3.5. Chemical composition of PGE
3.5.1. HPLC analysis. Twenty typical PGE chromatograms with good quality-control lots, obtained through HPLC analysis, are shown in Fig. 7A. Nineteen PGE peaks were identified from the HPLC fingerprint. Eight peaks of PGE, including arbutin (no. 1), syringin (no. 3), chlorogenic acid (no. 4), glycoside E (no. 6), platycodin D3 (no. 8), baicalin (no. 12), platycodin D (no.14), and luteolin (no. 18), were identified through comparison with corresponding reference standards (Fig. 7). The relative contents of individual components in the eight peaks of PGE are presented in Table 4.
According to relevant studies,cistanche is a common herb that is known as "the miracle herb that prolongs life". Its main component is cistanoside, which has various effects such as antioxidant, anti-inflammatory, and immune function promotion. The mechanism between cistanche and skin whitening lies in the antioxidant effect of cistanche glycosides. Melanin in human skin is produced by the oxidation of tyrosine catalyzed by tyrosinase, and the oxidation reaction requires the participation of oxygen, so the oxygen-free radicals in the body become an important factor affecting melanin production. Cistanche contains cistanoside, which is an antioxidant and can reduce the generation of free radicals in the body, thus inhibiting melanin production.
For more info:
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3.5.2. HPLC-MS analysis. The chemical composition of PGE was analyzed via HPLC-MS (Fig. 8). The molecular ion peaks [M - H]― and [M + H]+ of each chromatographic peak in the positive- and negative-ion modes were detected via ultrahigh-performance liquid chromatography coupled with electrospray ionization-quadrupole time-of-flight-mass spectrometry, and the possible molecular weight was determined through the molecular ion peak. The different components were determined based on their specific molecular ions and fragment ions and their chromatographic peak retention time. Moreover, 45 compounds in PGE were preliminarily identified (see Table 5), mainly including chlorogenic acid, arbutin, baicalin, platycodin D3, platycodin D, and glycoside E, with peak times of 0.91, 1.68, 8.39, 14.39, 16.79, and 23.75 min, respectively.
4. Discussion
Reactive oxygen species are a major cause of harmful skin conditions and can lead to irregular pigmentation, connective tissue degeneration, inflammatory reactions, and, in extreme cases, mutations.29 Through research confirmation, the oxygen-free radical that ultraviolet ray induces can promote tyrosinase expression, causing an increase in melanin generation.30 The increase in the number of free radicals in the skin is one of the important causes of skin aging; this increase not only damages the biological membrane but can also lead to the release of some hydrolytic enzymes from cells, the production of skin collagen fibers, the crosslinking of elastic fibers, brittleness, degeneration, elasticity loss, the thickening of the skin cutin layer, skin roughness, relaxation, and wrinkle formation.31 Therefore, the natural antioxidant substances contained in traditional Chinese medicine can capture and neutralize oxygen free radicals, thus preventing the damage caused by oxygen free radicals to the human body; delaying skin aging; maintaining skin elasticity and smoothness; improving skin condition and skin tone; and induce skin whitening.32 This study proves that when the PGE concentration was 6.25 mg mL―1, the scavenging rate of DPPH free radicals was 98.03 ± 0.60%, and the activity of ascorbic acid was almost the same; moreover, the ABTS radical showed strong scavenging activity (84.30 ± 0.53%), which was higher than that of the platycodin D control group. The results show that PGE had strong antioxidant activity, could reduce the generation of oxygen free radicals and oxidation reaction, weaken the tyrosinase activity, reduce melanin generation, delay skin aging, and whiten and protect the skin.
The inflammatory response is a biological process mediated by a complex cellular signaling system, and it is an important part of the body's defense mechanism against harmful stimuli (bacteria, irritants, and cell mediators). The excessive inflammatory response can lead to local blood circulation disorder, fever, parenchymal cell degeneration, necrosis, and organ dysfunction. In addition, individual components in cosmetics may promote the inflammatory response of sensitive skin; therefore, an anti-inflammatory function is the main requirement for cosmeceuticals to combat inflammatory responses.33 The key mediators of inflammation include NO, TNF-a, and IL-6. Evaluating the ability of samples to reduce NO, TNF-a, and IL-6 production in RAW264.7 macrophage is a key experimental method to measure the anti-inflammatory activity of substances.34 The results showed that PGE could reduce the NO level in primitive cells in a dose-dependent manner and down-regulate the TNF-a, IL-6, and other pro-inflammatory factors of RAW264.7 macrophage stimulated by LPS. This experiment proves that PGE has a good anti-inflammatory effect, which can reduce the damage caused by inflammation, delay skin aging, keep skin elastic and smooth, and effectively play the role of cooperative whitening.
Skin pigmentation is mainly related to melanin production, and tyrosinase is the key enzyme to catalyze melanin biosynthesis.35 Under the action of tyrosinase, the tyrosine in melanocytes is oxidized into dopa, dopa quinone, dopa pigment, 5,6-dihydroxy indole, indole-5, and 6-quinone, and finally converted into melanin.15 Therefore, when the tyrosinase activity is limited, melanin production is also limited, thus making the skin whiter or reducing hyperpigmentation.36 In this study, the melanin generation inhibition potential of PGE was first studied to determine whether the PGE could directly inhibit the tyrosinase activity in a cell-free assay system using mushroom tyrosinase as the enzyme source.37 The results show that the PGE had a strong inhibitory effect on tyrosinase, and the tyrosinase inhibitory activity of PGE increased significantly with the increase in the PGE concentration. The inhibitory rate (97.71 ±1.886%) was higher than that of the positive control group (arbutin and platycodin D) under the same concentration when the extract concentration was 3 mg mL―1. Next, we evaluated whether PGE could exert a skin-whitening effect by inhibiting tyrosinase activity and melanin production in B16F10 melanoma cells. We used a-MSH (a-MSH binds MC1R and activates the signaling protein adenylate cyclase to increase the production of cyclic adenylate and promote tyrosinase expression) to induce B16F10 cells to activate intracellular tyrosinase activity and produce a large amount of melanin. Then arbutin and platycodin D were used as positive controls to evaluate the inhibitory effect of PGE on intracellular tyrosinase and cellular melanin generation. The results showed that with the increase in the PGE concentration, the inhibitory activities of tyrosinase and melanin production on B16F10 cells significantly increased in a dose-dependent manner. With the increase in the administration time, the inhibitory activity of PGE on B16F10 cells tyrosinase and melanin production gradually increased. Moreover, PGE showed the strongest intracellular tyrosinase inhibitory activity (inhibition rate: 106.33±3.145%) and melanin generation inhibitory activity (inhibition rate: 59.80 ± 1.095%) after 48 h of administration. When the administration time was 72 h, the activity was lower than that under 48 h, indicating that the optimal PGE administration time was 48 h. The inhibitory activity of intracellular tyrosinase of PGE was significantly higher than those of arbutin and platycodin D control groups, demonstrating the excellent skin whitening activity of PGE.
The experimental results showed that the extraction rate of PGE in Platycodon grandiflorum was 8.9%, and the morphology was characterized as a milky amorphous powder with good solubility. Our research group has prepared a whitening cream with PGE as an active ingredient, in which the content of PGE is 2%. At the same time, we conducted a human pre-experiment to study the whitening effect of whitening creams. 1–2 mL whitening cream (containing 0.02–0.04 g PGE, containing 0.22–0.45 g Platycodon grandiflorum) was applied to the forearm every day. We used the PRIMOS system, Lab colorimetric system, and spectrophotometer® CM-2500d (Konica Minolta, Inc., Osaka, Japan) to analyze the skin color of the forearm of the subjects. The pre-experiment results showed that the whitening cream containing 2% PGE had a good whitening effect and no skin irritation.
In this experiment, 19 common peaks were determined via HPLC combined with similarity analysis. By comparing the retention times of chromatographic charts of mixed standard substances, eight chromatographic peaks were identified and quantitatively analyzed. HPLC combined with mass spectrometry was used to identify and analyze specific chemical components in PGE and 45 compounds in PGE were identified. By comparing the results with the experimental results of HPLC, we identified a variety of chemical components, which had different degrees of antioxidant properties, anti-inflammatory properties, anti-cancer properties, enzyme inhibition, and immune regulation. The chemical components mainly included arbutin, syringin, chlorogenic acid, glycoside E, platycodin D3, baicalin, platycodin D, and luteolin. Moreover, arbutin can increase the activity of the superoxide dismutase (SOD) enzyme in local skin tissue, reduce tyrosine and MDA contents, and exert a good therapeutic effect on chloasma model mice. As a new whitening ingredient, arbutin has been favored by cosmetics manufacturers and consumers.38–40 Syringin has a strong antioxidant capacity and shows a strong application potential in DPPH and DMPD free-radical inhibitory activity, ferric ion-reducing antioxidant power (FRAP), and metal chelating ability.41 Chlorogenic acid, the main active component of Onosma, has strong antioxidant and inhibitory activities against tyrosinase and a-amylase.42 Platycodin D has strong tyrosinase inhibitory activity and can be used as a whitening and skin-care component; thus, it is worth developing and utilizing.43 Baicalin is widely used in the preparation of whitening creams and sunscreens owing to its inhibitory effects on melanin production and antibacterial activity.44–46 Luteolin extracted from rose has strong antioxidant activity and tyrosinase inhibition and antibacterial effects, making it useful as natural raw material for skin care.47 Our research group isolated PGE via preparative HPLC and column chromatographic fractionation to obtain 14 compounds. The structures of all compounds were elucidated through spectroscopic methods. The compounds are saponins: platycodin D, platycodin D3, and glycoside E; glycosides: arbutin and syringin; acids: chlorogenic acid, and nicotinic acid; flavonoids: baicalin, luteolin, daidzein, quercetin, and diosmetin; amides: erucamide and docosanamide. The results of the tyrosinase experiment showed that saponins and glycosides had strong tyrosinase inhibitory activities, among which arbutin (inhibition rate: 96.54 ± 1.585%) and platycodin D (inhibition rate: 80.96 ± 1.978%) had the strongest inhibitory activities. Acids and flavonoids had the second-strongest tyrosinase inhibitory activity, among which chlorogenic acid (inhibition rate: 75.64 ± 0.978%) and luteolin (inhibition rate: 70.91 ± 2.054%) had the strongest activity. Amides had no tyrosinase inhibitory activity. Compared with the above compounds, PGE had a stronger tyrosinase inhibitory activity (inhibition rate: 97.82 ± 2.058%). Therefore, the skin whitening activity of PGE comprises the multi-component and multi-target effect of traditional Chinese medicine, and the biological whitening activity of PGE should be the result of the combined action of multiple components.
5. Conclusions
Good antioxidant and anti-inflammatory effects can inhibit the activation of oxygen free radicals on tyrosinase and reduce melanin production. Moreover, they can reduce the damage caused by oxidation and inflammation of the skin, delay skin aging, keep the skin elastic and smooth, and effectively exert a synergistic whitening effect. The good inhibition of tyrosinase and melanin production can reduce melanin production and pigmentation in the skin and result in skin whitening. In this study, the whitening activity mechanism and pharmacodynamic material basis of PGE were determined through molecular biology and cell biology. Moreover, PGE could effectively inhibit tyrosinase activity, reducing the excessive melanin in the skin and relieving skin damage caused by oxidation and inflammation; further, the whitening active extract could significantly inhibit tyrosinase activity and the activity of B16F10 cells without potential toxic effects. Given the results, PGE has wide application potential for manufacturing whitening skin-care cosmetics. Based on the literature, cosmetics prepared from Platycodon grandiflorum and its extract have a good whitening effect on the human body. Therefore, as a whitening active substance extracted from natural Chinese herbal medicine, PGE can be used as raw materials for whitening and skin care.
Author contributions
M. M. Y. and G. Z. L conceived and designed the experiments. X. T. M., R. R. Z., and M. W performed the experiments. X. T. M., Z. H. Y., and F. Q. X analyzed the data. X. T. M. and S. S wrote the paper. All of the authors have read and agreed to the final version of the manuscript.
Conflicts of interest
There are no conflicts to declare.
Acknowledgments
This study was supported by grants from the National Key Research and Development Program: Research on Key Technologies of Ginseng Industry and Development of Massive Health Products (2017YFC1702100); the Science and Technology Development Plan Project of Jilin Province (20180623041TC); and the Changchun Science and Technology Bureau Project: Key Technologies and Product Development of Traditional Chinese Medicine Health Food Based on Jingfang and Yanfang (17YJ007).
Notes and references
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