OBJECTIVE: The association between the total macular burden of hyperreflective foci (HRF) in eyes with intermediate AMD (iAMD) and the onset of persistent choroidal hypertransmission defects (hyperTDs) was studied using swept-source optical coherence tomography (SS-OCT).
METHODS: Post hoc subgroup analysis of a prospective study.
METHODS: A retrospective review of iAMD eyes from subjects enrolled in a prospective SS-OCT study was performed. All eyes underwent 6×6 mm SS-OCT angiography (SS-OCTA) imaging at baseline and follow-up visits. En face sub-retinal pigment epithelium (subRPE) slabs with segmentation boundaries positioned 64-400 µm beneath Bruch\'s membrane (BM) were used to identify persistent choroidal hyperTDs. None of the eyes had persistent hyperTDs at baseline. The same subRPE slab was used to identify choroidal hypotransmission defects (hypoTDs) attributable to HRF located either intraretinally (iHRF) or along the RPE (rpeHRF) based on corresponding B-scans. A semiautomated algorithm was used by two independent graders to validate and refine the HRF outlines. The HRF area and the drusen volume within a 5mm fovea-centered circle were measured at each visit.
RESULTS: The median follow-up time for the 171 eyes from 121 patients included in this study was 59.1 months (95%CI: 52.0-67.8 months). Of these, 149 eyes (87%) had HRF, and 82 (48%) developed at least one persistent hyperTD during the follow-up. Although univariable Cox regression analyses showed that both drusen volume and total HRF area were associated with the onset of the first persistent hyperTD, multivariable analysis showed that the area of total HRF was the sole significant predictor for the onset of hyperTDs (P<0.001). ROC analysis identified an HRF area ≥ 0.07 mm² to predict the onset of persistent hyperTDs within one year with an area under the curve (AUC) of 0.661 (0.570-0.753), corresponding to a sensitivity of 55% and a specificity of 74% (P<0.001).
CONCLUSIONS: The total macular burden of HRF, which includes both the HRF along the RPE and within the retina, is an important predictor of disease progression from iAMD to the onset of persistent hyperTDs and should serve as a key OCT biomarker to select iAMD patients at high-risk for disease progression in future clinical trials.

Diffuse hyperpigmentation with guttate hypopigmentation (DHGH) is a new acquired pigmentary disorder. Only a few cases have previously been reported in the Chinese population, in Chinese. To summarise the clinical, dermoscopic, and histopathological findings of DHGH in the English literature, to improve the recognition and management of this condition. This was a retrospective study to summarise the clinical, dermoscopic, and pathological findings of nine cases of DHGH. All nine patients with DHGH were female. The age at onset varied from 6 to 24 years (median 17 years). Patients were generally in good health without systemic disease. The lesions were often generalised to the trunk and extremities without any discomfort. Typical lesions were characterised by multiple uniform hypopigmented spots, 2-5 mm in diameter, irregularly distributed over diffuse hyperpigmentation. Dermoscopy revealed multiple blurred patchy areas of brownish pigmentation, sparse linear and dotted vessels, and perifollicular pigmentation on a white to bright white background, surrounded by brown hyperpigmentation. Histopathological findings included mild abnormal pigment of the epidermis, focal vacuolar degeneration of the basal cells, mild pigment incontinence and perivascular lymphocytic infiltration in the dermis. DHGH is a new entity with distinctive clinical manifestations that differ from those of other known pigmentary disorders. So far, DHGH has only been reported in the Chinese population. It may not be uncommon and has not received much attention due to the few reports. The aetiology and pathogenesis of DHGH are still unknown and require further investigation.

Hyperpigmentation (HP) is an unfavorable skin disease that typically caused by injury, inflammation, or photoaging and leads to numerous physical and psychological issues in patients. Recently, development and application of natural whitening substances, particularly compound curcumin (CUR), is one of the most prevalent treatments for HP. However, it is still a formidable challenge to improve the percutaneous delivery of CUR due to its inadequate solubility in water and excellent barrier function of skin. To overcome the limitations of conventional delivery and increase the percutaneous absorption of CUR, the efficient delivery of CUR is urgently required. Herein, we developed a new malic acid-sorbitol deep eutectic solvent (MS/DES) gel microneedle loaded with CUR as a transdermal delivery system for HP treatment. The MS/DES gel produces three-dimensional (3D) network structure by self-assembly of hydrogen bond interactions, which conferred the CUR-MS/DES-GMN with sufficient mechanical properties to successfully penetrate skin tissue while also helping to enhance the drug\'s release rate. The CUR-MS/DES-GMN exhibit high biocompatibility and mechanical property in vivo of mice. The zebrafish experiments also show that CUR-MS/DES gel has significant effect of anti-pigmentation. Therefore, the designed CUR-MS/DES-GMN system provides a novel strategy for HP treatment based on self-assembly of naturally molecules.

Skin hyperpigmentation is mainly caused by excessive synthesis of melanin; however, there is still no safe and effective therapy for its removal. Here, we found that the dermal freezer was able to improve UVB-induced hyperpigmentation of guinea pigs without causing obvious epidermal damage. We also mimic freezing stimulation at the cellular level by rapid freezing and observed that freezing treatments <2.5 min could not decrease cell viability or induce cell apoptosis in B16F10 and Melan-A cells. Critically, melanin content and tyrosinase activity in two cells were greatly reduced after freezing treatments. The dramatic decrease in tyrosinase activity was associated with the downregulation of MITF, TYR, TRP-1 and TRP-2 protein expression in response to freezing treatments for two cells. Furthermore, our results first demonstrated that freezing treatments significantly reduced the levels of p-GSK3β and β-catenin and the nuclear accumulation of β-catenin in B16F10 and Melan-A cells. Together, these data suggest that fast freezing treatments can inhibit melanogenesis-related gene expression in melanocytes by regulating the Wnt/β-catenin signalling pathway. The inhibition of melanin production eventually contributed to the improvement in skin hyperpigmentation induced by UVB. Therefore, fast freezing treatments may be a new alternative of skin whitening in the clinic in the future.

Senile skin hyperpigmentation displays remarkable histopathological features of dermal aging. The crosstalk between melanocytes and dermal fibroblasts plays crucial roles in aging-related pigmentation. While senescent fibroblasts can upregulate pro-melanogenic factors, the role of anti-melanogenic factors, such as dickkopf1 (DKK1), and the upstream regulatory mechanism during aging remain obscure. This study investigated the roles of yes-associated protein (YAP) and DKK1 in the regulation of dermal fibroblast senescence and melanogenesis. Our findings demonstrated decreased YAP activity and DKK1 levels in intrinsic and extrinsic senescent fibroblasts. YAP depletion induced fibroblast senescence and downregulated the expression and secretion of DKK1, whereas YAP overexpression partially reversed the effect. The transcriptional regulation of DKK1 by YAP was supported by dual-luciferase reporter and chromatin immunoprecipitation assays. Moreover, YAP depletion in fibroblasts upregulated Wnt/β-catenin in melanocytes and stimulated melanogenesis, which was partially rescued by the re-supplementation of DKK1. Conversely, overexpression of YAP in senescent fibroblasts decreased Wnt/β-catenin levels in melanocytes and inhibited melanogenesis. Additionally, reduced levels of YAP and DKK1 were verified in the dermis of solar lentigines. These findings suggest that, during skin aging, epidermal pigmentation may be influenced by YAP in the dermal microenvironment via the paracrine effect of DKK1.

Hydroxychloroquine (HCQ) is used as a traditional disease-modifying antirheumatic drugs (DMARDs), for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, it can cause serious adverse reactions, including hyperpigmentation of the skin and bull\'s-eye macular lesions. Here, we present a case of HCQ-induced hyperpigmentation of the skin and bull\'s-eye macular lesions in a patient who received HCQ for RA. A 65-year-old female patient developed blurred vision and hyperpigmentation of multiple areas of skin over the body for one month after 3 years of HCQ treatment for RA. Based on clinical presentation, ophthalmological examination and dermatopathological biopsy, a diagnosis of drug-induced cutaneous hyperpigmentation and bullous maculopathy of the right eye was made. After discontinuation of HCQ and treatment with iguratimod tablets, the hyperpigmentation of the patient \'s skin was gradually reduced, and the symptoms of blurred vision were not significantly improved. We also reviewed the available literature on HCQ-induced cutaneous hyperpigmentation and bull\'s-eye macular lesions and described the clinical features of HCQ-induced cutaneous hyperpigmentation and bull\'s-eye macular lesions. In conclusion, clinicians should be aware of early cutaneous symptoms and HCQ-associated ophthalmotoxicity in patients with rheumatic diseases on HCQ sulphate and should actively monitor patients, have them undergo regular ophthalmological examinations and give appropriate treatment to prevent exacerbation of symptoms.

Skin hyperpigmentation is a worldwide condition associated with augmented melanogenesis. However, conventional therapies often entail various adverse effects. Here, we explore the safety range and depigmentary effects of polysaccharides extract of Tricholoma matsutake (PETM) in an in vitro model and further evaluated its efficacy at the clinical level. An induced-melanogenesis model was established by treating B16-F10 melanoma cells with 8-methoxypsoralen (8-MOP). Effects of PETM on cell viability and melanin content were examined and compared to a commonly used depigmentary agent, α-arbutin. Expressions of key melanogenic factors and upstream signaling pathway were analysed by quantitative PCR and western blot. Moreover, a placebo-controlled clinical study involving Chinese females with skin hyperpigmentation was conducted to measure the efficacy of PETM on improving facial pigmented spots, melanin index, and individual typology angle (ITA°). Results demonstrated that PETM (up to 0.5 mg/mL) had little effect on the viability and motility of B16-F10 cells. Notably, it significantly suppressed the melanin content and expressions of key melanogenic factors induced by 8-MOP in B16-F10 melanoma cells. Western blotting results revealed that PETM inhibited melanogenesis by inactivating c-Jun N-terminal kinase (JNK), and this inhibitory role could be rescued by JNK agonist treatment. Clinical findings showed that PETM treatment resulted in a significant reduction of facial hyperpigmented spot, decreased melanin index, and improved ITA° value compared to the placebo-control group. In conclusion, these in vitro and clinical evidence demonstrated the safety and depigmentary efficacy of PETM, a novel polysaccharide agent. The distinct mechanism of action of PETM on melanogenic signaling pathway positions it as a promising agent for developing alternative therapies.

Acne, a highly prevalent skin disease, can be particularly bothersome for patients of Asian background because of its impact on self-confidence and social interactions. In addition to active acne lesions, some patients may develop sequelae such as scarring, macular/postinflammatory hyperpigmentation, or erythema. The tendency of Asian skin to develop sequelae because of its increased susceptibility to irritation, cultural preferences for lighter skin phototypes, and differences in skincare regimens may all contribute to the increased burden of acne. Moreover, many Asia-Pacific countries do not have their own guidelines for acne management, and those that do often have no schedule in place for regular updates. In this article, we provide a critical review of the published guidance for the management of acne and its sequelae in the Asia-Pacific region, identifying gaps in current recommendations that could be addressed to enhance standards of acne care in Asia-Pacific countries. Along with highlighting the importance of a comprehensive skincare regimen to increase treatment efficacy and adherence, we discuss topical retinoids and retinoid combination options in the acne armamentarium that may be beneficial for sequelae prevention and management, such as adapalene 0.3% ± benzoyl peroxide 2.5%, tretinoin 0.05%, tazarotene 0.1%, and trifarotene 0.005%. In particular, trifarotene 0.005% has been observed to significantly reduce acne scar counts in a Phase 4 study. The recent data highlight the need to establish up-to-date guidance for acne and acne sequelae management in Asia-Pacific countries to provide optimal care to Asian patients.

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UNASSIGNED: Hyperpigmentation, a common skin condition marked by excessive melanin production, currently has limited effective treatment options.
UNASSIGNED: This study explores the effects of Tao-Hong-Si-Wu decoction (THSWD) on hyperpigmentation and to elucidate the underlying mechanisms.
UNASSIGNED: We employed network pharmacology, Mendelian randomization, and molecular docking to identify THSWD\'s hub targets and mechanisms against hyperpigmentation. The Cell Counting Kit-8 (CCK-8) assay determined suitable THSWD treatment concentrations for PIG1 cells. These cells were exposed to graded concentrations of THSWD-containing serum (2.5%, 5%, 10%, 15%, 20%, 30%, 40%, and 50%) and treated with α-MSH (100 nM) to induce an in vitro hyperpigmentation model. Assessments included melanin content, tyrosinase activity, and Western blotting.
UNASSIGNED: ALB, IL6, and MAPK3 emerged as primary targets, while quercetin, apigenin, and luteolin were the core active ingredients. The CCK-8 assay indicated that concentrations between 2.5% and 20% were suitable for PIG1 cells, with a 50% cytotoxicity concentration (CC50) of 32.14%. THSWD treatment significantly reduced melanin content and tyrosinase activity in α-MSH-induced PIG1 cells, along with downregulating MC1R and MITF expression. THSWD increased ALB and p-MAPK3/MAPK3 levels and decreased IL6 expression in the model cells.
UNASSIGNED: THSWD mitigates hyperpigmentation by targeting ALB, IL6, and MAPK3. This study paves the way for clinical applications of THSWD as a novel treatment for hyperpigmentation and offers new targeted therapeutic strategies.