Search Results (137)

Melanin produced in melanocytes contributes to photoprotection, oxidative stress reduction, immune regulation, and epidermal homeostasis, while its dysregulation underlies diverse pigmentary disorders. Natural products modulate melanogenesis by regulating tyrosinase activity, intracellular signaling pathways such as extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and cyclicAMP/protein kinase A/cAMP response element-binding protein (cAMP/PKA/CREB), and cellular redox balance. Anti-melanogenic effects have been reported for various fruit-derived phytochemicals, ginseng-based metabolites, and plant polyphenols, which act through direct enzymatic inhibition, suppression of melanoenic signaling, modulation of melanosome dynamics, and antioxidant or anti-inflammatory activities. Advances in delivery systems, including nano- and microencapsulation platforms, further enhance the stability and topical bioavailability of these compounds. In contrast, certain methoxylated flavonoids and phenolic constituents can stimulate pigmentation by sustaining melanogenic signaling and promoting microphthalmia-associated transcription factor (MITF)-driven transcription, emphasizing the context-dependent and bidirectional influence of natural substances on pigmentation outcomes. Collectively, these findings highlight the therapeutic potential of natural product-based modulators of melanogenesis while underscoring the need for mechanistic clarification, safety evaluation, and translational studies to ensure effective and controlled pigmentation management. This review summarizes the biological functions of melanin and examines natural strategies for regulating pigmentation. Full article

The synthesis of the melanin pigment in melanocytes plays a crucial role in protecting the body from ultraviolet radiation. Tyrosinase, a key enzyme in melanogenesis, catalyzes the conversion of tyrosine to melanin in the melanosomes of melanocytes. During melanogenesis, Tyrosinase is abundantly synthesized in the lumen of the endoplasmic reticulum (ER) and subsequently transported from the ER to the melanosomes via the Golgi apparatus. In the present study, we demonstrate that Box B-binding factor 2 human homolog on chromosome 7 (BBF2H7), an ER-resident transmembrane transcription factor that functions as an ER stress sensor, is activated by mild ER stress caused by abundant Tyrosinase synthesis. Activated BBF2H7 enhances COPII-mediated anterograde transport by inducing the expression of Sec23a, which is a COPII component and transcriptional target of BBF2H7. Loss of BBF2H7 attenuates the transport of Tyrosinase, leading to its accumulation in the ER lumen and reduced melanin production. Restoration of BBF2H7 or Sec23a expression in Bbf2h7-deficient melanocytes rescues anterograde transport of Tyrosinase from the ER and melanin pigmentation. Collectively, these findings reveal that the BBF2H7-Sec23a axis is essential for the ER-to-melanosome transport of Tyrosinase and subsequent melanin synthesis. Thus, it may be a prospective therapeutic target for disorders related to melanin pigmentation. Full article

Percocypris pingi is an endangered protected fish species in China. Its albino variants exhibit growth retardation and physiological abnormalities. Understanding its albinism mechanism holds significant scientific importance for molecular breeding programs and disease model development. This study integrated transcriptomic and proteomic analyses, combined with histopathological and molecular biological techniques, to systematically compare molecular differences in skin tissues between albino and wild-type P. pingi, with a focus on elucidating the multidimensional regulatory mechanisms underlying skin albinism. Our findings suggest that albinism in P. pingi is synergistically driven by hyperactivation of ubiquitin-mediated proteolysis (which suppressed TYR/TYRP1 enzymatic activity and disrupted the pH homeostasis of melanosomes), and inhibition of calcium signaling (which impeded melanin transport). This discovery provides novel insights into the mechanisms of pigment loss in fish species and offers a valuable reference for molecular breeding of endangered species as well as research on pigmentation-related disorders. Full article

Background/Objectives: Chamaecyparis pisifera (C. pisifera; family Cupressaceae) is known to have insecticidal and antibacterial activities, but its effects on skin depigmentation-related activities have not been elucidated. Thus, in the present study, we aimed to investigate the anti-hyperpigmentation potential of C. pisifera var. filifera leaf essential oil (CPEO), specially focusing on responses related to melanogenesis and melanin transport, using B16BL6 cells. Methods: CPEO was extracted by steam distillation, and its composition was determined by GC/MS spectrometry. The biological activities of CPEO on B16BL6 melanoma cells were analyzed using the water soluble tetrazolium salt, BrdU incorporation, ELISA, and immunoblotting assays. Results: Twenty-eight components were identified in CPEO. CPEO was noncytotoxic to B16BL6 cells at 1–100 μg/mL and reduced serum-induced proliferation in B16BL6 cells. CPEO significantly inhibited α-MSH-stimulated increases in melanin synthesis and tyrosinase activity in the cells (e.g., at 100 μg/mL CPEO, melanin synthesis: 117.89 ± 0.00% vs. 571.94 ± 0.81% with α-MSH; tyrosinase activity: 73.62 ± 0.00% vs. 322.60 ± 3.10% with α-MSH). CPEO also downregulated the expression levels of melanogenesis-related proteins (MITF, tyrosinase, TRP-1 and -2) and melanosome transport-related proteins (Rab27a, melanophilin, myosin Va) in cells exposed to α-MSH. Moreover, the essential oil increased the phosphorylations of MAPKs (p38, ERK1/2, and JNK) in α-MSH-treated B16BL6 cells. In addition, CPEO reduced the ultraviolet A (UVA) induced increases in α-MSH levels in HaCaT cells. In addition, conditioned medium from HaCaT cells irradiated with UVA (CM-UVA) in the presence of CPEO reduced melanin synthesis and tyrosinase activity in B16BL6 cells (e.g., at CM-UVA with 100 μg/mL CPEO, melanin synthesis: 100.92 ± 0.99% vs. 134.44 ± 0.97% with CM-UVA; tyrosinase activity: 101.02 ± 1.81% vs. 133.77 ± 1.88% with CM-UVA). Conclusions: These findings suggest that CPEO inhibits melanin production (probably through the regulation of MAPKs) and transport-related activities in B16BL6 cells, and that CPEO may serve as a potential natural anti-hyperpigmentation or skin whitening. Full article

Uveal melanoma (UM) is the most prevalent primary intraocular tumor in adults. Transcription factor ZEB1 is one of the potential master regulators of melanocytes plasticity, because it is recognized as a “driver” of epithelial-to-mesenchymal transitions (EMTs) in carcinomas. We studied the correlation of tumor invasiveness with ZEB1 status and vascular endothelial growth factor/its receptor (VEGF-A/VEGFR2) in UM cells, and also with melanocyte’s differentiation rate. Eight UM cell cultures were characterized by melanosomes content using an ETM. ZEB1, VEGF-A and VEGFR2 levels in UM cells were detected by RT-PCR, Western blot, ELISA and flow cytometry. Effects of siRNA-dependent ZEB1 knockdown on UM cell proliferation and their sensitivity to the VEGF-A inhibitor Eylea (aflibercept) were tested by MTT and in a real-time proliferation assay. UMs with an invasive growth type can maintain a high degree of melanocyte differentiation. All ZEB1^low cells were obtained from spindle cell tumors. The sensitivity of UM cells to Eylea inversely correlated with the level of the VEGFR2 receptor. ZEB1 knockdown completely blocked VEGF-A production while anti-VEGF treatment stimulated ZEB1 increase. In UM cell cultures, ZEB1 is a positive regulator of VEGF-A expression. In addition, there is probably a ZEB1 feedback loop that is sensitive to a drop in VEGF-A concentration. The data obtained allow us to consider ZEB1 silencing as an auxiliary link for a combined strategy of killing UM cells. Full article

Melasma is a chronic, acquired hyperpigmentation disease that occurs on light-exposed skin, especially in women of childbearing age. This common dyschromic disorder significantly impairs quality of life, yet treatments are unsatisfactory due to an incomplete understanding of its etiology. Its pathogenesis is multifactorial: ultraviolet (UV) radiation exposure, sex hormone fluctuations, and familial genetics are known triggers. Meanwhile, the persistence of focal hyperpigmentation suggests additional mechanisms beyond enhanced melanocyte activity. Emerging evidence highlights that melasma skin exhibits features of chronic photoaging: solar elastosis, basement membrane (BM) disruption and increased vascularity can be seen in the skin lesions. Senescent dermal fibroblasts under UV stress secrete melanogenic cytokines (e.g., SCF, HGF) that further stimulate melanocytes. In addition, melasma lesions harbor subclinical inflammation: infiltrates of CD4⁺ T cells, macrophages, and mast cells are visible, accompanied by elevated IL-17 and COX-2, implying an immune-driven component sustains pigment production. Collectively, these observations suggest that melasma behaves as a chronic inflammatory disorder of the skin microenvironment, rather than an isolated pigmentary defect. Concurrently, epidermal alterations such as barrier dysfunction and abnormal melanosome transport exacerbate melanin retention. In this review, by integrating these emerging insights into a unified pathogenic framework, we recognize melasma as a disorder of epidermal–dermal crosstalk and immune modulation, offering novel therapeutic perspectives for this recalcitrant condition. Full article

Achieving even skin tone and controlling pigmentation are key goals in dermocosmetics, given the impact of disorders like melasma, post-inflammatory hyperpigmentation, and age spots. The process of pigmentation begins with melanin synthesis within melanosomes, specialized organelles in melanocytes. Once produced, melanin is transferred to neighboring keratinocytes, where it forms protective caps over cell nuclei before undergoing eventual degradation. Disruptions at any stage of this complex process, whether in melanin production, melanosome transport, or post-transfer processing, can lead to visible pigmentation irregularities. While traditional treatments primarily focus on inhibiting melanin production (e.g., through tyrosinase inhibitors), emerging research highlights the important role of melanosome transport and keratinocyte-mediated processing in determining visible pigmentation. This review focuses on the underexplored stages of melanosome transport, transfer, and keratinocyte-mediated processing as promising targets for therapeutic and cosmetic strategies in managing pigmentation disorders. Full article

Forensic DNA phenotyping (FDP) has emerged as an essential tool in criminal investigations, enabling the prediction of physical traits based on genetic information. This review explores the genetic factors influencing skin pigmentation, particularly within Asian populations, with a focus on Thailand. Key genes such as Oculocutaneous Albinism II (OCA2), Dopachrome Tautomerase (DCT), KIT Ligand (KITLG), and Solute Carrier Family 24 Member 2 (SLC24A2) are examined for their roles in melanin production and variations that lead to different skin tones. The OCA2 gene is highlighted for its role in transporting ions that help stabilize melanosomes, while specific variants in the DCT gene, including single nucleotide polymorphisms (SNPs) rs2031526 and rs3782974, are discussed for their potential effects on pigmentation in Asian groups. The KITLG gene, crucial for developing melanocytes, includes the SNP rs642742, which is linked to lighter skin in East Asians. Additionally, recent findings on the SLC24A2 gene are presented, emphasizing its connection to pigmentation through calcium regulation in melanin production. Finally, the review addresses the ethical considerations of using FDP in Thailand, where advances in genetic profiling raise concerns about privacy, consent, and discrimination. Establishing clear guidelines is vital to balancing the benefits of forensic DNA applications with the protection of individual rights. Full article

Melanogenesis is regulated by melanogenic enzymes such as tyrosinase (TYR), TRP-1, and TRP-2, whose expression is controlled by the microphthalmia-associated transcription factor (MITF). Various signaling pathways, including cAMP/PKA, MAPK/ERK, Wnt/β-catenin, and PI3K/Akt, are involved in this process and have been a focal point of research for treating pigmentation disorders. However, developing effective therapies for conditions like vitiligo remains a significant challenge. In this study, the effects of umckalin on melanogenesis and its molecular mechanisms were investigated using B16F10 cells, a mouse melanoma cell line widely used as a model for melanin production studies. B16F10 cells produce melanin via melanosomes and express key melanogenic enzymes such as TYR, TRP-1, and TRP-2, making them a reliable model system. Our findings demonstrate that umckalin promotes melanogenesis in a concentration-dependent manner by upregulating TRP-1 expression and activating the MITF signaling pathway. Additionally, umckalin modulated key signaling pathways, including GSK3β/β-catenin and MAPK, to enhance melanogenesis. In conclusion, umckalin enhances melanogenic enzyme activity by activating critical signaling pathways, thereby promoting melanin synthesis. These findings suggest that umckalin could be a promising candidate for developing therapeutic agents for pigmentation disorders such as vitiligo. Further studies are required to explore its mechanisms and clinical applications in greater detail. Full article

Background/Objectives: Research on cashmere goat coat color is crucial for optimizing cashmere goat breeds and increasing their economic value. To identify key genes associated with the formation of cashmere goat coat color and to provide molecular markers for breeding purposes, three healthy, 3-year-old does with similar weights and distinct coat colors—white, black, and light brown—were selected. Methods: Skin samples were collected for transcriptome sequencing, and bioinformatics methods were applied to screen for differentially expressed genes (DEGs) in the skin of cashmere goats with varying coat colors. Real-time fluorescence quantitative PCR (qRT-PCR) and immunofluorescence were subsequently conducted to examine the expression patterns of these DEGs. Results: The results showed that a total of 1153 DEGs were identified across the three groups of cashmere goats. According to GO and KEGG analyses, these DEGs were involved in key biological processes and structures, such as the melanin biosynthetic process (GO:0042438), melanosome membrane (GO:0033162), and melanin biosynthesis from tyrosine (GO:0006583). Employing Cytoscape, a gene interaction network was plotted, highlighting a compact network of DEGs associated with coat color formation. Critical genes identified included TYRP1, TYR, DCT, ASIP, PMEL, LOC102180584, MLANA, TSPAN10, TRPM1, CLDN16, AHCY, LOC106503350, and LOC102175263. qRT-PCR and fluorescence immunohistochemistry further determined that TYRP1, TYR, DCT, and PMEL expression levels were high in black goats (BGs), while ASIP and AHCY expression levels were high in white goats (WGs). The expression levels of these six genes in light brown goats (RGs) were intermediate between those in BGs and WGs. Conclusions: TYRP1, TYR, DCT, and PMEL were believed to play pivotal roles in the formation of black coat color, while ASIP and AHCY regulated the formation of white coat color in cashmere goats. Full article

We hypothesize that predictable variations in environmental conditions caused by night/day cycles created opportunities and hazards that initiated information dynamics central to life’s origin. Increased daytime temperatures accelerated key chemical reactions but also caused the separation of double-stranded polynucleotides, leading to hydrolysis, particularly of single-stranded RNA. Daytime solar UV radiation promoted the synthesis of organic molecules but caused broad damage to protocell macromolecules. We hypothesize that inter-related simultaneous adaptations to these hazards produced molecular dynamics necessary to store and use information. Self-replicating RNA heritably reduced the hydrolysis of single strands after separation during warmer daytime periods by promoting sequences that formed hairpin loops, generating precursors to transfer RNA (tRNA), and initiating tRNA-directed evolutionary dynamics. Protocell survival during daytime promoted sequences in self-replicating RNA within protocells that formed RNA–peptide hybrids capable of scavenging UV-induced free radicals or catalyzing melanin synthesis from tyrosine. The RNA–peptide hybrids are precursors to ribosomes and the triplet codes for RNA-directed protein synthesis. The protective effects of melanin production persist as melanosomes are found throughout the tree of life. Similarly, adaptations mitigating UV damage led to the replacement of Na⁺ by K⁺ as the dominant mobile cytoplasmic cation to promote diel vertical migration and selected for homochirality. We conclude that information dynamics emerged in early life through adaptations to predictably fluctuating opportunities and hazards during night/day cycles, and its legacy remains observable in extant life. Full article

Mutations in TSC1 or TSC2 in axons induce tuberous sclerosis complex. Neurological manifestations mainly include epilepsy and autism spectrum disorder (ASD). ASD is the presenting symptom (25–50% of patients). ASD was observed at significantly higher frequencies in participants with TSC2 than those with TSC1 mutations. The occurrence of TSC2 mutations is about 50% larger than TSC1. Therefore, ASD may develop due to TSC2 deficiency. TSC2 regulates microRNA biogenesis and Microprocessor activity via GSK3β. Of reference, everolimus has the best treatment target because of the higher potency of interactions with mTORC2 rather than rapamycin. Mutations in the TSC1 and TSC2 genes result in the constitutive hyperactivation of the mammalian target of the rapamycin (mTOR) pathway, contributing to the growth of benign tumors or hamartomas in various organs. TSC2 mutations were associated with a more severe phenotypic spectrum than TSC1 mutations because of the inhibition of the mTOR cascade. There are few studies on the peptide analysis of this disorder in relation to everolimus. Only one study reported that, in ten plasma samples, pre-melanosome protein (PMEL) and S-adenosylmethionine (SAM) were significantly changed as diagnostic prognostic effects. Our study on peptide analysis in Protosera Inc (Osaka, Japan) revealed that three peptides that were related to inflammation in two patients with tuberous sclerosis, who showed a 30% decrease in ASD symptoms following everolimus treatment. TSC2 mutations were associated with a more severe phenotypic spectrum due to the inhibition of the mTOR cascade. PMEL and SAM were significantly changed as diagnostic effects. Full article

Two-pore channel 2 (TPC2) is expressed in endolysosomes throughout the human body, as well as in melanosomes of melanocytes. Melanocytes produce pigment, i.e., melanin, which determines hair and skin color but also protects from UV light. Extensive exposure to UV light is one of the major risk factors for the development of melanoma, which develops from pigment-producing cells, i.e., melanocytes. In recent years, several human TPC2 single nucleotide polymorphisms have been identified to increase the likelihood of carriers presenting with blond hair and hypopigmentation. These variants were all characterized as gain-of-function versions of TPC2. Vice versa, the loss of function of TPC2 increases melanin production and reduces cancer hallmarks such as proliferation, migration, invasion, tumor growth, and metastasis formation. The activity of TPC2 is controlled in a complex manner, with several endogenous ligands as well as a number of interacting proteins being involved. We will discuss here the role of TPC2 in pigmentation and its potential to impact melanoma development and progression and highlight recent findings on Rab7a as an enhancer of TPC2 activity. Full article

Background: L-Shikonin, an active component of Arnebia euchroma (Royle) Johnst., has remarkable pharmacological effects, particularly in its anti-tumour activity. Nonetheless, the specific targets and mechanisms of action remain to be further explored. Methods: A novel Fe₃O₄@L-Shikonin was designed and synthesized in this study by linking Fe₃O₄ and L-Shikonin through benzophenone. Fe₃O₄@L-Shikonin was characterized using several techniques, including scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), and drug removal methods, to determine the content of L-Shikonin on the surface of the magnetic particles. Target hooking technology was utilized to identify the target proteins of the compound in melanoma. The synthesized Fe₃O₄@L-Shikonin was co-incubated with A375 cell lysate, followed by the target proteins, which were purified by magnetic enrichment using magnetic microspheres and identified by high-resolution mass spectrometry. Results: AutoDock Vina software was employed for molecular docking analysis, where it was found that L-Shikonin targets RPN1, CPEB4, and HNRNPUL1 proteins. Subsequently, A375 cells were treated with L-Shikonin at different concentrations (2.5, 5.0, 10.0 μM) for 48 h, and the expressions of the three proteins were observed. The results showed a significant reduction in the relative expression of CPEB4 in the high-dose group compared to the control group (p < 0.01). Moreover, the relative expression of HNRNPUL1 was decreased in the medium- and high-dose groups (p < 0.05). Conclusions: This study initially revealed from the source that L-Shikonin may regulate melanoma-specific markers, melanosomes, tyrosine kinases related to abnormal tyrosine metabolism, and melanoma through multiple targets such as CPEB4 and HNRNPUL1. Proliferation and metastasis work together to exert an anti-melanoma mechanism, which provides a new idea for the follow-up study of the molecular pharmacological mechanism of the complex system of total naphthoquinones in Arnebia euchroma (Royle) Johns. Full article

Xanthohumol (XN), representing the group of chalcones, is a hydroxyl and superoxide free radical scavenger. It also has antimicrobial properties, showing antibacterial activity against Staphylococcus aureus, Staphylococcus pyogenes, Staphylococcus epidermidis and Propionibacterium acnes. XN exerts an inhibitory effect on tyrosinase (it hinders the oxidation of l-tyrosine and l-DOPA). However, it also affects the transport of pigment (through a reduction in the number and length of dendrites) and its degradation (through damage to melanosomes). Additionally, it has been shown to inhibit the different activation pathways of the premeditated response in macrophages and reduce the secretion of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β. Xanthohumol also improves skin elasticity by reducing the activity of elastase and MMP 1, 2 and 9, and it increases the expression of type I, III and V collagen, as well as elastin and fibrillins in skin fibroblasts. It acts against the main factors contributing to the pathogenesis of acne by inhibiting pro-inflammatory mediators (e.g., COX-2, PGE2, IL-1β and TNF-α). Moreover, it shows antibacterial activity against P. acnes and S. aureus, as well as seboregulatory and antioxidant properties. It has also been recognized that XN intake could affect diabetic wound healing. XN shows antitumoral activity, e.g., in the case of skin melanoma, which is associated with the antioxidant, pro-apoptotic, anti-angiogenic and immunostimulating effects of this compound. Full article