Depigmentation Agents Research Articles

New Chalcone-Derived Molecule for the Topical Regulation of Hyperpigmentation and Skin Aging.

Background/Objectives: Skin hyperpigmentation is a biological process that results in an excessive production of melanin and is highly regulated by several mechanisms, tyrosinase being one of the key enzymes involved. Current reported inhibitors lack clinical efficacy, show toxic side effects, have poor bioavailability, or low formulation compatibility. The aim of this study was to design a new effective tyrosinase inhibitor for topical hyperpigmentation and anti-aging treatments. Methods: Homology modeling was used to build the tridimensional structure of human tyrosinase, and virtual docking was used to predict molecule-enzyme binding modes. The tyrosinase activity of the designed and synthesized compounds was assessed and water solubility was determined by HPLC. Cell assays were performed to determine melanin content, cytotoxicity, wound healing, anti-glycation, antioxidation, and autophagy efficacy. Gene expression and miRNA levels were quantified by qPCR and chromatin accessibility by ATAC-Seq. Human reconstructed epidermis was used to test the depigmenting efficacy as well as the skin irritation potential. Results: The 3D structure of human tyrosinase was designed and validated. The new molecule could effectively inhibit human tyrosinase and melanin synthesis in 2D monocultures and a 3D epidermis model. Two melanogenesis-related miRNAs were increased in treated cells. Anti-glycation, antioxidant, mitochondria protection, autophagy activation, and wound healing properties were also observed, with special emphasis on epigenetics. Conclusions: The designed molecule is a potential candidate to be used as a depigmenting and anti-aging agent, with suitable properties to be introduced in final product formulations for dermatology or cosmetics treatments.

Latin American consensus on the treatment of melasma.

Melasma is a chronic, relapsing hyperpigmentation disorder that primarily affects photoexposed areas, occurring most frequently in adult women with darker skin phototypes. The primary factors contributing to its development include sun exposure, sex hormones (e.g., pregnancy), and genetic predisposition. Melasma is highly prevalent in Latin America, where many countries lie in intertropical zones and exhibit significant ethnic diversity because of centuries of intermixing among Native Americans, Europeans, and Sub-Saharan Africans. Nine Latin American experts formulated a DELPHI-based consensus to develop a valuable approach for treating melasma in this diverse population. After establishing an accurate diagnosis, assessing the impact on quality of life, and determining disease severity, the consensus recommends mitigating known triggers and promoting rigorous photoprotection. Active therapy should be tailored based on individual characteristics (e.g., pregnancy status, previous treatments, skin sensitivity). Treatment options include topical depigmenting agents, systemic therapies, and procedural interventions such as laser therapy, microneedling, and chemical peels. Periodic reassessment of the treatment is essential, with strategies adjusted if targeted outcomes are not achieved. Once clinical remission is attained, patients should continue using topical depigmenting agents and maintain strict photoprotection measures to prevent recurrence.

Tyrosinase Inhibition: A Potent Mechanism of Action of Plants used in Treatment of Melasma

Melasma is a common skin problem causes brown to grey-brown patches on the several parts of face such as cheeks, chin, Nose Bridge, forehead, and above the upper lip. It is characterized as increased production and accumulation of melanin, which could be unfavourable and develops serious skin diseases. Finding natural depigmenting agents is necessary because many synthetic agents now on the market have a number of unfavourable side effects. In traditional Ayurvedic medicinal plants have been used for the treatment of skin diseases such as hyperpigmentation, melasma, age spot etc. In this study herbal medicines, for the treatment of melasma were searched in references, with their scientific names and chemical constituents showing depigmentation effect of these plants or their isolated compounds, with different melanogenesis and tyrosinase inhibition mechanism. This activity reviews the herbal plant used in melasma and highlights the role of plants constitutes responsible for treatment of melasma.

Structure-based Drug Design of New Cinnamic Acid Derivatives as Tyrosinase Inhibitors

Abstract: Tyrosinase is a critical enzyme responsible for pigmentation disorders, and tyrosinase inhibition is an established strategy to treat hyperpigmentation. In the current study, cinnamic acidbased derivatives were designed and synthesized. All synthesized compounds were confirmed using IR, 1HNMR, 13CNMR, and CNH analysis. The inhibitory potencies of all derivatives against tyrosinase were determined, and it was shown that 5m bearing para-chloro moiety exhibits an IC50 value of 77.62 μmol/L. Analysis of enzyme kinetic studies revealed that 5m is an uncompetitive inhibitor. In silico studies against tyrosinase predicted possible binding mode in the pocket such that 5m formed critical interactions with both Cu co-factors within the binding site. This study presents the potential of aryl-substituted cinnamic acids that can benefit various cosmetic formulations as depigmentation agents.

Dendropanax morbifera Leveille Extract-Induced Alteration of Metabolic Profile in Whitening Effects

This study aimed to evaluate the potential of Dendropanax morbifera Leveille (D. morbifera) extract as a natural melanin depigmentation agent to achieve skin whitening. Treating α-MSH-stimulated B16-F10 cells with the extract effectively inhibited melanin production and tyrosinase activity. The cellular metabolic profiles were analyzed to understand the mechanisms underlying the whitening-related metabolic processes. We identified 29 metabolites that were significantly altered in the α-MSH-stimulated B16-F10 cells. The melanin-synthesis-related pathways that were downregulated included phenylalanine, tyrosine, and tryptophan biosynthesis and phenylalanine metabolism. Simultaneously, alanine, aspartate, and glutamate metabolism; arginine and proline metabolism; arginine biosynthesis; butanoate metabolism; glutathione metabolism; and glyoxylate and dicarboxylate metabolism were upregulated. We found that the optimal extract concentration of 0.2 mg/mL showed the highest efficacy in reversing the alterations to the metabolite levels and metabolic pathways. Moreover, D. morbifera extract exerted low cytotoxicity and high efficacy in inhibiting melanin production. Thus, D. morbifera extract is a potential melanin inhibitor with application in the development of whitening cosmetics.

Investigation of inhibition kinetics of various plant extracts on polyphenol oxidase enzyme from Paulownia Tomentosa and binding mechanism by molecular docking

Polyphenol oxidase/tyrosinase enzyme, which contains binuclear copper clusters play an important role in melanogenesis and enzymatic browning. Therefore, its inhibitors can be attractive in cosmetics and medicinal industries as depigmentation agents and also in food and agriculture industries as antibrowning compounds. Our aim in this study is to find natural plant extracts that will inhibit the polyphenol oxidase enzyme. The inhibitory effects of Verbascum thapsus, Tanacetum vulgare, Solanum nigrum and Datura stramonium herbal plant extracts obtained from Kosovo on the polyphenol oxidase enzyme activity were investigated. Polyphenol oxidase from the Poulownia tomentosa plant was purified using the three-phase purification method. It is determined that T. vulgare extract showed the most effective inhibitory effect with 0.43 mg/mL IC50 value. In order to explain and support the binding mechanism of the best inhibitor extract, the phenolic content of the T. vulgare extract was determined by LC-MS/MS and the mechanism of the inhibitory effect was explained by performing a molecular docking study for the phenolic compounds it contained at the highest rate.

Carotenoids in red fruit (Pandanusconoideus Lam.) have a potential role as an anti‑pigmentation agent (Review).

Melasma is a persistent condition characterized by excessive melanin production in the skin. The management of melasma necessitates a protracted treatment duration, which is associated with diminished levels of patient satisfaction. One effective strategy for mitigating occurrence of melasma is consumption of nutricosmetics with depigmentation properties. The present review aimed to investigate the potential of red fruit as a depigmentation agent. Carotenoids serve a crucial role in human nutrition as a precursor to vitamin A. Carotenoids serve as scavengers of reactive oxygen species generated by ultraviolet radiation. Carotenoids promote skin health. Red fruit, a fruit originating from Papua (Indonesia) has anti-pigmentation properties associated with its ability to block melanogenesis through various protein pathways such as PKA, ERK, and AKT signaling pathways. The consumption of food rich in carotenoids, such as red fruit, has advantageous properties to reduce hyperpigmentation and skin brightening.

The Effect of Natural Essential Oil Depigmenting Agent for Alternative Treatment of Melasma

Melasma, known as a hyperpigmentation disorder, is more common in women of childbearing age with Fitzpatrick IV-VI skin types. Various factors of this disease, namely genetic factors, UV exposure, hormonal, thyroid disease, pregnancy, and drugs. The best treatment for melasma is with 2 – 4% hydroquinone, but because of the side effects, alternative treatments are mostly used for melasma. One of them is with essential oils. Essential oils have been investigated as depigmenting agents because of their anti-tyrosinase potential. In this literature, it is proven that the essential oils of sage (Salvia), hedgenettle / woundwort (Stachys), lavender (Lavandula), tea tree (Melaleuca alternifolia), cinnamon (Cinnamomum), mountain tea (Sideritis), pomelo (Citrus grandis ( L) Osbeck), and kaffir lime (Citrus hystrix DC) are effective against melasma. The purpose of this literature is to discuss the various effects of essential oils that can be used as depigmentation agents in the alternative treatment of melasma.

Review of Ruxolitinib for Treatment of Non-Segmental Vitiligo.

To review the pharmacokinetics, efficacy, and safety of topical ruxolitinib for treatment of nonsegmental vitiligo. Literature published between January 1983 and October 2022 was reviewed from MEDLINE and ClinicalTrials.gov. Relevant articles in English and data from clinical trials were included. In 2 phase II trials, treatment with ruxolitinib cream showed significant improvements in Vitiligo Area Scoring Index (VASI) scores compared with controls. The 1.5% concentration applied twice daily showed the best results after 52 weeks, with 50% VASI improvement in 58% of patients, 75% VASI improvement in 52% of patients, and 90% VASI improvement in 33% of patients. In 2 phase III trials, more patients achieved at least 75% improvement in facial VASI at 24 weeks (primary endpoint; trial 1: 29.9%, trial 2: 29.9%) than controls (trial 1: 7.5% [P < 0.0001], trial 2: 12.9% [P < 0.01]). Common adverse effects were erythema, pruritus, and acne; all events were mild. This review summarizes the pharmacokinetics, efficacy, and safety data regarding topical ruxolitinib for vitiligo. Ruxolitinib is associated with significant clinical improvements with low bioavailability and minimal adverse effects compared with conventional topical steroids, calcineurin inhibitors, phototherapy, and depigmentation agents. Ruxolitinib cream is the first therapy approved by the Food and Drug Administration for repigmentation of nonsegmental vitiligo. Clinicians should consider these benefits when recommending treatment as conventional therapies may be time-intensive and carry greater risks of adverse effects.

Application of traditional Chinese medicine as skin depigmentation agents

Traditional Chinese medicine (TCM) has been frequently used as skin lightning agents. However, the mechanism of action of their effect is unclear. The present study aims to evaluate anti-tyrosinase activity of 10 commonly used TCM on mushroom (ab), human (hs) and mouse melanoma B16F0 (mm) tyrosinase (TYR) respectively. The results showed that at 1.0 mg/mL, extracts from Rosa rugosa Thumb, Morus alba L. and Paeonia lactiflora Pall were active against both abTYR and hsTYR (>50% inhibition), extracts from Bletilla striata (Thunb.) Rchb. F., Centella asiatica (L.) Urb, Cynanchum atratum L., Rosa canina L., Rhus chinensis Mill. and Glycyrrhiza urolensis Fisch. Ex DC. inhibited either abTYR or hsTYR (>50%), while extract from Tribulus terrestris L. had no/minimal activity (<10% inhibition). When treated with melanoma B16F0 cells, M. alba also significantly reduced mmTYR activity (70% at 250 μg/mL) and melanin content (50% at 250 μg/mL). These findings demonstrated inhibitory effects of 9 TCM against TYR and hence support their application as skin lightning agents. Our results also showed discrepancies in TYR activity from different sources, suggesting a testing regime of combining abTYR, hsTYR and mmTYR when developing depigmentation agents for human application.

519 Design of a new molecule proven to be safe and effective for topical depigmenting and antiaging method

Skin hyperpigmentation is a biological process that results in an excess production of melanin. Tyrosinase inhibition is an effective approach to this condition, although inhibitors reported in the literature lack clinical efficacy or show toxic effects. Chalcone derivatives are well known tyrosinase inhibitors but insoluble in aqueous phase limiting its use in final product formulations. The aim of this study is to develop a new chalcone-related molecule that is safe and effective as a skin depigmenting and antiaging agent.

Toward New Depigmenting Agents through Repurposing Existing Drugs: Substituted Hydroxyquinolines as Melanogenesis Inhibitors

Disorders of pigmentation, a group of conditions that arise from underproduction or overproduction of melanin in the skin, represent a significant medical burden on individuals, particularly on patients of color (Maymone et al., 2017). Hyperpigmentation disorders, such as melasma and postinflammatory hyperpigmentation, are of particular concern because there are few safe and effective treatments (Chaowattanapanit et al., 2017). The small-molecule hydroquinone, currently the only approved drug to treat hyperpigmentation in the United States, faces regulatory scrutiny owing to its possible carcinogenicity, and its use in both the United States and elsewhere has recently been severely restricted (Liu et al., 2021).

Phytochemical characterization and mushroom tyrosinase inhibition of different extracts from Salvia officinalis L. leaves

Context: Sage (Salvia officinalis) is an ancient valuable plant used in the treatment of variant health issues. Aims: To evaluate the depigmentation activity of S. officinalis leaf chloroformic (SOCF) and ethanolic (SOMF) extracts via its efficacy to inhibit tyrosinase enzyme using in vitro model and bioassay-guided identification and quantification of the main active constituents. Methods: Plant extracts efficacy as a depigmentation agent has been studied via mushroom tyrosinase inhibition using in vitro model at two concentrations (100 and 200 µg/mL). Extracts were analyzed for phenolic compounds that could be responsible for the biological activity using LC-MS/MS analysis. Results: Significant potency at a high concentration of 200 µg/mL for the methanolic extract were recorded (p≤0.05). The LC-MS/MS analysis of S. officinalis leaf extracts revealed the presence of eight and fourteen analytes of origin of thirty-seven analytes in both SOCF and SOMF, respectively. Analytes’ quantification recorded the highest amount for rosmarinic acid (46 016 µg/g) in SOMF and the lowest was hesperidin (0.6 µg/g) in SOCF. Conclusions: S. officinalis extracts recorded significant tyrosinase inhibition potency could control the melanin synthesis process and exhibit beneficiary effect in hyperpigmentation issues.

Amorphigenin from Amorpha fruticosa L. Root Extract Induces Autophagy-Mediated Melanosome Degradation in mTOR-Independent- and AMPK-Dependent Manner.

In this study, we investigated the depigmentation effect of Amorpha fruticosa L. root extract (RE), an herbal medicine. A. fruticosa RE significantly induced depigmentation in α-MSH-treated B16F10 cells at noncytotoxic concentrations. Further, the RE decreased the protein levels of the melanosomal proteins Tyr and Pmel without decreasing their transcript levels. We found that MG132, a proteasome complex inhibitor, was unable to rescue the protein levels, but PepA/E-64D (a lysosomal enzyme inhibitor), 3-MA (a representative autophagy inhibitor), and ATG5 knockdown effectively rescued the protein levels and inhibited the depigmentation effect following RE treatment. Among rotenoids, amorphigenin composed in the RE was identified as a functional chemical that could induce depigmentation; whereas rapamycin, an mTOR inhibitor and a nonselective autophagy inducer, could not induce depigmentation, and amorphigenin effectively induced depigmentation through the degradation of melanosomal proteins. Amorphigenin activated AMPK without affecting mTOR, and knockdown of AMPK offset the whitening effect through degradation of melanosome proteins by amorphigenin. Results from this study suggested that amorphigenin can induce degradation of the melanosome through an AMPK-dependent autophagy process, and has the potential to be used as a depigmentation agent for the treatment of hyperpigmentation.

Bioactive constituents isolated from the Sri Lankan endemic plant Artocarpus nobilis and their potential to use in novel cosmeceuticals

Two novel compounds, dicarbonyl ester (2) and artolankanin A (3) were isolated from the sequential ethyl acetate and ethanol extracts of stem bark of A. nobilis along with the known compounds, artonin E (1) and artobiloxanthone (4) by bioassay-guided fractionation using a combination of normal phase and size exclusion column chromatography. Their structures were elucidated by spectroscopic techniques, including NMR (1H, 13C, APT, 1H–1H COSY, HSQC, and HMBC), Mass, IR, and UV. The isolated compounds were evaluated for DPPH free radical scavenging activity, tyrosinase, elastase, hyaluronidase, and A5-lipoxygenase enzyme inhibitory activities lipopolysaccharide-induced nitric oxide production inhibitory activity in SIM-A9 microglial cells. Artonin E exhibited marked tyrosinase and A5-lipoxygenase enzyme inhibitory activities and NO inhibition activity in LPS-stimulated microglia cells having IC50 values of 60.92 ± 3.45, 56.38 ± 1.05, and 23.94 ± 1.08 µg/mL, respectively. Kinetic studies showed that the tyrosinase inhibitory activity of artonin E is via a noncompetitive inhibition mechanism. Further, artolankanin A and artobiloxanthone exhibited good A5-lipoxygenase enzyme inhibitory activity having IC50 values of 59.48 ± 1.06 and 62.45 ± 2.25 µg/mL, respectively. Insights from molecular docking and molecular dynamics simulations align with these experimental observations and propose plausible mechanisms of inhibition. Collectively these results suggest that these compounds have the potential to be used as depigmenting and anti-inflammatory agents.

Application of hydroxylated multi-walled carbon nanotubes as depigmentation agent in the determination of multiple pesticide residues in Lonicerae japonicae flower buds

Lonicerae japonicae flower buds have been used as functional foods for many years, however, the problem of pesticide residues has attracted extensive attention in recent years. In this study, a sorbent package consisting of a combination of hydroxylated multi-walled carbon nanotubes (MWNTs-OH), primary secondary amine, and MgSO4 was developed for modified solid-phase extraction of 57 easily contaminated pesticides residues from Lonicerae japonicae flower bud samples. The pesticides were then detected by gas chromatography coupled to an electron impact ionization triple quadrupole mass spectrometer. Six multi-walled carbon nanotubes were compared for purification efficiency and recovery and found that the best results were achieved with MWNTs-OH (20–50 nm in diameter and 10–30 μm in length). Under optimized conditions, good linearities were obtained in the 1–100 ng·mL−1 range. The average recoveries at three spiked levels were in the 80.4–118.5% range, with relative standard deviations (RSDs) ≤ 20%. The quantification limits were 0.4–5.0 μg·kg−1. Compared with QuEChERS and traditional HLB purification methods, the application of MWNTs-OH could better remove the pigment from a complex sample matrix, as well retain the target analytes as much as possible. Advantages of this newly established method include less analytical time, less solvent consumption and good recovery.

Potency of moringa (Moringa oleifera L.) leaves extract containing quercetin as a depigmentation agent inhibiting the tyrosinase enzyme using in-silico and in-vitro assay

Hyperpigmentation is a disorder of facial skin pigments due to an increase in the process of melanogenesis, which can cause a darkening of skin color. A flavonoid compound with potential as a skin-lightening agent is quercetin, commonly found in Moringa oleifera L. leaves. This study aims to determine quercetin’s affinity and molecular mechanism on tyrosinase enzyme target proteins using an in-silico molecular docking method. Docking of quercetin with the tyrosinase enzyme produced a bond energy value of -7.08 kcal/mol. In comparison, the tropolone as a native ligand with the tyrosinase enzyme produced -4.79 kcal/mol. Quercetin has a strong affinity for the tyrosinase enzyme, indicated by the bond energy results from docking. Quercetin extraction from Moringa oleifera L. leaves using three different extraction methods: maceration, soxhlation, and reflux were made. The chromatogram from the TLC-Densitometry method showed the identification result in maceration and soxhlation extract containing quercetin, while reflux extract did not contain quercetin. The highest quercetin was obtained in the maceration method with a level of 21.57% w/w, while the soxhlation received quercetin as much as 18.49% w/w. In-vitro tests were carried out using a spectrophotometric method using a comparison of kojic acid. The in-vitro test found that IC50 from kojic acid was 48.90 µg/mL and IC50 of the extract from moringa leaf maceration of 115.36 µg/mL. Based on this research, quercetin compounds in Moringa oleifera L. leaves from maceration can potentially be skin-lightening agents.

Skin Depigmenting Agents in Anti-Aging Cosmetics: A Medicinal Perspective on Emerging Ingredients

Human skin aging results from intrinsic and extrinsic factors. Uneven pigmentation is one of the major changes of extrinsic aging. Many compounds have been tested for depigmenting activity but only a few are actually used by the cosmetic industry, which is continually looking for new ingredients. In this study, the trends in the use of skin depigmenting ingredients in a panel of anti-aging formulations commercialized in the Portuguese pharmacy market were analyzed, by comparing the composition of the products marketed in 2011 with products launched or reformulated in 2018 (59% and 74%, respectively). The analysis of the top 12 ingredients put forward three novelties for 2018: tranexamic acid, bakuchiol, and 4-butylresorcinol. Regarding their mechanisms of action, tranexamic acid inhibits melanin synthesis through inhibition of the plasminogen/plasmin system. Bakuchiol depigmenting efficacy was attributed to the ability to block both α-melanocyte-stimulating hormone and tyrosinase activation, while 4-butylresorcinol exerts its action through the inhibition of both tyrosinase and tyrosinase-related protein-1 (TRP-1). Industry-optimized and efficient synthetic methodologies that embrace green chemistry, reducing the environmental impact, are commonly used. This analysis aims to bring insights to both formulators, involved in the development of depigmenting cosmetic products, and chemists performing the synthesis of new and existing compounds intended for this purpose.

Effects of Monobenzyl ether of hydroquinone on 3T3 mouse fibroblast viability and ultrastructure

ABSTRACT Monobenzyl ether of hydroquinone (MBEH) is a topical depigmentation agent used by vitiligo patients to even the skin tone. We aimed to investigate the effects of MBEH on 3T3 mouse fibroblasts. Fibroblasts were treated with 250 µM, 500 µM, and 750 µM MBEH and vehicle (EtOH:DMSO) for 24 hours. Cell numbers of 250 µM, 500 µM, and 750 µM MBEH treated and vehicle groups decreased significantly compared to control group. TUNEL positive cell rate increased with MBEH concentration. In electron microscopic examination, control and vehicle groups showed active cells features, while mitochondrial swelling and cristae loss were seen in 250 µM MBEH-treated group. In cytoplasm of 500 µM MBEH-treated group, there were many multivesicular bodies and autophagic vacuoles. As an indication of apoptosis, cell membrane blebs and reduction in cell size were observed. In 750 μM MBEH-treated group, cells were completely degenerated. Our findings show that MBEH, which is used as a depigmentation agent to lighten the skin by destroying melanocytes, may also have dose-dependent negative effects on the viability of 3T3 mouse fibroblasts, and these may be mediated through autophagic and apoptotic cell death mechanisms.

Highly Sensitive and Ecologically Sustainable Reversed-Phase HPTLC Method for the Determination of Hydroquinone in Commercial Whitening Creams

Hydroquinone (HDQ) is a natural depigmenting agent, which is commonly used in skin-toning preparations. The safety and greenness of analytical methods of HDQ quantification were not considered in previous literature. Therefore, a highly sensitive and ecologically greener reversed-phase high-performance thin-layer chromatography (RP-HPTLC)-based assay was established for HDQ estimation in four different commercial whitening creams (CWCs). The binary ethanol–water (60:40, v·v−1) mixture was utilized as the green solvent system. The estimation of HDQ was carried out at 291 nm. The present RP-HPTLC-based assay was linear in the 20–2400 ng band−1 range. The present analytical method was highly sensitive based on the detection and quantification data. The other validation parameters, such as accuracy, precision, and robustness, were also suitable for the determination of HDQ. Maximum HDQ quantities were obtained in CWC A (1.23% w·w−1) followed by CWC C (0.81% w·w−1), CWC D (0.43% w·w−1), and CWC B (0.37% w·w−1). The analytical GREEnness (AGREE) score for the present analytical method was estimated as 0.91, indicating the excellent greener characteristics of the present RP-HPTLC assay. These results suggest that the present analytical method is highly sensitive and ecologically sustainable for the quantitation of HDQ in its commercial formulations.