Plants as Modulators of Melanogenesis: Role of Extracts, Pure Compounds and Patented Compositions in Therapy of Pigmentation Disorders

The kingdom of plants as a “green biofabric” of valuable bioactive molecules has long been used in many ailments. Currently, extracts and pure compounds of plant origin are used to aid in pigmentation skin problems by influencing the process of melanogenesis. Melanin is a very important pigment that protects human skin against ultraviolet radiation and oxidative stress. It is produced by a complex process called melanogenesis. However, disturbances in the melanogenesis mechanism may increase or decrease the level of melanin and generate essential skin problems, such as hyperpigmentation and hypopigmentation. Accordingly, inhibitors or activators of pigment formation are desirable for medical and cosmetic industry. Such properties may be exhibited by molecules of plant origin. Therefore, that literature review presents reports on plant extracts, pure compounds and compositions that may modulate melanin production in living organisms. The potential of plants in the therapy of pigmentation disorders has been highlighted.


Introduction
The human skin is an important organ in the body and a source of various cells, including melanocytes that residue on the basal layer of epidermis [1]. The main feature of melanocytes is the production of melanin in special organs-melanosomes during a physiological process, called melanogenesis. The quality, quantity and distribution pattern of melanin determines the color of mammalian skin, eyes and hairs. Constitutive pigmentation level of melanin is genetically determined. However, pigment cells have the ability to adopt their melanogenic potential via different internal or external stimuli. The internal stimuli are factors generated inside the organism, whereas the external stimuli are environmental agents including the most potent one, i.e., ultraviolet (UV) radiation [2].
Melanogenesis consists of different stages and involves action of various enzymes. Tyrosinase (TYR) is the key enzyme, which takes part in melanin synthesis by catalyzing hydroxylation of L-tyrosine to 3,4-dihydroxy-phenylalanine (DOPA) and oxidation of DOPA to DOPAquinone. The produced pigment is transferred from melanocytes into keratinocytes. This compound constitutes the first line of defense against UV radiation and provides scavenging of reactive oxygen species (ROS) [3]. However, the disturbance of melanogenesis process may lead to overproduction, deficiency, abnormal transport or transfer of melanin, which in turn may result in pigmentation disorders [4].
The primary function of melanocyte is melanin production. Melanins are responsible for pigmentation of the skin, as well as hair or eyes. There are two main groups of melanins: eumelanins and foemelanins. Eumelanins give a brownish to dark black color while foemelanins give a yellowish or reddish color. Pigment amount varies depending on the activity of melanosomes, differences in the production and deposition. A higher content of pheomelanin relative to eumelanin is observed for fair skin, while the opposite ratio is observed for dark skin. There are no significant differences in melanocyte density in different racial groups. However, the density is different in a different body region. It is estimated that there are between 900 and 1500 melanocytes per mm 2 on the back and genital area on average about 1000 melanocytes per mm 2 [14].
Biochemical pathway leading to synthesis of melanin is called melanogenesis. It is estimated that pigment production is regulated by more than 250 genes that determine melanocyte development, migration, proliferation, differentiation, and survival [15,16]. Pigment cells express among others TYR, TYRP1, TYRP2 and MITF proteins which are closely related to melanogenesis. TYR, being an oxidase located in the membrane of melanosomes, is responsible for converting L-tyrosine, a precursor of melanins to DOPAquinone [17]. Apart from TYR, TYRP-1 and TYRP-2 are other enzymes which are also involved in melanogenesis. These proteins are structurally similar to TYR. TYRP1 is an oxidase involved in the final stage of melanogenesis; it can increase the ratio of eumelanin to pheomelanin and it is also involved in activation and stabilization of TYR by forming a complex with it. TYRP2 is a tautomerase responsible for the conversion of DOPAchrome to carboxylic acid derivatives. In the melanosome, it forms complexes with TYR and TYRP1 [18]. MITF is a transcription factor which recognizes the sequences of TYR, TYRP1 and TYRP2 genes and modulate their transcription. The signaling cascade involving MITF is one of the most important for melanogenesis regulation [19].
Protection against UV radiation is the primary function of melanins. Melanins have both UV absorbing and scaterring properties. Black epidermis transmits only 7.4% of UVB and 17.5% of UVA, whereas 24% of UVB and 55% of UVA pass through white skin. This role is very important due to the fact that UVB radiation induces DNA bases damage, whereas UVA radiation leads to production of ROS as well as single strand breaks or crosslinks between DNA and proteins. Photodamage can cause mutations in critical genes. Therefore, UV radiation is a primary harmful environmental factor, inducing occurrence of skin cancers such as malignant melanoma, squamous cell carcinoma and basal cell carcinoma. In turn, melanosomes transferred from melanocytes to keratinocytes form characteristic perinuclear caps that create a DNA protection shield. In addition to its UV radiation protective role, melanin also exhibits antioxidant activity as well as anti-inflammatory and immunomodulatory properties [20][21][22].

Plant Extract and Pure Compounds-Biological Properties and Modulatory Effect on Melanocyte
Plants are a rich source of phytocompounds. It is estimated that any single species may contain as many as 5000 metabolites [23]. These are chemically diverse substances that can play many different roles, including determination of plant growth and development, protection against pathogens, and response to environmental stress. The metabolites produced by plants are classified as primary and secondary. The second group includes mainly intermediates or by-products of primary metabolism. Terpenoids, alkaloids, phenylpropanoids, polyketides, quinones and cyanogenic glycosides are formed in the process of carbon and nitrogen metabolism; glucosinolates are formed by sulfur metabolism, while alkylamides are formed by fatty acid metabolism. [24]. Plant secondary metabolites may also positively affect the human body [25]. Some of these substances demonstrate therapeutic effects on cells or tissues and may be useful in alleviating numerous aliments [26]. In addition, their contribution to disease prevention is being considered [27]. A lot of efforts are put to isolate highly desirable molecules and to determine their chemical structure, as well as activity, functions and toxicity [28,29].
Plant-derived compounds may counteract the harmful effects of UV exposure on human skin. Phenolic compounds are the most important class of phytochemicals that may be used as sunscreen agents. These molecules equipped with aromatic rings are able to absorb UVA and UVB radiation at wavelengths of 200-400 nm. Two flavonoids, quercitin and rutin at 10% (w/w) concentrations provide SPF values of about 12 [39]. Moreover, combining 0.1% (w/w) rutin with 6% benzophenone, a synthetic organic filter, increased the SPF value from about 24 to 33 [40]. Similarly, synergistic effects were observed between 0.1% rutin (w/w), 1% benzophenone (w/w) and 3.5% (w/w) ethylhexyl methoxycinnamate, another synthetic organic filter [41]. Choquenet tested twelve phenolic compounds at various concentrations, including myricetin, apigenin, luteolin, puerarin, baicalin, baicalein, naringenin, hesperidin, hesperetin, diosmin, caffeic acid and chlorogenic acid. Of these, apigenin and chlorogenic acid were found to be the most effective UVB and UVA filters, with SPF values at about 7 and 10, respectively [42]. Similarly, among fifteen tested phenolic compounds at 7% (w/v) concentrations (resveratrol, quercetin, catechin, kaempferol, piceid, galangin, apigenin, naringenin, chrysin, pinocembrin, ferulic acid, coumaric acid, caffeic acid, caffeic acid phenylethyl ester and dimethyl caffeic acid), the highest SPF value was observed for apigenin, i.e., about 28.8 [43]. In addition, studies show that plant extracts from different plant species have also a photoprotective action, especially plants of the species which stand out large amounts of phenolic compounds [30].
Bioactive compounds are known to improve the anti-inflammatory response via downregulation of different inflammatory pathways, including mitogen-activated protein kinases (MAPKs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activators of transcription (JAK/STAT) pathways. This stimulation contributes to production of various pro-inflammatory mediators, while their inhibition bestows an anti-cancer effect.
Oxidative stress is implicated in the pathogenesis of many chronic diseases, including diabetes, cardiovascular diseases, atherosclerosis, rheumatoid arthritis, chronic inflammation, cancer, aging, and various other neurodegenerative disorders. ROS activates signaling pathways, such as MAPK, NF-κB, nuclear factor erythroid 2-related factor 2 (Nrf2) and various transcription factors, including activator protein 1 (AP-1), tumor protein p53, hypoxia-inducible factor 1-alpha (HIF-1α), peroxisome proliferator-activated receptor gamma (PPARγ), and signal transducer and activator of transcription (STAT-3). Nrf2 pathway upregulates cell defense mechanisms and antioxidant gene expression. This pathway is known to be stimulated by plant-derived chemicals with antioxidant properties, thus providing beneficial effects against ROS-related disease, including cancer.
Phytochemicals also exert a direct detrimental effect on cancer cells by cell cycle arrest via downregulation of (MAPKs) and phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT) pathways [44]. Data indicate that suppression of PI3K/AKT signaling pathway leads to inhibition of proliferation, apoptosis, induction of autophagy of cancer cells [45]. In addition, molecules of natural origin can block cancer cell differentiation and angiogenesis by downregulation of the HIF-1α pathway and vascular endothelial growth factor (VEGF), and influence cancer cell survival by altering p53, death receptor expression and pro-apoptotic:anti-apoptotic protein balance [44].
Secondary metabolites obtained from plants can also modulate signaling pathways involved in the melanogenesis process in melanocyte cells. A lot of studies have been focused on the ability to regulate MC1R, c-KIT, WNT and ETBR pathways.
Induction of G-protein-coupled receptor MC1R is a canonical regulatory mechanism of melanin production by melanocytes. This occurs through its agonist, α-melanocytestimulating hormone (α-MSH) bounding. Activation of adenylyl cyclase is followed by an increase in the cyclic adenosine monophosphate (cAMP) level. cAMP is a second messenger produced from ATP by adenyl cyclase that regulates numerous cellular functions, including growth, proliferation, differentiation, migration, as well as genes expression. Protein kinase A (PKA) is one of effector proteins, which gets activated by high cAMP levels. Consequently, PKA activates target proteins including cAMP response element-binding protein (CREB) [46]. PKA is responsible for Ser133 phosphorylation of CREB, which is then followed by CREB-mediated MITF expression. It was also observed that the binding of α-MSH to MC1R contributes to triggering PI3K/AKT signaling pathway. PI3K activity results in recruitment of AKT to the cell membrane, where phosphorylation and activation of AKT occur. A direct target for AKT is, among others, glycogen synthase kinase 3β (GSK3β), which then phosphorylates on Ser298 and activates MITF [47][48][49]. Data also indicate that AKT can directly phosphorylate MITF on Ser510 [42]. In turn, cAMP levels in the cell can modulate the MAPKs pathway. Increased cAMP amounts induce ERKs and inhibit p38 activation [50]. Active ERK phosphorylates MITF on Ser73 and triggers proteasomal degradation mediated by ubiquitin [51]. In contrast, active p38 causes CREB phosphorylation and MITF activation [52]. Similarly, PI3K/AKT and MAPKs signals also regulate numerous cellular functions, including proliferation, differentiation and migration [53,54].
MITF can be also regulated via c-KIT receptor and its ligand stem cell factor (SCF) junction, which is dependent on PI3K/AKT and p38 signaling [55]. Data indicate that induction of c-KIT constitutively stimulates PI3K by its phosphorylation, as well as activate Src-homology 2 domain-containing proteins, of which the Src family kinases promote p38 action [56].
WNT signaling is initiated by binding of Wnt ligands to Frizzled receptor-related protein receptor complexes. In the absence of Wnt ligands, β-catenin phosphorylation by GSK3β results in its degradation by a protein complex consisting of Dishevelled, GSK3β, axin or conductin, and the adenomatous polyposis coli tumor suppressor protein. In the presence of Wnt ligand, β-catenin phosphorylation is blocked. This provides β-catenin stabilization followed by nuclear translocation, where it can interact with TCF/LEF transcription factor and regulate the expression of downstream genes. MITF is one of positively regulated genes targeted by WNT signaling [57,58].
ETBR is also a G-protein coupled receptor. Its activation by ligand-endothelin 3 (ET-3) results in elevated phosphorylation of ERK, CREB and MITF. ETBR acts synergistically with MC1R. The action is followed by MITF activation and increased expression of its target genes, including TYR, TYRP1 and TYRP2. In addition, increased phosphorylation of AKT was also observed [59].
Modulating of MITF activity can affect the efficiency of melanogenesis. In some cases, inhibition of MITF activity leads to reduced melanin production, while in some others, stimulation of MITF activity results in increased melanin production. Both the effects may be achieved through implementation of plant-derived compounds [60]. Therefore, these molecules may exert a beneficial therapeutic effect on skin of patients with hyperpigmentation or hypopigmentation, including postinflammatory hyperpigmentation, solar lentigines, melasma, café au lait macules, ephelides (freckles) as well as postinflammatory hypopigmentation, vitiligo, pityriasis alba, tinea versicolor [61][62][63][64][65].

The Effect of Plant Extracts or Pure Compounds on Melanin Content in the Danio rerio Model
Danio rerio (zebrafish) is a popular model for biomedical research. It is characterized with fully sequenced genome, being approximately in 70% orthologues to the human genome, easy genetic manipulation, rapid development, high fecundity, external fertilization, transparent embryo and presence of main organs necessary for metabolism. Moreover, that small freshwater fish is also easy to breed and maintain [66].
The zebrafish is also highly desirable in dermatological studies due to the fact that components of the epidermis and dermis get formed just 1 day post-fertilization (dpf), whereas skin structure is fully developed 6 dpf. As a consequence, after 6 dpf zebrafish skin is composed of multilayer epidermis and collagenous stroma with well-demarcated keratinocytes and numerous fibroblastic cells. Besides, presence of a pigment cell system is a crucial feature of zebrafish skin [67,68]. Interestingly, zebrafish skin is similar to human skin and consists of the epidermis, dermis and hypodermis. Unlike human skin, it does not have a keratinized outer layer and mammalian appendages, including sebaceous glands and hair follicles. However, studies on that non-mammalian vertebrate model constitute a fundamental part of skin-related research [69].
The zebrafish model is getting more and more applicable in exploration of pigment disorders due to having a conserved melanogenesis pathway and visible melanin development in melanophores from 1 dpf. The zebrafish pigment cells are derived from neural crest stem cells. They generate melanophores. Melanocytes and melanophores look alike similar. Melanophores are located in the epidermis and hypodermis and they do not transfer melanin, while melanocytes residue in the epidermis and transfer melanin to keratinocytes. However, the biology of melanophores is similar to that of melanocytes. In that model organism, numerous genes which control pigment production and function of melanocytes, such as MITF, TYR and TYRP1, are conserved and similar to those observed in a human body. In addition, regulation of MITF activity by signaling pathways, including MC1R, WNT, c-KIT and ETBR, has been found in both human and zebrafish pigment cells [70]. Studies on melanogenic potential of plant extracts and pure compounds of the zebrafish embryos are presented in Tables 1 and 2. According to that studies, analyzed extracts and pure compounds were mostly noncytotoxic towards zebrafish embryos in the range of tested concentration.

The Effect of Plant Extracts and Pure Compounds on Melanin Content in the Rodent Model
The rodent model allows both to evaluate the impact of molecules on the whole organ, i.e., the skin, and to observe interactions of this organ with other body organs, which makes this model advantageous. On the other hand, results of the rodent model obtained in preclinical studies are sometimes impossible to translate into clinical practice. Of all rodent models, the mouse model is most commonly used. Mice are easy to breed and maintain. They are genetically modifiable, have a short lifespan, and their skin properties are similar to those observed in human skin. However, there are some structural and molecular differences. The most obvious difference is the fact that rodent skin is more permeable than human skin, which is contributed by fur which covers most of its body. Besides, it is also thinner than human skin. Body areas not covered by fur, i.e., the ears and tail, have thicker epidermis, like in humans. In addition, the skin of rodents contains muscle tissue, which is not found in human skin and epidermal regeneration takes 8-10 days, whereas this process in humans takes 26-28 days. Moreover, a different distribution of melanocytes is observed in mice. They are found mainly in hair follicles, while in humans, they are present in both hair follicles and the basal layer of the epidermis [103].
Studies conducted on the rodent model and investigating melanogenic potential of plant extracts and single compounds which are administered topically are available in the literature. The experiment lasts on average from a few days to several months. The shortest-lasting research was conducted on UVB-irradiated HRM-2 hairless mice exhibited to Pueraria thunbergiana in the form of cream containing 1 or 3% of the extract on the dorsal skin. Findings show great efficacy of the extract on pigmentation and melanogenesis induction after 3 days of exposition [104]. Jegal et al. tested Juniperus communis extracts at concentration of 5 to 50 µg/mL for 11 days as well as their main constituent, i.e., hypolaetin-7-O-β-D-xylopyranoside at a concentration of 50 µM on UVBirradiated HRM-2 hairless mice. Solution at 200 µL volume was applied to a dorsal skin site 3 × 3 cm. Histological findings of skin samples indicate a reduction in melanin deposition after extract treatment and a reduced number of melanocytes after exposition to pure compounds [105]. Nelumbo nucifera extract, used at 1% or 2% concentration and administered to UVB-irradiated guinea pigs on the back region for 2 weeks demonstrates similar activity. The main identified constituent was gallic acid [106]. Data show that 200 µL of Nymphaea nouchali extract, applied on UVB-irradiated HRM-2 hairless mice at a concentration 100 µg/mL to a 3 cm × 3 cm designated area on the dorsal skin for 4 weeks exhibit antimelanogenic effects [107]. Medicago sativa extract used at 10% or 20% concentrations and administered to dorsal region of C57/BL6 mice for 4 weeks exhibit a remarkable skin and hair pigmentation [108]. A study conducted by Choi et al. on UVB-irradiated brown guinea pig skin models revealed that Cyrtomium fortunei used at 3% concentration on back area and administered for 6 weeks exhibited depigmenting properties [109]. In addition, UVB-irradiated C57BL/6 mice treated with Nelumbo nucifera extract at concentrations of 1.25 mg/cm 2 and 2.5 mg/cm 2 for 8 weeks inhibited melanin production in the ear skin sample. The main component of this extract was identified as epigallocatechin [110]. Pyrostegia venusta extract used at 10% and administered to dorsal region of Swiss mice mice for 65 days show a increased epidermal melanin level and diminished dermal depigmentation [111]. The longest studies, covering a period of 5 months, were conducted on C57BL/6J Ler-vit/vit mice. Lespedeza bicolor extract applied at an amount of 0.2 mL/cm 2 to those animals significantly increase the level of melanocytes in the skin. The main constituent of extract was identified as quercetin [112]. Application of 0.2 mL/cm 2 Rhododendron schlippenbachii extract for 5 months leads to melanin production [113].
Other research involves oral administration of plant extracts or pure compounds. The experiments lasted from few days to several weeks. The shortest-lasting study was provided by Niu et al. on SD rat serum exposed to Caesalpinia sappan extract, applied at a dose of 1.15 g/kg, significantly reduced the content of TYR. Isolated compounds were identified as sappanone B, brazilin, protosappanin A, protosappanin B, caesalpin J [114]. C57BL/6J mice exposed to Adenostemma lavenia extract administered at a concentration of 100 mg/kg for 2 weeks show inhibited hair pigmentation. The main constituent was identified as ent-11-hydroxy-15-oxo-kaur-16-en-19-oic acid [115]. Improved depigmentation was observed after UVB-irradiated HRM-2 hairless mice treatment with Panax ginseng extract at doses of 150 and 300 mg/kg for 5 weeks [116] as well as 100 and 200 mg/kg of Zingiber mioga extract for 6 weeks [117]. Moreover, C57BL/6 mice and brown guinea pigs undergoing hydroquinone and H 2 O 2 induced hypopigmentation, respectively. Both were then treated with Vernonia anthelmintica, administered at concentrations of 61.5-246 mg/kg to the mice and 22-88 mg/kg to the guinea pigs for 30 days. In consequence, the extract darkened the dorsal skin samples and hair both in the mice and the guinea pigs [118].

The Effect of Plant Extracts or Pure Compounds on Melanin Content in the Human Model
In the human model, analyzing plant extracts were administered primarily topically. The research was mainly focused on an analysis of extracts with whitening properties. The experiments lasted an average several weeks. The shortest-lasting studies, i.e., covering the period of 4 weeks, involved application of Perilla frutescens extract at a concentration of 0.1% in 30 patients to the forearms [119] and Salacca edulis, rich in flavonoids extract, applied at 3% concentration to the forearm of 17 participants [120]. Other studies included exposure of 24 volunteers to 1% Etlingera elatior extract [121] and 30 subjects to Piper betle extract applied at a dose of 5 mg/cm 2 [122] to the forearm. Another studies involved 30 volunteers that tested 0.2 or 0.3 g of Perilla frutescens [123] and phenolic-rich Punica granatum extracts [124], applied to the face. Panax ginseng extract was applied as 3% cream by 10 volunteers onto foreheads and cheeks [116]. Gnetum gnemon extract at 3.5% concentration was applied to upper arms of 38 patients [125]. A study lasting 6 weeks evaluated the effect of Rosa gallica 0.05%, extract on facial skin of 10 participants [126] and Chrysanthemum indicum 0.5% extract on facial skin of 30 patients. It was revealed, that luteolin and acacetin-7-Orutinoside are major flavonoid compounds in that extract [127]. For 7 weeks, 0.05 or 0.1% Litchi chinensis extracts were tested on 29 volunteers on the forearm [128]. Some other studies covered a period of 8 weeks. The 3% Crocus sativus extract was applied to cheeks and forearms by 10 volunteers [129] and 68.6% Aster yomena extract was applied to the face by 22 participants [130]. The effect on humans facial skin of a single compound isolated from Pterocarpus marsupium, called pterostilbene and administered at 0.4% concentration was evaluated in 38 participants for 8 weeks [131]. Another study took 12 weeks. A study conducted by Ali et al. evaluated phenolic-rich Acacia nilotica 3% extract [132], while that carried out by Khan et al. evaluated both Hippophae rhamnoides and Cassia fistula extracts applied at a concentration of 500 mg to cheeks of 11 and 25 volunteers, respectively [133].
On the other hand, oinment with Piper nigrum extract as well as its constituenta alkaloid piperine at concentration of 5 mg/mL and 2 mg/mL, respectively promote melanocyte activity. Pigmentation was achieved in all the treated areas of 3 vitiligo patients during 12 weeks [134]. Similar effects was observed for 20 patients treated for 12 weeks with ointment containing Psoralea corylifolia seed powder (10% w/w). Ointment could be an effective monotherapy for small circular white lesions of vitiligo [135].
Three studies involved oral administration of plant formulations in forms of syrup, tablets or infusion. Aafi et al. show that extracts of Ziziphus jujuba and other herbal plants rich in phenolics and flavonoids, used for 8 weeks by 46 healthy volunteers have a positive effect on patients with facial skin hyperpigmentation and can be used to treat this skin disorder. One daily dose of 7.5 mL of syrup containing Ziziphus jujuba was applied: 30% wt/wt, Berberis vulgaris: 10% wt/wt, Rhus coriaria 10% wt/wt, Prunus domestica 7% wt/wt, and Rosa damascene 3% wt/wt [136]. In addition, Cloucci et al. indicate that combination of Phyllanthus emblica extract and vitamin E and caroteinods showed a valuable instrument to increase the effectiveness of vitiligo treatments. Sixty-five subjects treated with one tablet of an oral supplement containing Phyllanthus emblica (100 mg), vitamin E (10 mg), and carotenoids (4.7 mg) three times/day for 6 months had a mild repigmentation on the head/neck regions and on the trunk [137]. Resende et al. revealed that combination of Solanum paniculatum, Jacaranda brasiliensis and Sonchus oleraceus extracts showed beneficial properties in the therapy of patients with vitiligo. Consumption of a 800 mL infusion per day (concentration of 15 g of each plant, in total 45 g/2 L) for one year resulted in depigmentation, manifesting with 80% or more of depigmented patches [138].

In Vitro Studies
Detailed analyses of the modulation of melanogenesis upon treatment with plant extracts and isolated plant compounds in in vitro model were presented in our previous study [60]. However, selected investigations of plant extracts and pure plant compounds on in vivo models, given above, were also conducted on melanocyte monocultures. They included an analysis of gene expression and signaling pathways modulation after treatment.
The detailed information about the impact of given above plant extracts and pure compounds on melanocytes biology are presented in Tables 3 and 4. According to that studies, analyzed extracts and pure compounds were noncytotoxic towards melanocytes in the range of tested concentration.

The Patented Plant-Based Compositions and Their Role in the Therapy of Hyperpigmentation and Hypopigmentation
Inventions in the field of cosmetics, including plant-based compositions of topically applied skin care products, effective in reducing and enhancing pigmentation are presented in Tables 5 and 6.
Some patented formulations contain also pure compounds isolated from plants. For example, the effect of skin lightening was exhibited for rebaudioside A, a diterpene glycoside obtained from Stevia genus (WO2014132217A1), B salvianolic acid, a phenolic acid from Salviae miltiorrhizae, (CN102895308A) and madecassoside, a triterpenoid saponin from Centella asiatica (WO2014003224A1). In contrast, silybin, a flavonoid from Silybum marianum shows stimulating properties for skin pigmentation (US8569358B2).
In addition, an invention entitled "Methods useful in studying or modulating skin or hair pigmentation, plant extracts used in compositions and cosmetic care method" (US8409633B2) presents methods useful in modulation of skin pigmentation. According to its inventors, myosin-X (Myo X) is a crucial protein that controls melanin transfer from melanocytes to keratinocytes. Therefore, compounds that have the ability to impact the expression and activation of Myo X can modulate the skin tone. Accordingly, the molecules that decrease expression of Myo X may reduce skin pigmentation, whereas molecules that increase expression of Myo X may enhance skin pigmentation. The first groups include extracts of the following genus plants: Artocarpus, Cyathea, Secale, Thalassiosira and Buddleja. The second group includes: a soybean extract, preferably a soy seed extract, more preferably a soy seed pericarp extract.

Conclusions
This literature review presents the impact of plant extracts or pure compounds on melanogenesis potential in in vivo models. Most of the reviewed studies focus on the whitening potential of plants. A relatively large number of studies were performed on the zebrafish model. This organism was used to evaluate the melanogenic potential of both plant extracts and pure compounds. Fewer studies were performed on rodent and human models and were mainly focused on the analysis of plant extracts. In rodent models, plant extracts were administered orally or topically to the skin, and with regard to the human model, they were administered mainly topically. In addition, the majority of patented plant-based compositions was formulations containing plant extracts, applied topically to the skin. The authors evaluated extracts isolated from plants belonging to different species and families as well as pure compounds belonging to different chemical classes. Panax ginseng plant, which exhibits significant whitening activity, was the most often studied in various model systems. In contrast, Salvia miltiorrhiza extract repeatedly added to patented plant-based formulations, demonstrated hypopigmentation properties. Selected investigations of plant extracts and pure plant compounds on the vivo models were also conducted on melanocyte monocultures. It was reveald that many of phytochemicals are able to modulate different cellular signaling pathways, including those which regulate the expression and activity of melanogenesis-related proteins. In conclusion, molecules of natural origin may play an important role in the therapy of dermatological disorders, including hyperpigmentation and hypopigmentation.

Conflicts of Interest:
The authors declare no conflict of interest.