Since in 1820, Widmark discovered the role played by sunlight in skin burns, it has been working on various strategies that can minimize the harmful effect of solar radiation on humans. Since then, the damage caused to living beings by exposure to ultraviolet radiation (UVR) has been studied, which has led to a desire to develop increasingly effective and safe substances that evolve the history of sunscreens (Urbach, 2001). The effects of UVR on the skin are diverse, and depend mainly on the duration of the exposure and the wavelength. In this sense, one of the acute effects of the UVR on the skin, specifically the UVB (290–320 nm), consists in sunburn (erythema), which if severe enough, can produce blisters and destruction of the superficial layers of the skin, with secondary infection and systemic effects, similar to a first- or second-degree heat burn. Furthermore, UVA radiation (320–400 nm) produces tanning, thickening of the stratum corneum, epidermis, and dermis, local and systemic immunosuppression, photokeratitis, and photoconjunctivitis, among others. In addition, the chronic changes due to UVR produce photoaging, induction of pre-malignant changes and malignant skin tumors, and so on (Kuchel et al., 2003; Samaniego et al., 2017).
Therefore, to prevent the effects of UVR exposure, topical sunscreens have been developed, with active ingredients that absorb or scatter radiation in the harmful UV range (wavelengths of 290–400 nm) that reaches the earth's surface (Food and Drug Administration, 2012). In addition, these compounds must have attributes, such as photostability greater than 80% and must not penetrate the skin where they may cause adverse effects. Commercial sunscreens contain chemical filters (organic substances, which absorb UVA and UVB radiation) or physical filters (inorganic substances, which reflect or disperse UVA and UVB radiation) and mostly present a combination of both (Schalka and Reis, 2011; Serpone et al., 2007).
In this regard, several studies have demonstrated that plant extracts have various biological properties, such as antioxidant, anti-inflammatory, immunomodulatory, antimutagenic, and photoprotective, which have been justified by the presence of polyphenolic compounds (De Oliveira-Júnior et al., 2017; Greul et al., 2002). Polyphenols are important compounds in plants, which constitute a wide variety of secondary metabolites that include flavonoids, phenolic acids, tannins, lignans and coumarins, among others (Costa et al., 2015; Dai and Mumper, 2010). Then, based on their chemical structure, phenolic compounds act as scavenger of reactive oxygen species (ROS), which are produced in excess under oxidative stress. In addition, polyphenols play an important role as sunscreens and protect plants against high exposure to UVR (Agati et al., 2013; Agati and Tattini, 2010; Bendová et al., 2007; Jansen et al., 1998).
Within the phenolic compounds, the flavonoids constitute a large and diverse group of secondary metabolites in the plants, with their basic structure of C6–C3–C6 ring represented, mainly by the glycosides of quercetin and kaempferol, which accumulate in the plants in the which fulfill a large number of functions (Agati et al., 2013; Gitelson et al., 2017; Harborne and Williams, 2000). Thereby, flavonoids perform a determining role mainly as a defense mechanism against the harmful effects of UVR in plants, and consequently improve the photosynthetic resistance against UVA and UVB radiation from solar spectrum. In addition, as mentioned, they act as free radical scavengers, with characteristics that could benefit current sunscreens, with a summing or synergic effect on their photoprotective potential (Agati et al., 2011; 2013; Nagula and Wairkar, 2019). Consequently, this review aims to determine the role of quercetin and kaempferol in photoprotection, analyzing the studies carried out in plant extracts during the last 20 years. The main objective was to analyze relevant information where the aglycone form of such polyphenols is studied and their role in terms of photoprotection and photostability with application in humans, in comparison to their corresponding glycosides.
MATERIALS AND METHODS
This systematic review included the articles from three databases: Pubmed, Science Direct, and Embase, since 1998 to the end of October 2018.
According to the research question, three main themes were identified: “skin,, “photoprotection,” and “polyphenols”; the latter were specified as “rutin,” “quercetin,” and “kaempferol”; also included are the terms “glycosides OR glucosides,” “hydrolysis of glycosides OR glucosides,” and the keywords “photoprotection OR fotoprotector” are used to formulate a search strategy that is applied in all the searches on the databases. Further relevant studies were identified through manual searches of reference lists. Studies have been first screened by title, then by abstract, and finally by reading of the full text.
Inclusion and exclusion criteria
Besides the search terms, articles were selected based on certain inclusion and exclusion criteria. The first one, peer reviewed journal articles were being included, whereas reviews, editorial material, meeting abstracts, letters, retracted publications, and book chapters were excluded. To be incorporated, the studies had to explore and assess at least one type of polyphenol or plant extract where photoprotection to be evaluated with application in humans. The language of the articles included was only English.
The quality of the studies selected was assessed in a systematic form. The quality score is composed of five items, and each item is allocated 0, 1, or 2 points for each category: quantification of flavonoids or polyphenols, characterization of extracts, photoprotection tests in vitro, ex vivo, and in vivo, in humans or animals. In total, each study can be awarded a maximum of 10 points.
Parameters evaluation of quality
Test of polyphenols and flavonoids
- If no polyphenols or flavonoids quantification test is performed: 0 points
- If a test of quantification of polyphenols or flavonoids is carried out: 1 point
- If polyphenols and flavonoids are quantified: 2 points
Chemical characterization of molecules of interest
- If the polyphenols are not characterized: 0 points
- If at least one specific molecule of interest is characterized: 1 point
- If they characterize or work with more than one molecule of our interest (rutin, quercetin, kaempferol): 2 points
Photoprotection tests in vitro
- If in vitro photoprotection tests are not carried out: 0 points
- If in vitro photoprotection tests are carried out: 1 point
- If in vitro photoprotection and photostability tests are carried out: 2 points
Photoprotection tests ex vivo
- If ex vivo photoprotection tests are not carried out: 0 points
- If ex vivo photoprotection tests are carried out: 1 point
- If ex vivo photoprotection and cytotoxicity or dermotoxicity tests are carried out: 2 points
Photoprotection tests in vivo in humans or animals
- If in vivo photoprotection tests are not carried out in humans or animals: 0 points
- If in vivo photoprotection tests are carried out on animals: 1 point
- If in vivo photoprotection tests are carried out in humans: 2 points
High: 8–10 points
Average: 4–7 points
Low: 0–3 points
The quantitative and qualitative data were extracted from all the included publications: authors, year of publication, country of origin, information about the objectives, and main findings of each study. The analysis of the information was carried out by three experts in the subject, who evaluated the reproducibility and the risk of bias in each phase of the review.
Selection of studies
The search of the information in databases resulted in the identification of a total of 1,230 records (research papers that met the selection criteria) from the initial searches, the reference lists and the elimination of duplicate records. After the exhaustive selection of the studies, 21 final studies were included. Figure 1 shows the flowchart of the present study with the inclusion and exclusion criteria. All studies were in the English language and were published between January 1998 and October 2018.
Characteristics of the studies
Among the articles included and analyzed, 13 of them evaluated the photoprotective effect of the plant extracts (Aquino et al., 2002; Bonina et al., 2002; 2000; Costa et al., 2015; De Oliveira-Júnior et al., 2017; Gajardo et al., 2016; Mejía-Giraldo et al., 2015; 2016a; 2016b; Puertas-mejía et al., 2015; Reis Mansur et al., 2016; Silva et al., 2016; Velasco et al., 2008), one study evaluated polyphenols in an agroindustrial waste (Mandalari et al., 2013), and seven of the studies evaluated rutin and quercetin pure in photoprotective formulations (De Oliveira et al., 2015; Graziola et al., 2016; Kamel and Mostafa, 2015; Kostyuk et al., 2018; Peres et al., 2015; Tomazelli et al., 2018; Vicentini et al., 2010). For the analysis of polyphenols, tests were carried out as total polyphenol content (TPC) or flavonoid content, antioxidant capacity by different methods, and in plant extracts their main compounds were chemically characterized. In addition, different in vitro, ex vivo, and in vivo photoprotection and photostability tests were carried out. Table 1 describes the main characteristics of each study, including the year of implementation, country, objectives, polyphenols, and the species of the plant used.
Results of individual studies
All studies promote the photoprotective capacity of polyphenols. A common denominator was the incorporation of these polyphenols into cosmetic formulations for the tests of interest, in which their effect was compared with antioxidants, UV filters, and polyphenols, such as quercetin and rutin or their additive; evaluating its possible applicability as sunscreens. Table 2 describes the main findings of the individually studies.
|Figure 1. Flowchart of selection of studies.|
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|Table 1. Summary of the main characteristics of the studies evaluated.|
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Evaluation of the quality of the studies
The evaluation of the quality of each study based on the inclusion and exclusion criteria was indicated in Table 3, according to the selected characteristics. The total average score was 4.6 ± 1.2. Thus, for articles where extracts were analyzed, an average quality of 4.5 ± 1.3 was presented and for studies evaluating specific polyphenols, such as rutin, quercetin, or kaempferol, an average quality of 4.9 ± 1.0 was found. Although it is not an excellent quality, in relation to the parameters defined by our self, these results indicated a sufficient level of quality to examine the conclusions in a valid way.
Summary of results
The main objective of the research was to carry out a systematic review of the evidence about the effect of hydrolyzed polyphenols, such as quercetin and kaempferol, on photoprotection and photostability, determining if they are better or not regarding these characteristics in comparison to their glycosides. It should be noted that none of the articles evaluated could find an analysis that may solve the propose question. However, in the research described by Kostyuk et al. (2018), the rutin is compared with its respective aglycone quercetin, finding better values for quercetin in some of analyzes carried out (Kostyuk et al., 2018). Nevertheless, all the analyzed papers showed that the photoprotective effect of plant extracts rich in polyphenols, especially flavonoids and their additive and synergistic effects when mixed with commercial sunscreens improve significantly the SPF and photostability of these formulations (Peres et al., 2015; Tomazelli et al., 2018).
Explanation of the results
Previous studies have proven that the photoprotective capacity of vegetable extracts is due to the presence of polyphenols, and especially flavonoids, such as rutin, quercetin, kaempferol, among others (Aquino et al., 2002; Costa et al., 2015; Gajardo et al., 2016; Mejía-Giraldo et al., 2016b; Silva et al., 2016). In addition, some authors have demonstrated that polyphenols could avoid the damage induced by the UVR, through mechanisms, such as capture and inactivation of ROS. It also increases its photostability, due to an additive effect produced by high polyphenolic antioxidant capacity and a co-active effect, so that antioxidants do not absorb radiation (Greul et al., 2002).
De Oliveira-Junior et al. (2017) found that after incorporation of Nv-HA (Hydro Alcoholic extract of Neoglaziovia variegata) into O/W emulsions, no photoprotective activity was presented for concentrations at 5.0% of Nv-HA (SPF = 0.008 ± 0.013) and 10.0% (SPF = 0.059 ± 0.057). However, the extracts were able to maximize the protective effect of the formulations that contained synthetic filters (5.43 ± 0.07 and 11.73 ± 0.04) extract concentrations of 0.5 and 1.0 % (v/v), respectively in a dose-response behavior. When compared to quercetin (SPF = 2.45 ± 0.13) and benzophenone-3 (SPF = 5.10 ± 0.15), the Nv-HA extract at 1.0%, showed the highest photoprotective effect. Likewise, the results propose that Nv-HA extract may be utilized as a coadjuvant or booster of chemical filters when added in a cosmetic sunscreen, reducing the necessary amount of synthetic filters, and therefore, lowering the risks of phototoxic reactions without affecting the photoprotective property of the formulation (De Oliveira-Júnior et al., 2017).
In addition, the molecules that prevent skin erythema produced by exposure to UVB, such as antioxidant and anti-inflammatory molecules, could significantly improve the UV protection of sunscreens, as demonstrated by Tomazelli et al. (2018) with the results of the in vivo SPF test, in which the formulation containing rutin, enhance the SPF by approximately 70%, compared to the rutin free formulation in a mixture with the UV filters (butylmethoxydibenzoylmethane and octyl dimethyl). This fact is evidence of the improvement in photoprotection efficiency, even at low concentration, decreasing significantly the formation of erythema, effects associated probably to its anti-inflammatory activity (Peres et al., 2015; Tomazelli et al., 2018). Similarly, the use of plant extracts mixed with chemical or physical sunscreens has shown that it can protect the skin more effectively against UV rays by preserving skin matrix damage against oxidative stress, and synergistically increasing the SPF of single filter formulations (De Oliveira-Júnior et al., 2017). Thus, Aquino et al. (2002) demonstrated that the beneficial photoprotective effect of the extract of Culcitium reflexum, which could be related to its antioxidant activity in vitro and, in turn, to the content of biophenols, where the EIP (Erythema Inhibition Percentage) was 43.5 compared to 21.7 of the TOC (Tocopheryl Acetate) a recognized antioxidant agent (Aquino et al., 2002).
|Table 2. Individual main findings.|
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On the other hand, in the study described by Kostyuk et al. (2018) compares the photoprotective effect of quercetin and rutin. There, an SPF of 5.71 ± 0.12 and a UVA/UVB ratio of 1.5 were found for quercetin (10 %), while the values for the rutin (10%) were SPF of 3.44 ± 0.16 and UVA/UVB of 1.2, which demonstrated the predominant absorption of quercetin in the UVA region. In addition, the photostability of both polyphenols was analyzed, finding the SPF of the rutin stable (SPF= 5.25 ± 0.13) against UV irradiation (66 % UVA and 33 % UVB) of 0–6.0 J/cm2, while the quercetin passed from an SPF of 4.31 ± 0.10 to 3.16 ± 0.20 under the same conditions, demonstrating the photostability of the rutin (Kostyuk et al., 2018). This case is the only one that could be conclusive with respect to the research question, but because it is a single study and it is also not specific regarding the research topic, it could not be conclusive to answer the objective question of this review.
|Table 3. Quality criteria.|
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Finally, the analysis of this review showed us that there remains a broad field of research in terms of the photoprotective capacity of natural products and their applications in cosmetic formulations, and how it can support the evolution of sunscreens and to correct their possible adverse effects, through an improvement in their effectiveness, safety and photostability, which could be attributed to natural products modified with safe, affordable, and economical procedures.
This review attempted to systematically analyze the current evidence on the photoprotective effects of glycosylated polyphenols and aglycones. A total of 21 studies were included in this review, which 13 of them evaluated plant extracts, one article studied an industrial waste and seven analyzed rutin and quercetin in cosmetic formulations. The results and analysis of the scientific literature suggest that the studies included in this review provide evidence of the protective effect of natural products. However, there are no specific investigations that can determine whether hydrolyzed polyphenols, such as quercetin and kaempferol, could improve the photoprotective effect and photostability with respect to their glycosides, which leaves a gap in this field of phytochemical research.
The authors acknowledge CODI-Universidad de Antioquia (Project No. CIQF 290) for financial support. Monsalve, Y.A., acknowledges master fellowship granted by SAPIENCIA-Alcaldía de Medellín. The authors would like to thank the International Passages Support Fund—Universidad de Antioquia.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest amongst them or with the parent institution.
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