Front. Pharmacol. Frontiers in Pharmacology Front. Pharmacol. 1663-9812 Frontiers Media S.A. 736370 10.3389/fphar.2021.736370 Pharmacology Original Research Ethnobotanical Survey on Skin Whitening Prescriptions of Traditional Chinese Medicine in Taiwan Ko et al. Skin Whitening Prescriptions in Taiwan Ko Chien-Yu 1 † Chao Jung 2 † Chen Pei-Yu 3 Su Shan-Yu 4 5 Maeda Tomoji 6 7 Lin Chin-Yu 7 8 Chiang Hung-Che 1 7 Huang Shyh-Shyun 1 7 9 * School of Pharmacy, China Medical University, Taichung, Taiwan Chinese Medicine Research Center, Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, Master Program for Food and Drug Safety, China Medical University, Taichung, Taiwan Department of Cosmeceutics, China Medical University, Taichung, Taiwan Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama, Japan Tsuzuki Institute for Traditional Medicine, China Medical University, Taichung, Taiwan Institute of New Drug Development, China Medical University, Taichung, Taiwan Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan

Edited by: Lie-Fen Shyur, Academia Sinica, Taiwan

Reviewed by: Hsing-Yu Chen, Chang Gung Memorial Hospital, Taiwan

Linchun Shi, Chinese Academy of Medical Sciences and Peking Union Medical College, China

 *Correspondence: Shyh-Shyun Huang, sshuang@mail.cmu.edu.tw

These authors have contributed equally to this work and share first authorship.

This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

 30 11 2021 2021 12 736370 05 07 2021 10 11 2021 Copyright © 2021 Ko, Chao, Chen, Su, Maeda, Lin, Chiang and Huang. 2021 Ko, Chao, Chen, Su, Maeda, Lin, Chiang and Huang

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

The increasing interest and demand for skin whitening products globally, particularly in Asia, have necessitated rapid advances in research on skin whitening products used in traditional Chinese medicine (TCM). Herein, we investigated 74 skin whitening prescriptions sold in TCM pharmacies in Taiwan. Commonly used medicinal materials were defined as those with a relative frequency of citation (RFC) > 0.2 and their characteristics were evaluated. Correlation analysis of commonly used medicinal materials was carried out to identify the core component of the medicinal materials. Of the purchased 74 skin whitening prescriptions, 36 were oral prescriptions, 37 were external prescriptions, and one prescription could be used as an oral or external prescription. After analysis, 90 traditional Chinese medicinal materials were obtained. The Apiaceae (10%; 13%) and Leguminosae (9%; 11%) were the main sources of oral and external medicinal materials, respectively. Oral skin whitening prescriptions were found to be mostly warm (46%) and sweet (53%), while external skin whitening prescriptions included cold (43%) and bitter (29%) medicinal materials. Additionally, mainly tonifying and replenishing effects of the materials were noted. Pharmacological analysis indicated that these medicinal materials may promote wound healing, treat inflammatory skin diseases, or anti-hyperpigmentation. According to the Spearman correlation analysis on interactions among medicinal materials with an RFC > 0.2 in the oral skin whitening prescriptions, Paeonia lactiflora Pall. (white) and Atractylodes macrocephala Koidz. showed the highest correlation (confidence score = 0.93), followed by Ziziphus jujuba Mill. (red) and Astragalus propinquus Schischkin (confidence score = 0.91). Seven medicinal materials in external skin whitening prescriptions with an RFC > 0.2, were classified as Taiwan qī bái sàn (an herbal preparation), including Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav., Wolfiporia extensa (Peck) Ginns, Bletilla striata (Thunb.) Rchb. f., Atractylodes macrocephala Koidz., Ampelopsis japonica (Thunb.) Makino, Paeonia lactiflora Pall. (white), and Bombyx mori Linnaeus. Skin whitening prescriptions included multiple traditional Chinese medicinal materials. Despite the long history of use, there is a lack of studies concerning skin whitening products, possibly due to the complex composition of traditional Chinese medicine. Further studies are required to assess the efficacy and safety of these traditional Chinese medicinal materials for inclusion in effective, safe, and functional pharmacological products.

 skin whitening ethnobotanical Taiwan traditional Chinese medicine pharmacy traditional Taiwanese medicine 1 Introduction

The global cosmetics market is undergoing an unprecedented boom due to economic development and growing aesthetic needs. Rapidly expanding Asian cosmetic markets, of which China, Japan, South Korea, and India are major consumer countries, are following in the footsteps of European and American countries with the ubiquitous use of cosmetic products, particularly skin whitening products. Moreover, a recent survey noted the increasing prevalence of males using skin whitening products in addition to females (Pillaiyar et al., 2017; Hu et al., 2020).

Skin whitening prescriptions can not only be used to lighten skin tone, but also clinically treat hyperpigmentary disorders by decreasing melanin synthesis (Gillbro and Olsson, 2011). Melanin, one of the important pigments, is synthesized in melanocytes in the basal layer of epidermis and can protect the skin from ultraviolet-induced damage (Brenner and Hearing, 2008). Epidermal melanin content is intimately associated with anthropological origins. As the level of ultraviolet radiation is higher in low-latitude regions, people in these regions have higher melanin content; conversely, melanin content is lower in people at high-latitude regions, hence they have whiter skin (Slominski et al., 2004). Melanogenesis involves the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) by tyrosinase before further conversion to L-dopaquinone. Finally, L-dopaquinone undergoes a series of chemical reactions to form melanin (Supplementary Figure S1). Tyrosinase is a rate-limiting enzyme in melanogenesis and is considered an important target for the development of therapies in treating hyperpigmentation (Sonthalia et al., 2016; Ullah et al., 2019; Zaidi et al., 2019).

At present, there are a variety of skin whitening products on the market classified as either “inhibiting melanogenesis” or “inhibiting melanogenesis and promoting melanin removal.” In Taiwan, only 13 skin whitening components (Supplementary Table S1) (Food and Drug Administration, 2014) have been approved for use in cosmetic preparations. While ascorbic acid (vitamin C) is a common component, it is unstable and easily oxidized which limits its direct use. In order to prevent premature degradation, derivatives such as magnesium ascorbyl phosphate, ascorbyl glucoside, and ascorbyl tetraisopalmitate (Balaguer et al., 2008) are often utilized. Caution must be exercised when using various skin whitening components as improper use may lead to dermatitis, erythema, burns, and other skin injuries (Nordin et al., 2021). Thus, manufacturers have begun to seek natural alternatives to develop gentle, hypoallergenic skin whitening products derived from traditional Chinese medicine (TCM).

In traditional Chinese medicine books, many words describe dark skin or spots on the face, such as miàn gǎn zèng. In addition, there are ancient descriptions regarding the use of TCM for skin whitening. The Shennong Materia Medica, an extant medicinal text published in 100 B.C., recorded that Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav. promotes skin growth and has moisturizing effects. Of additional interest is qī bái sàn, a well-known skin whitening herbal prescription. However, its composition varies among different historical dynasties, geographical regions, and environments. For example, different compositions of qī bái sàn can be found in related prescriptions such as yǒng lèi qián fāng, pǔ jì fāng, and tài píng shèng huì fāng (Table 1). To date, there is still no comprehensive study on skin whitening prescriptions in traditional Chinese medicine pharmacies in Taiwan. Therefore, the aim of this study was to examine the composition of skin whitening prescriptions sold in traditional Chinese medicine pharmacies in Taiwan to understand the usage, methods of preparation, and principles of skin whitening prescriptions in Taiwan.

Qī bái sàn-related prescriptions in ancient books.

Name of prescription Composition Source
qī bái sàn (七白散) Atractylodes macrocephala Koidz., Ampelopsis japonica (Thunb.) Makino, Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., Bombyx mori Linnaeus, Paeonia lactiflora Pall., Ipomoea nil (L.) Roth, Sauromatum giganteum (Engl.) Cusimano & Hett yǒng lèi qián fang (永類鈐方)
qī bái wán (七白丸) Atractylodes macrocephala Koidz., Ampelopsis japonica (Thunb.) Makino, Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., Bletilla striata (Thunb.) Rchb.f., Bombyx mori Linnaeus, Wolfiporia extensa (Peck) Ginns, Sauromatum giganteum (Engl.) Cusimano & Hett pǔ jì fang (普濟方)
qī bái sàn xǐ miàn yào (七白散洗面藥) Atractylodes macrocephala Koidz., Ampelopsis japonica (Thunb.) Makino, Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., Bombyx mori Linnaeus, Paeonia lactiflora Pall., Ipomoea nil (L.) Roth, Wolfiporia extensa (Peck) Ginns pǔ jì fang (普濟方)
qī bái tǐng zǐ gāo (七白挺子膏) Atractylodes macrocephala Koidz., Ampelopsis japonica (Thunb.) Makino, Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., Asarum heterotropoides F.Schmidt f. mandshuricum (Maxim.) Kitag., Bletilla striata (Thunb.) Rchb.f., Wolfiporia extensa (Peck) Ginns, Sauromatum giganteum (Engl.) Cusimano & Hett tài píng shèng huì fang (太平聖惠方)
(This prescription must be mixed with egg white for use)
2 Materials and Methods 2.1 Ethical Review

The research for this study was conducted from March 2020 to April 2021. The study was approved by the Central Regional Research Ethics Committee of China Medical University (CRREC-109-125) (Supplementary Figure S2).

 2.2 Research Process

This study complied with the ethnobotanical research guidelines (Rivera et al., 2014; Mullane et al., 2015; Heinrich et al., 2018; Heinrich et al., 2020), and could mainly divided into field investigation, medicinal material identification, and analysis. The complete study methods are shown in the study flowchart (Figure 1).

Study flowchart.

 2.2.1 Field Investigation

Taiwan is an island located at the intersection between Northeast Asia and Southeast Asia and a total area of 36,000 km2 (Tourism Bureau, 2021). The study was conducted over 12 months and we randomly visited the TCM pharmacies that appropriately represented the use of TCM medicine in Taiwan. The number of TCM pharmacies selected was directly proportional to the number of TCM pharmacies in each county and city published by the government (Ministry of Health and Welfare, 2015). A total of 75 TCM pharmacies were visited, included 16 pharmacies were visited but no prescription was obtained. Overall, 74 skin whitening prescriptions were obtained (with 13 TCM pharmacies providing more than one prescription) (Figure 2), including 36 oral prescriptions, 37 external prescriptions, and one prescription which could be used as an oral or external prescription.

Geographical distribution of pharmacies visited for skin whitening prescriptions in Taiwan. All dots were based on latitude and longitude coordinates. Red dots indicated successful pharmacies; blue dots indicated failed pharmacies.

 2.2.2 Identification of Medicinal Materials

This study examined the purchased medicinal materials and performed the five-sense identification to identify the origins and plant parts of the materials, and compared them with the medicinal material standards to distinguish authentic or misused medicinal materials (Figure 3). We also photographed the materials and recorded the weight of each material. Finally, the materials were numbered and stored in the herbarium of the China Medical University, Taiwan.

Flowchart for medicinal materials identification.

 2.2.3 Analysis of Medicinal Materials

The various medicinal materials were analyzed and collated based on biological taxonomy, relative frequency of citation (RFC), efficacy of traditional use, and skin-related pharmacological effects. Biological taxonomy included the Scientific name of the crude drug, family, and color. The Plant List (http://www.theplantlist.org/) was used as a source of botanical information. Medicinal materials with RFC > 0.2 were defined as commonly used medicinal materials. The RFC formula was defined as follows (Vitalini et al., 2013; Dixit and Tiwari, 2020; Abbas et al., 2021): RF C i = F C i / N ( 0 ≤ ¯ RFC i ≤ ¯ 1 ) Where R F C i is the relative frequency count of i species and it is commonly used in ethnopharmacology papers. F C i defines the count of prescriptions which used species i. N denotes the total number of prescriptions.

The medicinal materials were indexed against the Taiwan Herbal Pharmacopeia (3rd, 4th edition) (Taiwan Herbal Pharmacopeia 3rd Edition Committee, 2018; Taiwan Herbal Pharmacopeia 4th Edition Committee, 2021), Pharmacopoeia of the People’s Republic of China (Chinese Pharmacopoeia Commission, 2020), and Chinese Materia Medica (State Administration of Traditional Chinese Medicine, 1999). The effects, properties, and flavors of traditional Chinese medicine were cited from the Taiwan Herbal Pharmacopeia (3rd, 4th edition). The PubMed database was systematically searched from Jan 2010 to May 2021 for skin-related pharmacological effects, utilizing keywords such as “skin” and the scientific names of medicinal materials.

 2.2.4 Analysis

GraphPad Prism 9.0 (GraphPad Prism version 9.0 for Windows, GraphPad Software, San Diego, California, USA) was used to plot a heat map for Spearman correlation analysis of commonly used medicinal materials used in oral skin whitening prescriptions. The colors of the squares in the heat map were based on the visualization of Spearman correlation matrix of the two medicinal materials. The more intense red hue, the higher the correlation between the two medicinal materials. Conversely, the lighter the color, the lower the correlation between the two medicinal materials (Vacanti, 2019).

 3 Results 3.1 Biological Taxonomic Characteristics of Medicinal Materials Used in Skin Whitening Prescriptions

During this study, 74 skin whitening prescriptions were purchased from 59 TCM pharmacies in Taiwan, of which 36 were oral prescriptions, 37 were external prescriptions, and one prescription could be used orally or externally. Oral prescription use method is to add appropriate amount of water to decoct; external prescription use method is to mash the medicinal materials, then add water, honey or milk, and apply to the face. Among the oral and external skin whitening prescriptions, 79 and 56 medicinal materials were found respectively. Overall, a total of 90 medicinal materials were obtained from the 74 prescriptions, and 6 misused medicinal materials were found (Supplementary Table S2). The majority of these medicinal materials were Plantae (93.33%), 3 medicinal materials (3.33%) were obtained from Animalia [Bombyx mori Linnaeus, Crassostrea gigas (Thunberg), and Pteria martensii (Dunker)] and 3 (3.33%) were from Fungi [Tremella fuciformis, Wolfiporia extensa (Peck) Ginns cum pini radix, and Wolfiporia extensa (Peck) Ginns] (Figure 4A).

Taxonomy of 90 medicinal materials in 74 skin whitening prescriptions. (A) Kingdoms and (B) families.

The most used of medicinal material in oral skin whitening prescriptions was Wolfiporia extensa (Peck) Ginns (RFC = 0.51), followed by Glycyrrhiza uralensis Fisch. and Paeonia lactiflora Pall. (white) (RFC = 0.41), while Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav. (RFC = 0.89) was the most commonly used of medicinal material in external skin whitening prescriptions. When classified by family, the most common families in both oral and external skin whitening prescriptions were Apiaceae (10 and 13% respectively) and Leguminosae (9 and 11% respectively) (Figure 4B).

 3.2 Analysis of Traditional Efficacy, Skin-Related Pharmacological Effects and Dosage of Commonly Used Medicinal Materials in Skin Whitening Prescriptions

Commonly used medicinal materials were defined as those with RFC > 0.2. Thirteen and seven commonly used medicinal materials were obtained from oral and external skin whitening prescriptions, respectively (Table 2).

Medicinal properties and skin-related modern research of commonly used medicinal materials used in skin whitening prescriptions (RFC>0.2).

Scientific name/Latin name of crude drug/Local name/sample number RFC a Family Color Flavor and property Traditional usage Literature on skin modern research (PubMed) b
Oral
 Wolfiporia extensa (Peck) Ginns/Poria/白茯苓/CMU2021SWP 0.51 Polyporaceae white Sweet and plain; plain Dampness-draining diuretic Hyperpigmentation (Ho et al., 2021); inhibition of melanogenesis (Lee and Cha, 2018; Kang et al., 2019); moisturizing and increased skin barrier function (Choi et al., 2019); oxidative stress associated skin aging effects and inflammatory skin diseases (Kang et al., 2019; Fang et al., 2021)
 Glycyrrhiza uralensis Fisch./Glycyrrhizae radix et rhizoma/甘草/CMU2021SWGrr 0.41 Leguminosae brown Sweet; plain Tonifying and replenishing Accelerate wound healing and promote neovascularization (Hao et al., 2020) anti-photoaging effects (Kim et al., 2017; Xuan et al., 2017); human dermal fibroblasts (Kim et al., 2017); inflammatory skin diseases (Jeong et al., 2015; Cha et al., 2016; Lee et al., 2020); inhibition of melanogenesis (Lim et al., 2018); protection of skin barrier (Cha et al., 2017); viral skin diseases (Wang et al., 2013a)
 Paeonia lactiflora Pall. (white)/Paeoniae radix alba/白芍/CMU2021SWPra 0.41 Paeoniaceae white Bitter and sour; cold Tonifying and replenishing Ameliorated vascular damage (Chen et al., 2013); anti-photoaging effects (Lu et al., 2020); hyperpigmentation (Qiu et al., 2016; Ho et al., 2021); inflammatory skin diseases (Chen et al., 2011; Jeong et al., 2015; Kim et al., 2021); inhibition of melanogenesis (You et al., 2017); psoriasis (Sun et al., 2015a; Choi et al., 2015; Li et al., 2019); skin itching Zhu et al., 2019)
 Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav./Angelicae dahuricae radix/白芷/CMU2021SWAdr 0.35 Apiaceae white Pungent; warm Exterior-releasing Accelerate wound healing and promote neovascularization (Bai et al., 2012; Yang et al., 2017; Yang et al., 2020a); acne (Hwang et al., 2016); inflammatory skin diseases (Lee et al., 2012; Ku et al., 2017); inhibition of melanogenesis (Kim et al., 2016); melanoma (Hwangbo et al., 2020); skin itching (Zhu et al., 2019)
 Astragalus propinquus Schischkin/Astragali radix/黃耆/CMU2021SWApr 0.32 Leguminosae brown Sweet; warm Tonifying and replenishing Accelerate wound healing (Luo et al., 2016; Zhao et al., 2017); anti-photoaging effects (Hong et al., 2013; Berezutsky et al., 2019; Shan et al., 2019); hyperpigmentation (Tsao et al., 2017); inflammatory skin diseases (Kim et al., 2013; Deng et al., 2019)
 Angelica sinensis (Oliv.) Diels/Angelicae sinensis radix/當歸/CMU2021SWAsr 0.32 Apiaceae brown Sweet and pungent; warm Tonifying and replenishing Accelerate wound healing (Hsiao et al., 2012; Zhao et al., 2012; Wang et al., 2013b); inflammatory skin diseases (Gong et al., 2015; Choi et al., 2016; Lee et al., 2016; Saba et al., 2016; Nam et al., 2021); skin itching (Lee at al., 2016; Zhu et al., 2019); melanoma (Gao et al., 2018)
 Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf/Coicis semen/白薏仁/CMU2021SWCs 0.32 Poaceae white Sweet and plain; cool Dampness-draining diuretic Accelerate wound healing (Kalekhan et al., 2021); anti-photoaging effects (Shan et al., 2012); chapped skin and warts (Chung et al., 2011; Byun et al., 2016; Son et al., 2019); inhibition of melanogenesis (Huang et al., 2014; Amen et al., 2017)
 Ziziphus jujuba Mill. (red)/Jujubae fructus (red)/紅棗/CMU2021SWJf 0.3 Rhamnaceae red Sweet; warm Tonifying and replenishing Accelerate wound healing (Fazio et al., 2020); anti-wrinkle (Son and Lee, 2020); melanoma (Hung et al., 2012)
 Atractylodes macrocephala Koidz./Atractylodis macrocephalae rhizoma/白朮/CMU2021SWAmr 0.3 Compositae white Bitter and sweet; warm Tonifying and replenishing Hyperpigmentation (Ho et al., 2021); skin itching (Zhu et al., 2019)
 Dioscorea polystachya Turcz./Dioscoreae rhizoma/白山藥/CMU2021SWDr 0.24 Dioscoreaceae white Sweet; plain Tonifying and replenishing Inflammatory skin diseases (Jegal et al., 2017; Jegal et al., 2018); skin cancer (Tsukayama et al., 2018)
 Lycium chinense Mill./Lycii fructus/枸杞子/CMU2021SWLf 0.24 Solanaceae red Sweet; plain Tonifying and replenishing Anti-photoaging effects (Yi et al., 2013; Im et al., 2016; Li at el., 2017; Liang et al., 2018; Neves et al., 2020; Neves et al., 2021); inflammatory skin diseases (Wu et al., 2020); melanoma (Cenariu et al., 2021); moisturizing (Meng et al., 2020)
 Ophiopogon japonicus (Thunb.) Ker Gawl./Ophiopogonis radix/麥門冬/CMU2021SWOr 0.24 Asparagaceae white Sweet and bitter; cold Tonifying and replenishing Inflammatory skin diseases (Kitahiro et al., 2018; Mainzer et al., 2019; An et al., 2020)
 Ligusticum striatum DC./Chuanxiong rhizoma/川芎/CMU2021SWCr 0.22 Apiaceae brown Pungent; warm Tonifying and replenishing Inflammatory skin diseases (Lee et al., 2016; Yan et al., 2020); skin itching (Zhu et al., 2019)
External
 Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav./Angelicae dahuricae radix/白芷/CMU2021SWAdr 0.89 Apiaceae white Pungent; warm Exterior-releasing Accelerate wound healing and promote neovascularization (Bai et al., 2012; Yang et al., 2017; Yang et al., 2020b): acne (Hwang et al., 2016); inflammatory skin diseases (Lee et al., 2012; Ku et al., 2017); inhibition of melanogenesis (Kim et al., 2016); melanoma (Hwangbo et al., 2020); skin itching (Zhu et al., 2019)
 Wolfiporia extensa (Peck) Ginns/Poria/白茯苓/CMU2021SWP 0.82 Polyporaceae white Sweet and plain; plain Dampness-draining diuretic Hyperpigmentation (Ho et al., 2021); inhibition of melanogenesis (Lee and cha, 2018; Kang et al., 2019); moisturizing and increased skin barrier function (Choi et al., 2019); oxidative stress associated skin aging effects (Kang et al., 2019; Fang et al., 2021)
 Bletilla striata (Thunb.) Rchb.f./Bletillae rhizoma/白及/CMU2021SWBr 0.58 Orchidaceae white Bitter, sweet, and astringent; cold Hemostatic Accelerate wound healing (Yu et al., 2011; He et al., 2017; Song et al., 2017; Zhang et al., 2019; Yang et al., 2020a); chapped skin (He et al., 2017); hyperpigmentation (Ho et al., 2021)
 Atractylodes macrocephala Koidz./Atractylodis macrocephalae rhizoma/白朮/CMU2021SWAmr 0.53 Compositae white Bitter and sweet; warm Tonifying and replenishing Hyperpigmentation (Ho et al., 2021); skin itching (Zhu et al., 2019)
 Ampelopsis japonica (Thunb.) Makino/Ampelopsis radix/白蘞/CMU2021SWAr 0.37 Vitaceae white Bitter and pungent; cold Heat-clearing Accelerate wound healing and promote neovascularization (Lee et al., 2015); hyperpigmentation (Fong and Tong, 2012; Ho et al., 2021)
 Paeonia lactiflora Pall. (white)/Paeoniae radix alba/白芍/CMU2021SWPra 0.32 Paeoniaceae white Bitter and sour; cold Tonifying and replenishing Ameliorated vascular damage (Chen et al., 2013); anti-photoaging effect (Lu et al., 2020); hyperpigmentation (Qiu et al., 2016; Ho et al., 2021); inflammatory skin diseases (Chen et al., 2011; Jeong et al., 2015; Kim et al., 2020); inhibition of melanogenesis (You et al., 2017); psoriasis (Sun et al., 2015b; Choi et al., 2015; Li et al., 2019); skin itching (Zhu et al., 2019)
 Bombyx mori Linnaeus/Bombyx batryticatus/白殭蠶/CMU2021SWBb 0.26 Bombycidae white Salty and pungent; plain Liver-pacifying and wind-extinguishing Accelerate wound healing (Tariq et al., 2021)

RFC, relative frequency of citation.

Literature on skin modern research (PubMed) included pharmacological effects, clinical research and intervention research.

With regards to the properties (Figure 5A), commonly used medicinal materials used in oral skin whitening prescriptions were mostly warm (46%) and plain (31%), while those used in external were mostly cold (43%), followed by warm (29%) and plain (29%). About the flavors (Figure 5B), commonly used medicinal materials used in oral skin whitening prescriptions were mostly sweet (53%), while those used in external were mostly bitter (29%).

Characteristics of medicinal materials with an RFC > 0.2 in skin whitening prescriptions. (A) Properties and (B) Flavors. Histogram of traditional efficacy classifications. (C) oral prescriptions and (D) external prescriptions. (E) Modern research related to skin.

About classification by traditional effect (Figures 5C,D), commonly used medicinal materials used in both oral and external skin whitening prescriptions were mostly tonifying and replenishing. Integrated the modern research related to skin, including pharmacological effects, clinical studies and intervention studies, it is found that most of these medicinal materials could promote wound healing, treat inflammatory skin diseases, or anti-hyperpigmentation (Figure 5E).

The analysis of the various medicinal materials dosage used in prescriptions is presented in Supplementary Table S3. In commonly used oral medicinal materials (Figure 6A), the average dose of Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf was the highest and that Glycyrrhiza uralensis Fisch. was the lowest. Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf showed the largest dose difference across the various TCM pharmacies, while dose differences of the Angelica sinensis (Oliv.) Diels were the smallest. In commonly used external medicinal materials (Figure 6B), the average dosage of Wolfiporia extensa (Peck) Ginns was the highest, while the Bletilla striata (Thunb.) Rchb. f. and Paeonia lactiflora Pall. (white) were the lowest. The dosages of Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav. had the largest differences across various TCM pharmacies, while the dosages of the Paeonia lactiflora Pall. (white) exhibited the smallest difference.

Box plots of dose ranges of commonly used medicinal materials. The top line represents the maximum value, and the bottom line represents the minimum value; the bottom of each box represents the first quartile (Q1), the middle line represents the second quartile (Q2), and the top of each box represents the third quartile (Q3). The black dots represent the doses in the collected samples. (A) Oral prescriptions and (B) external prescriptions. Adr, Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav.; Amr, Atractylodes macrocephala Koidz; Apr, Astragalus propinquus Schischkin; Ar, Ampelopsis japonica (Thunb.) Makino; Asr, Angelica sinensis (Oliv.) Diels; Cr, Ligusticum striatum DC.; Cs, Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf; Dr, Dioscorea polystachya Turcz.; Grr, Glycyrrhiza uralensis Fisch.; Jf, Ziziphus jujuba Mill. (red); Lf, Lycium chinense Mill.; Or, Ophiopogon japonicus (Thunb.) Ker Gawl.; P, Wolfiporia extensa (Peck) Ginns; Pra, Paeonia lactiflora Pall. (white).

 3.3 Correlation Analysis of Commonly Used Medicinal Materials Used in Oral Skin Whitening Prescriptions

Spearman correlation analysis was performed for commonly used medicinal materials in oral skin whitening prescriptions and a heatmap was plotted (Figure 7A). The highest correlation was detected between Paeonia lactiflora Pall. (white) and Atractylodes macrocephala Koidz. (confidence score = 0.93), followed by the correlation between Ziziphus jujuba Mill. (red) and Astragalus propinquus Schischkin (confidence score = 0.91). In contrast, low correlation was observed between Dioscorea polystachya Turcz. and Glycyrrhiza uralensis Fisch (confidence score = −0.7). Dioscorea polystachya Turcz. also demonstrated a low correlation with Paeonia lactiflora Pall. (white) and Atractylodes macrocephala Koidz. Therefore, Dioscorea polystachya Turcz. is less likely to be present when Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall. (white), or Atractylodes macrocephala Koidz. are present. When network analysis was performed on medicinal materials with RFC > 0.2 in oral skin whitening prescriptions (Figure 7B) and two medicinal materials with confidence score >0.6 were connected by lines, it was found that Paeonia lactiflora Pall. (white) and Atractylodes macrocephala Koidz. frequently appeared together with Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav. or Wolfiporia extensa (Peck) Ginns and Glycyrrhiza uralensis Fisch.; Ziziphus jujuba Mill. (red) and Astragalus propinquus Schischkin were used in combination with Lycium chinense Mill. or Ligusticum striatum DC.; and Angelica sinensis (Oliv.) Diels, Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf, and Dioscorea polystachya Turcz. was a prescription. These combinations could be used as a reference for oral skin whitening prescriptions.

Spearman correlation analysis of commonly used medicinal materials used in oral skin whitening prescriptions. (A) Heat map and (B) Network map. Adr, Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav.; Amr, Atractylodes macrocephala Koidz.; Apr, Astragalus propinquus Schischkin; Asr, Angelica sinensis (Oliv.) Diels; Cr, Ligusticum striatum DC.; Cs, Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf; Dr, Dioscorea polystachya Turcz.; Grr, Glycyrrhiza uralensis Fisch.; Jf, Ziziphus jujuba Mill. (red); Lf, Lycium chinense Mill.; Or, Ophiopogon japonicus (Thunb.) Ker Gawl.; P, Wolfiporia extensa (Peck) Ginns; Pra, Paeonia lactiflora Pall. (white).

 3.4 Venn Diagram Analysis of Commonly Used Medicinal Materials Used in External Skin Whitening Prescriptions

In this study, medicinal materials with RFC >0.2 in external skin whitening prescriptions were defined as Taiwan qī bái sàn (Figure 8A). Taiwan qī bái sàn consists of Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav., Wolfiporia extensa (Peck) Ginns, Bletilla striata (Thunb.) Rchb. f., Atractylodes macrocephala Koidz., Ampelopsis japonica (Thunb.) Makino, Paeonia lactiflora Pall. (white), and Bombyx mori Linnaeus. Venn diagram analysis of these medicinal materials with qī bái sàn-related prescriptions in yǒng lèi qián fāng, pǔ jì fāng, and tài píng shèng huì fāng found that Taiwan qī bái sàn is the addition and subtraction formula from the qī bái sàn mentioned in ancient books (Figure 8B).

(A) Pictures of medicinal materials of Taiwan qī bái sàn. (B) Venn diagram of qī bái sàn-related prescriptions in ancient books and Taiwan qī bái sàn. Adr, Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav.; Amr, Atractylodes macrocephala Koidz.; Ar, Ampelopsis japonica (Thunb.) Makino; Asr, Asarum heterotropoides F. Schmidt f. mandshuricum (Maxim.) Kitag.; Bb, Bombyx mori Linnaeus; Br, Bletilla striata (Thunb.) Rchb. f.; P, Wolfiporia extensa (Peck) Ginns; Pra, Paeonia lactiflora Pall. (white); Ps, Ipomoea nil (L.). Roth; Tr, Sauromatum giganteum (Engl.) Cusimano & Hett.

 3.5 Misuse of Medicinal Materials in Skin Whitening Prescriptions

Due to the wide variety of traditional Chinese medicinal materials, some medicinal materials may have the same vernacular name but are composed of different materials, whereas some medicinal materials may have different names but same origin. During integration and analysis of medicinal materials used in skin whitening prescriptions, it was found that Ampelopsis japonica (Thunb.) Makino, Astragalus propinquus Schischkin, Reynoutria multiflora (Thunb.) Moldenke, Rosa rugosa Thunb., Scutellaria baicalensis Georgi, and Tribulus terrestris L. had misused sound alike or look alike medicinal materials (Table 3).

Summary of medicinal materials that tend to be misused in skin whitening prescriptions.

Latin name of crude drug Authentic or misused Scientific name Family Look alike or sound alike a Frequency/Use ratio (%)
Ampelopsis radix authentic Ampelopsis japonica (Thunb.) Makino Vitaceae look alike 11/73%
misused Momordica cochinchinensis (Lour.) Spreng Cucurbitaceae 4/27%
Astragali radix authentic Astragalus propinquus Schischkin [Astragalus membranaceus (Fisch.) Bunge] b Leguminosae look alike 1/7%
misused Hedysarum polybotrys Hand. -Mazz Leguminosae 13/93%
Reynoutriae multiflorae radix authentic Reynoutria multiflora (Thunb.) Moldenke [Polygonum multiflorum Thunb.] c Polygonaceae look alike 0/0%
misused Pteroxygonum giraldii Dammer and Diels Polygonaceae 1/100%
Rosae rugosae flos authentic Rosa rugosa Thunb Rosaceae look alike 1/50%
misused Rosa chinensis Jacq Rosaceae 1/50%
Scutellariae radix authentic Scutellaria baicalensis Georgi Lamiaceae look alike 3/60%
misused Scutellaria amoena C.H.Wright Lamiaceae 2/40%
Tribuli fructus authentic Tribulus terrestris L. Zygophyllaceae sound alike 5/83%
misused Astragalus complanatus Bunge Leguminosae 1/17%

“Look alike” refers to the similar appearance of two confusing medicinal materials, thus causing misuse. “Sound alike” means that the local names of two confusing medicinal materials are similar in pronunciation, which causes misuse.

Astragalus membranaceus (Fisch.) bunge is a commonly used synonym of astragalus propinquus schischkin.

Polygonum multiflorum Thunb. is a commonly used synonym of Reynoutria multiflora (Thunb.) moldenke.

 4 Discussion 4.1 Field Investigation Sites

In this study, field investigation was employed to study skin whitening prescriptions sold in TCM pharmacies in Taiwan. Field investigations are mostly used in sociology, geography, or cultural studies and was previously employed to examine the drug treatment habits for certain diseases in some regions, such as traditional Chinese medicine composition used in galactagogues prescriptions (Chao et al., 2020), herbal composition of Qīng-Căo-Chá tea (Huang et al., 2020), and medicinal materials used for hypertension (Baharvand-Ahmadi et al., 2016). Traditional Chinese Medicine, the mainstay of Asian culture, is a form of experience-based therapies, and is a medical care system for diagnosing, preventing, and treating diseases (Xu et al., 2013). Therefore, traditional Chinese pharmacies in Taiwan are important sites for retaining TCM culture.

 4.2 Types and Biological Taxonomic Characteristics of Medicinal Materials in Skin Whitening Prescriptions

This study on the composition of skin whitening prescriptions used in Taiwan found that most medicinal materials were from Apiaceae, including Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav., Angelica sinensis (Oliv.) Diels and Ligusticum striatum DC., followed by Leguminosae, including Glycyrrhiza uralensis Fisch. and Astragalus propinquus Schischkin. Apiaceae and Leguminosae plants can inhibit tyrosinase activity, thereby reducing melanogenesis. These plants are rich in phenolic compounds and flavonoids that are proven to have significant antioxidant activity. The previous experiments also showed that they can inhibit matrix metalloproteinases (MMPs), delay skin photoaging, and stimulate keratinocyte and fibroblast migration, which has significant effects on skin regeneration (Tundis et al., 2015; Waqas et al., 2015; Zofia et al., 2020).

Melanin is an important pigment that determines skin, hair, and eye colors, and can be mainly divided into pheomelanin and eumelanin (Zanetti et al., 2001). Melanin synthesis is intimately associated with tyrosinase. Pigmentation is an important photoprotective factor, and its regulatory mechanism is extremely complex and still not completely understood. However, a large volume of data shows that ultraviolet-induced DNA damage and its repair will activate tyrosinase in melanocytes, resulting in melanogenesis (Gilchrest and Eller, 1999; Brenner and Hearing, 2008; Lai et al., 2018). Therefore, inhibition of tyrosinase can inhibit melanogenesis.

 4.3 Analysis of Effects and Pharmacology of Commonly Used Medicinal Materials Used in Skin Whitening Prescriptions

TCM has a unique theory where medicinal materials are classified by properties (hot, warm, plain, cool, and cold) and flavors (sour, bitter, sweet, pungent, salty, plain, and astringent). Most TCM materials comprise a combination of flavors (Liao et al., 2008). The 1H-NMR spectrum was used to identify the properties of the medicinal materials, and it was found that their ingredients were very different (Zhang et al., 2020). A previous report showed that warm and hot medicinal materials can regulate the immune system; cold and cool medicinal materials can inhibit cell growth and proliferation (Liang et al., 2013); sweet medicinal materials have supplementation, moderation, and harmonization effects (He et al., 2012), while bitter medicinal materials mostly contain alkaloids with anti-inflammatory effects (Chen et al., 2015). The results of this study found that commonly used medicinal materials used in oral skin whitening prescriptions are mostly warm and sweet while those used in external skin whitening prescriptions are mostly cold and bitter. In combination with previous studies, it can be deduced that oral skin whitening prescriptions mostly focus on immune regulation while external skin whitening prescriptions focus on inflammation alleviation.

 4.4 Analysis of Commonly Used Medicinal Materials Used in Oral and External Skin Whitening Prescriptions

Wolfiporia extensa (Peck) Ginns, Paeonia lactiflora Pall. (white), Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav., and Atractylodes macrocephala Koidz. are commonly used medicinal materials used in oral and external skin whitening prescriptions. Wolfiporia extensa (Peck) Ginns regulates tyrosinase activity to inhibit melanogenesis (Lee and Cha, 2018). In past studies had found that Paeonia lactiflora Pall. (white) can be used to treat allergic dermatitis and reduce facial wrinkles. Paeoniflorin in Paeonia lactiflora Pall. (white) can reduce the expression of microphthalmia-associated transcription factor (MITF) and melanogenic enzymes (including tyrosinase, TRP-1, and TRP-2) by regulating the p38 MAPK pathway, thereby inhibiting melanogenesis (Qiu et al., 2016). Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav. is a good immunomodulatory agent, and it can significantly increase phagocytosis and the secretion of cytokines by macrophages (Wang et al., 2021). It can also inhibit melanogenesis. It is involved inhibition of tyrosinase synthesis, but it does not inhibit tyrosinase activity (Cho et al., 2006). A study highlighted that the extract of Atractylodes macrocephala Koidz. has immune-enhancing activities (Sun et al., 2015a). Its active ingredients are Atractylenolide I and 14-acetoxy-12-senecioyloxytetradeca-2E, 8E, 10E-trien-4,6-diyn-1-ol. They are both alkaloids that demonstrate anti-inflammatory effects and are tyrosinase inhibitors (Li et al., 2007; Ye et al., 2010).

 4.5 Misuse of Medicinal Materials in Skin Whitening Prescriptions

The Taiwan Herbal Pharmacopeia is a codex of management regulations for TCM in Taiwan. The medicinal materials recorded in monographs should comply with the pharmacopeia standards before being manufactured, sold, and dispensed for medical treatment and health care. Medicinal materials recorded in the Taiwan Herbal Pharmacopeia are defined as authentic medicinal materials, while the origins of medicinal materials not included in the pharmacopeia are regarded as misused or fake medicinal materials (Taiwan Herbal Pharmacopeia 3rd Edition Committee, 2018; Taiwan Herbal Pharmacopeia 4th Edition Committee, 2021). Although the government releases information about authentic medicinal materials every year, medicinal materials’ misuse is still commonly seen in markets in Taiwan. Such misused materials were also found in skin whitening prescriptions that were collected in this study, including medicinal materials that look alike, which refers to the similar appearance of two confusing medicinal materials, thus causing misuse, such as Momordica cochinchinensis (Lour.) Spreng. that was used instead of Ampelopsis japonica (Thunb.) Makino, Hedysarum polybotrys Hand-Mazz. that was used instead of Astragalus propinquus Schischkin, Scutellaria amoena C.H.Wright that was used instead of Scutellaria baicalensis Georgi, Pteroxygonum giraldii Dammer & Diels that was used instead of Reynoutria multiflora (Thunb.) Moldenke, and Rosa chinensis Jacq. that was used instead of Rosa rugosa Thunb.; and medicinal materials that sound alike, which means that the local names of two confusing medicinal materials are similar in pronunciation, thus causing misuse, such as Astragalus complanatus Bunge that was used instead of Tribulus terrestris L (Figure 9). Even though misused medicinal materials in skin whitening prescriptions do not seem to cause immediate harm to the human body, there is no way to prove whether they will have adverse interactions with other medicinal materials. Therefore, simple and clear pictures showing that appearance and properties of medicinal materials should be created, and rapid, simple, and convenient identification methods should be developed to disseminate knowledge for identification of misused medicinal materials and remind traditional Chinese medicine users to be cautious and prevent misuse of medicinal materials.

Pictures of authentic or misused medicinal materials.

 4.6 Limitations and Future Directions

This study had certain limitations that should be addressed in future research. The first limitation is that this study was a field survey study, which only investigated skin whitening prescriptions sold in Chinese medicine stores in Taiwan. The skin whitening prescriptions investigated in this study reflect local usage in Taiwan. Further research will be needed to examine the whitening prescriptions used in traditional Chinese medicine in other regions. The second limitation is that this study only analyzed the core medicinal materials and dosages of the prescriptions but not the efficacy of these botanical drugs. Therefore, animal or cell experiments can be used in future research to verify the effectiveness of the skin whitening medicinal materials or prescriptions. The last limitation is that the Spearman correlation analysis only shows the correlations between prescription drugs and not the drug interactions between them. When discussing prescriptions in future research, we may have to consider both the theoretical significance of traditional Chinese medicine and the practical significance. We should also conduct in vivo and in vitro experiments to further explore the efficacy and the interactions between the medicinal materials.

 5 Conclusion

In Asian countries, whiter skin color is synonymous with beauty for women and many Asian women look for natural and without side effects skin whitening products in order to reduce cutaneous pigmentation. This study is the first ethnobotanical survey on skin whitening prescriptions collected from TCM pharmacies in Taiwan. The purpose is to preserve the use of TCM for skin whitening in Taiwan. Although the use of TCM in skin whitening has been widely recorded and many skin whitening medicinal materials were collected from TCM pharmacies in this study, the ingredients of TCM are extremely complex and tends to be affected by many factors, may also be used in misused medicinal materials. Moreover, the efficacy and safety of most medicinal materials have not been scientifically validated. Further studies are needed to support the conversion of traditional skin whitening prescriptions to effective functional products. Thus, the results of this study may provide significant foundational data for subsequent studies The Royal Botanic Gardens, 2013, Li et al., 2017, Institute of Ecology et al., 2021.

 Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

 Ethics Statement

The studies involving human participants were reviewed and approved by the CRREC-109-125. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

 Author Contributions

C-YK, P-YC, JC, and S-SH performed the field investigation and organized and analyzed the database. C-YK, JC, S-SH, TM, and C-YL contributed conception and design of the study. S-SH and S-YS identified the botanical materials. C-YK, S-SH, JC, S-YS, TM, and C-YL drafted the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version. S-SH, JC, S-YS, and H-CC provided guidance for the project and supervised the experiment and manuscript review.

 Funding

This research was funded by the Tsuzuki Institute for Traditional Medicine, Grant numbers 108727B8, 109727B8 and 110727B8; China Medical University, Grant numbers CMU108-MF-116 and CMU108-N-22; the Ministry of Science and Technology, Grant number MOST 107-2320-B-039-030-MY3 and 109-2813-C-039-061-B. The China Medical University under the Higher Education Sprout Project and Teaching Practice Research Program, Grant number 1077170A, of the Ministry of Education of Taiwan.

 Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

The authors thank the herbarium of China Medical University for providing us with space to store the medicinal materials for this study. Also, we would like to thank the 63rd pharmacy students of China Medical University for their assistance in this study.

 Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2021.736370/full#supplementary-material

References Abbas Z. Kousar S. Aziz M. A. Pieroni A. Aldosari A. A. Bussmann R. W. (2021). Comparative Assessment of Medicinal Plant Utilization Among Balti and Shina Communities in the Periphery of Deosai National Park, Pakistan. Biology (Basel) 105, 434. 10.3390/biology10050434 Amen Y. Arung E. T. Afifi M. S. Halim A. F. Ashour A. Fujimoto R. (2017). Melanogenesis Inhibitors from Coix Lacryma-Jobi Seeds in B16-F10 Melanoma Cells. Nat. Prod. Res. 31, 2712–2718. 10.1080/14786419.2017.1292270 An E. J. Kim Y. Lee S. H. Choi S. H. Chung W. S. Jang H. J. (2020). Ophiopogonin D Ameliorates DNCB-Induced Atopic Dermatitis-like Lesions in BALB/c Mice and TNF-α- Inflamed HaCaT Cell. Biochem. Biophys. Res. Commun. 522, 40–46. 10.1016/j.bbrc.2019.10.190 Baharvand-Ahmadi B. Bahmani M. Tajeddini P. Rafieian-Kopaei M. Naghdi N. (2016). An Ethnobotanical Study of Medicinal Plants Administered for the Treatment of Hypertension. J. Ren. Inj Prev 5, 123–128. 10.15171/jrip.2016.26 Bai X. Z. Hu D. H. Wang Y. C. Liu J. Q. Shi J. H. Tang C. W. (2012). Effects of Angelica Dahurica Extract on Biological Behavior of Dermal Fibroblasts. Zhonghua Wai Ke Za Zhi 50, 357–360. Balaguer A. Chisvert A. Salvador A. (2008). Environmentally Friendly LC for the Simultaneous Determination of Ascorbic Acid and its Derivatives in Skin-Whitening Cosmetics. J. Sep. Sci. 31, 229–236. 10.1002/jssc.200700414 Berezutsky M. A. Durnova N. A. Vlasova I. A. (2019). Experimental and Clinical Studies of Mechanisms of the Anti-aging Effects of Chemical Compounds in Astragalus Membranaceus (Review). Adv. Gerontol. 32, 702–710. 10.1134/S2079057020020046 Brenner M. Hearing V. J. (2008). The Protective Role of Melanin against UV Damage in Human Skin. Photochem. Photobiol. 84, 539–549. 10.1111/j.1751-1097.2007.00226.x Byun A. R. Kwon S. Kim S. (2016). Administration of Herbal Complexes, Dangguijakyak-San (TJ-23) and Coix Seeds, for Treating Verruca Planae: A Case Report. Explore (NY) 12, 65–67. 10.1016/j.explore.2015.10.003 Cenariu D. Fischer-Fodor E. Țigu A. B. Bunea A. Virág P. Perde-Schrepler M. (2021). Zeaxanthin-Rich Extract from Superfood Lycium Barbarum Selectively Modulates the Cellular Adhesion and MAPK Signaling in Melanoma versus Normal Skin Cells In Vitro . Molecules 26, 333. 10.3390/molecules26020333 Cha H. Y. Ahn S. H. Cheon J. H. Park I. S. Kim J. T. Kim K. (2016). Hataedock Treatment Has Preventive Therapeutic Effects in Atopic Dermatitis-Induced NC/Nga Mice under High-Fat Diet Conditions. Evid. Based Complement. Alternat Med. 2016, 1739760. 10.1155/2016/1739760 Cha H. Y. Ahn S. H. Cheon J. H. Park S. Y. Kim K. (2017). Hataedock Treatment Has Preventive Therapeutic Effects for Atopic Dermatitis through Skin Barrier protection in Dermatophagoides Farinae-Induced NC/Nga Mice. J. Ethnopharmacol 206, 327–336. 10.1016/j.jep.2017.06.001 Chao J. Ko C. Y. Lin C. Y. Tomoji M. Huang C. H. Chiang H. C. (2020). Ethnobotanical Survey of Natural Galactagogues Prescribed in Traditional Chinese Medicine Pharmacies in Taiwan. Front. Pharmacol. 11, 625869. 10.3389/fphar.2020.625869 Chen H. Guo J. Pang B. Zhao L. Tong X. (2015). Application of Herbal Medicines with Bitter Flavor and Cold Property on Treating Diabetes Mellitus. Evid. Based Complement. Alternat Med. 2015, 529491. 10.1155/2015/529491 Chen T. Guo Z. P. Jiao X. Y. Jia R. Z. Zhang Y. H. Li J. Y. (2011). Peoniflorin Suppresses Tumor Necrosis Factor-α Induced Chemokine Production in Human Dermal Microvascular Endothelial Cells by Blocking Nuclear Factor-Κb and ERK Pathway. Arch. Dermatol. Res. 303, 351–360. 10.1007/s00403-010-1116-6 Chen T. Guo Z. P. Wang L. Qin S. Cao N. Li M. M. (2013). Paeoniflorin Suppresses Vascular Damage and the Expression of E-Selectin and ICAM-1 in a Mouse Model of Cutaneous Arthus Reaction. Exp. Dermatol. 22, 453–457. 10.1111/exd.12174 Chinese Pharmacopoeia Commission (2020). Pharmacopoeia of the People's Republic of China. China: China Medical Science Press. Cho Y. H. Kim J. H. Park S. M. Lee B. C. Pyo H. B. Park H. D. (2006). New Cosmetic Agents for Skin Whitening from Angelica Dahurica. J. Cosmet. Sci. 57, 11–21. Choi E. Kang Y. G. Hwang S. H. Kim J. K. Hong Y. D. Park W. S. (2019). In Vitro Effects of Dehydrotrametenolic Acid on Skin Barrier Function. Molecules 24, 4583. 10.3390/molecules24244583 Choi M. R. Choi D. K. Sohn K. C. Lim S. K. Kim D. I. Lee Y. H. (2015). Inhibitory Effect of Paeonia Lactiflora Pallas Extract (PE) on Poly (I:C)-induced Immune Response of Epidermal Keratinocytes. Int. J. Clin. Exp. Pathol. 8, 5236–5241. Choi Y. Y. Kim M. H. Hong J. Kim K. Yang W. M. (2016). Effect of Dangguibohyul-Tang, a Mixed Extract of Astragalus Membranaceus and Angelica Sinensis, on Allergic and Inflammatory Skin Reaction Compared with Single Extracts of Astragalus Membranaceus or Angelica Sinensis. Evid. Based Complement. Alternat Med. 2016, 5936354. 10.1155/2016/5936354 Chung C. P. Hsia S. M. Lee M. Y. Chen H. J. Cheng F. Chan L. C. (2011). Gastroprotective Activities of Adlay (Coix Lachryma-Jobi L. Var. Ma-Yuen Stapf) on the Growth of the Stomach Cancer AGS Cell Line and Indomethacin-Induced Gastric Ulcers. J. Agric. Food Chem. 59, 6025–6033. 10.1021/jf2009556 Deng G. Chen W. Wang P. Zhan T. Zheng W. Gu Z. (2019). Inhibition of NLRP3 Inflammasome-Mediated Pyroptosis in Macrophage by Cycloastragenol Contributes to Amelioration of Imiquimod-Induced Psoriasis-like Skin Inflammation in Mice. Int. Immunopharmacol 74, 105682. 10.1016/j.intimp.2019.105682 Dixit S. Tiwari S. (2020). Investigation of Anti-diabetic Plants Used Among the Ethnic Communities of Kanpur Division, India. J. Ethnopharmacol 253, 112639. 10.1016/j.jep.2020.112639 Fang C. L. Paul C. R. Day C. H. Chang R. L. Kuo C. H. Ho T. J. (2021). 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. 36, 729–736. 10.1002/tox.23075 Fazio A. La Torre C. Caroleo M. C. Caputo P. Plastina P. Cione E. (2020). Isolation and Purification of Glucans from an Italian Cultivar of Ziziphus Jujuba Mill. And In Vitro Effect on Skin Repair. Molecules 25, 968. 10.3390/molecules25040968 Fong P. Tong H. H. (2012). In Silico prediction of the Cosmetic Whitening Effects of Naturally Occurring lead Compounds. Nat. Prod. Commun. 7, 1287–1294. 10.1177/1934578x1200701010 Food and Drug Administration (2014). Know Cosmetic Whitening Ingredients. [Online]. Available: https://www.mohw.gov.tw/cp-3205-21666-1.html (Accessed Jun 17, 2021). Gao H. W. Chang K. F. Huang X. F. Lin Y. L. Weng J. C. Liao K. W. (2018). Antitumor Effect of N-Butylidenephthalide Encapsulated on B16/F10 Melanoma Cells In Vitro with a Polycationic Liposome Containing PEI and Polyethylene Glycol Complex. Molecules 23, 3224. 10.3390/molecules23123224 Gilchrest B. A. Eller M. S. (1999). DNA Photodamage Stimulates Melanogenesis and Other Photoprotective Responses. J. Investig. Dermatol. Symp. Proc. 4, 35–40. 10.1038/sj.jidsp.5640178 Gillbro J. M. Olsson M. J. (2011). The Melanogenesis and Mechanisms of Skin-Lightening Agents-Eexisting and New Approaches. Int. J. Cosmet. Sci. 33, 210–221. 10.1111/j.1468-2494.2010.00616.x Gong P. Lu Z. Xing J. Wang N. Zhang Y. (2015). Traditional Chinese Medicine Xuebijing Treatment Is Associated with Decreased Mortality Risk of Patients with Moderate Paraquat Poisoning. PLoS One 10, e0123504. 10.1371/journal.pone.0123504 Hao B. Wang X. Ma X. Jin Y. Fan W. Laba C. (2020). Preparation of Complex Microcapsules of Soluble Polysaccharide from Glycyrrhiza Uralensis and its Application in Wound Repair and Scar Inhibition. Int. J. Biol. Macromol 156, 906–917. 10.1016/j.ijbiomac.2020.03.121 He X. Wang X. Fang J. Zhao Z. Huang L. Guo H. (2017). Bletilla Striata: Medicinal Uses, Phytochemistry and Pharmacological Activities. J. Ethnopharmacol 195, 20–38. 10.1016/j.jep.2016.11.026 He Y. Zheng X. Sit C. Loo W. T. Wang Z. Xie T. (2012). Using Association Rules Mining to Explore Pattern of Chinese Medicinal Formulae (Prescription) in Treating and Preventing Breast Cancer Recurrence and Metastasis. J. Transl Med. 10 (1), S12. 10.1186/1479-5876-10-S1-S12 Heinrich M. Appendino G. Efferth T. Fürst R. Izzo A. A. Kayser O. (2020). Best Practice in Research - Overcoming Common Challenges in Phytopharmacological Research. J. Ethnopharmacol 246, 112230. 10.1016/j.jep.2019.112230 Heinrich M. Lardos A. Leonti M. Weckerle C. Willcox M. Applequist W. (2018). Best Practice in Research: Consensus Statement on Ethnopharmacological Field Studies - ConSEFS. J. Ethnopharmacol 211, 329–339. 10.1016/j.jep.2017.08.015 Ho C. C. Ng S. C. Chuang H. L. Chen J. Y. Wen S. Y. Kuo C. H. (2021). Seven Traditional Chinese Herbal Extracts Fermented by Lactobacillus Rhamnosus Provide Anti-pigmentation Effects by Regulating the CREB/MITF/tyrosinase Pathway. Environ. Toxicol. 36, 654–664. 10.1002/tox.23069 Hong M. J. Ko E. B. Park S. K. Chang M. S. (2013). Inhibitory Effect of Astragalus Membranaceus Root on Matrix Metalloproteinase-1 Collagenase Expression and Procollagen Destruction in Ultraviolet B-Irradiated Human Dermal Fibroblasts by Suppressing Nuclear Factor Kappa-B Activity. J. Pharm. Pharmacol. 65, 142–148. 10.1111/j.2042-7158.2012.01570.x Hsiao C. Y. Hung C. Y. Tsai T. H. Chak K. F. (20122012). A Study of the Wound Healing Mechanism of a Traditional Chinese Medicine, Angelica Sinensis, Using a Proteomic Approach. Evid. Based Complement. Alternat Med. 2012, 467531. 10.1155/2012/467531 Hu Y. Zeng H. Huang J. Jiang L. Chen J. Zeng Q. (2020). Traditional Asian Herbs in Skin Whitening: The Current Development and Limitations. Front. Pharmacol. 11, 982. 10.3389/fphar.2020.00982 Huang H. C. Hsieh W. Y. Niu Y. L. Chang T. M. (2014). Inhibitory Effects of Adlay Extract on Melanin Production and Cellular Oxygen Stress in B16F10 Melanoma Cells. Int. J. Mol. Sci. 15, 16665–16679. 10.3390/ijms150916665 Huang S. S. Chen T. Y. Deng J. S. Pao L. H. Cheng Y. C. Chao J. (2020). An Ethnobotanical Study on Qīng-Căo-Chá Tea in Taiwan. Front. Pharmacol. 11, 931. 10.3389/fphar.2020.00931 Hung C. F. Hsu B. Y. Chang S. C. Chen B. H. (2012). Antiproliferation of Melanoma Cells by Polysaccharide Isolated from Zizyphus Jujuba. Nutrition 28, 98–105. 10.1016/j.nut.2011.05.009 Hwang Y. L. Im M. Lee M. H. Roh S. S. Choi B. W. Kim S. J. (2016). Inhibitory Effect of Imperatorin on Insulin-like Growth Factor-1-Induced Sebum Production in Human Sebocytes Cultured In Vitro . Life Sci. 144, 49–53. 10.1016/j.lfs.2015.11.027 Hwangbo H. Choi E. O. Kim M. Y. Kwon D. H. Ji S. Y. Lee H. (2020). Suppression of Tumor Growth and Metastasis by Ethanol Extract of Angelica Dahurica Radix in Murine Melanoma B16F10 Cells. Biosci. Trends 14, 23–34. 10.5582/bst.2019.01230 Im A. R. Lee H. J. Youn U. J. Hyun J. W. Chae S. (2016). Orally Administered Betaine Reduces Photodamage Caused by UVB Irradiation through the Regulation of Matrix Metalloproteinase-9 Activity in Hairless Mice. Mol. Med. Rep. 13, 823–828. 10.3892/mmr.2015.4613 Institute of Ecology and Evolutionary Biology, NTU (2021). Plants of Taiwan. [Online]. Available: http://tai2.ntu.edu.tw (Accessed May 6, 2021). Jegal J. Park N. J. Bong S. K. Jegal H. Kim S. N. Yang M. H. (2017). Dioscorea Quinqueloba Ameliorates Oxazolone- and 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis Symptoms in Murine Models. Nutrients 9, 1324. 10.3390/nu9121324 Jegal J. Park N. J. Jo B. G. Bong S. K. Jegal H. Yang M. H. (2018). Anti-Atopic Properties of Gracillin Isolated from Dioscorea Quinqueloba on 2,4-Dinitrochlorobenzene-Induced Skin Lesions in Mice. Nutrients 10, 1205. 10.3390/nu10091205 Jeong S. J. Lim H. S. Seo C. S. Kim J. H. Jin S. E. Yoo S. R. (2015). Traditional Herbal Formula Jakyakgamcho-Tang (Paeonia Lactiflora and Glycyrrhiza Uralensis) Impairs Inflammatory Chemokine Production by Inhibiting Activation of STAT1 and NF-Κb in HaCaT Cells. Phytomedicine 22, 326–332. 10.1016/j.phymed.2014.12.002 Kalekhan F. Kudva A. K. Raghu S. V. Rao S. Hegde S. K. Simon P. (2021). Traditionally Used Natural Products in Preventing Ionizing Radiation-Induced Dermatitis: First Review on the Clinical Studies. Anticancer Agents Med. Chem. 21. 10.2174/1871520621666210405093236 Kang K. Y. Hwang Y. H. Lee S. J. Jang H. Y. Hong S. G. Mun S. K. (2019). Verification of the Functional Antioxidant Activity and Antimelanogenic Properties of Extracts of Poria Cocos Mycelium Fermented with Freeze-Dried Plum Powder. Int. J. Biomater. 2019, 9283207. 10.1155/2019/9283207 Kim J. H. Kim M. H. Yang G. Huh Y. Kim S. H. Yang W. M. (2013). Effects of Topical Application of Astragalus Membranaceus on Allergic Dermatitis. Immunopharmacol Immunotoxicol 35, 151–156. 10.3109/08923973.2012.733708 Kim K. H. Shim J. S. Kim H. J. Son E. D. (2020). Penta-O-galloyl-β-D-glucose from Paeonia Lactiflora Pall. Root Extract Enhances the Expression of Skin Barrier Genes via EGR3. J. Ethnopharmacol 248, 112337. 10.1016/j.jep.2019.112337 Kim K. J. Xuan S. H. Park S. N. (2017). Licoricidin, an Isoflavonoid Isolated from Glycyrrhiza Uralensis Fisher, Prevents UVA-Induced Photoaging of Human Dermal Fibroblasts. Int. J. Cosmet. Sci. 39, 133–140. 10.1111/ics.12357 Kim M. K. Bang C. Y. Kim M. Y. Lee J. H. Ro H. Choi M. S. (2016). Traditional Herbal Prescription LASAP-C Inhibits Melanin Synthesis in B16F10 Melanoma Cells and Zebrafish. BMC Complement. Altern. Med. 16, 223. 10.1186/s12906-016-1209-7 Kitahiro Y. Koike A. Sonoki A. Muto M. Ozaki K. Shibano M. (2018). Anti-inflammatory Activities of Ophiopogonis Radix on Hydrogen Peroxide-Induced Cellular Senescence of normal Human Dermal Fibroblasts. J. Nat. Med. 72, 905–914. 10.1007/s11418-018-1223-9 Ku J. M. Hong S. H. Kim H. I. Seo H. S. Shin Y. C. Ko S. G. (2017). Effects of Angelicae Dahuricae Radix on 2, 4-Dinitrochlorobenzene-Induced Atopic Dermatitis-like Skin Lesions in Mice Model. BMC Complement. Altern. Med. 17, 98. 10.1186/s12906-017-1584-8 Lai X. Wichers H. J. Soler-Lopez M. Dijkstra B. W. (2018). Structure and Function of Human Tyrosinase and Tyrosinase-Related Proteins. Chemistry 24, 47–55. 10.1002/chem.201704410 Lee H. Cha H. J. (2018). Poria Cocos Wolf Extracts Represses Pigmentation In Vitro and In Vivo . Cel Mol Biol (Noisy-le-grand) 64, 80–84. 10.14715/cmb/2018.64.5.13 Lee H. Lee J. K. Ha H. Lee M. Y. Seo C. S. Shin H. K. (2012). Angelicae Dahuricae Radix Inhibits Dust Mite Extract-Induced Atopic Dermatitis-like Skin Lesions in NC/Nga Mice. Evid. Based Complement. Alternat Med. 2012, 743075. 10.1155/2012/743075 Lee J. Choi Y. Y. Kim M. H. Han J. M. Lee J. E. Kim E. H. (2016). Topical Application of Angelica Sinensis Improves Pruritus and Skin Inflammation in Mice with Atopic Dermatitis-like Symptoms. J. Med. Food 19, 98–105. 10.1089/jmf.2015.3489 Lee J. H. Lim J. Y. Jo E. H. Noh H. M. Park S. Park M. C. (2020). Chijabyukpi-Tang Inhibits Pro-inflammatory Cytokines and Chemokines via the Nrf2/HO-1 Signaling Pathway in TNF-Α/ifn-γ-Stimulated HaCaT Cells and Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-like Skin Lesions in Mice. Front. Pharmacol. 11, 1018. 10.3389/fphar.2020.01018 Lee K. Lee B. Lee M. H. Kim B. Chinannai K. S. Ham I. (2015). Effect of Ampelopsis Radix on Wound Healing in Scalded Rats. BMC Complement. Altern. Med. 15, 213. 10.1186/s12906-015-0751-z Li B. He S. Liu R. Huang L. Liu G. Wang R. (2019). Total Glucosides of Paeony Attenuates Animal Psoriasis Induced Inflammatory Response through Inhibiting STAT1 and STAT3 Phosphorylation. J. Ethnopharmacol 243, 112121. 10.1016/j.jep.2019.112121 Li C. Q. He L. C. Dong H. Y. Jin J. Q. (2007). Screening for the Anti-inflammatory Activity of Fractions and Compounds from Atractylodes Macrocephala Koidz. J. Ethnopharmacol 114, 212–217. 10.1016/j.jep.2007.08.002 Li H. Li Z. Peng L. Jiang N. Liu Q. Zhang E. (2017). Lycium Barbarum Polysaccharide Protects Human Keratinocytes against UVB-Induced Photo-Damage. Free Radic. Res. 51, 200–210. 10.1080/10715762.2017.1294755 Liang B. Peng L. Li R. Li H. Mo Z. Dai X. (2018). Lycium Barbarum Polysaccharide Protects HSF Cells against Ultraviolet-Induced Damage through the Activation of Nrf2. Cell Mol Biol Lett 23, 18. 10.1186/s11658-018-0084-2 Liang F. Li L. Wang M. Niu X. Zhan J. He X. (2013). Molecular Network and Chemical Fragment-Based Characteristics of Medicinal Herbs with Cold and Hot Properties from Chinese Medicine. J. Ethnopharmacol 148, 770–779. 10.1016/j.jep.2013.04.055 Liao H. Banbury L. K. Leach D. N. (2008). Antioxidant Activity of 45 Chinese Herbs and the Relationship with Their TCM Characteristics. Evid. Based Complement. Alternat Med. 5 (4), 429–434. 10.1093/ecam/nem054 Lim J. W. Ha J. H. Jeong Y. J. Park S. N. (2018). Anti-melanogenesis Effect of Dehydroglyasperin C through the Downregulation of MITF via the Reduction of Intracellular cAMP and Acceleration of ERK Activation in B16F1 Melanoma Cells. Pharmacol. Rep. 70, 930–935. 10.1016/j.pharep.2018.02.024 Lu Y. S. Jiang Y. Yuan J. P. Jiang S. B. Yang Y. Zhu P. Y. (2020). UVA Induced Oxidative Stress Was Inhibited by Paeoniflorin/Nrf2 Signaling or PLIN2. Front. Pharmacol. 11, 736. 10.3389/fphar.2020.00736 Luo X. Huang P. Yuan B. Liu T. Lan F. Lu X. (2016). Astragaloside IV Enhances Diabetic Wound Healing Involving Upregulation of Alternatively Activated Macrophages. Int. Immunopharmacol 35, 22–28. 10.1016/j.intimp.2016.03.020 Mainzer C. Le Guillou M. Vyumvuhore R. Chadoutaud B. Bordes S. Closs B. (2019). Clinical Efficacy of Oligofructans from Ophiopogon Japonicus in Reducing Atopic Dermatitis Flare-Ups in Caucasian Patients. Acta Derm Venereol. 99, 858–864. 10.2340/00015555-3224 Meng H. Li J. Dong Y. He Y. Ren H. Liu Y. (2020). Poly Traditional Chinese Medicine Formulation Prepared with Skin Moisturizing Properties. Dermatol. Ther. 33, e14105. 10.1111/dth.14105 Ministry of Health and Welfare (2015). Drug Administration. [Online]. Available: https://dep.mohw.gov.tw/DOS/cp-1729-2939-113.html (Accessed May 6, 2021). Mullane K. Enna S. J. Piette J. Williams M. (2015). Guidelines for Manuscript Submission in the Peer-Reviewed Pharmacological Literature. Biochem. Pharmacol. 97, 225–235. 10.1016/j.bcp.2015.06.023 Nam Y. K. Kim M. H. Ha I. J. Yang W. M. (2021). Derma-Hc, a New Developed Herbal Formula, Ameliorates Cutaneous Lichenification in Atopic Dermatitis. Int. J. Mol. Sci. 22, 2359. 10.3390/ijms22052359 Neves L. M. G. Parizotto N. A. Tim C. R. Floriano E. M. Lopez R. F. V. Venâncio T. (2020). Polysaccharide-rich Hydrogel Formulation Combined with Photobiomodulation Repairs UV-Induced Photodamage in Mice Skin. Wound Repair Regen. 28, 645–655. 10.1111/wrr.12826 Neves L. M. G. Tim C. R. Floriano E. M. da Silva de Avó L. R. Fernandes J. B. Parizotto N. A. (2021). Lycium Barbarum Polysaccharide Fraction Associated with Photobiomodulation Protects from Epithelium Thickness and Collagen Fragmentation in a Model of Cutaneous Photodamage. Lasers Med. Sci. 36, 863–870. 10.1007/s10103-020-03132-w Nordin F. N. M. Aziz A. Zakaria Z. Wan Mohamed Radzi C. W. J. (2021). A Systematic Review on the Skin Whitening Products and Their Ingredients for Safety, Health Risk, and the Halal Status. J. Cosmet. Dermatol. 20, 1050–1060. 10.1111/jocd.13691 Pillaiyar T. Manickam M. Namasivayam V. (2017). Skin Whitening Agents: Medicinal Chemistry Perspective of Tyrosinase Inhibitors. J. Enzyme Inhib. Med. Chem. 32, 403–425. 10.1080/14756366.2016.1256882 Qiu J. Chen M. Liu J. Huang X. Chen J. Zhou L. (2016). The Skin-Depigmenting Potential of Paeonia Lactiflora Root Extract and Paeoniflorin: In Vitro Evaluation Using Reconstructed Pigmented Human Epidermis. Int. J. Cosmet. Sci. 38, 444–451. 10.1111/ics.12309 Rivera D. Allkin R. Obón C. Alcaraz F. Verpoorte R. Heinrich M. (2014). What Is in a Name? the Need for Accurate Scientific Nomenclature for Plants. J. Ethnopharmacol 152, 393–402. 10.1016/j.jep.2013.12.022 Saba E. Lee C. H. Jeong da. H. Lee K. Kim T. H. Roh S. S. (2016). Fermented rice Bran Prevents Atopic Dermatitis in DNCB-Treated NC/Nga Mice. J. Biomed. Res. 30, 334–343. 10.7555/JBR.30.2016K0001 Shan H. Zheng X. Li M. (2019). The Effects of Astragalus Membranaceus Active Extracts on Autophagy-Related Diseases. Int. J. Mol. Sci. 20, 1904. 10.3390/ijms20081904 Shan S. J. Xiao T. Chen J. Geng S. L. Li C. P. Xu X. (2012). Kanglaite Attenuates UVB-Induced Down-Regulation of Aquaporin-3 in Cultured Human Skin Keratinocytes. Int. J. Mol. Med. 29, 625–629. 10.3892/ijmm.2011.873 Slominski A. Tobin D. J. Shibahara S. Wortsman J. (2004). Melanin Pigmentation in Mammalian Skin and its Hormonal Regulation. Physiol. Rev. 84, 1155–1228. 10.1152/physrev.00044.2003 Son E. S. Kim S. H. Kim Y. O. Lee Y. E. Kyung S. Y. Jeong S. H. (2019). Coix Lacryma-Jobi Var. Ma-Yuen Stapf Sprout Extract Induces Cell Cycle Arrest and Apoptosis in Human Cervical Carcinoma Cells. BMC Complement. Altern. Med. 19, 312. 10.1186/s12906-019-2725-z Son J. Lee S. Y. (2020). Ursonic Acid Exerts Inhibitory Effects on Matrix Metalloproteinases via ERK Signaling Pathway. Chem. Biol. Interact 315, 108910. 10.1016/j.cbi.2019.108910 Song Y. Zeng R. Hu L. Maffucci K. G. Ren X. Qu Y. (2017). In Vivo wound Healing and In Vitro Antioxidant Activities of Bletilla Striata Phenolic Extracts. Biomed. Pharmacother. 93, 451–461. 10.1016/j.biopha.2017.06.079 Sonthalia S. Daulatabad D. Sarkar R. (2016). Glutathione as a Skin Whitening Agent: Facts, Myths, Evidence and Controversies. Indian J. Dermatol. Venereol. Leprol. 82, 262–272. 10.4103/0378-6323.179088 State Administration of Traditional Chinese Medicine (1999). Chinese Materia Medica" Editorial Board (1999). Chinese Materia Medica. Shanghai: Shanghai Scientific & Technical Publishers. Sun W. Meng K. Qi C. Yang X. Wang Y. Fan W. (2015a). Immune-enhancing Activity of Polysaccharides Isolated from Atractylodis Macrocephalae Koidz. Carbohydr. Polym. 126, 91–96. 10.1016/j.carbpol.2015.03.034 Sun Y. Zhang J. Huo R. Zhai T. Li H. Wu P. (2015b). Paeoniflorin Inhibits Skin Lesions in Imiquimod-Induced Psoriasis-like Mice by Downregulating Inflammation. Int. Immunopharmacol 24, 392–399. 10.1016/j.intimp.2014.12.032 Taiwan Herbal Pharmacopeia 3rd Edition Committee (2018). Taiwan Herbal Pharmacopeia. Republic of China: Ministry of Health and Welfare. Taiwan Herbal Pharmacopeia 4th Edition Committee (2021). Taiwan Herbal Pharmacopeia. Republic of China: Ministry of Health and Welfare. Tariq M. Tahir H. M. Butt S. A. Ali S. Ahmad A. B. Raza C. (2021). Silk Derived Formulations for Accelerated Wound Healing in Diabetic Mice. PeerJ 9, e10232. 10.7717/peerj.10232 The Royal Botanic Gardens (2013). The Plant List. [Online]. Available: http://www.theplantlist.org/ (Accessed May 7, 2021). Tourism Bureau (2021). General Information. [Online]. Available: https://www.taiwan.net.tw/m1.aspx?sNo=0027009 (Accessed May 6, 2021). Tsao Y. T. Kuo C. Y. Kuan Y. D. Lin H. C. Wu L. H. Lee C. H. (2017). The Extracts of Astragalus Membranaceus Inhibit Melanogenesis through the ERK Signaling Pathway. Int. J. Med. Sci. 14, 1049–1053. 10.7150/ijms.20335 Tsukayama I. Toda K. Takeda Y. Mega T. Tanaka M. Kawakami Y. (2018). Preventive Effect of Dioscorea Japonica on Squamous Cell Carcinoma of Mouse Skin Involving Down-Regulation of Prostaglandin E2 Synthetic Pathway. J. Clin. Biochem. Nutr. 62, 139–147. 10.3164/jcbn.17-54 Tundis R. Loizzo M. R. Bonesi M. Menichini F. (2015). Potential Role of Natural Compounds against Skin Aging. Curr. Med. Chem. 22, 1515–1538. 10.2174/0929867322666150227151809 Ullah S. Park C. Ikram M. Kang D. Lee S. Yang J. (2019). Tyrosinase Inhibition and Anti-melanin Generation Effect of Cinnamamide Analogues. Bioorg. Chem. 87, 43–55. 10.1016/j.bioorg.2019.03.001 Vacanti N. M. (2019). The Fundamentals of Constructing and Interpreting Heat Maps. Methods Mol. Biol. 1862, 279–291. 10.1007/978-1-4939-8769-6_20 Vitalini S. Iriti M. Puricelli C. Ciuchi D. Segale A. Fico G. (2013). Traditional Knowledge on Medicinal and Food Plants Used in Val San Giacomo (Sondrio, Italy)--an alpine Ethnobotanical Study. J. Ethnopharmacol 145, 517–529. 10.1016/j.jep.2012.11.024 Wang H. Wang X. Zhou L. Zhang S. An L. Bao J. (2021). Structural Characteristics and In Vitro and In Vivo Immunoregulatory Properties of a Gluco-Arabinan from Angelica Dahurica. Int. J. Biol. Macromol 183, 90–100. 10.1016/j.ijbiomac.2021.04.077 Wang J. Chen X. Wang W. Zhang Y. Yang Z. Jin Y. (2013a). Glycyrrhizic Acid as the Antiviral Component of Glycyrrhiza Uralensis Fisch. Against Coxsackievirus A16 and Enterovirus 71 of Hand Foot and Mouth Disease. J. Ethnopharmacol 147, 114–121. 10.1016/j.jep.2013.02.017 Wang R. Lechtenberg M. Sendker J. Petereit F. Deters A. Hensel A. (2013b). Wound-healing Plants from TCM: In Vitro Investigations on Selected TCM Plants and Their Influence on Human Dermal Fibroblasts and Keratinocytes. Fitoterapia 84, 308–317. 10.1016/j.fitote.2012.12.020 Waqas M. K. Akhtar N. Mustafa R. Jamshaid M. Khan H. M. Murtaza G. (2015). Dermatological and Cosmeceutical Benefits of Glycine max (Soybean) and its Active Components. Acta Pol. Pharm. 72, 3–11. Wu P. Y. Li T. M. Chen S. I. Chen C. J. Chiou J. S. Lin M. K. (2020). Complementary Chinese Herbal Medicine Therapy Improves Survival in Patients with Pemphigus: A Retrospective Study from a Taiwan-Based Registry. Front. Pharmacol. 11, 594486. 10.3389/fphar.2020.594486 Xu Q. Bauer R. Hendry B. M. Fan T. P. Zhao Z. Duez P. (2013). The Quest for Modernisation of Traditional Chinese Medicine. BMC Complement. Altern. Med. 13, 132. 10.1186/1472-6882-13-132 Xuan S. H. Park Y. M. Ha J. H. Jeong Y. J. Park S. N. (2017). The Effect of Dehydroglyasperin C on UVB-Mediated MMPs Expression in Human HaCaT Cells. Pharmacol. Rep. 69, 1224–1231. 10.1016/j.pharep.2017.05.012 Yan N. Tang Z. Xu Y. Li X. Wang Q. (2020). Pharmacokinetic Study of Ferulic Acid Following Transdermal or Intragastric Administration in Rats. AAPS PharmSciTech 21, 169. 10.1208/s12249-020-01709-w Yang L. Han Z. Chen C. Li Z. Yu S. Qu Y. (2020a). Novel Probiotic-Bound Oxidized Bletilla Striata Polysaccharide-Chitosan Composite Hydrogel. Mater. Sci. Eng. C Mater. Biol. Appl. 117, 111265. 10.1016/j.msec.2020.111265 Yang W. T. Ke C. Y. Wu W. T. Harn H. J. Tseng Y. H. Lee R. P. (2017). Effects of Angelica Dahurica and Rheum Officinale Extracts on Excisional Wound Healing in Rats. Evid. Based Complement. Alternat Med. 2017, 1583031. 10.1155/2017/1583031 Yang W. T. Ke C. Y. Wu W. T. Tseng Y. H. Lee R. P. (2020b). Antimicrobial and Anti-inflammatory Potential of Angelica Dahurica and Rheum Officinale Extract Accelerates Wound Healing in Staphylococcus Aureus-Infected Wounds. Sci. Rep. 10, 5596. 10.1038/s41598-020-62581-z Ye Y. Chu J. H. Wang H. Xu H. Chou G. X. Leung A. K. (2010). Involvement of P38 MAPK Signaling Pathway in the Anti-melanogenic Effect of San-Bai-tang, a Chinese Herbal Formula, in B16 Cells. J. Ethnopharmacol 132, 533–535. 10.1016/j.jep.2010.09.007 Yi R. Liu X. M. Dong Q. (2013). A Study of Lycium Barbarum Polysaccharides (LBP) Extraction Technology and its Anti-aging Effect. Afr. J. Tradit Complement. Altern. Med. 10, 171–174. 10.4314/ajtcam.v10i4.27 You O. H. Shin E. A. Lee H. Kim J. H. Sim D. Y. Kim J. H. (2017). Apoptotic Effect of Astragalin in Melanoma Skin Cancers via Activation of Caspases and Inhibition of Sry-Related HMg-Box Gene 10. Phytother Res. 31, 1614–1620. 10.1002/ptr.5895 Yu L. Nie X. Pan H. Ling S. Zhang D. Bian K. (2011). Diabetes Mellitus Ulcers Treatment with Bletilla Striata Polysaccharide. Zhongguo Zhong Yao Za Zhi 36, 1487–1491. 10.4268/cjcmm20111118 Zaidi K. U. Ali S. A. Ali A. Naaz I. (2019). Natural Tyrosinase Inhibitors: Role of Herbals in the Treatment of Hyperpigmentary Disorders. Mini Rev. Med. Chem. 19, 796–808. 10.2174/1389557519666190116101039 Zanetti R. Prota G. Napolitano A. Martinez C. Sancho-Garnier H. Østerlind A. (2001). Development of an Integrated Method of Skin Phenotype Measurement Using the Melanins. Melanoma Res. 11, 551–557. 10.1097/00008390-200112000-00001 Zhang C. He Y. Chen Z. Shi J. Qu Y. Zhang J. (2019). Effect of Polysaccharides from Bletilla Striata on the Healing of Dermal Wounds in Mice. Evid. Based Complement. Alternat Med. 2019, 9212314. 10.1155/2019/9212314 Zhang J. Guo W. Li Q. Sun F. Xu X. Xu H. (2020). Discriminant Analysis of Traditional Chinese Medicinal Properties Based on Holistic Chemical Profiling by 1H-NMR Spectrometry. Evid. Based Complement. Alternat Med. 2020, 3141340. 10.1155/2020/3141340 Zhao B. Zhang X. Han W. Cheng J. Qin Y. (2017). Wound Healing Effect of an Astragalus Membranaceus Polysaccharide and its Mechanism. Mol. Med. Rep. 15, 4077–4083. 10.3892/mmr.2017.6488 Zhao H. Deneau J. Che G. O. Li S. Vagnini F. Azadi P. (2012). Angelica Sinensis Isolate SBD.4: Composition, Gene Expression Profiling, Mechanism of Action and Effect on Wounds, in Rats and Humans. Eur. J. Dermatol. 22, 58–67. 10.1684/ejd.2011.1599 Zhu C. S. Nie A. Z. Zhang B. Lin Z. J. (2019). Medication Rules of Professor Zhang Bing in Treatment of Skin Itching Based on Data Mining. Zhongguo Zhong Yao Za Zhi 44, 597–601. 10.19540/j.cnki.cjcmm.20181128.001 Zofia N. Ł. Martyna Z. D. Aleksandra Z. Tomasz B. (2020). Comparison of the Antiaging and Protective Properties of Plants from the Apiaceae Family. Oxid Med. Cel Longev 2020, 5307614. 10.1155/2020/5307614