Search Results (1,126)

Ultraviolet B (UVB) radiation is a key factor in the overproduction of melanin in the skin. Melanocytes produce melanin through melanogenesis to protect the skin from UVB radiation-induced damage. However, excessive melanogenesis can lead to hyperpigmentation and increase the risk of malignant melanoma. Tyrosinase is the rate-limiting enzyme in melanogenesis; it catalyzes the oxidation of tyrosine to 3,4-dihydroxy-L-phenylalanine and subsequently to dopaquinone. Thus, inhibiting tyrosinase is a promising strategy for preventing melanogenesis and skin hyperpigmentation. White mulberry (Morus alba L.) is rich in antioxidants, and mulberry fruit extracts have been used as cosmetic skin-lightening agents. However, data on the capacity of mulberry fruit extracts to inhibit tyrosinase under UVB radiation-induced melanogenic conditions remain scarce, especially in an in vivo model. In this study, we evaluated the effects of a mulberry crude extract (MCE) on UVB radiation-induced melanogenesis in B16F10 melanoma cells and zebrafish embryos. The MCE significantly reduced tyrosinase activity and melanogenesis in a dose-dependent manner without inducing cytotoxicity. These effects are likely attributable to the antioxidant constituents of the extract. Our findings highlight the potential of this MCE as an effective tyrosinase inhibitor for the prevention of UVB radiation-induced skin hyperpigmentation. Full article

Background and Clinical Significance: Osteonevus of Nanta is a rare histological phenomenon characterized by bone formation within a benign melanocytic nevus, most commonly in intradermal nevi of the head and neck. Although osteonevus of Nanta is rare, ossification in a cellular blue nevus is even more uncommon. To date, only one case of a cellular blue nevus with ossification has been documented. This case report adds to the limited literature and emphasizes the clinical importance of recognizing this rare phenomenon, as osteonevus of Nanta has been potentially associated with malignant melanoma. Case Presentation: A 72-year-old woman presented with an asymptomatic, pigmented scalp lesion that had recently increased in size. On clinical examination, the tumor appeared as a well-demarcated, firm, and nodular mass with dark blueish to violet pigmentation that measured 15 × 12 × 7 mm. To ensure a definitive diagnosis and rule out malignancy, the lesion was excised with narrow margins. Histological examination revealed a cellular blue nevus with prominent osseous metaplasia. Due to the absence of clear margins, a wider re-excision was performed. No residual tumor was found, and the patient remained asymptomatic with no recurrence. Conclusions: This case represents only the second published example of a cellular blue nevus with ossification. While osteonevus of Nanta is benign, its potential association with malignant melanoma, as well as its clinical resemblance to malignant entities such as nodular melanoma, malignant blue nevus, and pigmented basal cell carcinoma, underscores the need for thorough clinical and histopathologic evaluation. Full article

Melanoma is a highly aggressive skin cancer with limited therapeutic response. Targeting intracellular signaling pathways and promoting tumor cell differentiation are promising therapeutic strategies. Pentoxifylline (PTX) and norcantharidin (NCTD) have demonstrated antitumor properties, but their combined mechanisms of action in melanoma remain poorly understood. The effects of PTX (30 and 60 mg/kg) and NCTD (0.75 and 3 mg/kg), administered alone or in combination, in a DBA/2J murine B16-F1 melanoma model via intraperitoneal and intratumoral (IT) routes were evaluated. Tumor growth was monitored, and molecular analyses included RNA sequencing and immunofluorescence quantification of PI3K, AKT1, mTOR, ERBB2, BRAF, and MITF protein levels, and molecular docking simulations were performed. In the final stage of the experiment, combination therapy significantly reduced tumor volume compared to monotherapies, with the relative tumor volume decreasing from 18.1 ± 1.2 (SD) in the IT Control group to 0.6 ± 0.1 (SD) in the IT combination-treated group (n = 6 per group; p < 0.001). RNA-seq revealed over 3000 differentially expressed genes in intratumoral treatments, with enrichment in pathways related to oxidative stress, immune response, and translation regulation (KEGG and Reactome analyses). Minimal transcript-level changes were observed for BRAF and PI3K/AKT/mTOR genes; however, immunofluorescence showed reduced total and phosphorylated levels of PI3K, AKT1, mTOR, BRAF, and ERBB2. MITF protein levels and pigmentation increased, especially in PTX-treated groups, indicating enhanced melanocytic differentiation. Docking analyses predicted direct binding of both drugs to PI3K, AKT1, mTOR, and BRAF, with affinities ranging from −5.7 to −7.4 kcal/mol. The combination of PTX and NCTD suppresses melanoma progression through dual mechanisms: inhibition of PI3K/AKT/mTOR signaling and promotion of tumor cell differentiation. Full article

Skin dullness contributes to a fatigued and aged appearance, often exceeding one’s biological age. It is a common dermatological concern influenced by aging and poor lifestyle habits, regardless of ethnicity or age. This study aimed to examine advanced glycation end products (AGEs) and their receptor (receptor for AGEs [RAGE]) as contributing factors to skin dullness. AGEs themselves have a yellowish hue, contributing to “yellow dullness.” Additionally, AGE–RAGE signaling promotes melanin production in melanocytes and impairs keratinocyte differentiation as a result of inflammation. Therefore, regulating the AGE–RAGE interaction may help reduce skin dullness. Through screening various natural ingredients, we found that peony root extract (PRE) inhibits AGE formation and blocks AGE–RAGE binding. Furthermore, the presence of PRE leads to the suppression of AGE-induced melanin production in melanocytes and the restoration of impaired keratinocyte differentiation in glycated basement membrane components. In a human clinical study, topical application of a 1% PRE-containing lotion for 2 weeks significantly reduced melanin content, with a trend toward decreased AGE accumulation and visible spots on the cheeks. These findings support the potential of PRE as a multifunctional cosmetic ingredient that comprehensively addresses skin dullness by modulating the AGE–RAGE interaction. Full article

Background and Clinical Significance: Blue nevi are a dubious pigmented lesion. While somewhat common throughout the population, they are significantly less common than other melanocytic neoplasms, and both their morphology and development bring them closer to true hamartomas than neoplasms. An exceedingly rare occurrence is the development of melanoma from a preexisting blue nevus. This nosological unit, defined as melanoma arising in a blue nevus, also known as malignant blue nevus, blue naevus–like melanoma, melanoma ex-blue naevus, and melanoma mimicking cellular blue naevus, is required to either originate from an area of previously excised blue nevus or have a blue nevus remnant adjacent to it. Due to the spindle cell morphology of melanoma arising in blue nevus, the terminology is often misused by some authors to include spindle cell melanomas, which exhibit a distinct pathogenesis and, although morphologically similar, have differing molecular profiles as well. Case presentations: The following manuscript discusses comparative morphological features in a case series of blue nevi and melanoma arising in blue nevi. Discussion: Blue nevi present with unique morphological features, with melanomas originating from them having a unique molecular pathology profile, which significantly differs from other cutaneous melanomas and is closer to that of uveal melanomas. Full article

Background and clinical significance: Trichoblastomas are rare, mixed epithelial tumors with a mesenchymal component and hair follicle differentiation. Case presentation: Herein, we present a case report of a 51-year-old female patient presenting to the obstetrics and gynecology department with complaints of edema and erythema of the right Bartholin gland, and a lesion measuring 2 cm on the right lateral edge of the mons pubis, towards the inguinal fold. Marsupialization of the Bartholin gland was performed, as well as an incision into the pubo-inguinal lesion, which the patient depicted as grossly resembling an ingrown hair. Upon incision into the pubic–inguinal lesion, it was dark brown in color and spontaneously popped out of the subcutis, without an attempt at enucleation. Histology and subsequent immunohistochemistry of the lesion showed a blue basaloid tumor with an extensive pigment component located deep in the dermis that was sharply demarcated from the surrounding tissues. Conclusion: Immunohistochemistry was diffusely and strongly positive for epithelial markers; melanocytic markers were positive only in dendritic melanocytes dispersed within the tumors, and the proliferative index was low. As such, the tumor was identified as melanotrichoblastoma. Full article

Background: Melanoma metastasis, driven by tumor microenvironment (TME)-mediated crosstalk facilitated by extracellular vesicles (EVs), remains a major therapeutic challenge. A critical barrier to clinical translation is the overlap in protein cargo between tumor-derived and healthy cell EVs. Objective: To address this, we developed Scaffold-free Functional Deconvolution (SFD), a novel computational approach that leverages a comprehensive healthy cell EV protein database to deconvolute non-oncogenic background signals. Methods: Beginning with 1915 proteins (identified by MS/MS analysis on an Orbitrap Fusion Lumos Mass Spectrometer using the IonStar workflow) from melanoma EVs isolated using REIUS, SFD applies four sequential filters: exclusion of normal melanocyte EV proteins, prioritization of metastasis-linked entries (HCMDB), refinement via melanocyte-specific databases, and validation against TCGA survival data. Results: This workflow identified 21 high-confidence targets implicated in metabolic-associated acidification, immune modulation, and oncogenesis, and were analyzed for reduced disease-free and overall survival. SFD’s versatility was further demonstrated by surfaceome profiling, confirming enrichment of H7-B3 (CD276), ICAM1, and MIC-1 (GDF-15) in metastatic melanoma EV via Western blot and flow cytometry. Meta-analysis using Vesiclepedia and STRING categorized these targets into metabolic, immune, and oncogenic drivers, revealing a dense interaction network. Conclusions: Our results highlight SFD as a powerful tool for identifying clinically relevant biomarkers and therapeutic targets within melanoma EVs, with potential applications in drug development and personalized medicine. Full article

Background: Vitiligo, a chronic depigmentation disorder driven by oxidative stress and immune dysregulation, remains poorly understood mechanistically. The Keap1/NRF2/ARE pathway is critical for melanocyte protection against oxidative damage; however, the role of Cullin-3 (CUL3), a scaffold for E3 ubiquitin ligases that regulate NRF2 degradation, and its interplay with inflammatory mediators in vitiligo pathogenesis are underexplored. This study investigates CUL3, NRF2, and the associated regulatory networks in vitiligo, integrating clinical profiling and computational docking to identify therapeutic targets. Methods: A case-control study compared non-segmental vitiligo patients with age-/sex-matched controls. Lesional skin biopsies were analyzed by qRT-PCR for the expression of CUL3, NRF2, miRNA-146a, FOXP3, NF-κB, IL-6, TNF-α, and P53. Molecular docking was used to evaluate vitexin’s binding affinity to Keap1, validated by root mean square deviation (RMSD) calculations. Results: Patients with vitiligo exhibited significant downregulation of CUL3 (0.27 ± 0.03 vs. 1 ± 0.58; p = 0.013), NRF2 (0.37 ± 0.26 vs. 1 ± 0.8; p = 0.001), and FOXP3 (0.09 ± 0.2 vs. 1 ± 0.3; p = 0.001), alongside the upregulation of miRNA-146a (4.7 ± 1.9 vs. 1 ± 0.8; p = 0.001), NF-κB (4.7 ± 1.9 vs. 1 ± 0.5; p = 0.001), IL-6 (2.8 ± 1.5 vs. 1 ± 0.4; p = 0.001), and TNF-α (2.2 ± 1.1 vs. 1 ± 0.3; p = 0.001). P53 showed no differential expression (p > 0.05). Docking revealed a strong binding of vitexin to Keap1 (RMSD: 0.23 Å), mirroring the binding of the control ligand CDDO-Im. Conclusions: Dysregulation of the CUL3/Keap1/NRF2 axis and elevated miRNA-146a levels correlate with vitiligo progression, suggesting a role for oxidative stress and immune imbalance. Vitexin’s high-affinity docking to Keap1 positions it as a potential modulator of the NRF2 pathway, offering novel therapeutic avenues. This study highlights the translational potential of targeting the ubiquitin–proteasome and antioxidant pathways in the management of vitiligo. Full article

Malignant cutaneous melanoma is among the most aggressive forms of skin cancer, characterized by high metastatic potential and frequent resistance to standard therapies. Hydroxytyrosol, a phenolic compound derived from extra virgin olive oil, has shown promising anticancer properties in various models, yet its effects in 3D melanoma systems remain poorly understood. In this study, we used paired 3D spheroid models of non-tumorigenic (HEMa) and melanoma (C32) to assess the therapeutic potential of hydroxytyrosol. To evaluate the anti-tumoral effect of hydroxytyrosol, we performed cytotoxicity, metastasis, invasiveness, cell cycle arrest, apoptotic, and proteomic assays. Hydroxytyrosol treatment significantly impaired spheroid growth, reduced cell viability, and induced cell cycle arrest and apoptosis in C32 spheroids, with minimal cytotoxicity observed in HEMa models. Proteomic profiling further demonstrated that hydroxytyrosol selectively downregulated a network of oncogenic proteins, including ERBB2, ERBB3, ERBB4, VEGFR-2, and WIF-1, along with suppression of downstream PI3K-Akt and MAPK/ERK signaling pathways. In conclusion, compared to dabrafenib, hydroxytyrosol exerted a broader range of molecular effects and was more selective toward tumor cells. These findings support the use of hydroxytyrosol as a multi-targeted agent capable of attenuating melanoma progression through suppression of kinase signaling and tumor-stromal interactions. Full article

Background and Clinical Significance: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic syndrome characterized by bilateral uveal melanocyte proliferation and progressive visual disturbance. While most commonly associated with solid tumors, its occurrence in hematologic malignancies is exceedingly rare. Case Presentation: We report a case of BDUMP in a 64-year-old male recently diagnosed with chronic myelomonocytic leukemia (CMML), who presented with subacute, painless bilateral blurred vision. Multimodal imaging revealed suggestive features of BDUMP, including orange-red subretinal patches, retinal pigment epithelium mottling, and diffuse choroidal thickening, consistent with early structural involvement despite preserved central vision. No intraocular mass or signs of inflammation were observed. The patient did not receive specific treatment for BDUMP, and visual acuity remained stable during follow-up. Conclusions: This case underscores the importance of considering BDUMP in the differential diagnosis of bilateral visual symptoms in patients with hematologic malignancies. Although rare, BDUMP may occur in the context of CMML. Recognition through multimodal imaging and interdisciplinary collaboration is essential, and further research is needed to clarify its pathogenesis and improve management strategies. Full article

In this study, two color morphs (red and green) of Asian swimming crab (Charybdis japonica) commonly distributed in the China Sea area were analyzed for their L*a*b* values, carapace and inner membrane histology, morphological characteristics, mitochondrial DNA sequences, muscle texture, and amino acid composition. The results showed that compared with the green morph group, the red morph group exhibits higher aggregation of melanocytes and fewer pigment cells in the inner membrane. In addition, L* and b* of the carapace, and L* values of the inner membrane were lower in red morph group. Both populations of C. japonica also exhibit significant differences in their morphological parameters, including carapace length, body weight, and pincer width. However, the coefficient of variation for these morphological parameters did not correspond to the subspecies level. The mitochondrial DNA analysis also revealed sequence identity of COI (98.96%) and ITS-1 (99.71%) genes in both groups, supporting them to belong to the same species. Both groups also presented significant differences in their muscle texture characteristics, including adhesiveness, springiness, and gumminess, but no significant differences were observed in the muscle amino acid composition. Overall, red and green morphs of C. japonica show differences in their body color, morphological characteristics, and muscle quality, but still belong to the same species. Full article

Solar lentigines, commonly caused by prolonged ultraviolet exposure, raise the risk of skin disorders and remain challenging to manage due to their complex mechanisms. Understanding the molecular mechanisms driving the progression of solar lentigines is crucial for developing effective protective strategies. In this study, we introduced a novel method, Dynamic Network Driver (DND), which identifies upstream regulators that drive disease progression by integrating the Dynamic Network Biomarker (DNB) approach with network control theory. By applying DND to multi-omics data from solar lentigines subjects, we (1) identified the key drivers associated with solar lentigo progression, with their functions involved in differentiation and dermal–epidermal junction; and (2) highlighted ARNT2 and TBX2 as significant master factors supported by in vitro validation in melanocytes and pigmented 3D living skin equivalent models. These results demonstrate the potency of DND for uncovering the molecular mechanisms behind solar lentigines and informing therapeutic strategies. In summary, the DND approach identified novel drivers of solar lentigo progression, acting as new markers for spot mitigation in 3D spot mimic models. Full article

This study evaluated diagnostic trends and the overall utility of cytology in feline patients through the analysis of a large, multicentric dataset from Portugal. A retrospective review of 3068 cytological cases from 130 veterinary practices was conducted, with samples categorised by anatomical location and lesion type. Diagnostic outcomes were statistically assessed, revealing an overall success rate of 66.20%. The highest diagnostic yields occurred in fluid samples (83.48%), glandular tissues (76.67%), and mucous membranes (75.81%), followed by organ-based samples (67.79%), miscellaneous tissues (66.98%), cutaneous/subcutaneous nodules (62.16%), and lymph nodes (57.93%). Neoplastic lesions showed age-associated prevalence, being more common in older cats, with epithelial and melanocytic lesions more frequent in females and round cell/mesenchymal lesions predominating in males. Non-diagnostic samples (33.80%) primarily resulted from insufficient cellularity or suboptimal quality, though no significant correlation existed between diagnostic success and clinical setting. This study underscores that cytology remains a fundamental diagnostic tool in feline medicine, particularly when combined with proper sampling techniques and complementary diagnostic methods, and reinforces its value in clinical decision-making, thereby supporting its broader utilisation in routine veterinary practice. Full article

Autoimmune CD8⁺ T cell-driven melanocyte destruction constitutes a key pathogenic mechanism in the development of vitiligo. Therefore, the pharmacological inhibition of CD8⁺ T cell effector functions and skin trafficking is a clinically viable therapeutic strategy. This study investigates leflunomide (LEF), an immunomodulatory drug with established safety in autoimmune diseases, for its therapeutic potential in a tyrosine-related protein (TRP) 2-180-induced vitiligo mouse model. Through flow cytometry, immunofluorescence, ELISA, and histopathological analyses, we systematically evaluated LEF’s effects on T cell regulation, chemokine expression, and cytokine profiles. Key findings demonstrated that LEF (20 mg/kg/day) significantly attenuated depigmentation by reducing CD8⁺ T cell infiltration and suppressing the IFN-γ-driven expression of CXCL9/10. Furthermore, LEF restored CD4⁺/CD8⁺ T cell homeostasis and rebalanced pro-inflammatory (IFN-γ, TNF-α, IL-2) and anti-inflammatory (IL-4, IL-10) cytokines, inducing a shift from Th1 to Th2. These results position LEF as an effective immunomodulator that disrupts the IFN-γ-CXCL9/10 axis and re-establishes immune balance, offering a promising repurposing strategy for halting vitiligo progression. Full article