum and Ocimum basilicium leaves extracts. Z. Arznei Gewurzpflanzen 2020, 25, 60–62. [Google Scholar]
  104. Vlase, L.; Benedec, D.; Hanganu, D.; Damian, G.; Csillag, I.; Sevastre, B.; Mot, A.; Silaghi-Dumitrescu, R.; Tilea, I. Evaluation of Antioxidant and Antimicrobial Activities and Phenolic Profile for Hyssopus officinalis, Ocimum basilicum and Teucrium chamaedrys. Molecules 2014, 19, 5490–5507. [Google Scholar] [CrossRef]
  105. Bernhardt, B.; Bernath, J.; Gere, A.; Kokai, Z.; Komaromi, B.; Tavaszi-Sarosi, S.; Varga, L.; Sipos, L.; Szabo, K. The Influence of Cultivars and Phenological Phases on the Accumulation of Nevadensin and Salvigenin in Basil (Ocimum basilicum). Nat. Prod. Commun. 2015, 10, 1699–1702. [Google Scholar] [CrossRef]
  106. Ibrahim, R.Y.M.; Mansour, S.M.; Elkady, W.M. Phytochemical profile and protective effect of Ocimum basilicum aqueous extract in doxorubicin/irradiation-induced testicular injury. J. Pharm. Pharmacol. 2019, 72, 101–110. [Google Scholar] [CrossRef]
  107. Ruiz-Vargas, J.A.; Morales-Ferra, D.L.; Ramirez-Avila, G.; Zamilpa, A.; Negrete-Leon, E.; Jose Acevedo-Fernandez, J.; Pena-Rodriguez, L.M. α-Glucosidase inhibitory activity and in vivo antihyperglycemic effect of secondary metabolites from the leaf infusion of Ocimum campechianum mill. J. Ethnopharmacol. 2019, 243, 112081. [Google Scholar] [CrossRef]
  108. Ahmad, H.; Matsubara, Y.-I. Suppression of Anthracnose in Strawberry Using Water Extracts of Lamiaceae Herbs and Identification of Antifungal Metabolites. Hort. J. 2020, 89, 359–366. [Google Scholar] [CrossRef]
  109. Bunghez, F.; Morar, M.A.; Pop, R.M.; Romanciuc, F.; Csernatoni, F.; Fetea, F.; Diaconeasa, Z.; Socaciu, C. Comparative Phenolic Fingerprint and LC-ESI+QTOF-MS Composition of Oregano and Rosemary Hydrophilic Extracts in Relation to their Antibacterial Effect. Bull. Univ. Agric. Sci. Vet. Med. Cluj-Napoca. Food Sci. Technol. 2015, 72, 33–40. [Google Scholar] [CrossRef] [Green Version]
  110. Elmastas, M.; Celik, S.M.; Genc, N.; Aksit, H.; Erenler, R.; Gulcin, İ. Antioxidant activity of an anatolian herbal tea—Origanum minutiflorum: Isolation and characterization of its secondary metabolites. Int. J. Food Prop. 2018, 21, 374–384. [Google Scholar] [CrossRef] [Green Version]
  111. Erenler, R.; Sen, O.; Aksit, H.; Demirtas, I.; Yaglioglu, A.S.; Elmastas, M.; Telci, I. Isolation and identification of chemical constituents from Origanum majorana and investigation of antiproliferative and antioxidant activities. J. Sci. Food Agric. 2016, 96, 822–836. [Google Scholar] [CrossRef]
  112. Koldaş, S.; Demirtas, I.; Ozen, T.; Demirci, M.A.; Behçet, L. Phytochemical screening, anticancer and antioxidant activities of Origanum vulgare L. ssp viride (Boiss.) Hayek, a plant of traditional usage. J. Sci. Food Agric. 2015, 95, 786–798. [Google Scholar] [CrossRef] [PubMed]
  113. Amaghnouje, A.; Mechchate, H.; Es-safi, I.; Boukhira, S.; Aliqahtani, A.S.; Noman, O.M.; Nasr, F.A.; Conte, R.; Calarco, A.; Bousta, D. Subacute Assessment of the Toxicity and Antidepressant-Like Effects of Origanum Majorana L. Polyphenols in Swiss Albino Mice. Molecules 2020, 25, 5653. [Google Scholar] [CrossRef] [PubMed]
  114. De Torre, M.P.; Vizmanos, J.L.; Cavero, R.Y.; Calvo, M.I. Improvement of antioxidant activity of oregano (Origanum vulgare L.) with an oral pharmaceutical form. Biomed. Pharmacother. 2020, 129, 110424. [Google Scholar] [CrossRef]
  115. Roby, M.H.H.; Sarhan, M.A.; Selim, K.A.-H.; Khalel, K.I. Evaluation of antioxidant activity, total phenols and phenolic compounds in thyme (Thymus vulgaris L.), sage (Salvia officinalis L.), and marjoram (Origanum majorana L.) extracts. Ind. Crops Prod. 2013, 43, 827–831. [Google Scholar] [CrossRef]
  116. Erenler, R.; Meral, B.; Sen, O.; Elmastas, M.; Aydin, A.; Eminagaoglu, O.; Topcu, G. Bioassay-guided isolation, identification of compounds from Origanum rotundifolium and investigation of their antiproliferative and antioxidant activities. Pharm. Biol. 2017, 55, 1646–1653. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Dall’Acqua, S.; Peron, G.; Ferrari, S.; Gandin, V.; Bramucci, M.; Quassinti, L.; Martonfi, P.; Maggi, F. Phytochemical investigations and antiproliferative secondary metabolites from Thymus alternans growing in Slovakia. Pharm. Biol. 2017, 55, 1162–1170. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Delgado, T.; Marinero, P.; Asensio-S-Manzanera, M.C.; Asensio, C.; Herrero, B.; Pereira, J.A.; Ramalhosa, E. Antioxidant activity of twenty wild Spanish Thymus mastichina L. populations and its relation with their chemical composition. Lebensm. Wiss. Technol. 2014, 57, 412–418. [Google Scholar] [CrossRef] [Green Version]
  119. Rtibi, K.; Selmi, S.; Wannes, D.; Jridi, M.; Marzouki, L.; Sebai, H. The potential of Thymus vulgaris aqueous extract to protect against delayed gastric emptying and colonic constipation in rats. RSC Adv. 2019, 9, 20593–20602. [Google Scholar] [CrossRef] [Green Version]
  120. Sonmezdag, A.S.; Kelebek, H.; Selli, S. Characterization of bioactive and volatile profiles of thyme (Thymus vulgaris L.) teas as affected by infusion times. J. Food Meas. Charact. 2018, 12, 2570–2580. [Google Scholar] [CrossRef]
  121. Taghouti, M.; Martins-Gomes, C.; Schäfer, J.; Félix, L.M.; Santos, J.A.; Bunzel, M.; Nunes, F.M.; Silva, A.M. Thymus pulegioides L. as a rich source of antioxidant, anti-proliferative and neuroprotective phenolic compounds. Food Funct. 2018, 9, 3617–3629. [Google Scholar] [CrossRef]
  122. Kontogiorgis, C.; Ntella, M.; Mpompou, L.; Karallaki, F.; Athanasios, P.; Hadjipavlou-Litina, D.; Lazari, D. Study of the antioxidant activity of Thymus sibthorpii Bentham (Lamiaceae). J. Enzyme Inhib. Med. Chem. 2016, 31, 154–159. [Google Scholar] [CrossRef] [Green Version]
  123. Adham, A.N.; Hegazy, M.E.F.; Naqishbandi, A.M.; Efferth, T. Induction of Apoptosis, Autophagy and Ferroptosis by Thymus vulgaris and Arctium lappa Extract in Leukemia and Multiple Myeloma Cell Lines. Molecules 2020, 25, 5016. [Google Scholar] [CrossRef]
  124. Brahmi, Z.; Niwa, H.; Yamasato, M.; Shigeto, S.; Kusakari, Y.; Sugaya, K.; Onose, J.-i.; Abe, N. Effective Cytochrome P450 (CYP) Inhibitor Isolated from Thyme (Thymus saturoides) Purchased from a Japanese Market. Biosci. Biotechnol. Biochem. 2011, 75, 2237–2239. [Google Scholar] [CrossRef] [Green Version]
  125. Gordo, J.; Máximo, P.; Cabrita, E.; Lourenço, A.; Oliva, A.; Almeida, J.; Filipe, M.; Cruz, P.; Barcia, R.; Santos, M.; et al. Thymus mastichina: Chemical Constituents and their Anti-Cancer Activity. Nat. Prod. Commun. 2012, 7, 1934578X1200701. [Google Scholar] [CrossRef]
  126. Pogacar, M.S.; Klancnik, A.; Bucar, F.; Langerholc, T.; Mozina, S.S. Anti-adhesion activity of thyme (Thymus vulgaris L.) extract, thyme post-distillation waste, and olive (Olea europea L.) leaf extract against Campylobacter jejuni on polystyrene and intestine epithelial cells. J. Sci. Food Agric. 2016, 96, 2723–2730. [Google Scholar] [CrossRef]
  127. Srivedavyasasri, R.; Hayes, T.; Ross, S.A. Phytochemical and biological evaluation of Salvia apiana. Nat. Prod. Res. 2017, 31, 2058–2061. [Google Scholar] [CrossRef] [Green Version]
  128. Exarchou, V.; Kanetis, L.; Charalambous, Z.; Apers, S.; Pieters, L.; Gekas, V.; Goulas, V. HPLC-SPE-NMR Characterization of Major Metabolites in Salvia fruticosa Mill. Extract with Antifungal Potential: Relevance of Carnosic Acid, Carnosol, and Hispidulin. J. Agric. Food Chem. 2015, 63, 457–463. [Google Scholar] [CrossRef] [PubMed]
  129. Honari, N.; Pouraboli, I.; Gharbi, S. Antihyperglycemic property and insulin secreting activity of hydroalcoholic shoot extract of Thymus caramanicus Jalas: A wild predominant source of food additive in folk medicine. J. Funct. Foods 2018, 46, 128–135. [Google Scholar] [CrossRef]
  130. Sarfaraz, D.; Rahimmalek, M.; Saeidi, G. Polyphenolic and molecular variation in Thymus species using HPLC and SRAP analyses. Sci. Rep. 2021, 11, 5019. [Google Scholar] [CrossRef]
  131. Niculae, M.; Hanganu, D.; Oniga, I.; Benedec, D.; Ielciu, I.; Giupana, R.; Sandru, C.D.; Ciocârlan, N.; Spinu, M. Phytochemical Profile and Antimicrobial Potential of Extracts Obtained from Thymus marschallianus Willd. Molecules 2019, 24, 3101. [Google Scholar] [CrossRef] [Green Version]
  132. Mendez-Tovar, I.; Sponza, S.; Asensio-S-Manzanera, M.C.; Novak, J. Contribution of the main polyphenols of Thymus mastichina subsp mastichina to its antioxidant properties. Ind. Crops Prod. 2015, 66, 291–298. [Google Scholar] [CrossRef]
  133. Aras, A.; Türkan, F.; Yildiko, U.; Atalar, M.N.; Kılıç, Ö.; Alma, M.H.; Bursal, E. Biochemical constituent, enzyme inhibitory activity, and molecular docking analysis of an endemic plant species, Thymus migricus. Chem. Pap. 2021, 75, 1133–1146. [Google Scholar] [CrossRef]
  134. Ziani, B.E.C.; Barros, L.; Boumehira, A.Z.; Bachari, K.; Heleno, S.A.; Alves, M.J.; Ferreira, I. Profiling polyphenol composition by HPLC-DAD-ESI/MSn and the antibacterial activity of infusion preparations obtained from four medicinal plants. Food Funct. 2018, 9, 149–159. [Google Scholar] [CrossRef] [Green Version]
  135. Sevindik, H.G.; Ozgen, U.; Atila, A.; Er, H.O.; Kazaz, C.; Duman, H. Phtytochemical Studies and Quantitative HPLC Analysis of Rosmarinic Acid and Luteolin 5-O-β-D-Glucopyranoside on Thymus praecox subsp grossheimii var. grossheimii. Chem. Pharm. Bull. 2015, 63, 720–725. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Taşkın, T.; Çam, M.E.; Taşkın, D.; Rayaman, E. In vitro and In vivo biological activities and phenolic characterization of Thymus praecox subsp. skorpilii var. skorpilii. J. Food Meas. Charact. 2019, 13, 536–544. [Google Scholar] [CrossRef]
  137. Sonmezdag, A.S.; Kelebek, H.; Selli, S. Characterization of aroma-active and phenolic profiles of wild thyme (Thymus serpyllum) by GC-MS-Olfactometry and LC-ESI-MS/MS. Food Sci. Technol. 2016, 53, 1957–1965. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  138. Gökbulut, A. Validated RP-HPLC Method for Quantification of Phenolic Compounds in Methanol Extracts of Aerial Parts and Roots of Thymus sipyleus and Evaluation of Antioxidant Potential. Trop. J. Pharm. Res. 2015, 14, 1871. [Google Scholar] [CrossRef] [Green Version]
  139. Ustuner, O.; Anlas, C.; Bakirel, T.; Ustun-Alkan, F.; Diren Sigirci, B.; Ak, S.; Akpulat, H.A.; Donmez, C.; Koca-Caliskan, U. In Vitro Evaluation of Antioxidant, Anti-Inflammatory, Antimicrobial and Wound Healing Potential of Thymus Sipyleus Boiss. Subsp. Rosulans (Borbas) Jalas. Mol. 2019, 24, 3353. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  140. Kosakowska, O.; Bączek, K.; Przybył, J.L.; Pawełczak, A.; Rolewska, K.; Węglarz, Z. Morphological and Chemical Traits as Quality Determinants of Common Thyme (Thymus vulgaris L.), on the Example of ‘Standard Winter’ Cultivar. Agronomy 2020, 10, 909. [Google Scholar] [CrossRef]
  141. Silva, A.M.; Martins-Gomes, C.; Souto, E.B.; Schäfer, J.; Santos, J.A.; Bunzel, M.; Nunes, F.M. Thymus zygis subsp. zygis an Endemic Portuguese Plant: Phytochemical Profiling, Antioxidant, Anti-Proliferative and Anti-Inflammatory Activities. Antioxidants 2020, 9, 482. [Google Scholar] [CrossRef]
  142. Panja, P. Green extraction methods of food polyphenols from vegetable materials. Curr. Opin. Food Sci. 2018, 23, 173–182. [Google Scholar] [CrossRef]
  143. Sulniute, V.; Pukalskas, A.; Venskutonis, P.R. Phytochemical composition of fractions isolated from ten Salvia species by supercritical carbon dioxide and pressurized liquid extraction methods. Food Chem. 2017, 224, 37–47. [Google Scholar] [CrossRef]
  144. Zengin, G.; Mahomoodally, F.; Picot-Allain, C.; Diuzheva, A.; Jeko, J.; Cziaky, Z.; Cvetanovic, A.; Aktumsek, A.; Zekovic, Z.; Rengasamy, K.R.R. Metabolomic profile of Salvia viridis L. root extracts using HPLC-MS/MS technique and their pharmacological properties: A comparative study. Ind. Crops Prod. 2019, 131, 266–280. [Google Scholar] [CrossRef]
  145. Cvetkovikj, I.; Stefkov, G.; Acevska, J.; Stanoeva, J.P.; Karapandzova, M.; Stefova, M.; Dimitrovska, A.; Kulevanova, S. Polyphenolic characterization and chromatographic methods for fast assessment of culinary Salvia species from South East Europe. J. Chromatogr. A 2013, 1282, 38–45. [Google Scholar] [CrossRef]
  146. Borras Linares, I.; Arraez-Roman, D.; Herrero, M.; Ibanez, E.; Segura-Carretero, A.; Fernandez-Gutierrez, A. Comparison of different extraction procedures for the comprehensive characterization of bioactive phenolic compounds in Rosmarinus officinalis by reversed-phase high-performance liquid chromatography with diode array detection coupled to electrospray time-of-flight mass spectrometry. J. Chromatogr. A 2011, 1218, 7682–7690. [Google Scholar] [CrossRef] [Green Version]
  147. Hossain, M.B.; Brunton, N.P.; Patras, A.; Tiwari, B.; O’Donnell, C.P.; Martin-Diana, A.B.; Barry-Ryan, C. Optimization of ultrasound assisted extraction of antioxidant compounds from marjoram (Origanum majorana L.) using response surface methodology. Ultrason. Sonochem. 2012, 19, 582–590. [Google Scholar] [CrossRef] [Green Version]
  148. Zengin, G.; Cvetanovic, A.; Gasic, U.; Dragicevic, M.; Stupar, A.; Uysal, A.; Senkardes, I.; Sinan, K.I.; Picot-Allain, M.C.N.; Ak, G.; et al. UHPLC-LTQ OrbiTrap MS analysis and biological properties of Origanum vulgare subsp. viridulum obtained by different extraction methods. Ind. Crops Prod. 2020, 154, 12. [Google Scholar] [CrossRef]
  149. Rodriguez-Solana, R.; Manuel Salgado, J.; Manuel Dominguez, J.; Cortes-Dieguez, S. Comparison of Soxhlet, Accelerated Solvent and Supercritical Fluid Extraction Techniques for Volatile (GC-MS and GC/FID) and Phenolic Compounds (HPLC-ESI/MS/MS) from Lamiaceae Species. Phytochem. Anal. 2015, 26, 61–71. [Google Scholar] [CrossRef] [PubMed]
  150. Jovanović, A.A.; Đorđević, V.B.; Zdunić, G.M.; Pljevljakušić, D.S.; Šavikin, K.P.; Gođevac, D.M.; Bugarski, B.M. Optimization of the extraction process of polyphenols from Thymus serpyllum L. herb using maceration, heat- and ultrasound-assisted techniques. Sep. Purif. Technol. 2017, 179, 369–380. [Google Scholar] [CrossRef] [Green Version]
  151. Zhumakanova, B.S.; Korona-Głowniak, I.; Skalicka-Woźniak, K.; Ludwiczuk, A.; Baj, T.; Wojtanowski, K.K.; Józefczyk, A.; Zhaparkulova, K.A.; Sakipova, Z.B.; Malm, A. Phytochemical Fingerprinting and In Vitro Antimicrobial and Antioxidant Activity of the Aerial Parts of Thymus marschallianus Willd. and Thymus seravschanicus Klokov Growing Widely in Southern Kazakhstan. Molecules 2021, 26, 3193. [Google Scholar] [CrossRef]
  152. Munekata, P.E.S.; Alcantara, C.; Zugcic, T.; Abdelkebir, R.; Collado, M.C.; Garcia-Perez, J.V.; Jambrak, A.R.; Gavahian, M.; Barba, F.J.; Lorenzo, J.M. Impact of ultrasound-assisted extraction and solvent composition on bioactive compounds and in vitro biological activities of thyme and rosemary. Food Res. Int. 2020, 134, 12. [Google Scholar] [CrossRef] [PubMed]
  153. Tzima, K.; Brunton, N.P.; Lyng, J.G.; Frontuto, D.; Rai, D.K. The effect of Pulsed Electric Field as a pre-treatment step in Ultrasound Assisted Extraction of phenolic compounds from fresh rosemary and thyme by-products. Innov. Food Sci. Emerg. Technol. 2021, 69, 12. [Google Scholar] [CrossRef]
  154. Palmieri, S.; Pellegrini, M.; Ricci, A.; Compagnone, D.; Lo Sterzo, C. Chemical Composition and Antioxidant Activity of Thyme, Hemp and Coriander Extracts: A Comparison Study of Maceration, Soxhlet, UAE and RSLDE Techniques. Foods 2020, 9, 1221. [Google Scholar] [CrossRef]
  155. Sanchez-Vioque, R.; Polissiou, M.; Astraka, K.; de los Mozos-Pascual, M.; Tarantilis, P.; Herraiz-Penalver, D.; Santana-Meridas, O. Polyphenol composition and antioxidant and metal chelating activities of the solid residues from the essential oil industry. Ind. Crops Prod. 2013, 49, 150–159. [Google Scholar] [CrossRef]
  156. Mrkonjić, Ž.; Rakić, D.; Kaplan, M.; Teslić, N.; Zeković, Z.; Pavlić, B. Pressurized-Liquid Extraction as an Efficient Method for Valorization of Thymus serpyllum Herbal Dust towards Sustainable Production of Antioxidants. Molecules 2021, 26, 2548. [Google Scholar] [CrossRef] [PubMed]
  157. Upadhyay, R.; Nachiappan, G.; Mishra, H.N. Ultrasound-assisted extraction of flavonoids and phenolic compounds from Ocimum tenuiflorum leaves. Food Sci. Biotechnol. 2015, 24, 1951–1958. [Google Scholar] [CrossRef]
  158. Grigorakis, S.; Halahlah, A.; Makris, D.P. Batch Stirred-Tank Green Extraction of Salvia fruticosa Mill. Polyphenols Using Newly Designed Citrate-Based Deep Eutectic Solvents and Ultrasonication Pretreatment. Appl. Sci. 2020, 10, 4774. [Google Scholar] [CrossRef]
  159. Dragovic-Uzelac, V.; Garofulic, I.E.; Jukic, M.; Penic, M.; Dent, M. The Influence of Microwave-Assisted Extraction on the Isolation of Sage (Salvia officinalis L.) Polyphenols. Food Technol. Biotechnol. 2012, 50, 377–383. [Google Scholar]
  160. Santana-Meridas, O.; Polissiou, M.; Izquierdo-Melero, M.E.; Astraka, K.; Tarantilis, P.A.; Herraiz-Penalver, D.; Sanchez-Vioque, R. Polyphenol composition, antioxidant and bioplaguicide activities of the solid residue from hydrodistillation of Rosmarinus officinalis L. Ind. Crops Prod. 2014, 59, 125–134. [Google Scholar] [CrossRef]
  161. Velderrain-Rodríguez, G.R.; Palafox-Carlos, H.; Wall-Medrano, A.; Ayala-Zavala, J.F.; Chen, C.Y.O.; Robles-Sánchez, M.; Astiazaran-García, H.; Alvarez-Parrilla, E.; González-Aguilar, G.A. Phenolic compounds: Their journey after intake. Food Funct. 2014, 5, 189–197. [Google Scholar] [CrossRef]
  162. Heleno, S.A.; Martins, A.; Queiroz, M.J.R.P.; Ferreira, I.C.F.R. Bioactivity of phenolic acids: Metabolites versus parent compounds: A review. Food Chem. 2015, 173, 501–513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Brodkorb, A.; Egger, L.; Alminger, M.; Alvito, P.; Assunção, R.; Ballance, S.; Bohn, T.; Bourlieu-Lacanal, C.; Boutrou, R.; Carrière, F.; et al. INFOGEST static in vitro simulation of gastrointestinal food digestion. Nat. Protoc. 2019, 14, 991–1014. [Google Scholar] [CrossRef] [PubMed]
  164. Gonzales, G.B.; Van Camp, J.; Vissenaekens, H.; Raes, K.; Smagghe, G.; Grootaert, C. Review on the Use of Cell Cultures to Study Metabolism, Transport, and Accumulation of Flavonoids: From Mono-Cultures to Co-Culture Systems. Compr. Rev. Food Sci. Food Saf. 2015, 14, 741–754. [Google Scholar] [CrossRef]
  165. Cardoso, C.; Afonso, C.; Lourenço, H.; Costa, S.; Nunes, M.L. Bioaccessibility assessment methodologies and their consequences for the risk–benefit evaluation of food. Trends Food Sci. Technol. 2015, 41, 5–23. [Google Scholar] [CrossRef]
  166. Domínguez-Avila, J.A.; Wall-Medrano, A.; Velderrain-Rodríguez, G.R.; Chen, C.Y.O.; Salazar-López, N.J.; Robles-Sánchez, M.; González-Aguilar, G.A. Gastrointestinal interactions, absorption, splanchnic metabolism and pharmacokinetics of orally ingested phenolic compounds. Food Funct. 2017, 8, 15–38. [Google Scholar] [CrossRef] [PubMed]
  167. Lucas-González, R.; Viuda-Martos, M.; Pérez-Alvarez, J.A.; Fernández-López, J. In vitro digestion models suitable for foods: Opportunities for new fields of application and challenges. Food Res. Int. 2018, 107, 423–436. [Google Scholar] [CrossRef]
  168. Alminger, M.; Aura, A.M.; Bohn, T.; Dufour, C.; El, S.N.; Gomes, A.; Karakaya, S.; Martínez-Cuesta, M.C.; McDougall, G.J.; Requena, T.; et al. In Vitro Models for Studying Secondary Plant Metabolite Digestion and Bioaccessibility. Compr. Rev. Food Sci. Food Saf. 2014, 13, 413–436. [Google Scholar] [CrossRef] [Green Version]
  169. Bermúdez-Soto, M.-J.; Tomás-Barberán, F.-A.; García-Conesa, M.-T. Stability of polyphenols in chokeberry (Aronia melanocarpa) subjected to in vitro gastric and pancreatic digestion. Food Chem. 2007, 102, 865–874. [Google Scholar] [CrossRef]
  170. D’Archivio, M.; Filesi, C.; Varì, R.; Scazzocchio, B.; Masella, R. Bioavailability of the Polyphenols: Status and Controversies. Int. J. Mol. Sci. 2010, 11, 1321. [Google Scholar] [CrossRef]
  171. Tang, D.; Chen, K.; Huang, L.; Li, J. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. Expert Opin. Drug Metab. Toxicol. 2017, 13, 323–330. [Google Scholar] [CrossRef]
  172. Chohan, M.; Naughton, D.P.; Jones, L.; Opara, E.I. An investigation of the relationship between the anti-inflammatory activity, polyphenolic content, and antioxidant activities of cooked and in vitro digested culinary herbs. Oxid. Med. Cell. Longev. 2012, 2012, 627843. [Google Scholar] [CrossRef] [Green Version]
  173. Gayoso, L.; Roxo, M.; Cavero, R.Y.; Calvo, M.I.; Ansorena, D.; Astiasarán, I.; Wink, M. Bioaccessibility and biological activity of Melissa officinalis, Lavandula latifolia and Origanum vulgare extracts: Influence of an in vitro gastrointestinal digestion. J. Funct. Foods 2018, 44, 146–154. [Google Scholar] [CrossRef] [Green Version]
  174. Rubió, L.; Macià, A.; Castell-Auví, A.; Pinent, M.; Blay, M.T.; Ardévol, A.; Romero, M.P.; Motilva, M.J. Effect of the co-occurring olive oil and thyme extracts on the phenolic bioaccesibility and bioavailability assessed by in vitro digestion and cell models. Food Chem. 2014, 149, 277–284. [Google Scholar] [CrossRef]
  175. Villalva, M.; Jaime, L.; Aguado, E.; Nieto, J.A.; Reglero, G.; Santoyo, S. Anti-Inflammatory and Antioxidant Activities from the Basolateral Fraction of Caco-2 Cells Exposed to a Rosmarinic Acid Enriched Extract. J. Agric. Food Chem. 2018, 66, 1167–1174. [Google Scholar] [CrossRef] [PubMed]
  176. Rubió, L.; Serra, A.; Chen, C.Y.O.; Macià, A.; Romero, M.P.; Covas, M.I.; Solà, R.; Motilva, M.J. Effect of the co-occurring components from olive oil and thyme extracts on the antioxidant status and its bioavailability in an acute ingestion in rats. Food. Funct. 2014, 5, 740–747. [Google Scholar] [CrossRef] [PubMed]
  177. Zhang, L.; Liu, X.; Yang, H.; Zhao, R.; Liu, C.; Zhang, R.; Zhang, Q. Comparative pharmacokinetic study on phenolic acids and flavonoids in spinal cord injury rats plasma by UPLC-MS/MS after single and combined oral administration of danshen and huangqin extract. J. Pharm. Biomed. Anal. 2019, 172, 103–112. [Google Scholar] [CrossRef] [PubMed]
  178. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2012, 64, 4–17. [Google Scholar] [CrossRef]
  179. Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; et al. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res. 2021, 49, D1388–D1395. [Google Scholar] [CrossRef]
  180. Wishart, D.S.; Feunang, Y.D.; Marcu, A.; Guo, A.C.; Liang, K.; Vázquez-Fresno, R.; Sajed, T.; Johnson, D.; Li, C.; Karu, N.; et al. HMDB 4.0: The human metabolome database for 2018. Nucleic Acids Res. 2018, 46, D608–D617. [Google Scholar] [CrossRef]
  181. Wishart, D.S.; Jewison, T.; Guo, A.C.; Wilson, M.; Knox, C.; Liu, Y.; Djoumbou, Y.; Mandal, R.; Aziat, F.; Dong, E.; et al. HMDB 3.0—The Human Metabolome Database in 2013. Nucleic Acids Res. 2013, 41, D801–D807. [Google Scholar] [CrossRef] [PubMed]
  182. Wishart, D.S.; Knox, C.; Guo, A.C.; Eisner, R.; Young, N.; Gautam, B.; Hau, D.D.; Psychogios, N.; Dong, E.; Bouatra, S.; et al. HMDB: A knowledgebase for the human metabolome. Nucleic Acids Res. 2009, 37, D603–D610. [Google Scholar] [CrossRef]
  183. Wishart, D.S.; Tzur, D.; Knox, C.; Eisner, R.; Guo, A.C.; Young, N.; Cheng, D.; Jewell, K.; Arndt, D.; Sawhney, S.; et al. HMDB: The Human Metabolome Database. Nucleic Acids Res. 2007, 35, D521–D526. [Google Scholar] [CrossRef] [PubMed]
Figure 1. General graphic representation of flavones.
Figure 1. General graphic representation of flavones.
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Figure 3. Literature research strategy.
Figure 3. Literature research strategy.
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Table 6. Predicted passive absorption of some flavones found in plants of the Ocimum, Origanum, Salvia, and Thymus genus.
Table 6. Predicted passive absorption of some flavones found in plants of the Ocimum, Origanum, Salvia, and Thymus genus.
MoleculeMolecular Weight 1H Bond Donors 1H Bond Acceptors 1Log p * 1Predicted Bioavailability
Apigenin270.2369353.07Yes
Luteolin286.2363462.73Yes
Diosmetin300.2629363.06Yes
Cirsimaritin314.29263.21Yes
Scutellarein286.24462.74Yes
Hispidulin300.26363.09Yes
Luteolin-7-glucoside448.37697110.58No
Apigenin-7-glucoside432.3816100.68No
Luteolin-7-glucuronide462.36047121.22No
Apigenin-7-glucuronide446.3616111.03No
Baicalein270.2369353.19Yes
Baicalin446.3616111.27No
Wogonin284.26252.092Yes
Wogonoside460.45111.44No
* Log p is defined as the partition coefficient. 1 Chemical data obtained from Kim et al. [179], Wishart et al. [180], Wishart et al. [181], Wishart et al. [182], and Wishart et al. [183].
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Picos-Salas, M.A.; Heredia, J.B.; Leyva-López, N.; Ambriz-Pérez, D.L.; Gutiérrez-Grijalva, E.P. Extraction Processes Affect the Composition and Bioavailability of Flavones from Lamiaceae Plants: A Comprehensive Review. Processes 2021, 9, 1675. https://0-doi-org.brum.beds.ac.uk/10.3390/pr9091675

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Picos-Salas MA, Heredia JB, Leyva-López N, Ambriz-Pérez DL, Gutiérrez-Grijalva EP. Extraction Processes Affect the Composition and Bioavailability of Flavones from Lamiaceae Plants: A Comprehensive Review. Processes. 2021; 9(9):1675. https://0-doi-org.brum.beds.ac.uk/10.3390/pr9091675

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Picos-Salas, Manuel Adrian, José Basilio Heredia, Nayely Leyva-López, Dulce Libna Ambriz-Pérez, and Erick Paul Gutiérrez-Grijalva. 2021. "Extraction Processes Affect the Composition and Bioavailability of Flavones from Lamiaceae Plants: A Comprehensive Review" Processes 9, no. 9: 1675. https://0-doi-org.brum.beds.ac.uk/10.3390/pr9091675

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