1. Introduction
The functional classification of secondary metabolites is used in conjunction with other classifications since the compounds of different structures might be included in one group according to their functions. Using the chemical classification, secondary metabolites are divided into three main classes: polyphenols (see below in Section 1.1), alkaloids (see below in Section 1.2), and isoprenoids (see below in Section 1.3).
1.1. Polyphenols
Phenolic compounds are aromatic molecules containing one or more hydroxyl group in the benzene rings [1]. Substances with one or more than two hydroxyl groups are called phenols and polyphenols, respectively. Preclinical and clinical studies support the protective action of polyphenols in cardiovascular diseases [2], neurodegenerative diseases [3], and cancer [4] due to high anti-oxidant activity, which is related to the number of OH groups. Phenolic compounds are mainly represented in plants by flavonoids, lignans (polymer phenolic compounds), and tannins, and are accumulated in flower petals, fruits, roots (licorice), shoots (motherwort), etc. About 8000 plant phenolic compounds are known to date, and their number is growing every day. The classification of phenolic compounds occurs depending on the number of aromatic rings and the number of carbon atoms attached to the ring. Figure 1 demonstrates the classification of plant polyphenols with typical chemical structures in each class: simple phenols, without extra carbon atoms; phenolcarboxyls, containing one additional carbon atom; acetophenones, containing two additional carbon atoms; phenylpropanoids, containing three additional carbon atoms; naphthoquinones, containing four additional carbon atoms; benzophenones, containing two aromatic rings linked by a bridge of one carbon atom; stilbenoids, containing two aromatic rings linked by two carbon atoms; and flavonoids, containing three aromatic rings linked by three carbon atoms.
Flavonoids are the most numerous groups of phenolic compounds [5,6,7]. There are at least 11 subclasses of flavonoids. The most studied subclasses are shown in Figure 1; they include flavones, flavonols, flavan-3-ols, flavanones, flavononols, chalcones, dihydrochalcones, anthocyanidins, isoflavonoids, and neoflavonoids. All flavonoid molecules contain two benzene rings, which are usually connected by a heterocycle with one oxygen atom or propane fragment and a carboxyl group (Figure 1). The aromatic rings of flavonoids might contain a number of hydroxyl substituents, and some of them even contain one more phenyl substituent.
Stilbenoids have a similar structure with two aromatic rings and several hydroxyl groups [8]. However, unlike flavonoids, they have a diene chain like an ‘elastic stick’ connecting the two aromatic rings instead of the third ring structure found in flavonoids or the oxidized propane chain in chalcones. The stilbenoid resveratrol is involved in the modulation of different signaling pathways in the cell [9] and provides anti-oxidant [10], anti-inflammatory [11], anti-microbial [12], anti-neoplastic [13], anti-diabetic [14] and cardio- and neuroprotective activities [15,16]. The description of each subclass of flavonoids and the most studied representatives are given below.
Flavones have a double bond between C2 and C3 in the flavonoid skeleton; the molecules are not substituted at the C3 position, and they are oxidized at the C4 position [17]. Flavones are components found in vegetables, fruits, nuts, seeds, and tea. They have been reported to possess anti-malarial, anti-microbial, anti-tuberculous, anti-allergic, anti-oxidant, anti-inflammatory, and anti-cancer activities [18,19,20,21,22]. The main representative of this subclass is luteolin, which is found in carrots, celery, olive oil, mint, and chamomile; it exhibits anti-inflammatory effects and improves mental performance [23]. Moreover, luteolin showed a binding affinity for the ACE-2 receptor in silico [24]. The flavone baicalein and its glucuronated derivative baicalin, produced by Scutellaria baicalensis, are used for the treatment of various types of cancer, hepatitis, T-cell leukemia, fever, inflammation, and several kinds of infections [25,26]. Apigenin was found to be a potent inhibitor of cell proliferation and angiogenesis in the human endothelial cells [27].
Flavonols not only contain a carbonyl group at the C4 position, but they also have a hydroxyl group at the C3 position of the pyran C-ring. Grape skin flavonols are found in the form of glycosides, quercitrin, isoquercitrin, quercetin-3-monoglucoside, quercetin-3-monoglucuronoside, and myricetin-3-monoglucoside, and, in wine, they are found in the form of aglycones, kaempferol, quercetin, and myricetin [28]. Kaempferol exhibits dramatic anti-inflammatory properties and has been used to cure many acute and chronic inflammation-induced diseases, such as intervertebral disc degeneration, colitis, post-menopausal bone loss, and acute lung injury [29]. Quercetin and myricetin demonstrate wide biological activities, including anti-oxidant, anti-inflammatory, anti-bacterial, anti-viral, gastroprotective, and immune-modulatory actions [30,31,32]. It has been recently demonstrated that quercetin has anti-viral activity, against coronavirus in particular, and a binding affinity for the ACE-2 receptor in silico [24,33,34].
Flavan-3-ols (also called catechins) were named after Acacia catechu because they were first isolated from its wood. Their molecules contain a hydroxyl group at the C3 position and are not oxidized at the C4 position. Catechins are widely distributed in plants, demonstrate P-vitamin activity, and are used in the treatment of diseases that are associated with capillary dysfunction or edema of a vascular origin [35]. It is widely recognized that green tea containing catechins, (-)-epicatechin-3-gallate, (-)-epigallocatechin, (-)-epicatechin, and (-)-epigallocatechin-3-gallate, protects against cardiovascular diseases, stimulates weight loss, and has protective effects against neurodegeneration, and against Alzheimer’s and Parkinson’s disease in particular [35].
Flavanones are characterized by a pale-yellow color; their structures contain a carbonyl group in the C4 position and do not have a double bond in the C-ring. They are found in tomatoes and aromatic plants, such as mint, but their major sources are citrus fruits [36,37,38], especially grapefruits [39]. The flavanone naringenin has potential therapeutic activity in neurological, cardiovascular, gastrointestinal, and malignant disorders [40]. Liquiritigenin demonstrates high anti-inflammatory activity [41] and promising neuroprotective effects and, therefore, may be useful in developing a specific treatment for Alzheimer’s disease [42]. Rutin has P-vitamin activity and promotes the assimilation of ascorbic acid, and is used along with naringenin for the treatment of obesity [43].
Flavanonols have a structure similar to that of flavanones with an additional hydroxyl group in the C3 position. Most flavanonols were isolated from coniferous and hardwood wood species. Taxifolin and aromadendrin are the main representatives of this class. Taxifolin exhibits anti-oxidant, anti-toxic, regeneration, and anti-edematous activities [44,45].
Chalcones and dihydrochalcones are often considered to be open pyran C-ring flavonoids, and they demonstrate significant anti-oxidant, anti-inflammatory, anti-tumor, anti-diabetic, and anti-bacterial properties [46]. Cardamonin exhibits anti-inflammatory activity and, therefore, has the ability to prevent tumorigenesis [47]. Several studies have shown that the anti-proliferative effects of a substance on cancer cells are associated with its anti-oxidant properties [48]. The dihydrochalcone phloretin and its glycoside phlorizin are known as inhibitors of glucose transport in the intestinal and renal epithelium cells [49]. Phloretin is also able to inhibit the transport of urea in various cells, including the cells of the renal epithelium, liver, and erythrocytes [50].
Anthocyanidins are present in plants as glycosides. These plant pigments give color to flowers, fruits, and leaves. It is known that several anthocyanidins differ by the radicals in the 3′- and 5′-positions of the B-ring. The biological role of anthocyanins has not yet been fully established. There is information on the anti-inflammatory, anti-oxidant, and cancer-inhibitory properties of anthocyanidins [51,52].
Isoflavones possess a B-ring attached at the C3 position of the C-ring. Isoflavonoids have shown anti-oxidant effects due to their free-radical scavenging capacity by donating the hydrogen atoms of the hydroxyl group attached to the benzene ring, thus protecting against oxidative damage and macromolecule damage and reducing low-density lipoproteins [53]. Isoflavonoids have been found in two chemical forms; aglycones (biochanin A, daidzein, and genistein) and glycosides (daidzin and genistin). These isoflavonoids demonstrate vitamin activity and help to strengthen the bones [54]. The synthesis of isoflavonoids is characteristic of leguminous plants, where they act as phytoalexins.
Neoflavonoids are a class of polyphenolic compounds with a 4-phenylchromene backbone at the C2 position. Neoflavonoids display a variety of pharmacological activities, such as anti-osteoporosis, anti-inflammatory, anti-tumor, anti-androgen, anti-allergic, and anti-oxidative activities [55,56].
1.2. Alkaloids
Alkaloids are heterocyclic compounds containing one or more nitrogen atoms and are characterized by significant structural diversity. They are usually divided into several main groups [57]. As a rule, alkaloids are found in plants in the form of salts of malic, tartaric, citric, and other acids. They are divided into true alkaloids; protoalkaloids, which have nitrogen in the side chain; and pseudoalkaloids, which are synthesized through transamination [58] (Figure 2). Figure 2 demonstrates the typical chemical structures of alkaloids belonging to different chemical groups. Vasodilators, anti-hypertensive and anti-arrhythmic compounds, anesthetics, and analgesics have been found among plant alkaloids [59,60]. Alkaloids also demonstrate anti-proliferative, anti-bacterial, and anti-oxidant properties [61]. The therapeutic potential of alkaloids determines their wide industrial application. The immunomodulatory properties of plant alkaloids are also actively discussed [62]. Information on the pharmacological action of some representatives of alkaloids is presented below.
True alkaloids are obtained from amino acids; they share a nitrogen-containing heterocyclic ring and have potent biological activity. Almost all true alkaloids are bitter in taste and are solid, except nicotine, which is a brown bitter liquid [57]. Various amino acids, such as L-phenylalanine, L-tyrosine, L-ornithine, L-histidine, and L-lysine, are the main sources of true alkaloids [63,64]. The tropane derivative cocaine was used as a local numbing agent and vasoconstrictor to help control pain and bleeding during surgery [65]. The anti-malarial effect of quinine has been shown [66]. The piperidine derivative piperine and the purine derivative caffeine possess therapeutic potential for Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, cerebral ischemia, and schizophrenia [67,68]. Moreover, it has been shown that the administration of oral curcumin with piperine as an adjuvant symptomatic therapy in COVID-19 treatment could substantially reduce morbidity and mortality [69].
Protoalkaloids contain a nitrogen atom which is derived from an amino acid but not part of the heterocyclic ring system. Colchicine and capsaicin are very popular examples of protoalkaloids. Colchicine demonstrates protective cardiovascular effects [70] and putative efficacy in the treatment of patients with COVID-19 [71]. Using various types of oncological models, the modulation of signaling pathways, oncogenes, and tumor suppressor genes through the addition of capsaicin has been shown [72], and the possibility of combined drugs based on alkaloids and other anti-cancer compounds is being discussed [73,74].
The basic carbon skeleton of pseudoalkaloids is not directly derived from amino acids; instead, they are synthesized through an amination or transamination reaction by the forerunners or postcursors of amino acids [63]. The pseudoalkaloid solanidine is responsible for neuromuscular syndromes via cholinesterase inhibition [75,76].
1.3. Isoprenoids
Isoprenoids (also called terpenoids) are compounds composed of several C5H8 isoprene units. The isoprene skeleton can be found in naturally occurring compounds, such as carotene, phytol, retinol (vitamin A), tocopherol (vitamin E), and squalene [77]. Figure 3 demonstrates the classification of isoprenoids and the chemical structures of their representatives.
Monoterpenes and sesquiterpenes include more than 3000 compounds and are highly volatile liquids with an odor [78]. They are the main components of essential oils [79]. Diterpenes are also a large group that contains several thousand structures, possesses a rich pharmacology, and includes important compounds such as retinol and phytol [80]. Diterpenes are widely represented in the resins of spruce, pine, fir, and other coniferous trees and are found in the form of cyclic structures. Triterpenes are the components of plants and accumulate in the form of acid esters and glycosides [81,82]. Triterpene glycosides (i.e., saponins) are surfactants and are poisonous to animals. The pronounced hemolytic activity of saponins is explained by their interaction with cholesterol in the erythrocyte membrane [83,84,85]. The great structural diversity of saponins that can be found in nature is due to the presence of various sugars, such as branching sugars, and sapogenins [86,87]. Tetraterpenes include one structural group called carotenoids. At the present time, about 500 representatives of this group are known, which are synthesized in plants and have a color ranging from yellow to red orange [88].
The classification of saponins is based on the structure of aglycones: triterpenoid saponins are synthesized directly from squalene and contain 30 carbon atoms. The structural diversity of saponins explains their diverse physicochemical, pharmacological, and biological properties, which determine their applied significance in the food, cosmetic, and pharmaceutical fields [89]. The pharmacological actions of saponins and related compounds include anti-inflammatory, anti-nociceptive, anti-pyretic, anti-allergic, and anti-cancer properties [90,91]. The steroid alkaloid solasodine exhibits diuretic, anti-cancer, anti-fungal, cardiotonic, anti-spermatogenetic, anti-androgenic, immunomodulatory, and anti-pyretic activities in the central nervous system [92].
2. Phytochemicals Alter the Electrical Properties of the Model Lipid Membranes
An analysis of the literature has shown that the diverse mechanisms of the biological actions of plant metabolites might be associated with the amphiphilicity of their molecules, which determines an ability to interact with cell membranes. Amphiphilic compounds, characterized by the presence of an electric charge and/or significant dipole moment, when interacting with biological membranes, can affect their electrical properties.
The electrical properties of the membrane primarily include the interfacial electrical potential jump called the membrane boundary potential, which consists of two components; the surface and the dipole potential. The first component is related to the charges of the membrane lipids and adsorbed molecules, the ionizing groups of the amino acid residues of the membrane-associated proteins, and the electrolyte counterions in the aqueous solution which, altogether, create a double electric layer. The theoretical consideration of this phenomenon was developed in the works of Gui and Chapman and subsequently supplemented by Stern [93].
Liberman and Topaly suggested the existence of one more potential jump at the membrane–aqueous solution interface in 1969 [94]. Hladky and Haydon first used the term “dipole potential” in 1973 and supposed that it is related to lipid dipoles [95]. At present, the dipole potential is considered to be the unshielded part of the potential jump at the interface which arises due to the specific orientation of the dipoles of the membrane lipids and adsorbed water molecules. As a result, the electric potential of the hydrocarbon core of the membrane turns out to be more positive relative to the aqueous phase surrounding the bilayer, which prevents the penetration of cations and facilitates the transmembrane transport of anions [96,97]. From the above definition of the dipole potential, it follows that its value can be changed in two fundamentally different ways, namely, by changing the hydration of the membrane or by incorporating compounds with high dipole moments oriented along the normal membrane surface.
The relationship between the value of the membrane dipole potential, the dipole moment of the molecules located at the interface, the surface density of the dipoles, and the dielectric constant of the membrane is expressed by the Helmholtz equation [96]:
(1)
where μ is the effective dipole moment projection to the normal membrane surface, n is the effective surface density of the molecular dipoles, ε is the dielectric permeability of the membrane, and ε0 is the permeability of the free space.The value of the membrane dipole potential depends on its lipid composition and varies from 200 to 400 mV [97,98,99,100,101,102]. It has been shown that the membrane dipole potential affects the peptide–lipid interactions, in particular, the membrane fusion caused by the virus fusion peptides [103,104]; the binding of amphiphilic drugs with membranes, local anesthetics in particular [105,106,107]; and the functioning of different ion channels, especially those formed by anti-microbial peptides and lipopeptides [108,109,110,111,112,113,114,115,116,117].
As has been noted above, small amphiphilic molecules and plant metabolites in particular can influence the surface and dipole components of the membrane boundary potential. This is schematically illustrated in Figure 4.
Using different ionophores and lipophilic ions, Andersen et al. [118] found that dihydrochalcone phloretin significantly increases the cationic conductance of the membranes and decreases the anionic conductance of the membranes. Similar results were obtained by Melnik and colleagues [119]. The authors suggested that the introduction of phloretin into the bilayer leads to a decrease in the membrane dipole potential. According to Bechinger and Seelig [120], this occurs due to the reorientation of the dipoles of the lipid molecules and the changes in the hydration of the bilayer. Cseh and Benz suggested that the adsorption of phloretin into the membrane is accompanied by changes in the lipid packing density [121]. A comparative study on the dipole-modifying effects of a number of plant polyphenols, including flavonoids, belonging to different structural groups was carried out by [117,122,123]. Table 1 presents the maximum reduction in the boundary (Δφb(max)) and dipole (Δφd(max)) potential of bilayers composed of pure phosphocholine. By comparing the Δφb(max) and Δφd(max) values, one can assume the presumable role of the dipole component (Table 1).
By analyzing the data obtained with the polyphenols presented in Table 1, one can draw the following conclusions:
(1). The ability of chalcones to reduce the boundary/dipole potential increases in the following order: 4′-hydroxychalcone ≈ isoliquiritigenin (about −40 mV) ≤ cardamonin ≈ licochalcone A (about −60 ÷ −70 mV) < butein −120 mV). Despite the lower lipophilicity of butein among the other tested chalcones, its great efficiency might be explained by its higher dipole moment, which is probably related to the electron density shift in the A and B rings produced by the four hydroxyl groups.
(2). The chalcone butein and the dihydrochalcone phloretin are almost equally effective (the Δφb(max) values coincide within the estimation error). This might indicate that the presence/absence of a double bond in the propane fragment linking the phenolic rings in the molecule of butein/phloretin, which significantly affects the mobility of the rings relative to each other, is not of key importance (Figure 5a).
(3). The chalcone isoliquiritigenin and the flavanone liquiritigenin are almost equally effective (Δφb(max) values coincide within the measurement error), indicating that cyclization (the formation of a heterocycle) does not practically affect the ability of the compounds to modify the potential jump at the membrane–aqueous solution interface (Figure 5a).
(4). The exclusion of the carbonyl group from the structure (catechin compared to taxifolin, Δφb(max) does not exceed 6 mV) does not affect the compound’s dipole-modifying effect (Figure 5a).
(5). The inclusion of an additional OH group in the molecules of flavanones (naringenin compared to liquiritigenin, Δφb(max) ≈ −70 mV)), flavonols (myricetin compared to quercetin, Δφb(max) ≈ −100 mV)), and stilbenoids (piceatannol compared to resveratrol, Δφb(max) ≈ −10 mV) does not alter the dipole-modifying properties of the compounds (Figure 5b). This is not true in the case of chalcones/dihydrochalcones (phloretin (about −150 mV) compared to isoliquiritigenin (about −40 mV)), or isoflavones (genistein (about −70 mV) compared to daidzein (about −20 mV)) (Figure 5c).
(6). The methylation of the hydroxyl group in the B-ring of biochanin A compared to genistein leads to a significant potentiation of the dipole-modifying ability of isoflavones (Figure 5c).
(7). The reduction of the double bond in the heterocycle eliminates the dipole-modifying ability of the compound (taxifolin (about 0 mV) compared to quercetin (about −100 mV)) (Figure 5d). This effect can be explained by the difference in the dipole moments of the structurally related flavononols and flavonols.
(8). The replacement of the oxidized propane chain connecting the two aromatic rings in the chalcone butein with the diene chain in the stilbenoid piceatannol eliminates the dipole-modifying properties (Figure 5d).
(9). All glycosides are less effective at modulating the boundary potential than the related aglycones (phlorizin (about −90 mV) vs. phloretin (about −150 mV); rutin (about −40 mV) vs. quercetin (about −100 mV); and genistin (about −10 mV) vs. genistein (about −70 mV)) (Figure 5e).
Table 1 also presents the maximum magnitude of reduction in the boundary and dipole potential of bilayers composed of pure phosphatidylcholine in the presence of different alkaloids according to [125]. The high structural diversity of the presented series of alkaloids allows us to draw only a few structure–function parallels, while a more detailed penetration requires the systematic testing of many structurally similar analogues in each subgroup. By comparing the structures of the tested alkaloids and their dipole-modifying ability (Table 1), one notices the following:
(1). The xanthine derivatives caffeine, pentoxifylline, 3,9-dimethylxanthine, and 7-(β-hydroxyethyl)theophylline do not affect the potential jump at the membrane–aqueous solution interface. The ability of the other tested xanthines to reduce the boundary/dipole potential increases in the following series: 1,7-dimethylxanthine ≈ 3-isobutyl-1-methylxanthine (about −20 mV) ≤ theophylline (about −40 mV). It can be assumed that the orientation of the dipole moment of xanthines relative to the normal membrane surface, which strongly depends on the type and localization of the hydrophobic substituents, is of decisive importance (Figure 6a).
(2). The pronounced ability of the benzylamines capsaicin and dihydrocapsaicin to influence the membrane boundary/dipole potential (about −120 mV) can be associated with their high lipophilicity and polarity. Moreover, the saturation of the side chain (dihydrocapsaicin compared to capsaicin) is irrelevant for the dipole-modifying properties of benzylamines (Figure 6b).
(3). The derivatives of β-phenylethylamine, synephrine and hordenine are almost equally effective (Δφb(max) values coincide within the measurement error), indicating that the presence of an additional OH group in the side chain (synephrine compared to hordenine) does not affect the compounds’ dipole-modifying effect (−30 ÷ −40 mV) (Figure 6b).
(4). One can also note a significant decrease in the boundary/dipole potential in the presence of quinine, piperine, melatonin, colchicine, and conessine. The absence of information on several structurally similar compounds does not allow one to draw any strictly defined conclusions, and only some trends can be noted. The significant dipole-modifying activity of the effects of quinine and melatonin (about −30 mV) might be related to their structurally close quinoline and indole fragments. The ability of piperine to reduce the boundary/dipole potential (about −50 mV) might be associated with its piperidine fragment and is unlikely to be related to the piperonyl moiety, which is also present in the structure of inactive berberine. The attachment of dimethylamine to the A ring of the steroid core in the molecule of conessine instead of the hydroxyl group in the molecules of solasodine and solanidine might be responsible for the slight dipole-modifying effect of the first molecule (about −20 mV).
By comparing the structures of all the tested saponins and related compounds to their potential-modifying properties (Table 1), one notices the following:
(1). Contrary to polyphenols, all glycosylated analogs (saponins: digitonin, tribulosin, dioscin, and escin) are more effective in modulating the membrane boundary potential (Δφb(max) = −20 ÷ −50 mV)) than the corresponding aglycones (sapogenins: diosgenin, uvaol, lupeol, betulin, solasodine, and solanidine) (Δφb(max) does not exceed −6 mV) (Figure 7).
(2). Dipole-modifying effects do not depend on the structure of the sapogenin (steroid or triterpenoid). Steroids (diosgenin, solasodine, and solanidine) and triterpenoids (uvaol, lupeol, and betulin) are all ineffective (Figure 7).
The different effect of glycosylation on the dipole-modifying ability of flavonoids and sapogenins indicates fundamental differences in the mechanisms of the modulation of the electric potential jump at the bilayer–aqueous solution interface by these compounds. Taking into account the fact that only glycosylated sapogenins, i.e., true saponins, which cannot significantly immerse into the bilayer, are able to reduce the bilayer boundary potential, it can be thought that they affect the potential jump by changing membrane hydration (Figure 8a). In confirmation, digitonin, tribulosin, dioscin, and escin do not affect the φb of membranes composed of hexadecyl oleoyl phosphatidylcholine [126]. It is believed that the carbonyl in the ester group linking the hydrocarbon chain to the glycerol fragment of phosphatidylcholine mainly determines the number of water molecules that bind to the membrane [125,127]. Hexadecyl oleoyl phosphatidylcholine has one ether and one ester group instead of the two ester links in the molecules of the phosphatidylcholines mentioned in Table 1, which defines the different structure of the hydration layers of membranes composed of ester and ether phosphatidylcholines and, consequently, the possibility of it being restructured by saponins.
Unlike saponins, some chalcones/dihydrochalcones, piperine, and benzylamines, whose molecules have relatively high octanol–water distribution coefficients (Table 1), are able to incorporate into the membrane and affect its dipole potential (Figure 8b). The latter may be due to the relatively high dipole moments of their molecules, which can be oriented opposite to the existing total dipole moment of the membrane-forming lipids and water sorbed on the surface of the bilayer, and may be due to a decrease in the packing density of the lipids (i.e., a decrease in the surface density of the dipoles, n). The latter assumption is confirmed by a decrease in the melting temperature of saturated phosphocholines of more than 1 °C upon the incorporation of phloretin, 4-hydroxychalcone, butein, cardamonin, isoliquiritigenin, naringenin, licochalcone A, biochanin A, piperine, capsaicin, and dihydrocapsaicin [117,125,128]. The exceptions are highly hydroxylated flavonols, such as quercetin and myricetin, which significantly reduce the dipole potential of the membrane (Table 1) but do not practically affect the packing density of the lipids in the membrane [129]. This indicates that the mechanism of the change in the interfacial electric potential jump during their adsorption into the bilayer is similar to that of saponins (an alteration in membrane hydration) (Figure 8a).
3. The Role of Phytochemicals in the Formation and Functioning of the Ion Channels Formed by Anti-Microbial Agents
The study of the formation and functioning of the ion channels formed by anti-microbial agents is one of the central problems of modern molecular biology and pharmacology due to the need to overcome the antibiotic resistance of pathogenic strains. In this case, the small-molecule-induced alteration in the lipid matrix is of key importance because it might enhance the pore-forming activity of the anti-microbial agent.
It is well known that the membrane dipole potential affects the pore-forming activity of anti-microbial peptides and lipopeptides, such as gramicidin A (GrA) [110,125,126,130,131], alamethicin [108,111,132], cecropins (CeC) [116,125], syringomycin E (SrE) [112,117,125], surfactin (SuF) [115], polymyxin B (PmB) [133], the lantibiotic nisin (NiS) [134], and the polyene macrolide antibiotic amphotericin B (AmB), at their symmetrical addition [135].
Table 2 summarizes the data concerning the changes in the properties of single ion channels when modulating the membrane dipole potential with different phytochemicals. The dimers of the Bacillus brevis peptide GrA in planar lipid bilayers form symmetrical pores with practically ideal cation selectivity [130,136,137,138]. The one-sided addition of the anti-fungal lipopeptide Pseudomonas syringae SrE causes the appearance of asymmetric lipopeptide-lipid pores of a conical shape with predominant anion selectivity [139,140]. The two-sided addition of AmB, the anti-fungal polyene macrolide antibiotic from the Streptomyces sp., leads to the formation of double-length channels with predominant anion selectivity [141,142,143]. The decrease in the dipole potential (with the hydrocarbon region being positive relative to the aqueous phase) is expected to diminish the electrostatic energy at the center of the pore for cations and to increase it for anions [118]. This should cause an increase in the conductance of the cationic GrA channels and a decrease in the amplitude of the anionic SrE and AmB pores. The quantitative assessment of the decrease in the dipole potential in the presence of small molecules of plant origins (Table 1) makes it possible to calculate the changes in the conductance of the GrA, SrE, and AmB channels, taking into account the shielding of part of the dipole potential in the pores of various geometries [144]. Table 3 summarizes the mean ratios between the steady-state transmembrane currents induced by SrE, SuF, CeC, PmB, and NiS in the presence and absence of different phytochemicals. The Imc/Iomc ratio is proportional to the ratio of the steady-state number of opened single channels before and after the adsorption of the plant metabolites into the lipid bilayer.
By analyzing the data presented in Table 2 and Table 3, one can draw the following conclusions:
(1). As expected, a reduction in the membrane dipole potential causes a decrease in the conductance of anionic channels and an increase in the conductance of cationic pores. The flavonoids phloretin and genistein, the alkaloids capsaicin and dihydrocapsaicin, and the steroid saponin tribulosin, which drastically reduce the membrane dipole potential, (Table 1) lead to an increase in the amplitude of the GrA channels, but the observed changes are small due to the significant (about 80%) shielding of the dipole potential in the aqueous pore of the GrA channel [125,144,145]. The other tested phytochemicals that are not characterized by significant dipole-modifying effects (Table 1), such as the alkaloids pentoxifylline, piperine, and synephrine and the triterpenoid sapogenin lupeol, do not practically change the conductance of the GrA channels (Table 2).
The opposite effects are observed in the cases of the SrE and AmB channels (Table 2). The dipole-potential-diminishing polyphenols phloretin, myricetin, butein, and naringenin (Table 1) cause a significant reduction in SrE pore conductance (Table 2). The changes are not expressed due to about a 90% shielding of the membrane dipole potential in the SrE pore [145]. The high shielding of the dipole potential in the SrE pore practically eliminates the effect of the phytochemicals that reduce the dipole potential by less than 50 mV, such as 4′-hydroxychalcone, cardamonin, liquiritigenin, licochalcone A, resveratrol, pentoxifylline, piperine, and synephrine (Table 1 and Table 2). The schematic representation of the mechanism of action of phloretin in the conductance of the single GrA and SrE channels is presented in Figure 9a,b.
The double-length AmB channels are more sensitive to the changes in the bilayer dipole potential probably due to lower shielding (about 60%) in the aqueous pore: phloretin and quercetin, which decrease the dipole potential by more than 100 mV, lead to a 2–3-fold decrease in AmB conductance (Table 1 and Table 2).
(2). In contrast to the very modest changes in the conductance of the GrA and SrE channels with the decrease in the membrane dipole potential, the changes in the lifetime of the channels are more dramatic (Table 2). Phytochemicals that diminish the membrane dipole potential might induce a several-fold increase in the dwell time of the GrA channels and a more than 100-fold reduction in the lifetime of the SrE pores. The authors of the cited publications in Table 2 attributed the changes in the lifetime of the channels to the fact that the gating particles cross the region of the potential jump during the opening/closing of the channels.
(3). A decrease in the membrane dipole potential causes a significant increase in the steady-state transmembrane currents induced by SrE, PmB, and NiS and a decrease in the pore-forming activity of SuF and CeC. Taking into account that the molecules of SrE, PmB, and NiS possess a positive net charge while SuF has a negative charge, the observed changes in the transmembrane current might be rationalized by the assumption that pore formation includes the immersion of the cations/anions of the channel-forming agents into the lipid bilayer. The decrease in the membrane dipole potential facilitates the incorporation of the cations of SrE, PmB, and NiS and inhibits the introduction of the SuF anions (Figure 9c). Despite the net positive charge of the CeC molecules, a decrease in their pore-forming ability with the diminishing membrane dipole potential might be explained by the embedment of the C-terminal domain of CeC into the lipid bilayer by its negative pole [116] (Figure 9d).
4. Conclusions and Outlook
In summary we made the following conclusions:
(i).. Phytochemicals are able to change the membrane dipole potential through two different methods: an alteration in the membrane hydration (flavonols and saponins) and an incorporation of polar plant molecules into the membrane (chalcones/dihydrochalcones, piperine, and benzylamines).
(ii).. The most significant structural features that determine the effect of phytochemicals on the membrane dipole potential include the following:
-. The glycosylation of sapogenin and flavonoid molecules;
-. The oxidation of the hydrocarbon fragment connecting the two phenolic rings in polyphenol molecules;
-. The double bond in the C-ring of flavonoids;
-. The localization of the hydrophobic substituents in xanthine molecules.
(iii).. The decrease in the membrane dipole potential with a phytochemical’s addition leads to moderate changes in the conductance of single ion-selective channels and to dramatic alterations in the lifetime and number of pores formed by anti-microbial agents.
The summarized data concerning the possibility of a phytochemical influence on the transmembrane distribution of the electrical potential should be taken into account when discussing the molecular mechanisms of phytochemical’s biological and pharmacological actions, including the changes in the membrane permeability and activity of voltage-dependent integral proteins and the subsequent alterations in the signal transduction.
Conceptualization, S.S.E. and O.S.O.; formal analysis, S.S.E. and O.S.O.; investigation, S.S.E. and O.S.O.; resources, S.S.E. and O.S.O.; data curation, S.S.E. and O.S.O.; writing—original draft preparation, S.S.E.; writing—review and editing, O.S.O.; supervision, O.S.O.; project administration, O.S.O.; funding acquisition, S.S.E. All authors have read and agreed to the published version of the manuscript.
Not applicable.
The authors declare no conflict of interest.
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Figure 1. The classification of plant polyphenols and the chemical structures of some representatives.
Figure 2. The classification of plant alkaloids and the chemical structures of some representatives.
Figure 3. The classification of isoprenoids and the chemical structures of some representatives.
Figure 4. The schematic representations of the decrease in the absolute value of membrane surface (green curves) (a) and dipole (dark blue curves) potential (b) at addition of phytochemicals (blue ovals). The applied transmembrane voltage (brown curves) remains constant while dipole potential profile is altered due to the adsorption of the plant molecules. This results in dramatical changes in the inter-membrane electric potential, which is shown as virtual plus in the center of hydrocarbon core (orange cycle).
Figure 5. The relationships between the structure of polyphenols and their dipole-modifying ability. (a) The independence of dipole-modifying effect of polyphenols on the presence of the carbonyl group, heterocycle and double bond in the fragment linking the phenolic rings of molecules (from top to bottom); (b) The independence of dipole-modifying effect on inclusion of an additional OH group in the molecules of flavanones, flavonols, and stilbenoids (from top to bottom); (c) The dependence of dipole-modifying ability of isoflavones (left side) and chalcones/dihydrochalcones (right side) on the inclusion of additional OH- and methyl groups; (d) The dependence of dipole-modifying ability of flavonoid on the presence of the double bond in the heterocycle (left side) and the oxidation and length of the fragment linking the phenolic rings (right side); (e) The dependence of dipole-modifying ability of flavonoids on the glycosylation of isoflavones/dihydrochalcones (left side) and flavonols (right side).
Figure 6. The relationships between the structure of alkaloids and their dipole-modifying ability. (a) The dependence of dipole-modifying ability of xanthines on the localization of the methyl groups; (b) The independence of dipole-modifying effect of protoalkaloids on the presence of OH-group and the double bond in the side chain of phenylethylamines and benzylamines respectively (from top to bottom). The color intensity designation is shown in the caption of Figure 5.
Figure 7. The relationships between the structure of saponins and related compounds and their modifying ability. Glycosylated analogs are more effective in modulating the membrane boundary potential than the corresponding aglycones independently of sapogenin core structure, steroid (left side) or triterpenoid (right side). The color intensity designation is shown in the caption of Figure 5.
Figure 8. Two different ways of modulating dipole potential with various phytochemicals: (a) change in the membrane hydration and (b) intercalation of a compound’s own dipoles into the membrane along with disordering of membrane lipids. The grey color indicates the hydrocarbon core of the lipid bilayer; the blue color indicates the membrane bathing solution.
Figure 9. Schematic representation of the changes in the pore-forming activity of anti-microbial agents induced by decrease in the membrane dipole potential at phloretin’s addition: (a) an increase in the conductance of single cation-selective gramicidin A channels (colored with olive); (b) a decrease in the conductance of single anion-permeable syringomycin E channels (colored with violet); (c) facilitation of immersion of polymyxin B/syringomycin E cations (colored with purple) accompanied by an increase in the number of open channels; and (d) suppression of the immersion of the C-terminal domain of cecropin A (colored with dark cyan), resulting in a decrease in the number of cecropin A channels.
The quantitative characteristics of phytochemical-induced alteration in the membrane boundary and dipole potential.
Class | Phytochemical | Charge * | LogD * | µ $, D | −Δφb(max), mV | −Δφd(max), mV | References |
---|---|---|---|---|---|---|---|
polyphenols # | phloretin | −0.23 | 3.79 | 3.22 | 147 ± 7 |
– | [ |
phlorizin | −0.27 | 0.85 | 1.63 | 92 ± 4 | nd | [ |
|
4′-hydroxychalcone | −0.25 | 3.46 | 2.43 | 38 ± 7 | 35 ± 10 | [ |
|
butein | −0.76 | 2.84 | 5.90 | 120 ± 19 | 150 ± 12 | ||
cardamonin | −0.66 | 3.36 | 1.83 | 59 ± 12 | 38 ± 9 | ||
licochalcone A | −0.30 | 4.67 | 3.79 | 66 ± 12 | 43 ± 11 | ||
isoliquiritigenin | −0.75 | 3.15 | 2.69 | 41 ± 12 | 31 ± 11 | unpublished data | |
liquiritigenin | −0.30 | 2.34 | 0.34 | 66 ± 25 | 30 ± 13 | [ |
|
naringenin | −0.28 | 2.70 | 1.30 | 72 ± 11 | 73 ± 14 | ||
quercetin | −1.25 | 1.00 | 4.42 | 104 ± 7 | nd | [ |
|
myricetin | −1.42 | 0.65 | 4.95 | 111 ± 11 | nd | ||
rutin | −1.20 | −2.02 | 2.51 | 42 ± 6 | nd | ||
biochanin A | −1.02 | 2.27 | 3.29 | 109 ± 11 | nd | ||
genistein | −1.06 | 2.12 | 3.81 | 70 ± 10 | nd | ||
genistin | −0.60 | 0.44 | 3.52 | 7 ± 2 | nd | ||
daidzein | −0.92 | 1.77 | 2.57 | 20 ± 6 | nd | ||
catechin | −0.03 | 1.78 | 3.67 | 6 ± 2 | nd | ||
taxifolin | −0.34 | 1.65 | 2.52 | 2 ± 1 | nd | ||
resveratrol | −0.11 | 3.37 | 0.53 | 11 ± 4 | 9 ± 5 | [ |
|
piceatannol | −0.12 | 3.06 | 1.59 | 15 ± 4 | 10 ± 6 | unpublished data | |
alkaloids § | caffeine | 0 | −0.55 | 3.29 | 2 ± 2 | nd | [ |
pentoxifylline | 0 | 0.23 | 5.44 | 4 ± 2 | nd | ||
1,7–dimethylxanthine | 0 | 0.24 | 3.59 | 23 ± 5 | 21 ± 6 | ||
3,9–dimethylxanthine | −0.02 | −0.82 | 7.29 | 4 ± 3 | nd | ||
theophylline | −0.28 | −0.89 | 6.53 | 41 ± 16 | 40 ± 5 | ||
3–isobutyl–1–methylxanthine | −0.09 | 0.40 | 6.99 | 22 ± 3 | 20 ± 9 | ||
7–(β–hydroxyethyl) theophylline | 0 | −1.24 | 2.26 | 6 ± 2 | nd | ||
lupinine | 1.00 | −1.52 | 1.24 | 3 ± 3 | nd | ||
cotinine | 0 | 0.21 | 4.95 | 6 ± 2 | nd | ||
atropine | 0.99 | −0.41 | 3.58 | 4 ± 4 | nd | ||
quinine | 0.98 | 0.86 | 2.39 | 26 ± 9 | 16 ± 6 | ||
berberine | 1.00 | −1.28 | nd | 3 ± 2 | nd | ||
piperine | 0 | 2.78 | 5.37 | 51 ± 8 | 40 ± 13 | ||
melatonin | 0 | 1.15 | 4.93 | 26 ± 9 | 15 ± 8 | ||
tabersonine | 0.98 | 0.90 | 1.28 | 6 ± 2 | nd | ||
colchicine | 0 | 1.46 | 6.53 | 27 ± 5 | nd | ||
capsaicin | 0 | 3.75 | 4.66 | 118 ± 11 | 92 ± 11 | ||
dihydrocapsaicin | 0 | 4.11 | 4.95 | 119 ± 12 | 92 ± 15 | ||
hordenine | 0.98 | 0.06 | 0.99 | 29 ± 8 | 23 ± 11 | ||
synephrine | 0.97 | −1.39 | 2.32 | 41 ± 12 | 24 ± 9 | ||
conessine | nd | −1.45 | 1.81 | 19 ± 6 | 12 ± 7 | ||
solasodine | 0.99 | 2.50 | nd | 5 ± 2 | nd | ||
solanidine | 0.98 | 1.39 | 1.24 | 2 ± 2 | nd | [ |
|
saponins and related compounds & | digitonin | 0 | −4.96 | 3.79 | 36 ± 4 | na | |
tribulosin | nd | nd | 5.96 | 47 ± 6 | nd | ||
dioscin | 0 | 1.71 | 4.27 | 39 ± 8 | nd | ||
diosgenin | 0 | 4.93 | 1.38 | 6 ± 2 | nd | ||
escin | −1.00 | −4.29 | 7.71 | 20 ± 5 | nd | ||
uvaol | 0 | 6.11 | 1.41 | 1 ± 1 | nd | ||
lupeol | 0 | 7.45 | 1.23 | 1 ± 1 | nd | ||
betulin | 0 | 6.17 | 0.99 | 1 ± 1 | nd |
*—the values of the charge and logarithm of octanol–water distribution coefficient at pH of 7.4, LogDo/w, were predicted by ChemAxon (Chemicalize, JChem Technology Marvin, Hungary). $—the calculations of the dipole moments were performed by HyperChem 7.0 (Hypercube, Inc., Gainesville, FL, USA) by applying MNDO semi-empirical quantum chemical method with STO-3G basis. Δφb(max)—the maximum changes in the boundary potential of the membranes at the adsorption of metabolites. The magnitudes were estimated using the ratio of K+-nonactin-induced membrane conductance values before and after addition of the phytochemicals as described in [
The effects of phytochemicals on the properties of ion channels formed by gramicidin A, syringomycin E, and amphotericin B.
Agent | Phytochemical * | Parameters | References | |
---|---|---|---|---|
gsc/gosc | τsc/τosc | |||
GrA | phloretin | 1.4 ± 0.2 | 12.7 ± 4.4 | [ |
genistein | 1.1 ± 0.1 | 4.3 ± 1.5 | [ |
|
daidzein | 1.0 ± 0.1 | 2.4 ± 0.3 | ||
pentoxifylline | 1.0 ± 0.1 | 1.2 ± 0.6 | [ |
|
piperine | 0.9 ± 0.1 | 0.9 ± 0.6 | ||
capsaicin | 1.1 ± 0.1 | 2.0 ± 1.3 | ||
dihydrocapsaicin | 1.2 ± 0.1 | 1.6 ± 0.8 | ||
synephrine | 1.1 ± 0.1 | 0.9 ± 0.6 | ||
tribulosin | 1.1 ± 0.1 | 1.6 ± 0.6 | [ |
|
lupeol | 1.0 ± 0.1 | 1.0 ± 0.5 | ||
SrE | phloretin | 0.6 ± 0.1 | 0.01 ± 0.01 | [ |
myricetin | 0.6 ± 0.2 | 0.05 ± 0.01 | unpublished data & | |
4′-hydroxychalcone | 0.9 ± 0.2 | nd | [ |
|
butein | 0.6 ± 0.1 | nd | ||
cardamonin | 1.0 ± 0.2 | nd | ||
liquiritigenin | 0.9 ± 0.2 | nd | ||
naringenin | 0.7 ± 0.1 | nd | ||
licochalcone A | 1.0 ± 0.2 | nd | ||
resveratrol | 0.9 ± 0.2 | nd | ||
pentoxifylline | 1.0 ± 0.1 | 1.2 ± 0.1 | [ |
|
piperine | 1.0 ± 0.1 | 0.04 ± 0.01 | ||
capsaicin | 0.9 ± 0.1 | 0.01 ± 0.01 | ||
dihydrocapsaicin | 0.9 ± 0.1 | 0.01 ± 0.01 | ||
synephrine | 1.0 ± 0.1 | 0.6 ± 0.1 | ||
AmB | phloretin | 0.3 ± 0.1 | nd | [ |
quercetin | 0.6 ± 0.1 | nd |
gsc/gosc and τsc/τosc—the ratio of the conductance and the ratio of the dwell time of the single channels in the presence (gsc, τsc) and absence (gosc, τosc) of phytochemicals, respectively; *—the concentration of polyphenols, alkaloids, and saponins was equal to 20, 400, and 50 μM, respectively; &—membranes were composed of diphytanoyl phosphocholine and were bathed in 1.0 M NaCl at pH of 6.0; and nd = not determined.
The effects of phytochemicals on the multi-channel activity of anti-microbial agents: syringomycin E, surfactin, cecropin A, polymyxin B, and nisin.
Agent | Phytochemical * | Imc/Iomc | References |
---|---|---|---|
SrE | phloretin | ~20,000 | [ |
SuF | phloretin | 0.02 ÷ 0.2 | [ |
CeC | phloretin | 0.3 ± 0.2 | [ |
myricetin | 1.1 ± 0.1 | ||
pentoxifylline | 0.9 ± 0.1 | ||
piperine | 0.3 ± 0.1 | ||
capsaicin | 0.1 ± 0.1 | ||
dihydrocapsaicin | 0.2 ± 0.1 | ||
synephrine | 1.1 ± 0.4 | ||
PmB | phloretin | 28 ± 4 | [ |
NiS | phloretin | 5.3 ± 1.3 | [ |
capsaicin | 11.3 ± 1.9 |
Imc/Iomc—ratio of the transmembrane currents induced by antibiotics in the presence (Imc) and absence (Iomc) of phytochemicals in the bilayers at V = 50 mV; *—the concentration of polyphenols and alkaloids was equal to 20 and 400 μM, respectively.
References
1. Al Mamari, H.H. Phenolic compounds: Classification, chemistry, and updated techniques of analysis and synthesis. Phenolic Compounds; 1st ed. Badria, F. IntechOpen: London, UK, 2021; [DOI: https://dx.doi.org/10.5772/intechopen.98958]
2. Chiva-Blanch, G.; Badimon, L. Effects of polyphenol intake on metabolic syndrome: Current evidences from human trials. Oxid. Med. Cell Longev.; 2017; 2017, 5812401. [DOI: https://dx.doi.org/10.1155/2017/5812401] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28894509]
3. West, T.; Atzeva, M.; Holtzman, D.M. Pomegranate polyphenols and resveratrol protect the neonatal brain against hypoxic-ischemic injury. Dev. Neurosci.; 2007; 29, pp. 363-372. [DOI: https://dx.doi.org/10.1159/000105477] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17762204]
4. Kampa, M.; Nifli, A.P.; Notas, G.; Castanas, E. Polyphenols and cancer cell growth. Rev. Physiol. Biochem. Pharmacol.; 2007; 159, pp. 79-113. [DOI: https://dx.doi.org/10.1007/112_2006_0702] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17551696]
5. Shen, N.; Wang, T.; Gan, Q.; Liu, S.; Wang, L.; Jin, B. Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity. Food Chem.; 2022; 383, 132531. [DOI: https://dx.doi.org/10.1016/j.foodchem.2022.132531] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35413752]
6. Ramesh, P.; Jagadeesan, R.; Sekaran, S.; Dhanasekaran, A.; Vimalraj, S. Flavonoids: Classification, function, and molecular mechanisms involved in bone remodelling. Front. Endocrinol; 2021; 12, 779638. [DOI: https://dx.doi.org/10.3389/fendo.2021.779638]
7. Luiza Koop, B.; Nascimento da Silva, M.; Diniz da Silva, F.; Thayres Dos Santos Lima, K.; Santos Soares, L.; José de Andrade, C.; Ayala Valencia, G.; Rodrigues Monteiro, A. Flavonoids, anthocyanins, betalains, curcumin, and carotenoids: Sources, classification and enhanced stabilization by encapsulation and adsorption. Food Res. Int.; 2022; 153, 110929. [DOI: https://dx.doi.org/10.1016/j.foodres.2021.110929]
8. Pecyna, P.; Wargula, J.; Murias, M.; Kucinska, M. More than resveratrol: New insights into stilbene-based compounds. Biomolecules; 2020; 10, 1111. [DOI: https://dx.doi.org/10.3390/biom10081111]
9. Athar, M.; Back, J.H.; Kopelovich, L.; Bickers, D.R.; Kim, A.L. Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms. Arch. Biochem. Biophys.; 2009; 486, pp. 95-102. [DOI: https://dx.doi.org/10.1016/j.abb.2009.01.018]
10. Kerem, Z.; Bilkis, I.; Flaishman, M.A.; Sivan, L. Antioxidant activity and inhibition of alpha-glucosidase by trans-resveratrol, piceid, and a novel trans-stilbene from the roots of Israeli Rumex bucephalophorus L. J. Agric. Food Chem.; 2006; 54, pp. 1243-1247. [DOI: https://dx.doi.org/10.1021/jf052436+]
11. Murias, M.; Handler, N.; Erker, T.; Pleban, K.; Ecker, G.; Saiko, P.; Szekeres, T.; Jäger, W. Resveratrol analogues as selective cyclooxygenase-2 inhibitors: Synthesis and structure-activity relationship. Bioorg. Med. Chem.; 2004; 12, pp. 5571-5578. [DOI: https://dx.doi.org/10.1016/j.bmc.2004.08.008]
12. Gehm, B.D.; McAndrews, J.M.; Chien, P.Y.; Jameson, J.L. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc. Natl. Acad. Sci. USA; 1997; 94, pp. 14138-14143. [DOI: https://dx.doi.org/10.1073/pnas.94.25.14138] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9391166]
13. Kraft, T.E.; Parisotto, D.; Schempp, C.; Efferth, T. Fighting cancer with red wine? Molecular mechanisms of resveratrol. Crit. Rev. Food Sci. Nutr.; 2009; 49, pp. 782-799. [DOI: https://dx.doi.org/10.1080/10408390802248627] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20443159]
14. Szkudelska, K.; Szkudelski, T. Resveratrol, obesity and diabetes. Eur. J. Pharmacol.; 2010; 635, pp. 1-8. [DOI: https://dx.doi.org/10.1016/j.ejphar.2010.02.054]
15. Petrovski, G.; Gurusamy, N.; Das, D.K. Resveratrol in cardiovascular health and disease. Ann. N. Y. Acad. Sci.; 2011; 1215, pp. 22-33. [DOI: https://dx.doi.org/10.1111/j.1749-6632.2010.05843.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21261638]
16. Bastianetto, S.; Ménard, C.; Quirion, R. Neuroprotective action of resveratrol. Biochim. Biophys. Acta.; 2015; 1852, pp. 1195-1201. [DOI: https://dx.doi.org/10.1016/j.bbadis.2014.09.011]
17. Martens, S.; Mithöfer, A. Flavones and flavone synthases. Phytochemistry; 2005; 66, pp. 2399-2407. [DOI: https://dx.doi.org/10.1016/j.phytochem.2005.07.013]
18. Boniface, P.K.; Elizabeth, F.I. Flavones as a privileged scaffold in drug discovery: Current developments. Curr. Org. Synth.; 2019; 16, pp. 968-1001. [DOI: https://dx.doi.org/10.2174/1570179416666190719125730]
19. Hostetler, G.L.; Ralston, R.A.; Schwartz, S.J. Flavones: Food sources, bioavailability, metabolism, and bioactivity. Adv. Nutr.; 2017; 8, pp. 423-435. [DOI: https://dx.doi.org/10.3945/an.116.012948]
20. Jeong, S.H.; Kim, H.H.; Ha, S.E.; Park, M.Y.; Bhosale, P.B.; Abusaliya, A.; Park, K.I.; Heo, J.D.; Kim, H.W.; Kim, G.S. Flavones: Six selected flavones and their related signaling pathways that induce apoptosis in cancer. Int. J. Mol. Sci.; 2022; 23, 10965. [DOI: https://dx.doi.org/10.3390/ijms231810965]
21. Chagas, M.D.S.S.; Behrens, M.D.; Moragas-Tellis, C.J.; Penedo, G.X.M.; Silva, A.R.; Gonçalves-de-Albuquerque, C.F. Flavonols and flavones as potential anti-inflammatory, antioxidant, and antibacterial compounds. Oxid. Med. Cell Longev.; 2022; 2022, 9966750. [DOI: https://dx.doi.org/10.1155/2022/9966750]
22. Havsteen, B.H. The biochemistry and medical significance of the flavonoids. Pharmacol. Ther.; 2002; 96, pp. 67-202. [DOI: https://dx.doi.org/10.1016/S0163-7258(02)00298-X] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12453566]
23. López-Lázaro, M. Distribution and biological activities of the flavonoid luteolin. Mini Rev. Med. Chem.; 2009; 9, pp. 31-59. [DOI: https://dx.doi.org/10.2174/138955709787001712] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19149659]
24. Junior, A.G.; Tolouei, S.E.L.; Dos Reis Lívero, F.A.; Gasparotto, F.; Boeing, T.; de Souza, P. Natural agents modulating ACE-2: A review of compounds with potential against SARS-CoV-2 infections. Curr. Pharm. Des.; 2021; 27, pp. 1588-1596. [DOI: https://dx.doi.org/10.2174/1381612827666210114150607] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33459225]
25. Malikov, V.M.; Yuldashev, M.P. Phenolic compounds of plants of the Scutellaria L. genus. Distribution, structure, and properties. Chem. Nat. Comp.; 2002; 38, pp. 358-406. [DOI: https://dx.doi.org/10.1023/A:1021638411150]
26. Woźniak, D.; Lamer-Zarawska, E.; Matkowski, A. Antimutagenic and antiradical properties of flavones from the roots of Scutellaria baicalensis georgi. Food/Nahrung; 2004; 48, pp. 9-12. [DOI: https://dx.doi.org/10.1002/food.200200230]
27. Osada, M.; Imaoka, S.; Funae, Y. Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1alpha protein. FEBS Lett.; 2004; 575, pp. 59-63. [DOI: https://dx.doi.org/10.1016/j.febslet.2004.08.036]
28. Formica, J.V.; Regelson, W. Review of the biology of quercetin and related bioflavonoids. Food Chem. Toxicol.; 1995; 33, pp. 1061-1080. [DOI: https://dx.doi.org/10.1016/0278-6915(95)00077-1]
29. Ren, J.; Lu, Y.; Qian, Y.; Chen, B.; Wu, T.; Ji, G. Recent progress regarding kaempferol for the treatment of various diseases. Exp. Ther Med.; 2019; 18, pp. 2759-2776. [DOI: https://dx.doi.org/10.3892/etm.2019.7886]
30. Anand David, A.V.; Arulmoli, R.; Parasuraman, S. Overviews of biological importance of quercetin: A bioactive flavonoid. Pharmacogn. Rev.; 2016; 10, pp. 84-89. [DOI: https://dx.doi.org/10.4103/0973-7847.194044]
31. Massi, A.; Bortolini, O.; Ragno, D.; Bernardi, T.; Sacchetti, G.; Tacchini, M.; De Risi, C. Research progress in the modification of quercetin leading to anticancer agents. Molecules; 2017; 22, 1270. [DOI: https://dx.doi.org/10.3390/molecules22081270]
32. Park, K.S.; Chong, Y.; Kim, M.K. Myricetin: Biological activity related to human health. Appl. Biol. Chem.; 2016; 59, pp. 259-269. [DOI: https://dx.doi.org/10.1007/s13765-016-0150-2]
33. Jo, S.; Kim, H.; Kim, S.; Shin, D.H.; Kim, M.S. Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors. Chem. Biol. Drug Des.; 2019; 94, pp. 2023-2030. [DOI: https://dx.doi.org/10.1111/cbdd.13604] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31436895]
34. Mehany, T.; Khalifa, I.; Barakat, H.; Althwab, S.A.; Alharbi, Y.M.; El-Sohaimy, S. Polyphenols as promising biologically active substances for preventing SARS-CoV-2: A review with research evidence and underlying mechanisms. Food Biosci.; 2021; 40, 100891. [DOI: https://dx.doi.org/10.1016/j.fbio.2021.100891] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33495727]
35. Mak, J.C. Potential role of green tea catechins in various disease therapies: Progress and promise. Clin. Exp. Pharmacol. Physiol.; 2012; 39, pp. 265-273. [DOI: https://dx.doi.org/10.1111/j.1440-1681.2012.05673.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22229384]
36. Manach, C.; Scalbert, A.; Morand, C.; Rémésy, C.; Jiménez, L. Polyphenols: Food sources and bioavailability. Am. J. Clin. Nutr.; 2004; 79, pp. 727-747. [DOI: https://dx.doi.org/10.1093/ajcn/79.5.727] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15113710]
37. Majo, D.D.; Giammanco, M.; Guardia, M.L.; Tripoli, E.; Giammanco, S.; Finotti, E. Flavanones in Citrus fruit: Structure–antioxidant activity relationships. Food Res. Int.; 2005; 38, pp. 1161-1166. [DOI: https://dx.doi.org/10.1016/j.foodres.2005.05.001]
38. D’Archivio, M.; Filesi, C.; Di Benedetto, R.; Gargiulo, R.; Giovannini, C.; Masella, R. Polyphenols, dietary sources and bioavailability. Ann. Ist. Super. Sanita; 2007; 43, pp. 348-361.
39. Zhang, J. Flavonoids in grapefruit and commercial grapefruit juices: Concentration, distribution, and potential health benefits. Proc. Fla. State Hort. Soc.; 2007; 120, pp. 288-294.
40. Kim, T.H.; Kim, G.D.; Ahn, H.J.; Cho, J.J.; Park, Y.S.; Park, C.S. The inhibitory effect of naringenin on atopic dermatitis induced by DNFB in NC/Nga mice. Life Sci.; 2013; 93, pp. 516-524. [DOI: https://dx.doi.org/10.1016/j.lfs.2013.07.027]
41. Kim, Y.W.; Zhao, R.J.; Park, S.J.; Lee, J.R.; Cho, I.J.; Yang, C.H.; Kim, S.G.; Kim, S.C. Anti-inflammatory effects of liquiritigenin as a consequence of the inhibition of NF-kappaB-dependent iNOS and proinflammatory cytokines production. Br. J. Pharmacol.; 2008; 154, pp. 165-173. [DOI: https://dx.doi.org/10.1038/bjp.2008.79]
42. Liu, R.T.; Zou, L.B.; Lü, Q.J. Liquiritigenin inhibits Abeta(25-35)-induced neurotoxicity and secretion of Abeta(1-40) in rat hippocampal neurons. Acta Pharmacol. Sin.; 2009; 30, pp. 899-906. [DOI: https://dx.doi.org/10.1038/aps.2009.74] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19574995]
43. Bengmark, S.; Mesa, M.D.; Gil, A. Plant-derived health: The effects of turmeric and curcuminoids. Nutr. Hosp.; 2009; 24, pp. 273-281. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19721899]
44. Selway, J.W.T. Antiviral activity of flavones and flavans. Plant Flavonoids in Biology and Medicine: Biochemical, Pharmacological, and Structure-Activity Relationships; Cody, V.; Middleton, E.; Harborne, J.B. Alan R. Liss, Inc.: New York, NY, USA, 1986; pp. 521-536.
45. Nakayama, T.; Yamada, M.; Osawa, T.; Kawakishi, S. Suppression of active oxygen-induced cytotoxicity by flavonoids. Biochem. Pharmacol.; 1993; 45, pp. 265-267. [DOI: https://dx.doi.org/10.1016/0006-295290402-i]
46. Song, Z.; Shanmugam, M.K.; Yu, H.; Sethi, G. Butein and its role in chronic diseases. Adv. Exp. Med. Biol.; 2016; 928, pp. 419-433. [DOI: https://dx.doi.org/10.1007/978-3-319-41334-1_17] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27671826]
47. Yadav, V.R.; Prasad, S.; Sung, B.; Aggarwal, B.B. The role of chalcones in suppression of NF-κB-mediated inflammation and cancer. Int. Immunopharmacol.; 2011; 11, pp. 295-309. [DOI: https://dx.doi.org/10.1016/j.intimp.2010.12.006] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21184860]
48. Loa, J.; Chow, P.; Zhang, K. Studies of structure-activity relationship on plant polyphenol-induced suppression of human liver cancer cells. Cancer Chemother. Pharmacol.; 2009; 63, pp. 1007-1016. [DOI: https://dx.doi.org/10.1007/s00280-008-0802-y] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18766342]
49. Yamaguchi, K.; Kato, M.; Suzuki, M.; Asanuma, K.; Aso, Y.; Ikeda, S.; Ishigai, M. Pharmacokinetic and pharmacodynamic modeling of the effect of an sodium-glucose cotransporter inhibitor, phlorizin, on renal glucose transport in rats. Drug Metab. Dispos.; 2011; 39, pp. 1801-1807. [DOI: https://dx.doi.org/10.1124/dmd.111.040048]
50. vom Dahl, S.; Haussinger, D. Characterization of phloretin-sensitive urea export from the perfused rat liver. Biol. Chem. Hoppe Seyler; 1996; 377, pp. 25-37. [DOI: https://dx.doi.org/10.1515/bchm3.1996.377.1.25]
51. Silva, S.; Costa, E.M.; Calhau, C.; Morais, R.M.; Pintado, M.E. Anthocyanin extraction from plant tissues: A review. Crit. Rev. Food Sci. Nutr.; 2017; 57, pp. 3072-3083. [DOI: https://dx.doi.org/10.1080/10408398.2015.1087963]
52. de Sousa Moraes, L.F.; Sun, X.; Peluzio, M.D.C.G.; Zhu, M.J. Anthocyanins/anthocyanidins and colorectal cancer: What is behind the scenes?. Crit. Rev. Food Sci. Nutr.; 2019; 59, pp. 59-71. [DOI: https://dx.doi.org/10.1080/10408398.2017.1357533]
53. Yoon, G.A.; Park, S. Antioxidant action of soy isoflavones on oxidative stress and antioxidant enzyme activities in exercised rats. Nutr. Res. Pract.; 2014; 8, pp. 618-624. [DOI: https://dx.doi.org/10.4162/nrp.2014.8.6.618] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25489400]
54. Middleton, E., Jr.; Kandaswami, C.; Theoharides, T.C. The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol. Rev.; 2000; 52, pp. 673-751. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11121513]
55. Liu, R.H.; Lin, S.; Zhang, P.Z.; Chen, L.Y.; Huang, H.L.; Mei, D.Y. Neoflavonoids and their pharmacological activities in Dalbergia genus. Zhongguo Zhong Yao Za Zhi; 2017; 42, pp. 4707-4715. (In Chinese) [DOI: https://dx.doi.org/10.19540/j.cnki.cjcmm.20170928.013]
56. Mukerjee, S.; Saroja, T.; Seshadri, T.R. Dalbergichromene: A new neoflavonoid from stem-bark and heartwood of Dalbergia sissoo. Tetrahedron; 1971; 27, pp. 799-803. [DOI: https://dx.doi.org/10.1016/S0040-4020(01)92474-3]
57. Aniszewski, T. Alkaloids—Secrets of Life. Alkaloid Chemistry, Biological Significance, Applications and Ecological Role; Elsevier: Amsterdam, The Netherlands, 2007; [DOI: https://dx.doi.org/10.1016/B978-0-444-52736-3.X5000-4]
58. Dey, P.; Kundu, A.; Kumar, A.; Gupta, M.; Lee, B.M.; Bhakta, T.; Dash, S.; Kim, H.S. Analysis of alkaloids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids). Rec. Adv. Nat. Prod. Anal.; 2020; pp. 505-567. [DOI: https://dx.doi.org/10.1016/B978-0-12-816455-6.00015-9]
59. Sultana, S.; Asif, H.M. Review: Medicinal plants combating against hypertension: A green antihypertensive approach. Pak. J. Pharm. Sci.; 2017; 30, pp. 2311-2319. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29175804]
60. Tsuchiya, H. Anesthetic agents of plant origin: A review of phytochemicals with anesthetic activity. Molecules; 2017; 22, 1369. [DOI: https://dx.doi.org/10.3390/molecules22081369]
61. Qiu, S.; Sun, H.; Zhang, A.H.; Xu, H.Y.; Yan, G.L.; Han, Y.; Wang, X.J. Natural alkaloids: Basic aspects, biological roles, and future perspectives. Chin. J. Nat. Med.; 2014; 12, pp. 401-406. [DOI: https://dx.doi.org/10.1016/S1875-5364(14)60063-7]
62. Tiwari, R.; Latheef, S.K.; Ahmed, I.; Iqbal, H.M.N.; Bule, M.H.; Dhama, K.; Samad, H.A.; Karthik, K.; Alagawany, M.; El-Hack, M.E.A. et al. Herbal immunomodulators—A remedial panacea for designing and developing effective drugs and medicines: Current scenario and future prospects. Curr. Drug. Metab.; 2018; 19, pp. 264-301. [DOI: https://dx.doi.org/10.2174/1389200219666180129125436]
63. Dewick, P.M. Medicinal Natural Products: A Biosynthetic Approach; 3rd ed. Dewick, P.M. John Wiley & Sons: Hoboken, NJ, USA, 2002; 552.
64. Pelletier, S.W. Alkaloids: Chemical and Biological Perspectives; 1st ed. Springer: Berlin/Heidelberg, Germany, 1999; pp. 1-542.
65. MacNeil, S.D.; Rotenberg, B.; Sowerby, L.; Allen, B.; Richard, L.; Shariff, S.Z. Medical use of cocaine and perioperative morbidity following sinonasal surgery-A population study. PLoS ONE; 2020; 15, e0236356. [DOI: https://dx.doi.org/10.1371/journal.pone.0236356]
66. Kluska, M.; Marciniuk-Kluska, A.; Prukała, D.; Prukała, W. Analytics of quinine and its derivatives. Crit. Rev. Anal. Chem.; 2016; 46, pp. 139-145. [DOI: https://dx.doi.org/10.1080/10408347.2014.996700] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25831406]
67. Patil, S.; Tawari, S.; Mundhada, D.; Nadeem, S. Protective effect of berberine, an isoquinoline alkaloid ameliorates ethanol-induced oxidative stress and memory dysfunction in rats. Pharmacol. Biochem. Behav.; 2015; 136, pp. 13-20. [DOI: https://dx.doi.org/10.1016/j.pbb.2015.07.001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26159088]
68. Hussain, G.; Rasul, A.; Anwar, H.; Aziz, N.; Razzaq, A.; Wei, W.; Ali, M.; Li, J.; Li, X. Role of plant derived alkaloids and their mechanism in neurodegenerative disorders. Int. J. Biol. Sci.; 2018; 14, pp. 341-357. [DOI: https://dx.doi.org/10.7150/ijbs.23247] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29559851]
69. Pawar, K.S.; Mastud, R.N.; Pawar, S.K.; Pawar, S.S.; Bhoite, R.R.; Bhoite, R.R.; Kulkarni, M.V.; Deshpande, A.R. Oral curcumin with piperine as adjuvant therapy for the treatment of COVID-19: A randomized clinical trial. Front. Pharmacol.; 2021; 12, 669362. [DOI: https://dx.doi.org/10.3389/fphar.2021.669362] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34122090]
70. Gasparyan, A.Y.; Ayvazyan, L.; Yessirkepov, M.; Kitas, G.D. Colchicine as an anti-inflammatory and cardioprotective agent. Expert. Opin. Drug Metab. Toxicol.; 2015; 11, pp. 1781-1794. [DOI: https://dx.doi.org/10.1517/17425255.2015.1076391]
71. Mikolajewska, A.; Fischer, A.L.; Piechotta, V.; Mueller, A.; Metzendorf, M.I.; Becker, M.; Dorando, E.; Pacheco, R.L.; Martimbianco, A.L.C.; Riera, R. et al. Colchicine for the treatment of COVID-19. Cochrane Database Syst. Rev.; 2021; 10, CD015045. [DOI: https://dx.doi.org/10.1002/14651858]
72. Clark, R.; Lee, S.H. Anticancer properties of capsaicin against human cancer. Anticancer Res.; 2016; 36, pp. 837-843.
73. Isah, T. Anticancer alkaloids from trees: Development into drugs. Pharmacogn. Rev.; 2016; 10, pp. 90-99. [DOI: https://dx.doi.org/10.4103/0973-7847.194047]
74. Hashmi, M.A.; Khan, A.; Farooq, U.; Khan, S. Alkaloids as cyclooxygenase inhibitors in anticancer drug discovery. Curr. Protein Pept. Sci.; 2018; 19, pp. 292-301. [DOI: https://dx.doi.org/10.2174/1389203718666170106103031]
75. Nikolic, N.C.; Stankovic, M.Z. Solanidine hydrolytic extraction and separation from the potato (Solanum tuberosum L.) vines by using solid-liquid-liquid systems. J. Agric. Food Chem.; 2003; 51, pp. 1845-1849. [DOI: https://dx.doi.org/10.1021/jf020426s]
76. Bushway, R.J.; Savage, S.A.; Ferguson, B.S. Inhibition of acetyl cholinesterase by solanaceous glycoalkaloids and alkaloids. Am. Potato J.; 1987; 64, pp. 409-413. [DOI: https://dx.doi.org/10.1007/BF02853703]
77. Järvinen, R. Carotenoids, retinoids, tocopherols and tocotrienols in the diet; the Finnish Mobile Clinic Health Examination Survey. Int. J. Vitam. Nutr. Res.; 1995; 65, pp. 24-30. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/7657476]
78. Simon, J.E. Essential oils and culinary herbs. Advances in New Crops; Janick, J.; Simon, J.E. Timber Press: Portland, OR, USA, 1990; pp. 472-483.
79. Gao, J.M.; Wu, W.J.; Zhang, J.W.; Konishi, Y. The dihydro-beta-agarofuran sesquiterpenoids. Nat. Prod. Rep.; 2007; 24, pp. 1153-1189. [DOI: https://dx.doi.org/10.1039/b601473a] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17898902]
80. Hanson, J.R. Diterpenoids. Nat. Prod. Rep.; 2009; 26, pp. 1156-1171. [DOI: https://dx.doi.org/10.1039/b807311m] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19693413]
81. Connolly, J.D.; Hill, R.A. Triterpenoids. Nat. Prod. Rep.; 2010; 27, pp. 79-132. [DOI: https://dx.doi.org/10.1039/B808530G] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20024095]
82. Connolly, J.D.; Hill, R.A. Triterpenoids. Nat. Prod. Rep.; 2007; 24, pp. 465-486. [DOI: https://dx.doi.org/10.1039/b507872p]
83. Bangham, A.D.; Horne, R.W.; Glauret, A.M.; Dingle, J.T.; Lucy, J.A. Action of saponin on biological cell membranes. Nature; 1962; 196, pp. 952-955. [DOI: https://dx.doi.org/10.1038/196952a0]
84. Gestetner, B.; Assa, Y.; Henis, Y.; Tencer, Y.; Rotman, M.; Birk, Y.; Bondi, A. Interaction of leucerne saponins with steroids. Biochim. Biophys. Acta; 1972; 270, pp. 181-187. [DOI: https://dx.doi.org/10.1016/0005-2760(72)90190-7]
85. Vinarova, L.; Vinarov, Z.; Atanasov, V.; Pantcheva, I.; Tcholakova, S.; Denkov, N.; Stoyanov, S. Lowering of cholesterol bioaccessibility and serum concentrations by saponins: In vitro and in vivo studies. Food Funct.; 2015; 6, pp. 501-512. [DOI: https://dx.doi.org/10.1039/C4FO00785A]
86. Bruneton, J. Pharmacognosie-Phytochimie, Plantes Médicinales, Lavoisier 4e éd, revue et augmentée; Tec & Dac-Editions Médicinales Internationals: Paris, France, 2009; 1288.
87. Dinda, B.; Debnath, S.; Mohanta, B.C.; Harigaya, Y. Naturally occurring triterpenoid saponins. Chem. Biodivers.; 2010; 7, pp. 2327-2580. [DOI: https://dx.doi.org/10.1002/cbdv.200800070]
88. Langi, P.; Kiokias, S.; Varzakas, T.; Proestos, C. Carotenoids: From plants to food and feed industries. Methods Mol. Biol.; 2018; 1852, pp. 57-71. [DOI: https://dx.doi.org/10.1007/978-1-4939-8742-9_3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30109624]
89. Netala, V.R.; Kotakadi, V.S.; Bobbu, P.; Gaddam, S.A.; Tartte, V. Endophytic fungal isolate mediated biosynthesis of silver nanoparticles and their free radical scavenging activity and anti microbial studies. 3 Biotech; 2016; 6, 132. [DOI: https://dx.doi.org/10.1007/s13205-016-0433-7] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28330204]
90. Yan, L.L.; Zhang, Y.J.; Gao, W.Y.; Man, S.L.; Wang, Y. In vitro and in vivo anticancer activity of steroid saponins of Paris polyphylla var. yunnanensis. Exp. Oncol.; 2009; 31, pp. 27-32.
91. Yassin, A.M.; El-Deeb, N.M.; Metwaly, A.M.; Fawal, G.F.; Radwan, M.M.; Hafez, E.E. Induction of apoptosis in human cancer cells through extrinsic and intrinsic pathways by balanites Aegyptiaca furostanol saponins and saponin-coated silvernanoparticles. Der. Pharm. Lett.; 2013; 182, pp. 1675-1693. [DOI: https://dx.doi.org/10.1007/s12010-017-2426-3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28236195]
92. Patel, A.S.; Supan, E.M.; Ali, S.N. Toxic epidermal necrolysis associated with rifaximin. Am. J. Health Syst. Pharm.; 2013; 70, pp. 874-876. [DOI: https://dx.doi.org/10.2146/ajhp120137] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23640348]
93. McLaughlin, S. Electrostatic potentials at membrane-solution interfaces. Curr. Topics Membr. Transp.; 1977; 9, pp. 71-144.
94. Liberman, E.A.; Topaly, V.P. Permeability of bimolecular phospholipid membranes for fat-soluble ions. Biofizika; 1969; 14, pp. 452-461.
95. Hladky, S.B.; Haydon, D.A. Ion transfer across lipid membranes in the presence of gramicidin A. I. Studies of the unit conductance channel. Biochim. Biophys. Acta; 1972; 274, pp. 294-312. [DOI: https://dx.doi.org/10.1016/0005-2736(72)90178-2]
96. Brockmann, H. Dipole potential of lipid membranes. Chem. Phys. Lipids; 1994; 73, pp. 57-79. [DOI: https://dx.doi.org/10.1016/0009-3084(94)90174-0]
97. Peterson, U.; Mannock, D.A.; Lewis, R.N.; Pohl, P.; McElhaney, R.N.; Pohl, E.E. Origin of membrane dipole potential: Contribution of the phospholipid fatty acid chains. Chem. Phys. Lipids; 2002; 117, pp. 19-27. [DOI: https://dx.doi.org/10.1016/S0009-3084(02)00013-0]
98. Flewelling, R.F.; Hubbell, W.L. Hydrophobic ion interactions with membranes. Thermodynamic analysis of tetraphenylphosphonium binding to vesicles. Biophys. J.; 1986; 49, pp. 531-540. [DOI: https://dx.doi.org/10.1016/S0006-3495(86)83663-3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/3006814]
99. Flewelling, R.F.; Hubbell, W.L. The membrane dipole potential in a total membrane potential model. Applications to hydrophobic ion interactions with membranes. Biophys. J.; 1986; 49, pp. 541-552. [DOI: https://dx.doi.org/10.1016/S0006-3495(86)83664-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/3955184]
100. Franklin, J.C.; Cafiso, D.S. Internal electrostatic potentials in bilayers: Measuring and controlling dipole potentials in lipid vesicles. Biophys. J.; 1993; 65, pp. 289-299. [DOI: https://dx.doi.org/10.1016/S0006-3495(93)81051-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8396456]
101. Cseh, R.; Benz, R. The adsorption of phloretin to lipid monolayers and bilayers cannot be explained by langmuir adsorption isotherms alone. Biophys. J.; 1998; 74, pp. 1399-1408. [DOI: https://dx.doi.org/10.1016/S0006-3495(98)77852-X]
102. Brockman, H.L.; Momsen, M.M.; Brown, R.E.; He, L.; Chun, J.; Byun, H.S.; Bittman, R. The 4,5-double bond of ceramide regulates its dipole potential, elastic properties, and packing behavior. Biophys. J.; 2004; 87, pp. 1722-1731. [DOI: https://dx.doi.org/10.1529/biophysj.104.044529]
103. Cladera, J.; Martin, I.; Ruysschaert, J.M.; O’Shea, P. Characterization of the sequence of interactions of the fusion domain of the simian immunodeficiency virus with membranes: Role of the membrane dipole potential. J. Biol. Chem.; 1999; 274, pp. 29951-29959. [DOI: https://dx.doi.org/10.1074/jbc.274.42.29951]
104. Guillén, J.; Kinnunen, P.K.; Villalaín, J. Membrane insertion of the three main membranotropic sequences from SARS-CoV S2 glycoprotein. Biochim. Biophys. Acta; 2008; 1778, pp. 2765-2774. [DOI: https://dx.doi.org/10.1016/j.bbamem.2008.07.021]
105. Mojumdar, E.H.; Lyubartsev, A.P. Molecular dynamics simulations of local anesthetic articaine in a lipid bilayer. Biophys. Chem.; 2010; 153, pp. 27-35. [DOI: https://dx.doi.org/10.1016/j.bpc.2010.10.001]
106. Efimova, S.S.; Zakharova, A.A.; Schagina, L.V.; Ostroumova, O.S. Local anesthetics affect gramicidin A channels via membrane electrostatic potentials. J. Membr. Biol.; 2016; 249, pp. 781-787. [DOI: https://dx.doi.org/10.1007/s00232-016-9926-x]
107. Efimova, S.S.; Chulkov, E.G.; Ostroumova, O.S. Lipid-mediated mode of action of local anesthetics on lipid pores induced by polyenes, peptides and lipopeptides. Colloids Surf. B Biointerfaces; 2018; 166, pp. 1-8. [DOI: https://dx.doi.org/10.1016/j.colsurfb.2018.02.051]
108. Latorre, R.; Donovan, J.J. Modulation of alamethicin-induced conductance by membrane composition. Acta Physiol. Scand. Suppl.; 1980; 481, pp. 37-45. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/6254328]
109. Busath, D.D.; Thulin, C.D.; Hendershot, R.W.; Phillips, L.R.; Maughan, P.; Cole, C.D.; Bingham, N.C.; Morrison, S.; Baird, L.C.; Hendershot, R.J. et al. Noncontact dipole effects on channel permeation. I. Experiments with (5F-indole)Trp13 gramicidin A channels. Biophys. J.; 1998; 75, pp. 2830-2844. [DOI: https://dx.doi.org/10.1016/S0006-3495(98)77726-4] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9826605]
110. Hwang, T.C.; Koeppe, R.E.; Andersen, O.S. Genistein can modulate channel function by a phosphorylation-independent mechanism: Importance of hydrophobic mismatch and bilayer mechanics. Biochemistry; 2003; 42, pp. 13646-13658. [DOI: https://dx.doi.org/10.1021/bi034887y] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/14622011]
111. Luchian, T.; Mereuta, L. Phlorizin- and 6-ketocholestanol-mediated antagonistic modulation of alamethicin activity in phospholipid planar membranes. Langmuir; 2006; 22, pp. 8452-8457. [DOI: https://dx.doi.org/10.1021/la0613777] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16981762]
112. Ostroumova, O.S.; Kaulin, Y.A.; Gurnev, A.P.; Schagina, L.V. Effect of agents modifying the membrane dipole potential on properties of syringomycin E channels. Langmuir; 2007; 23, pp. 6889-6892. [DOI: https://dx.doi.org/10.1021/la7005452]
113. Mereuta, L.; Luchian, T.; Park, Y.; Hahm, K.S. Single-molecule investigation of the interactions between reconstituted planar lipid membranes and an analogue of the HP(2-20) antimicrobial peptide. Biochem. Biophys. Res. Commun.; 2008; 373, pp. 467-472. [DOI: https://dx.doi.org/10.1016/j.bbrc.2008.04.046]
114. Apetrei, A.; Mereuta, L.; Luchian, T. The RH 421 styryl dye induced, pore model-dependent modulation of antimicrobial peptides activity in reconstituted planar membranes. Biochim. Biophys. Acta; 2009; 1790, pp. 809-816. [DOI: https://dx.doi.org/10.1016/j.bbagen.2009.04.002]
115. Ostroumova, O.S.; Malev, V.V.; Ilin, M.G.; Schagina, L.V. Surfactin activity depends on the membrane dipole potential. Langmuir; 2010; 26, pp. 15092-15097. [DOI: https://dx.doi.org/10.1021/la102691y]
116. Efimova, S.S.; Schagina, L.V.; Ostroumova, O.S. Channel forming activity of cecropins in lipid bilayers. Effect of agents modifying the membrane dipole potential. Langmuir; 2014; 30, pp. 7884-7892. [DOI: https://dx.doi.org/10.1021/la501549v]
117. Efimova, S.S.; Zakharova, A.A.; Medvedev, R.Y.; Ostroumova, O.S. Ion channels induced by antimicrobial agents in model lipid membranes are modulated by plant polyphenols through surrounding lipid media. J. Membr. Biol.; 2018; 251, pp. 551-562. [DOI: https://dx.doi.org/10.1007/s00232-018-0031-1]
118. Andersen, O.S.; Finkelstein, A.; Katz, I.; Cass, A. Effect of phloretin on the permeability of thin lipid membranes. J. Gen. Physiol.; 1976; 67, pp. 749-771. [DOI: https://dx.doi.org/10.1085/jgp.67.6.749] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/946975]
119. Melnik, E.; Latorre, R.; Hall, J.E.; Tosteson, D.C. Phloretin-induced changes in ion transport across lipid bilayer membranes. J. Gen. Physiol.; 1977; 69, pp. 243-257. [DOI: https://dx.doi.org/10.1085/jgp.69.2.243] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/576427]
120. Bechinger, B.; Seelig, J. Interaction of electric dipoles with phospholipid head groups. A 2H and 31P NMR study of phloretin and phloretin analogues in phosphatidylcholine membranes. Biochemistry; 1991; 30, pp. 3923-3929. [DOI: https://dx.doi.org/10.1021/bi00230a017] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/1850293]
121. Cseh, R.; Benz, R. Interaction of phloretin with lipid monolayers: Relationship between structural changes and dipole potential change. Biophys. J.; 1999; 77, pp. 1477-1488. [DOI: https://dx.doi.org/10.1016/S0006-3495(99)76995-X] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10465758]
122. Efimova, S.S.; Ostroumova, O.S. Effect of dipole modifiers on the magnitude of the dipole potential of sterol-containing bilayers. Langmuir; 2012; 28, pp. 9908-9914. [DOI: https://dx.doi.org/10.1021/la301653s]
123. Ostroumova, O.S.; Efimova, S.S.; Schagina, L.V. Phloretin induced reduction in dipole potential of sterol containing bilayers. J. Membr. Biol.; 2013; 246, pp. 985-991. [DOI: https://dx.doi.org/10.1007/s00232-013-9603-2]
124. Pohl, P.; Rokitskaya, T.I.; Pohl, E.E.; Saparov, S.M. Permeation of phloretin across bilayer lipid membranes monitored by dipole potential and microelectrode measurements. Biochim. Biophys. Acta; 1997; 1323, pp. 163-172. [DOI: https://dx.doi.org/10.1016/S0005-2736(96)00185-X]
125. Efimova, S.S.; Zakharova, A.A.; Ostroumova, O.S. Alkaloids modulate the functioning of ion channels produced by antimicrobial agents via an influence on the lipid host. Front. Cell Dev. Biol.; 2020; 8, 537. [DOI: https://dx.doi.org/10.3389/fcell.2020.00537]
126. Efimova, S.S.; Ostroumova, O.S. Is the membrane lipid matrix a key target for action of pharmacologically active plant saponins?. Int. J. Mol. Sci.; 2021; 22, 3167. [DOI: https://dx.doi.org/10.3390/ijms22063167]
127. Gawrisch, K.; Ruston, D.; Zimmerberg, J.; Parsegian, V.A.; Rand, R.P.; Fuller, N. Membrane dipole potentials, hydration forces, and the ordering of water at membrane surfaces. Biophys. J.; 1992; 61, pp. 1213-1223. [DOI: https://dx.doi.org/10.1016/S0006-3495(92)81931-8]
128. Zlodeeva, P.D.; Shekunov, E.V.; Ostroumova, O.S.; Efimova, S.S. The degree of hydroxylation of phenolic rings determines the ability of flavonoids and stilbenes to inhibit calcium-mediated membrane fusion. Nutrients; 2023; 15, 1121. [DOI: https://dx.doi.org/10.3390/nu15051121]
129. Efimova, S.S.; Zakharova, A.A.; Chernyshova, D.N.; Ostroumova, O.S. The specific effect of grapefruit seed, sea-buckthorn leaves, and chaga extracts on the properties of model lipid membranes. Cell Tiss. Biol.; 2023; 17, pp. 72-80. [DOI: https://dx.doi.org/10.1134/S1990519X23010030]
130. Rokitskaya, T.I.; Antonenko, Y.N.; Kotova, E.A. Effect of the dipole potential of a bilayer lipid membrane on gramicidin channel dissociation kinetics. Biophys. J.; 1997; 73, pp. 850-854. [DOI: https://dx.doi.org/10.1016/S0006-3495(97)78117-7]
131. Rokitskaya, T.I.; Kotova, E.A.; Antonenko, Y.N. Membrane dipole potential modulates proton conductance through gramicidin channel: Movement of negative ionic defects inside the channel. Biophys. J.; 2002; 82, pp. 865-873. [DOI: https://dx.doi.org/10.1016/S0006-3495(02)75448-9] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11806928]
132. Latorre, R.; Alvarez, O. Voltage-dependent channels in planar lipid bilayer membranes. Physiol. Rev.; 1981; 61, pp. 77-150. [DOI: https://dx.doi.org/10.1152/physrev.1981.61.1.77] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/6258181]
133. Zakharova, A.A.; Efimova, S.S.; Ostroumova, O.S. Lipid microenvironment modulates the pore-forming ability of polymyxin B. Antibiotics; 2022; 11, 1445. [DOI: https://dx.doi.org/10.3390/antibiotics11101445]
134. Chernyshova, D.N.; Tyulin, A.A.; Ostroumova, O.S.; Efimova, S.S. Discovery of the potentiator of the pore-forming ability of lantibiotic nisin: Perspectives for anticancer therapy. Membranes; 2022; 12, 1166. [DOI: https://dx.doi.org/10.3390/membranes12111166]
135. Ostroumova, O.S.; Efimova, S.S.; Schagina, L.V. Probing amphotericin B single channel activity by membrane dipole modifiers. PLoS ONE.; 2012; 7, e30261. [DOI: https://dx.doi.org/10.1371/journal.pone.0030261]
136. Finkelstein, A.; Andersen, O.S. The gramicidin A channel: A review of its permeability characteristics with special reference to the single-file aspect of transport. J. Membr. Biol.; 1981; 59, pp. 155-171. [DOI: https://dx.doi.org/10.1007/BF01875422]
137. Kelkar, D.A.; Chattopadhyay, A. The gramicidin ion channel: A model membrane protein. Biochim. Biophys. Acta; 2007; 1768, pp. 2011-2025. [DOI: https://dx.doi.org/10.1016/j.bbamem.2007.05.011]
138. Andersen, O.S.; Koeppe, R.E., 2nd. Molecular determinants of channel function. Physiol. Rev.; 1992; 72, (Suppl. 4), pp. S89-S158. [DOI: https://dx.doi.org/10.1152/physrev.1992.72.suppl_4.S89] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/1279736]
139. Malev, V.V.; Schagina, L.V.; Gurnev, P.A.; Takemoto, J.Y.; Nestorovich, E.M.; Bezrukov, S.M. Syringomycin E channel: A lipidic pore stabilized by lipopeptide?. Biophys. J.; 2002; 82, pp. 1985-1994. [DOI: https://dx.doi.org/10.1016/S0006-3495(02)75547-1] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11916856]
140. Ostroumova, O.S.; Gurnev, P.A.; Schagina, L.V.; Bezrukov, S.M. Asymmetry of syringomycin E channel studied by polymer partitioning. FEBS Lett.; 2007; 581, pp. 804-808. [DOI: https://dx.doi.org/10.1016/j.febslet.2007.01.063] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17289034]
141. Andreoli, T. The structure and function of amphotericin B cholesterol pores in lipid bilyer membranes. Ann. N. Y. Acad. Sci.; 1974; 235, pp. 448-468. [DOI: https://dx.doi.org/10.1111/j.1749-6632.1974.tb43283.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/4528067]
142. Marty, A.; Finkelstein, A. Pores formed in lipid bilayer membranes by nystatin, Differences in its one-sided and two-sided action. J. Gen. Physiol.; 1975; 65, pp. 515-526. [DOI: https://dx.doi.org/10.1085/jgp.65.4.515]
143. Borisova, M.P.; Brutyan, R.A.; Ermishkin, L.N. Mechanism of anion-cation selectivity of amphotericin B channels. J. Membr. Biol.; 1986; 90, pp. 13-20. [DOI: https://dx.doi.org/10.1007/BF01869681]
144. Jordan, P.C. Electrostatic modeling of ion pores. II. Effects attributable to the membrane dipole potential. Biophys. J.; 1983; 41, pp. 189-195. [DOI: https://dx.doi.org/10.1016/S0006-3495(83)84419-1]
145. Ostroumova, O.S.; Shchagina, L.V.; Malev, V.V. The effect of dipole potential of lipid bilayers on the properties of ion channels formed by cyclic lipodepsipeptide syringomycin E. Biochem. (Moscow) Suppl. Ser. A Membr. Cell Biol.; 2008; 2, pp. 259-270. [DOI: https://dx.doi.org/10.1134/S1990747808030100]
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Abstract
Phytochemicals, such as flavonoids, stilbenoids, alkaloids, terpenoids, and related compounds, have a wide range of useful pharmacological properties which cannot be ascribed to binding to a single peptide or protein target alone. Due to the relatively high lipophilicity of phytochemicals, the lipid membrane is thought to mediate their effects via changes in the properties of the lipid matrix, in particular, by modulating the transmembrane distribution of the electrical potential and, consequently, the formation and functioning of the ion channels reconstituted in the lipid bilayers. Therefore, biophysical studies on the interactions between plant metabolites and model lipid membranes are still of interest. This review represents an attempt to provide a critical analysis of a variety of studies on altering membranes and ion channels with phytochemicals via disturbing the potential drop at the membrane–aqueous solution interface. Critical structural motifs and functioning groups in the molecules of plant polyphenols (alkaloids and saponins are identified) and the possible mechanisms of dipole potential modulation with phytochemicals are discussed.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer