10.1. Use of Flavonoids in Cosmetics and Dermatology, Effects on the Skin
Phenolic acid, flavonoids, stilbenes, lignans, coumarins, and tannins are the most important polyphenols used in modern cosmetology and dermatology [61]. The antioxidant, anti-aging, anti-inflammatory, antimicrobial and anticancer properties of flavonoids are frequently deployed in skincare products. Their antiradical function, as well as the ability to inhibit the creation of enzymes and proteins, is one of their important effects. Flavonoids‟
high chemical reactivity can prevent injury caused by free radicals by the following mechanisms: direct scavenging of ROS, activation of antioxidant enzymes, chelating of metal compounds, reduction of α-tocopheryl radicals, inhibition of oxidases, reduction of oxidative stress caused by nitric oxide, increase in uric acid levels, and increase in antioxidant properties of low molecular antioxidant [58].
Flavonoids have an influence on skin microcirculation and can be used as ingredients in cream for vascular, oily and/or atopic skin [61]. Van der Waals forces, dipole-dipole and hydrogen bonding interaction, and the specific design of the compound, make them capable of reacting with other biomolecules, especially proteins. Dermal bioavailability and antioxidant activity of glycosides is lower compared to their aglycon forms, due to their low permeability [61].
Absorption of ultraviolet radiation is one of the chemical properties of flavonoids, based on the presence of the conjugated double bonds. These compounds may absorb UV radiation in the range of 240-285 nm and 300-550 nm, which is associated with the presence of the electron-donating substituents attached to the phenol rings, as well as intramolecular and intermolecular hydrogen bonds and steric effects. Polyphenol molecules can act as an exogenous chromophore or photosensitizer. After the absorption of quantum energy, they become excited and emit excess energy in the form of infrared radiation. Concentrations found in cosmetics cannot replace conventionally used synthetic UVA and UVB filters, but they can reduce erythema and skin burns caused by exposure to UVB radiation and IR rays of sunlight [61].
The anti-aging properties of flavonoids are associated with their effect on the modulation of protease activity, especially matrix metalloproteinase, which is dependent on the Zn2+ ion of enzymes involved in connective tissue remodeling.
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A significant role is in their activity, either by sequestering metal ions or the effect they have on the expression of endogenous protein tissue inhibitors of metalloproteinase [61].
Flavonoids‟ skin-whitening activity is connected with their modulation of the tyrosinase activity through their chelating ability of Cu2+ ion in the formation of L-dopaquinone, which is part of the melanogenesis process. This ability is found for quercetin, cyaniding, and kaempferol, while the glycosidic forms have not shown this capability [61].
Dr Albert Szent-Gyorgi found that citrus peel flavonoids were effective in preventing capillary bleeding, and was the first to report on the biological activity of flavonoids on capillary fragility associated with scurvy [38]. Skin circulation may be improved by phenolic compounds through their protective effect on blood vessel walls and reduction of capillary permeability, and by facilitation of the free flow of blood through capillaries as a result of platelet aggregation. Inhibition of this process is associated with chelation of Ca2+ ions necessary for the proper operation of thromboplastin, catalyzing conversion of prothrombin into thrombin, which is in turn responsible for the conversion of fibrinogen to fibrin.
Inhibition of hyaluronidase activity, the enzyme responsible for the enzymatic degradation of hyaluronic acid, which is a building block of the blood vessel wall and dermis, is one of the protective functions of the flavonoids [61].
Furthermore, they may also protect skin against exogenous, pathogenic bacteria, fungi, and viruses, inhibiting the activity of proteolytic enzymes by disturbing the synthesis of nucleic acids and increasing the permeability of the cell wall to exogenous substances.
Additionally, phenolic compounds may have antimicrobial properties and assist in the preservation of cosmetics by protecting the physicochemical form of the product against secondary infection [61].
Apigenin, catechin, rutin, quercetin, luteolin, baicalin, hesperidin, and diosmin have the ability to prevent the aggregation of platelets in clot formation [61].
10.2. Hesperidin and Hesperetin in Cosmetics Uses
Hesperidin and its aglycon hesperetin are bioflavonoids with interesting bioactive properties that remain foci of intensive research for topical application. Sulfonated or phosphorylated hesperidin derivatives are extremely potent inhibitors of hyaluronidase, and acetylated hesperidin may cause inhibitory action of ascorbic acid on hyaluronidase. It has been found that hesperidin reduces superoxide in electron transfer as well as concerted proton transfer reaction in vivo. Hesperidin might be a topical photo-protective agent, by protecting phosphatidylcholine liposomes from UV-irradiation-induced peroxidation by scavenging oxygen free radicals generated by UV irradiation. It has also been shown to be able to penetrate through the stratum corneum [38].
In vitro study has shown that hesperidin and hesperetin penetrate the skin much faster in the presence of D-limonene and lecithin [79]. Transport of active ingredients through the stratum corneum occurs through the following steps: vehicle penetration to the stratum corneum, diffusion of active ingredients, and finally penetration below the stratum corneum in the living layers of epidermis. How quickly these processes occur depends on biological factors (age, skin condition, cardiovascular function and metabolism) and also physicochemical ones, such as the partition coefficient between the stratum corneum and the vehicle, and is related to lipophilicity as well as the size and spatial structure of the molecule,
Exploring Bioactivity of Hesperidin … 59 polarity and load. In vitro studies of stratum corneum have shown that individual flavonoids exhibit differences in penetration capacity, which depend in large part on the composition of the formulation in which the compound is present. It has been proven that the penetration rate of flavonoids (rutin, quercetin, and catechin) is affected by moisturizing substances (glycerol, glycols, polyglycols, ethoxylated methylglucoside, and urea) and also by cosmetic formulation (hydrogel, emulsion, microemulsion, and micellar system), or content of the mixture in which the active ingredients occur. Water/oil microemulsion formulation significantly enhances quercetin skin penetration 12 h after application [80]. Improvement of low drug permeability through human skin implies the use of penetration enhancers (including lipophilic solvents, surfactant, fatty acids and terpens), which reversibly modify the barrier resistance of the skin. Rutin, catechin, epicatechin, and quercetin have a limited penetration. Quercetin‟s poor permeability, for example, even in the presence of the enhancers, might be explained by its absolute insolubility in water [79]. Several authors suggest that the permeability of this compound can be increased by uploaded flavonoids in liposomes or other kinds of carrier systems. It can also be affected by the presence of promoters of permeability, such as glycerin and propylene glycol [61].
In the skin, hesperidin may significantly stimulate epidermal hyperplasia and improve epidermal permeability through epidermal proliferation, osteoblasts differentiation, and lipid secretion. Different skin layers and skin proteins can respond differently to hesperidin treatment. Involucrin, present in the stratum spinosum, does not respond to hesperidin treatment. Filaggrin and loricrin (located in stratum granulosum and stratum spinosum) expression is increased. These beneficial effects of improving epidermal permeability, barrier function and regulation of filaggrin can be useful in the treatment of certain skin disorders, such as cutaneous inflammation and atopic dermatitis [81]. In vitro, hesperidin can reduce the process of melanogenesis through the inhibition of tyrosinase activity in melanocytes, or through a reduction in melanocytes proliferation. Therefore, the possibility of affecting tyrosinase activity, and the practical application thereof in the field of anti-aging preparations designed to prevent the formation of senile lentigines (lentigo senilis) and solar lentigo (lentigo solaris), makes bioflavones very interesting for skin whitening [61]. Daily topical applications of hesperidin microemulsion have shown a significant skin whitening effect, reduction of trans-epidermal water loss and inhibition of irritation effect after exposure to UV-rays after 4 weeks [82]. In this study, Kim et al. showed that hesperidin had a depigmentation effect by blocking the melanophilin, the tripartite protein complex, which is responsible for transport of the melanosome into the melanocytes. This was proven by melanosome aggregation testing in cells. The hesperidin did not inhibit melanin production in melanoma cells, but reduced skin pigmentation in reconstruction of human epidermal skin [83]. Among other things, hesperidin may affect polyoxygenase, cyclooxygenase, hyaluronidase, collagenase, elastase, and tyrosinase, and can thus contribute to the reduction of modifications in the skin under the influence of enzymes involved in connective tissue remodeling [61]. Hyaluronidase plays a significant role in regulating the permeability of capillary walls and supporting tissues by causing the breakdown of hyaluronic acid and increasing the permeability of the tissue [38]. The ability to chelate multivalent metals such as Fe3+, Fe2+, Cu2+, Zn2+ and Mn2+ (Figure 13) is as relevant to inhibition of enzymes, which contain metal ions in their reaction center or require metal cations as cofactors, as to inhibition of inflammatory processes and function of vascular vessels [61, 84].
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Figure 13. Hesperidin as a chelating agent of metal multivalent ions (Me+). The creation of the complex involves OH groups in ortho- position that coordinate with divalent cations.