Melanin in skin and hair protects cells from UV damage; however, uneven skin color or hyperpigmentation is a common aesthetic concern. Melanin is synthesized in melanosomes, organelles within melanocytes, where tyrosinase converts tyrosine to melanin. Trafficking of tyrosinase or other cargo (eg, premelanosome protein [PMEL]) may depend on vesicle-associated membrane proteins (VAMPs); interfering with VAMPs has been reported to impact melanogenesis. Botulinum neurotoxin type DC (BoNT/DC) is a naturally occurring mosaic serotype that cleaves the SNARE proteins VAMP1-3. This study evaluated BoNT/DC as a potential treatment for hyperpigmentation by testing if it affects melanogenesis. In melanocytes, BoNT/DC cleaved VAMP2 and VAMP3, and knockdown of VAMP3, but not VAMP2, reduced melanin content, which suggests that BoNT/DC may affect melanogenesis via VAMP3 cleavage. Indeed, BoNT/DC (5 nM) produced a ∼50 % reduction in melanin content in melanocytes, and in 2 human melanocyte models, BoNT/DC, but not BoNT/A, significantly reduced melanin content (∼40-50 %) without cytotoxicity. Electron microscopy showed that BoNT/DC-treated melanocytes contained more early-stage (II) and fewer late-stage (IV) melanosomes than vehicle- or BoNT/A-treated melanocytes. Overall, BoNT/DC reduced melanin content in multiple melanocyte models, and its lightening effects are likely due to VAMP3 cleavage interfering with trafficking of cargo (eg, tyrosinase, PMEL) required for melanogenesis.

In this study, five popular EC liquid flavors-strawberry, banana, vanilla, tobacco, and menthol-were examined on human melanocyte functions. Each flavored e-liquid (in 80/20 PG/VG vehicle) was tested without or with 18 mg/mL nicotine. The effects of PG/VG and nicotine-containing vehicles were also evaluated. Results revealed that nicotine-free and nicotine-containing e-liquids had comparable cytotoxicity, with menthol> > banana> tobacco> vanilla> strawberry. This cytotoxicity was unrelated to either nicotine or the vehicle. PG/VG (1 and 2 %) increased melanin production without influencing cellular tyrosinase activity. The flavored e-liquids did not further affect melanin production, suggesting that the vehicle's effect, not the flavor, was responsible for the increased melanin production. Interestingly, nicotine at 2 % in the vehicle restored the stimulated melanin production to the control. Flavors suppressed cellular tyrosinase activity, with vanilla and banana flavors robustly inhibiting it. Vanilla and banana e-liquids also enhanced reactive oxygen species (ROS) production, which did not originate from the vehicle or nicotine-containing vehicle. Banana e-liquid with nicotine lowered ROS generation compared to nicotine-free banana e-liquid. Common flavors in e-liquids can cause cytotoxicity and influence melanogenesis even without nicotine, indicating that the use of ECs may not completely avoid the harmful effects of cigarette smoking. Further studies are warranted to investigate e-liquid aerosol effects on melanocytes.

Despite ongoing advancements in medical aesthetics, there remains a lack of consensus regarding a standardized postoperative care protocol following laser treatment for skin pigmentation disorders.

To evaluate the influence of postoperative facial cleansing practices on the efficacy and safety of laser therapy among patients diagnosed with pigmentary skin diseases.

Thirty patients diagnosed with pigmented lesions (freckles and/or solar lentigines) were randomly allocated to two distinct groups. Following treatment with a 755-nm alexandrite laser, patients in one group were instructed to perform water cleansing, while the other followed a water-avoidance care protocol. Follow-up visits were conducted on days 1, 3, 7 and 14 after treatment and 3 months postoperatively. These visits included taking standardized photographs, performing VISIA imaging assessments, collecting patient satisfaction questionnaires and recording any potential adverse events.

No serious complications were reported in either group. Most patients demonstrated improvement in their lesions to varying degrees with a single treatment session. No statistically significant differences were identified between the two groups in terms of postoperative visual analogue scale scores (P = 0.17). VISIA analysis revealed a significant decrease in brown spot count in both groups at the 3-month follow-up compared with baseline, with no significant differences between groups (P = 0.99). The average score of patients' satisfaction in the water-cleansing group was significantly higher than that in the water-avoidance group (P = 0.039).

Our studies have demonstrated that laser treatment of epidermal hyperpigmentation disorders without strict water avoidance can have equally good results with no added adverse effects.

Acne-induced post-inflammatory hyperpigmentation (AI-PIH) can occur without any visible clinical evidence of significant inflammation, even in patients with mild to moderate acne. Currently, visual assessment is the main criterion for evaluating the severity of PIH, including that of AI-PIH in daily clinical practice. Treatment indications are lacking. This work provides an easy-to-use AI-PIH severity grading tool for daily clinical practice as well as indications on how to prevent and treat AI-PIH using currently available treatment options. Five experts in acne provided a short overview concerning the epidemiology and physiopathology of AI-PIH, developed an AI-PIH severity grading tool, and proposed preventive measures as well as an AI-PIH treatment algorithm. Only a small number of epidemiological data on AI-PIH are available, confirming that the condition is mainly observed in patients with Phototypes IV to VI. The physiopathology of AI-PIH is still not completely understood. Innate immunity, Cutibacterium acnes, and external factors such as UV radiation, visible light, and air pollution play a role in its development. An easy-to-use AI-PIH severity grading tool (Acne PIgmentation Grading) allows quick assessment of acne severity during the consultation, and, in addition to proposed preventive measures, a treatment algorithm is proposed according to AI-PH severity. Patient education remains key. Providing an AI-PIH severity assessment tool as well as preventive and treatment recommendations may help to manage AI-PIH more efficiently.

Background/Purpose Photobiomodulation (PBM) using light-emitting diodes (LEDs) benefits tissue regeneration and wound healing. However, evidence regarding the efficacy of LED for post-inflammatory erythema (PIE) and post-inflammatory hyperpigmentation (PIH) is limited. The aim of this study was to explore the effect of medical LED (830 nm and 590 nm) in the prevention and treatment of PIE and PIH. Methods The in vivo PIE/PIH model was simplified to erythema and pigmentation reaction after acute UVB exposure. 308 nm LED light (225 or 270 mJ/cm2) was induced in vivo in the PIE/PIH model on the thigh of ten healthy subjects. Every subject received therapeutic and preventive irradiation (n = 10 in each group). 830 nm (60 J/cm2) and 590 nm LEDs (20 J/cm2) were irradiated, respectively. For therapeutic irradiation, the PIE/PIH model was induced on D1, and LEDs were irradiated on D0, 1, 3, 6 and 8. For preventive irradiation, LEDs were irradiated on D0, 1, 3, 6, and 8 and the PIE/PIH model was induced on D9. Erythema index (EI), melanin index (MI), transdermal water loss (TEWL), and C-Cube photography were measured during 10-day follow-up visits. Results For therapeutic irradiation, ΔEI and ΔMI in the 830 nm treatment group were significantly lower than in the control group (ΔEI: 9.30 vs. 11.52, p = 0.027; ΔMI: 7.79 vs. 9.25, p = 0.026). No significant difference was found between the 590 nm treatment group and the control group in ΔEI or ∆MI (p > 0.05). For preventive irradiation, ΔEI in the 830 nm prevention group and the 590 nm prevention group were both significantly lower than the control group (830 nm: 9.85 vs. 19.90, p = 0.001; 590 nm: 12.50 vs. 19.90, p = 0.008). No significant difference was found between the two prevention LED groups (p > 0.05). Conclusions Both 830 nm and 590 nm LEDs showed preventive effects for PIE, and 830 nm LEDs could effectively improve PIE and PIH.

Post-inflammatory hyperpigmentation (PIHP) predominantly affects patients with melanin-rich skin, significantly impacting them psychosocially due to more frequent and severe pigmentary changes. In this study, the efficacy of a novel depigmenting agent 2-mercaptonicotinoyl glycine (Melasyl) in a dermocosmetic (DC) serum formulation is assessed as a stand-alone treatment of PIHP without sunscreen.

Thirty-two Mauritian subjects aged 18-50 years of phototype IV-VI presenting mild acne (GEA2) and moderate to severe PIHP (PAHPI > 10) participated in this study. Subjects applied the DC serum twice a day on the whole face for 3 months. Efficacy was assessed through PAHPI score, mean darkness of lesions (0-8 scores), and colorimetric measurements at D0, D14, D28, D56, and D84. Self-perceived efficacy, tolerability, stigmatization, cosmeticity, and satisfaction were also gathered.

A significant decrease of 15.8% (p < 0.05) in PAHPI score was reported at D84. The PAHPI score showed marked changes (p < 0.05) in pigmentation intensity at D56. Visible significant changes in mean darkness were observed from D28, with a 25.1% decrease at D84. A significant brightening effect was observed in both the spots and adjacent areas, with their mean ITA values increasingly converging toward the ITA of the non-treated, non-exposed zone. This effect was more pronounced in the spots, which showed a significant increase from -34.1 to -14.2 by D14. Instrumental measurements revealed a 60% reduction in spot color intensity at D84 compared to the adjacent area Delta E (p < 0.05), significant from D14. Subjects reported self-perceived improvements in appearance and well-being that matched clinical results, enhancing their quality of life and satisfaction. The product was reported as very well tolerated by the subjects after 84 days of usage.

This study demonstrated the efficacy and tolerability of the serum in the treatment of post acne PIHP. Good clinical results are confirmed by the objective measurement of the ITA and Delta E. Cosmeticity was excellent and will help observance in real life. The reduction of the stigmatization score illustrates the impact of PIHP and its improvement over time. These results can be considered highly encouraging with the new serum, as in real life, its use in combination with a UVA/visible light filtration sunscreen would probably increase patients benefit.

Eczema is the most common category of inflammatory skin disorders as dermatologists see many patients with eczematous diseases in daily practice. It is characterized by the three major morphological features: multiple-pinpoint condition, polymorphism, and itch. To describe polymorphism, "eczema triangle" has been used in German/Japanese dermatology. The multiple pinpoints correspond to numerous tiny foci from which individual papules/vesicles arise. The polymorphism betrays composition of erythema, papule, seropapule, vesicle, pustule, scale, and crust, which are seen in acute eczema. Meanwhile, chronic eczema is represented by lichenification and hyperpigmentation, and possibly by hypopigmentation. In acute eczema, spongiosis is associated with overproduction of hyaluronic acid, secretion of self-protective galectin-7, and decreased expression of E-cadherin. In the upper dermis, Th1/Tc1 or Th2/Tc2, and additional Th17, Th22, and/or Tc22 infiltrate, depending on each eczematous disease. Innate lymphoid cells are also involved in the formation of eczema. In chronic eczema, periostin contributes to remodeling of inflammatory skin with dermal fibrosis, and epidermal melanogenesis and dermal pigment deposition result in hyperpigmentation. Finally, eczematous diseases are potentially associated with increased risk of comorbidities, including not only other allergic diseases but also coronary heart disease and mental problems such as depression. Although the original word for eczema is derived from old Greek "ekzein," eczema remains a major target of modern science and novel therapies.

Photoprotection remains the foundation of treatment for all dyschromias and cosmetic camouflage as it provides concealment of pigmentation until therapeutic agents are effective. Innovations in the treatment of dyschromias encompass topical, systemic, and procedural modalities.

Skin problems are common, affecting up to one-third of the population during their lifetime, and they are frequently encountered by advanced clinical practitioners (ACPs) in both primary and secondary care settings. Despite the prevalence of dermatological presentations, ACPs often feel unprepared to conduct a thorough dermatological history and examination. This article aims to provide guidance to trainees and qualified ACPs, whether in acute hospital settings or primary care, to perform dermatological assessments and examinations systematically. This is the first article in a two-part series on dermatological assessment.

As in other organs, the diagnosis of endogenous cutaneous overload diseases is based on histopathological analysis of the lesions using special stainings, even if the clinical appearance is sometimes very suggestive. The lesions are sometimes very subtle and can be included in the group of "invisible" dermatoses, such as primary macular cutaneous amyloidosis or calciphylaxis. Superficial dermal melanosis or pigmentary incontinence generally reflects the post-inflammatory stage of a chronic or recurrent interface dermatitis. Section levels should be systematically performed to look for active lesions of diagnostic interest: Alcian blue staining to identify dermal mucinosis (connectivitis) and pan-T markers (fixed pigmented erythema, lichenoid mycosis fungoides, and vitiligo). Some pathologies have a prognostic impact, either because they reflect an underlying disease, monoclonal gammopathies, in particular myeloma, being one of the most common conditions in this context (AL amyloidosis, xanthoma and xanthogranuloma, scleromyxedema), or because they can be associated with visceral damage (AL amyloidosis, scleromyxedema). The clinical-pathological comparison is mandatory to rule out differential diagnoses, especially for life-threatening diseases: nodular amyloidosis and primary cutaneous amyloidosis versus systemic AL amyloidosis, papular mucinosis versus scleromyxedema and calcific panniculitis versus calciphylaxis.

Melasma is a prevalent pigmented disease, yet its pathogenesis remains unclear, posing challenges for effective treatment. Bibliometric analysis, a novel approach to literature research, offers the opportunity to evaluate research trends through qualitative and quantitative methods. This study utilizes bibliometric methods to analyze the existing literature on melasma treatment, examining influential publications, institutions, countries, and authors through statistical analysis.

In order to retrieve manuscripts related to the topic of melasma treatment, we conducted a search using the search formula: (TS = (melasma or Chloasma or "mask of pregnancy")) AND TS = (treatment or therapy). We searched through the Web of Science Core Collection database, covering publications from 2000 to 2023. VOSviewer, CiteSpace and the Bibliometric online site (https://bibliometric.com/app) were used to conduct this bibliometric analysis. Our analysis focused on various factors including publications, authors co-authorship, institutions, countries, citation analysis, keywords co-occurrence, references co-citation and journal co-citation.

A total of 943 articles and 200 reviews were published between 2000 and 2023, accumulating a total of 8628 citations. The average number of citations per item was 18.85, and the average number of citations per year was 292.69. The most prolific author, Sungeun Chang, contributed a total of 9 articles. Cario University emerged as the top research institution. The United States led in terms of article publications with a count of 276. In the past 5 years, the research trends in this field have primarily focused on tranexamic acid and epidermal melasma, as indicated by the burst analysis of publications and keywords.

The United States continues to lead in terms of institutions and research output. The current emphasis is on the meticulous implementation of tranexamic acid and laser therapy. It is crucial to foster enhanced collaboration among countries, institutions, and authors to facilitate improved research.

Persimmon (Diospyros kaki) leaf is widely used as a tea substitute in East Asia, offering potential health benefits. Although studies have highlighted their effects on hyperpigmentation disorders, the active components remain unidentified. This study introduces a novel approach combining LC-MS/MS-based molecular networking with AlphaFold2-enabled virtual screening to expedite the identification of bioactive components in persimmon leaf. A total of 105 compounds were identified by MS/MS analysis. Further, virtual screening identified five flavonoids with potential anti-melanogenic properties. Bioassays confirmed myricetin, quercetin, and kaempferol inhibited melanogenesis in human melanocytes in a dose-dependent manner. Biolayer interferometry assays revealed strong binding affinity between these flavonols and hsTYR, with KD values of 23.26 ± 11.77 for myricetin, 12.43 ± 0.37 for quercetin, and 14.99 ± 3.80 μM for kaempferol. Molecular dynamics simulations provided insights into the binding interactions of these flavonols with hsTYR, particularly highlighting the essential role of the 3-OH group on the C-ring. This study elucidates the bioactive components responsible for the anti-melanogenic effects of persimmon leaf, supporting their use in product development.

After winemaking, tannins with high polymerization remain in the pomace. Utilizing these tannin fractions is a concern for the wine industry. While tannins show potential in treating hyperpigmentation, their mechanisms in vivo and at the cellular level are unclear. Herein, pomace tannin fractions (PTFs) were isolated post-winemaking. Nuclear magnetic resonance spectroscopy and mass spectrometry analysis showed PTFs were composed of (epi)catechin gallate and (epi)catechin as terminal and extensional units, with polymerization degrees of 10, 16, and 35. In vivo studies demonstrated that PTFs removed ∼76 % of skin melanin, comparable to hydroquinone. The inhibition by PTFs is due to: (1) Inhibition of the Wnt and melanogenesis pathways, downregulating key melanin synthesis proteins (TYR, TYRP1, TYRP2); (2) Inducing cell cycle arrest at the G1/S checkpoint, disrupting DNA, decreasing mitochondrial membrane potential and integrity, and slowing melanocyte proliferation; (3) Superior tyrosinase inhibitory activity by binding to tyrosinase, chelating copper ions, and demonstrating antioxidant properties. These findings suggest that PTFs inhibit melanin synthesis by the combination of the above mentioned ways, supporting the medical use of winemaking tannins.

Hyperpigmentation disorders are very frequent, affect the quality of life and may become a psychological burden for afflicted patients. Many anti-pigmenting or depigmenting agents are available with various efficacy and almost no comparative data. 2-mercaptonicotinoyl glycine (2-MNG) was recently proposed as a viable candidate showing safe and effective results on hyperpigmentation control in vitro and in vivo.

A Bayesian network meta-analysis (BNMA) was conducted to map and rank the anti-pigmenting and depigmenting efficacy of 2-MNG 0.5% on UV daylight (UVDL)-induced pigmentation together with 13 other reference molecules. A comparison in the kinetics of 2-MNG 0.5% was also performed.

Fourteen studies were conducted, for each, on 15-30 women of skin phototype III in Shanghai, China and Paris, France. The products were applied on mini zone, in randomized and blinded protocol, on the back, 5 days a week during 6 weeks, at a dose of 4 mg/cm2. During the second week, volunteers were exposed under to varying minimum erythemal dose of UVDL during 4 consecutive days-adapted to obtain a similar induction of skin pigmentation regardless of the population. Assessments were performed instrumentally using Chromameter®. Ascorbic acid 7% was used as a positive control for all experiments. A Bayesian network meta-analysis was then established to map and follow the kinetics of 2-MNG 0.5% performance with 13 reference molecules (glutathione 2%, kojic acid 1%, hydroquinone 4%, ascorbyl glucoside 2%, niacinamide 4%, etc.).

2-MNG 0.5% dominated the ranking at all time points with a significant high probability of strong efficacy against UVDL-induced pigmentation. Ascorbic acid 7% ranks second after 4 days of irradiations (D12) whereas hydroquinone 4% ranks second 1 month after irradiations (D40). In the kinetics, 2-MNG at 0.5% was effective as from the end of irradiations (D12) to the study endpoint (D40). This suggested an immediate and persistent efficacy across all timepoints evaluated.

The BNMA revealed a rapid and lasting efficacy of 2-MNG 0.5% on the anti-pigmenting and depigmenting phases of the clinical protocol. 2-MNG 0.5% ranked first, with immediate and lasting effect compared to 13 other references. This study is the first allowing comparison between reference anti-pigmenting and depigmenting agents and will help clinicians for proposing the most effective approach for their patients.

Aim: The aim of this study was to optimize, develop, characterize and evaluate a topical nanobigel (BG) formulation containing Berberine (BRB) that exhibits anti-melanogenic properties.Materials & methods: The Berberine-loaded bigel (BRB@BG) formulation was prepared by homogenously mixing the optimized hydrogel and oleogel. BRB@BG was characterized in vitro and cytotoxicity study was conducted to evaluate its effects on murine skin melanoma B16F10 cell lines.Results: The optimized BRB@BG exhibited uniform texture with nanometric size, desirable spreadability and extrudability, suitable for topical applications. Cytotoxicity studies revealed that BRB@BG had a lower IC50 value (4.84 μg/ml) on B16F10 cell lines compared with drug alone.Conclusion: In conclusion, the developed BRB@BG formulation showed good potential as safe and effective topical treatment for hyperpigmentation.

Inherited hyperpigmented skin disorders comprise a group of entities with considerable clinical and genetic heterogenicity. The genetic basis of a majority of these disorders remains to be elucidated.

This study aimed to identify the underlying gene for an unclarified disorder of autosomal-dominant generalized skin hyperpigmentation with or without glomuvenous malformation.

Whole-exome sequencing was performed in five unrelated families with autosomal-dominant generalized skin hyperpigmentation. Variants were confirmed using Sanger sequencing and a minigene assay was employed to evaluate the splicing alteration. Immunofluorescence and transmission electron microscopy (TEM) were used to determine the quantity of melanocytes and melanosomes in hyperpigmented skin lesions. GLMN knockdown by small interfering RNA assays was performed in human MNT-1 cells to examine melanin concentration and the underlying molecular mechanism.

We identified five variants in GLMN in five unrelated families, including c.995_996insAACA(p.Ser333Thrfs*11), c.632 + 4delA, c.1470_1473dup(p.Thr492fs*12), c.1319G > A(p.Trp440*) and c.1613_1614insTA(Thr540*). The minigene assay confirmed that the c.632 + 4delA mutant resulted in abolishment of the canonical donor splice site. Although the number of melanocytes remained unchanged in skin lesions, as demonstrated by immunofluorescent staining of tyrosinase and premelanosome protein, TEM revealed an increased number of melanosomes in the skin lesion of a patient. The GLMN knockdown MNT-1 cells demonstrated a higher melanin concentration, a higher proportion of stage III and IV melanosomes, upregulation of microphthalmia-associated transcription factor and tyrosinase, and downregulation of phosphorylated p70S6 K vs. mock-transfected cells.

We found that loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation. Our study implicates a potential role of glomulin in human skin melanogenesis, in addition to vascular morphogenesis.

Although reports suggest that tranexamic acid (TXA) has clinical benefits for melasma patients by oral, intralesional and topical treatment, the optimal route of TXA therapy and the underlying mechanism involved remain poorly defined.

To compare the skin lightening effect between oral TXA and topical TXA and to dissect the molecular mechanisms using ultraviolet B (UVB)-induced hyperpigmentation mouse model, ex vivo cultured human skin explant, and cultured melanocytes (MCs) and endothelial cells.

Melanin content and cluster of differentiation 31 (CD31)-positive cell numbers were measured in tail skins from UVB-irradiated mice treated by intragastral or topical TXA using immunofluorescent and Fontana-Masson staining. The conditioned medium (CM) was harvested from human umbilical vein endothelial cells treated with or without 3 mM TXA and was used to treat MCs for 48 hours. mRNA and protein levels of tyrosinase and microphthalmia-associated transcription factor were measured using quantitative real-time reverse transcription polymerase chain reaction and western blotting assays. HMB45- and CD31-positive cell numbers as well as melanin content were also examined in ex vivo cultured human skin explants.

The hyperpigmented phenotype were significantly mitigated in UVB-irradiated tail skin plus intragastral TXA-treated mice compared with mice treated with UVB only or with UVB plus topical TXA. CD31-positive cell numbers correlated with the anti-melanogenic activity of TXA therapy. The data from cultured cells and skin tissues showed that suppression of endothelin-1 (ET-1) in vascular endothelial cells by TXA reduced melanogenesis and MC proliferation.

Oral TXA outperforms topical TXA treatment in skin lightening, which contributes to suppression of ET-1 in dermal microvascular endothelial cells by TXA.

Petanin, an acylated anthocyanin from the Solanaceae family, shows potential in tyrosinase inhibitory activity and anti-melanogenic effects; however, its mechanism remains unclear. Therefore, to investigate the underlying mechanism of petanin's anti-melanogenic effects, the enzyme activity, protein expression and mRNA transcription of melanogenic and related signaling pathways in zebrafish using network pharmacology, molecular docking and molecular dynamics simulation were combined for analysis. The results showed that petanin could inhibit tyrosinase activity and melanogenesis, change the distribution and arrangement of melanocytes and the structure of melanosomes, reduce the activities of catalase (CAT) and peroxidase (POD) and enhance the activity of glutathione reductase (GR). It also up-regulated JNK phosphorylation, inhibited ERK/RSK phosphorylation and down-regulated CREB/MITF-related protein expression and mRNA transcription. These results were consistent with the predictions provided through network pharmacology and molecular docking. Thus, petanin could inhibit the activity of tyrosinase and the expression of tyrosinase by inhibiting and negatively regulating the tyrosinase-related signaling pathway ERK/CREB/MITF through p-JNK. In conclusion, petanin is a good tyrosinase inhibitor and anti-melanin natural compound with significant market prospects in melanogenesis-related diseases and skin whitening cosmetics.

Cutaneous adverse reactions to epidermal growth factor receptor inhibitors (EGFRi) are some of the most common side effects that patients experience. However, cutaneous adverse reactions that cause dyspigmentation in patients have been rarely reported. Erythema dyschromicum perstans (EDP) is a rare pigmentary condition that causes ashy-grey hyperpigmented macules and patches, with a few cases reported from EGFRi in the literature. The disfiguration caused by this condition may negatively impact patients' quality of life. Our study aimed to describe the clinical characteristics of EDP induced by EGFRi to better recognize and manage the condition.

We conducted a multicenter retrospective review at three academic institutions to identify patients with EDP induced by EGFRi from 2017 to 2023 and included sixteen patients in our study.

The median age of patients was 66 years old, with 63% female and 37% male (Table 1). The majority of our patients were Asian (88%). All patients had non-small cell lung cancer and most patients received osimertinib. Median time to EDP was 6 months. The most common areas of distribution were the head/neck region, lower extremities, and upper extremities. Various topical ointments were trialed; however, approximately less than half had improvement in their disease and most patients had persistent EDP with no resolution. All patients desired treatment except one with EDP on the tongue, and there was no cancer treatment discontinuation or interruption due to EDP. Table 1 Patient demographics and clinical characteristics of 16 patients with EDP induced by EGFRi Case no Demographics: age, race, and sex Fitzpatrick skin type Cancer type EGFR therapy Concomitant photosensitive drug(s) Time to EDP (months) Clinical features Distribution Symptoms Treatments and clinical course EDP status from most recent follow up 1 47 y/o Asian male III Stage IV NSCLC Erlotinib None Unknown Brown-blue-gray hyperpigmented patches Bilateral shins Left thigh Xerosis Pruritus Triamcinolone 0.1% ointment for 4 months, improvement of blue discoloration Tacrolimus 0.1% BID for 9 months, improvement but no resolution Ongoing 2 62 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown hyperpigmented patches Bilateral arms Back Forehead Neck Right shin None Tacrolimus 0.1% ointment for 1 year with minor improvement Ongoing 3 69 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown macules and patches Chest Face Forehead Bilateral legs None Tacrolimus 0.1% ointment for 10 months, no improvement Ongoing 4 79 y/o White male II Stage IV NSCLC Osimertinib None 15 Mottled grey-blue hyperpigmented patches and plaques with mild scaling Bilateral arms Back Forehead Neck None Photoprotection, no improvement Ongoing 5 69 y/o Asian female III Stage IV NSCLC Osimertinib Ibuprofen 4 Blue-grey hyperpigmented macules and patches Abdomen Bilateral arms None Tacrolimus 0.1% ointment for 7 months, no improvement Ongoing 6 65 y/o Asian male III Stage IV NSCLC Osimertinib None 20 Hyperpigmented blue gray macules and patches Helix Bilateral shins None Photoprotection, no improvement Ongoing 7 66 y/o Asian female IV Stage IV NSCLC Erlotinib TMP-SMX 6 Ashy grey-brown thin plaques Back Forehead None 2.5% hydrocortisone ointment for 8 months, resolved Resolved 8 82 y/o Asian male III Stage III NSCLC Erlotinib Simvastatin 20 Ash-grey hyperpigmented patches Dorsal feet Forehead Scalp None Photoprotection Ongoing 9 57 y/o Asian female III Stage II NSCLC Erlotinib None 1 Bue-grey discoloration Tongue None No intervention Ongoing 10 51 y/o Asian female III Stage IV NSCLC Osimertinib None 9 Blue-grey hyperpigmented macules and patches Bilateral arms Axillae Groin Neck Trunk None 2.5% hydrocortisone ointment, triamcinolone 0.1% ointment, photoprotection with mild improvement Ongoing 11 67 y/o Asian male III Stage IV NSCLC Osimertinib None 7 Gray-blue macules and patches with mild background erythema and scaling Bilateral arms Ears Face Bilateral shins None Triamcinolone 0.1% ointment, protection for 6 months with mild improvement Ongoing 12 75 y/o Asian female IV Stage III NSCLC Osimertinib TMP-SMX 3 Gray-blue hyperpigmented patches Bilateral arms Abdomen Back Face Bilateral shins Pruritus Triamcinolone 0.1% and betamethasone 0.01% with relief of pruritus, lesions unchanged Triluma cream 6 months, mild improvement Ongoing 13 42 y/o Asian male IV Stage IV NSCLC Afatinib TMP-SMX 24 Grey-brown hyperpigmented patches Back Face None Hydroquinone 4% cream for 2 years with mild improvement Ongoing 14 74 y/o White female III Stage II NSCLC Osimertinib Atorvastatin 4 Grey-brown hyperpigmented patches Bilateral legs Trunk None Photoprotection Ongoing 15 64 y/o Asian female IV Stage IV NSCLC Osimertinib None 3 Gray-brown hyperpigmentation Abdomen Bilateral arms Back Bilateral legs Pruritus Triamcinolone 0.1% cream; No change, minimal concern to patient Ongoing 16 52 y/o Asian female IV Stage IV NSCLC Osimertinib None 42 Gray hyperpigmented patches with digitate shape Abdomen Bilateral flanks None Triamcinolone 0.1% cream Ongoing NSCLC, non-small cell lung cancer, TMP-SMX, Trimethoprim/Sulfamethoxazole CONCLUSIONS: We highlight the largest case series describing EDP from EGFR inhibitors, which mostly affected Asian patients with lung malignancy and on EGFR tyrosine kinase inhibitors. Clinicians should be able to recognize this condition in their patients and assess how it is affecting their quality of life, and refer to dermatology to help with management.

Artificial intelligence (AI) de novo molecular generation is a highly promising strategy in the drug discovery, with deep reinforcement learning (RL) models emerging as powerful tools. This study introduces a fragment-by-fragment growth RL forward molecular generation and optimization strategy based on a low activity lead compound. This process integrates fragment growth-based reaction templates, while target docking and drug-likeness prediction were simultaneously performed. This comprehensive approach considers molecular similarity, internal diversity, synthesizability, and effectiveness, thereby enhancing the quality and efficiency of molecular generation. Finally, a series of tyrosinase inhibitors were generated and synthesized. Most compounds exhibited more improved activity than lead, with an optimal candidate compound surpassing the effects of kojic acid and demonstrating significant antipigmentation activity in a zebrafish model. Furthermore, metabolic stability studies indicated susceptibility to hepatic metabolism. The proposed AI structural optimization strategies will play a promising role in accelerating the drug discovery and improving traditional efficiency.

The heightened awareness of ethnic dermatology aligns with the growing prevalence of skin of color communities globally, where hyperpigmentation disorders pose a common dermatological challenge. Effectively addressing dermal pigmentation is challenging due to its resistance to conventional therapies and its association with impaired quality of life. This underscores the need for effective treatments and a thorough grasp of laser advancements. A relevant literature search spanning the last 7 years across the PubMed database reveals core studies, challenges, and the evolution of laser technologies tailored for various forms of congenital and acquired dermal hyperpigmentation in skin of color. This comprehensive review explores the mechanisms, applications, and recommendations for pigmentary laser technologies, highlighting the key role of Q-switched lasers in their established millisecond/ nanosecond forms and emerging picosecond lasers, fractional non-ablative and ablative lasers, Intense Pulsed Light, etc. The summary of evidence includes studies on dermal melanocytosis (nevus of Ota and Hori's nevus), tattoos, acquired dermal macular hyperpigmentation, etc., and also entities with mixed epidermal-dermal components, such as melasma and post-inflammatory hyperpigmentation. The review offers valuable insights for clinicians to make informed decisions based on diagnosis, skin type, and the latest technologies to optimize results and minimize complications, especially in darker Fitzpatrick skin types. In their five-year study with 122 Indian patients, the authors applied specific laser combinations for diverse dermal melanoses, including tattoos, dermal/mixed melasma, acquired dermal macular hyperpigmentation, and dermal nevi. Substantial pigmentation reduction, subjectively assessed by both physicians and patients, was observed across all groups. A one-way ANOVA indicated a significant difference in mean improvement scores across various pigmentary conditions (F = 3.39, p = 0.02), with melasma patients exhibiting a significantly higher improvement score than tattoos (p = 0.03). The results affirmed the safety and efficacy of sequential laser therapy for dermal pigmentation in skin of color, advocating for flexibility in approach while maintaining the rationale behind the laser sequences. Despite advancements, challenges persist, and gaps in the current literature are identified. In conclusion, this summary highlights the ongoing pursuit of optimal protocols in dermatological laser treatments for dermal melanoses, offering valuable insights for future research and clinical practice.

Congenital dermal melanocytosis (DM) represents a common birthmark mainly found in children of Asian and darker skin phototype descent, clinically characterized by an oval blue-grey macule or macules, commonly located on the lumbosacral area. In rare DM cases, when presenting with diffuse macules persisting during the first years of life, it could represent a cutaneous feature of mucopolysaccharidoses (MPS). Extensive congenital DM is actually associated with Hurler syndrome (MPS type I) and Hunter syndrome (MPS type II), although several reports also described this association with MPS type VI and other lysosomal storage disorders (LySD), including GM1 gangliosidosis, mucolipidosis, Sandhoff disease, and Niemann-Pick disease. Here, we present the case of a two-year-old boy presenting with extensive dermal melanocytosis, generalized hypertrichosis, and chronic itch, harboring a heterozygous variant of uncertain significance, NM_152419.3: c.493C>T (p.Pro165Ser), in the exon 4 of HGSNAT gene, whose mutations are classically associated with MPS IIIC, also known as Sanfilippo syndrome. This is the first report that highlights the association between extensive congenital DM and MPS type IIIC, as well as a pathogenetic link between heterozygous LySD carrier status and congenital DM. We speculate that some cases of extensive congenital DM could be related to heterozygous LySD carriers, as a manifestation of a mild clinical phenotype.

Objective: Metformin has recently been demonstrated to have an anti-melanogenic activity. Nevertheless, clinical evidence of the effectiveness of metformin in melasma is lacking. The objective of this study was to assess the efficacy and safety of metformin in the treatment of melasma. Methods: MEDLINE, Embase, PubMed, Cochrane Library (CENTRAL), Scopus, CINAHL, and grey literature databases were searched to 4 October 2022 and updated on 26 February 2023. Randomized controlled trials (RCTs), quasi-RCTs, observational studies, case series, and case reports investigating the efficacy and safety of metformin for melasma were included. The Melasma Area Severity Index (MASI) scores that changed from baseline were pooled using fixed-effects model and expressed as standardized mean differences (SMDs) and 95% confidence intervals (CIs). Results: Three RCTs including 140 patients with melasma were included. The results demonstrated that after 8 weeks, 15% topical metformin significantly reduced the Melasma Area Severity Index (MASI) score compared to placebo (1 trial; n = 60; MD, -0.56; 95% CI, -1.07 to -0.04; p = 0.034). Furthermore, when compared to triple combination cream (TCC), 30% topical metformin demonstrated similar efficacy in reducing the MASI score after 8 weeks (2 trials; n = 80; MD, 0.19, 95% CI, -0.25 to 0.63; p = 0.390). Patients using 30% topical metformin had fewer adverse events compared to TCC users, although no statistical difference was found. Conclusion: Topical metformin was as effective as triple combination cream (TCC) in decreasing changes in the MASI score in patients with melasma, with minimum adverse events. Further studies with larger sample sizes, longer follow-up times, and well-designed trials are required. Systematic Review Registration: Identifier PROSPERO (CRD42022351966).

Topical application of tyrosinase inhibitors, such as hydroquinone and arbutin, is the most common clinical treatment for hyperpigmentation. Glabridin (Gla) is a natural isoflavone that inhibits tyrosinase activity, free radical scavenging, and antioxidation. However, its water solubility is poor, and it cannot pass through the human skin barrier alone. Tetrahedral framework nucleic acid (tFNA), a new type of DNA biomaterial, can penetrate cells and tissues and can be used as carriers to deliver small-molecule drugs, polypeptides, and oligonucleotides. This study aimed to develop a compound drug system using tFNA as the carrier to transport Gla and deliver it through the skin to treat pigmentation. Furthermore, we aimed to explore whether tFNA-Gla can effectively alleviate the hyperpigmentation caused by increased melanin production and determine whether tFNA-Gla exerts substantial synergistic effects during treatment. Our results showed that the developed system successfully treated pigmentation by inhibiting regulatory proteins related to melanin production. Furthermore, our findings showed that the system was effective in treating epidermal and superficial dermal diseases. The tFNA-based transdermal drug delivery system can thus develop into novel, effective options for non-invasive drug delivery through the skin barrier.

Skin pigmentation abnormalities, ranging from aesthetic concerns to severe hyperpigmentation disease, have profound implications for individuals' psychological and economic wellbeing. The intricate etiology of hyperpigmentation and our evolving comprehension of its underlying mechanisms underscore the need for robust animal models. Zebrafish, renowned for their transparent embryos and genetic parallels to humans, have been spotlighted as a pivotal model for skin pigmentation studies. This review offers a concise overview of zebrafish skin attributes, highlighting the shared melanin production pathways with humans. We systematically dissect the diverse strategies to craft zebrafish models of abnormal skin pigmentation, spanning physical, chemical, and genetic interventions, while critically appraising the merits and constraints of each approach. Additionally, we elucidate the metrics employed to gauge the efficacy of these models. Concluding, we cast a visionary gaze on prospective breakthroughs in the domain, aiming to steer forthcoming efforts in refined zebrafish models for skin pigmentation research.

(1) Background: Genodermatoses are a clinically and genetically heterogenous group of inherited skin disorders. Diagnosing inherited skin diseases is a challenging task due to their rarity and diversity. Dermoscopy is a non-invasive, easily accessible, and rapid tool used in dermatology not only for diagnostic processes but also for monitoring therapeutic responses. Standardized terminologies have been published for its proper use, reproducibility, and comparability of dermoscopic terms. (2) Methods: Here, we aimed to investigate dermoscopic features in various genodermatoses by conducting a systematic review and comparing its results to our own findings, data of patients diagnosed with genodermatoses at the Department of Dermatology, Venereology and Dermatooncology, Semmelweis University. (3) Results: Our systematic search provided a total of 471 articles, of which 83 reported both descriptive and metaphoric dermoscopic terminologies of 14 genodermatoses. The literature data were then compared to the data of 119 patients with 14 genodermatoses diagnosed in our department. (4) Conclusion: Dermoscopy is a valuable tool in the diagnosis of genodermatoses, especially when symptoms are mild. To enable the use of dermoscopy as an auxiliary diagnostic method, existing standardized terminologies should be extended to more genodermatoses.

Ultraviolet (UV) radiation is the primary exogenous inducer of skin pigmentation, although the mechanism has not been fully elucidated. N6-methyladenosine (m6 A) modification is one of the key epigenetic form of gene regulation that affects multiple biological processes. The aim of this study was to explore the role and underlying mechanisms of m6 A modification in UVB-induced melanogenesis. Low-dose UVB increased global m6 A modification in melanocytes (MCs) and MNT1 melanoma cell line. The GEPIA database predicted that methyltransferase METTL3 is positively correlated with the melanogenic transcription factor MITF in the sun-exposed skin tissues. After METTL3 respectively overexpressed and knocked down in the MNT1, the melanin content and melanogenesis-related genes were significantly upregulated after overexpression of METTL3, especially with UVB irradiation, and downregulated after METTL3 knockdown. METTL3 levels were also higher in melanocytic nevi with high melanin content. METTL3 overexpression and knockdown also altered the protein level of YAP1. SRAMP analysis predicted four high-potential m6 A modification sites on YAP1 mRNA, of which three were confirmed by methylated RNA immunoprecipitation. Inhibition of YAP1 expression can partially reverse melanogenesis induced by overexpression of METTL3. In conclusion, UVB irradiation promotes global m6 A modification in MCs and upregulates METTL3, which increases the expression level of YAP1 through m6 A modification, thereby activating the co-transcription factor TEAD1 and promoting melanogenesis.

Minocycline is an antibiotic used for several dermatologic conditions, including rosacea. The development of skin, scleral, and nail hyperpigmentation may occur with long-term use of minocycline, and this is associated with no adverse effect on function. We present a case of a 66-year-old male who developed blue-gray hyperpigmentation of his nail beds after treating rosacea with systemic minocycline for over 20 years. The remainder of the physical exam was unremarkable for hyperpigmentation elsewhere. The patient was informed that this was likely an adverse effect of his chronic minocycline use. He insisted upon the continuation of minocycline, so he was counseled on the adverse effects of the medication and scheduled for follow-up.