Attenuation of in vitro and in vivo melanin synthesis using a Chinese herbal medicine through the inhibition of tyrosinase activity

doi:10.1016/j.phymed.2021.153876

Phytomedicine

Volume 95, January 2022, 153876

https://doi.org/10.1016/j.phymed.2021.153876 Get rights and content

Highlights

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Seven kinds of traditional Chinese herbal medicines heat-extracted solutions individually exposure in zebrafish embryos is first confirmed to safe concentration.
•
Chi-Bai-San extracts as a potential inhibitor of melanin is first investigated using both in aMSH-induced B16F10 cells and zebrafish model.
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Suppression of tyrosinase activity pathway could be a possible anti-pigment response mechanism for Chi-Bai-San extracts exposure.
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Chi-Bai-San extracts might be a potential traditional Chinese herbal medicinestarget and a plausible candidate for anti-melanogenesis components.

Abstract

Background

In traditional Chinese medicine, the skin reflects the health of body organs. A skin whitening agent, named seven whitening creams (also called Chi-Bai-San), has been used since ancient times in China. Chi-Bai-San reduces melanin and helps to reduce wrinkles.

Purpose

We aimed to determine the skin-whitening ability and safe dose of the seven compounds in Chi-Bai-San.

Study design

A common use for Chinese medicine is decocted in water. To mimic the function of Chi-Bai-San apply in clinical, we boiled all seven compound in water, respectively. These single recipe extractions and a mixture of these seven items were used in zebrafish embryo and B16F10 melanoma cell to identify the anti-melanogenesis function.

Methods

Chi-Bai-San comprises Bai-Lian (Ampelopsis japonica), Bai-Ji (Bletilla striata), Bai-Zhi (Angelica dahurica), Bai-Zhu (Atractylodes macrocephala), Bai-Shau (Paeonia lactiflora), Fu-Ling (Wolfiporia cocos), and Jen-Ju-Fen (Pearl powder). All components were extracted by heating in distilled water. The supernatant was collected after centrifugation. The extracted components were introduced into zebrafish embryos at different doses to determine the safe dose. B16F10 melanoma cells were treated with the final dose of each component and the component mixture. Melanin content and tyrosinase activity were assessed in zebrafish and B16F10 cells. Chi-Bai-San and its components were exposed to α MSH-induced B16F10 cells, and detected for mechanism of anti-melanogenesis pathway.

Results

Most compounds were not toxic at a low dose (0.1 mg/ml), except A. macrocephala, which resulted in a survival rate of only 30% at 72 hpf. The final dose of A. dahurica, P. lactiflora, W. cocos, and pearl was 1 mg/ml; that of A. japonica was 0.5 mg/ml; and that of A. macrocephala and B. striata was 0.1 mg/ml. Chi-Bai-San markedly decreased melanin content 37.47% in zebrafish embryos. Further, Chi-Bai-San abolished tyrosinase activity and MITF-mediated tyrosinase expression by down regulating the upstream transcription factors ZEB2, β-catenin, and CREB2 in α MSH-induced B16F10 cells. Additionally, Chi-Bai-San might reduce melanosome secretion from melanocytes.

Conclusion

Our findings indicate that safety and efficacy of heat-extracted Chi-Bai-San, which can reduce αMSH-induced melanin production by inhibiting the key role of melogenic-related transcription factor and promote the synergic effect of seven types of traditional Chinese herbal medicines.

Graphical abstract

Introduction

Skin whitening is desired by many individuals; however, various environmental factors might lead to ill-regulated melanin deposition and hyperpigmented macula, even melanoma, which requires therapeutic interventions. Ultraviolet radiation-induced pigment deposition has become increasingly important in cosmetic studies. Therefore, there is an urgent need to develop clinical drugs and cosmetic reagents. Natural skin whitening reagents have recently become more acceptable than chemical reagents. Further, the presence of natural reagents in a skincare formulation has become an important marketing factor. In the past, the compounds of Chi-Bai-San, a Chinese traditional herbal medicine, were found to exhibit potential whitening effects; however, the toxicity and effectiveness of the extracts of its raw materials obtained by heating have not been clarified.

Melanogenesis is defined as the process of high polymer black pigment (i.e., melanin) formation in melanosomes through a series of enzymatic and chemical processes (Qian et al., 2020). Melanosome maturation is a four-step process, including the development of a vesicle containing glycoprotein-formed fibrillar matrix (STAGE1), followed by the combination of tyrosinase and other enzymes of melanogenesis (STAGE2), which polymerizes and settles on the internal fibrils (STAGE3), and fulfills with melanin (STAGE4). Melanin in melanosomes (at STAGE3 and 4) is secreted into the epidermal microenvironment and transferred to the supranuclear melanin cap in keratinocytes (Cichorek et al., 2013). Sunlight-inducedα-melanocyte-stimulating hormone (αMSH), adrenocorticotropin (ACTH), basic fibroblast growth factor (bFGF), and endothelin (EDN1) released from keratinocytes promote micro phthalmia transcription factor (MITF)-mediated melanosome secretion from melanocytes in the skin epidermis (Nguyen and Fisher, 2019). α MSH is derived from the precursor hormone, proopiomelanocortin (POMC), through prohormone convertases (PC2). Although α MSH induces pigmentation, it is photoprotective and reduces many proinflammatory cytokines produced from epidermal and dermal cells (Serre et al., 2018). Nevertheless, many studies detailing the regulation of melanin deposits, focusing on αMSH-induced downstream signaling pathways, have been conducted. The αMSH-induced pathway has been considered the primary target for effective inhibition of melanin production.

Tyrosinase is the dominant enzyme in melanogenesis and is transcriptionally regulated by MITF. Tyrosinase in mammals is dramatically restricted. Tyrosinase uses L-tyrosine or DOPA as substrates and requires L-DOPA as a cofactor. L-tyrosine or DOPA catalyzes DOPAchrome, which is then polymerized through tyrosinase-related proteins (TRP1 and TRP2). MITF is a transcription factor that plays a central role in melanogenesis, which is transcriptionally regulated by CREB2, β-catenin, SOX10, and ZEB2 or by post-translation modification (PTM) through the EDNR/PKC and FGFR/MAPK pathways (Serre et al., 2018). α MSH binds to melanocortin 1 receptor (MC1R), which activates CREB transcriptional activity on the MITF promoter through cyclic adenosine monophosphate (cAMP). β-Catenin not only serves as a transcriptional regulator of MITF but also acts as a cofactor of MITF to transcribe downstream genes (Hocker et al., 2008). Tyrosinase activity assays have been well established in mammalian and non-mammalian organisms by analyzing the turnover of L-DOPA. Therefore, in recent years, tyrosinase has become an important therapeutic target for the development of whitening products and agents that induce depigmentation.

Chi-Bai-San is composed of seven Chinese traditional herbs that can treat many dermatologic disorders. These herbs include Bai-Lian (Ampelopsis japonica), Bai-Ji (Bletilla striata), Bai-Zhi (Angelica dahurica), Bai-Zhu (Atractylodes macrocephala), Bai-Shau (Paeonia lactiflora), Fu-Ling (Wolfiporia cocos), and Jen-Ju-Fen (Pearl powder) in China. Atractylodes macrocephala was reported to exert anti-inflammatory activity, which inhibits allergic eczematous contact dermatitis. Extraction from Ampelopsis japonica and Paeonia lactiflora abolished TGFβ-induced inflammation in keratinocytes. Moreover, the function of wound healing exhibited by Ampelopsis japonica and Bletilla striata has been applied in scald repair (He et al., 2017). Ampelopsis japonica, Paeonia lactiflora, and Wolfiporia cocos have also been demonstrated to reduce melanin content by eliminating the activity of tyrosinase (Adki and Kulkarni, 2020; Ohbayashi and Fukuda, 2020). To our knowledge, the present study is the first to analyze the safety and anti-melanogenesis during the heat-extraction of Chi-Bai-San.

The mechanism of melanin inhibition by the Chi-Bai-San extraction mixture is still unknown. The aim of this study was to clarify the safe dosage for Chi-Bai-San extraction and the related anti-melanogenesis pathway. We used seven Chinese traditional herbs and their mixture to illustrate their applicability as skin-whitening agents. The results demonstrated that Chi-Bai-San effectively reduced tyrosinase-mediated melanin synthesis in B16F10 cells and zebrafish. We found that Chi-Bai-San reduced tyrosinase protein expression and enzyme activity. Chi-Bai-San not only reduced the dominant transcription factor of TYR (known as MITF), but also ZEB2, SOX10, CREB, and β-catenin, which are the upstream transcription factors of MITF. Additionally, we explored the biological mechanisms and pathways mediated by Chi-Bai-San to inhibit melanogenesis. Overall, this study provides important in vitro and in vivo information regarding the heat extraction of components from Chi-Bai-San for the development of clinical drugs or cosmetic reagent materials.

Section snippets

Chi-Bai-San extraction

The seven types of traditional Chinese herbal medicines, known as Bai-Lian (Ampelopsis japonica), Bai-Ji (Bletilla striata), Bai-Zhi (Angelica dahurica), Bai-Zhu (Atractylodes macrocephala), Bai-Shau (Paeonia lactiflora), Fu-Ling (Wolfi poriacocos), and Jen-Ju-Fen (Pearl powder) were purchased from source information list in Table 4. Images of the original materials are included in (Supplementary materials Fig. 1A–H). The components were ground roughly, and 200 mg was extracted by heating (95

The survival and hatching rates of zebrafish embryos treated with different concentrations of each heat-extracted solution

To determine the safe dose for the seven types of heat-extracted solutions, we recorded the survival and hatching rates of zebrafish embryos. After spawning for 12-16 hpf, A. japonica (0.1, 0.5, 1, 5, and 25 mg/ml), B. striata (0.1, 0.5, and 1 mg/ml), Pearl powder (0.1, 0.5, and 1 mg/ml), A. dahurica (0.1, 0.5, 1, 5, 10 mg/ml), A. macrocephala (0.1, 0.5, and 1 mg/ml), W. cocos (0.1, 0.5, 1, 5, and 25 mg/ml), and P. lactiflora (0.1, 0.5, and 1 mg/ml), respectively. Phenylthiourea (PTU) (30

Discussion

Chi-Bai San is the Chinese herbal medicine formula, mainly comprises Atractylodes macrocephala, Paeonia lactiflora, Bletilla striata, Wolfiporia cocos, Ampelopsis japonica, Angelica dahurica and pearl powder (Hu et al., 2020b) . Natural herb extracts that impart skin whitening effects are increasingly being considered in cosmetic products. However, many skin whitening agents are associated with side effects, such as contact dermatitis (Oiso et al., 2017; Victoria-Martínez and

Conclusion

In summary, we demonstrated that Chi-Bai-San could down-regulate melanogenesis in αMSH-induced B16F10 mouse melanoma cells and a zebrafish animal model. Collectively, our results demonstrate the potent anti-melanogenic effect of Chi-Bai-San via inhibition of CREB, ZEB2, β-catenin, and MITF/tyrosinase signaling pathways. Our findings strongly imply that Chi-Bai-San can be developed as a herbal medicine for skin whitening or other types of hyper-pigmentation diseases treatment through targeting

CRediT authorship contribution statement

Shu-Chun Liu: Conceptualization, Resources, Funding acquisition. Meei-Ling Sheu: Conceptualization, Writing – original draft. Yi-Ching Tsai: Formal analysis, Investigation. Yu-Chin Lin: Methodology, Software. Ching-Wen Chang: Conceptualization, Resources, Methodology. De-Wei Lai: Conceptualization, Data curation, Funding acquisition, Supervision, Project administration, Writing – review & editing.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgments

This work was supported research grants from Chang Bing Show Chwan Memorial Hospital (BRD-109014, BRD-108024), and the Ministry of Science and Technology, Taiwan, R.O.C. (MOST 109-2314-B-758-002). We also thank the core facility, animal center of Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan; National Cheng Kung University; and Taiwan Animal Consortium for their technical support in the Zebrafish Core Facility.

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¹: This authors contributed equally to first author.

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Attenuation of in vitro and in vivo melanin synthesis using a Chinese herbal medicine through the inhibition of tyrosinase activity

Highlights

Abstract

Background

Purpose

Study design

Methods

Results

Conclusion

Graphical abstract

Introduction

Section snippets

Chi-Bai-San extraction

The survival and hatching rates of zebrafish embryos treated with different concentrations of each heat-extracted solution

Discussion

Conclusion

CRediT authorship contribution statement

Declaration of Competing Interest

Acknowledgments

Life Sci.

J. Ethnopharmacol.

J. Invest. Dermatol.

Fitoterapia

J. Biosci. Bioeng.

J. Ethnopharmacol.

Involvement of pigment globules containing multiple melanosomes in the transfer of melanosomes from melanocytes to keratinocytes

Cell Logist.

Nitric oxide synthase induction in astroglial cell cultures: effect on heat shock protein 70 synthesis and oxidant/antioxidant balance

J. Neurosci. Res.

Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders

Antioxid. Redox Signal.

Heterogeneity of neural crest-derived melanocytes

Open Life Sci.

Heat shock proteins and hormesis in the diagnosis and treatment of neurodegenerative diseases

Immun. Ageing.

Poria cocos (Fuling) targets TGFβ/Smad7 associated collagen accumulation and enhances Nrf2-antioxidant mechanism to exert anti-skin aging effects in human dermal fibroblasts

Environ. Toxicol.

Heme oxygenase-1 induction and anti-inflammatory actions of atractylodes macrocephala and taraxacum herba extracts prevented colitis and was more effective than sulfasalazine in preventing relapse

Gut Liver

Traditional Asian herbs in skin whitening: the current development and limitations

Front. Pharmacol.

Antioxidant, antityrosinase and antitumor activity comparison: the potential utilization of fibrous root part of Bletilla striata (Thunb.) Reichb.f

PLoS One