MC1R x TYR

Skin hyperpigmentation disorders, such as melasma and age spots, result from abnormal melanin overproduction and remain a significant dermatological concern. Tyrosinase, a key enzyme in melanogenesis, represents a critical target for depigmenting therapies. Cinnamophilin (CINN), a lignan isolated from Machilus species, exhibits strong antioxidant properties and potential tyrosinase inhibitory activity. However, its poor water solubility and limited skin permeability restrict its topical application. In this study, a self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the dermal delivery and efficacy of CINN. Molecular docking revealed the binding of CINN at the tyrosinase catalytic site through hydrogen bonding and π-π interactions, without direct coordination to catalytic copper ions. CINN also exhibited concentration-dependent tyrosinase inhibition in vitro, with an IC₅₀ value of 39.4 ± 0.1 μM. Enzyme kinetics indicated a mixed-type inhibition mechanism. The optimized CINN-loaded SNEDDS formulation exhibited a mean droplet size of 266.8  nm with a polydispersity index of 0.295 and enhanced skin permeability by approximately threefold in a PAMPA model. In α-MSH-stimulated B16F10 cells, CINN-loaded SNEDDS significantly reduced both melanin secretion and intracellular tyrosinase activity. These findings identify CINN as a natural tyrosinase inhibitor and demonstrate the potential of SNEDDS to improve its solubility, skin permeability, and anti-melanogenic efficacy for topical application.

Hyperpigmentation is a skin disorder characterized by the abnormal accumulation of melanin, in which the melanocortin-1 receptor (MC1R) was recognized as a key target for melanin production. Antisense oligonucleotide (ASO), by targeting mRNA to inhibit protein synthesis, holds a promising gene therapy for hyperpigmentation. However, challenges such as nonspecific activation, off-target toxicity, and limited cellular permeability hinder their broader clinical application. Inspired by the Chinese proverb "Turn an enemy into a friend", we introduce a dual-gated, ultraviolet (UV)-tyrosinase (TYR) cascade-responsive modified ASO (m-ASO) that enables spatiotemporally controlled silencing of MC1R. The engineered m-ASO is caged via thymidine modification, rendering it inactive until sequentially exposed to exogenous UV and intracellular TYR. UV irradiation, conventionally hyperpigmentation trigger, is repurposed to initiate decaging of m-ASO into an intermediate form, ph-ASO. This intermediate is then enzymatically activated by TYR overexpressed in melanocytes within pigmented tissues, ultimately restoring the native conformation and therapeutic function of the ASO. This "enemy-to-ally" strategy allows for disease-specific, precision activation of ASO therapeutics. Notably, to enhance transdermal delivery, the m-ASO nanocomplex is integrated into a biocompatible, dissolvable microneedle system for painless and localized epidermal administration. The resulting platform demonstrates precise MC1R silencing and effective melanin suppression, while sparing normal melanocytes. Together, this cascade-caged, cell-selective, and minimally invasive strategy presents a novel framework for programmable nucleic acid therapeutics in dermatological and enzyme-overexpressing diseases.

Yuexi Frizzled Feather Chicken (YFC), an indigenous breed in China noted for its curly feathers, primarily comprises yellow, white, and black plumage color strains. However, the genetic mechanism underlying the regulation of plumage colors remains unknown. In this study, whole genome resequencing was employed to systematically analyze and evaluate the genetic diversity of these three distinctive plumage color strains, as well as to screen and identify crucial genes related to the plumage color. Population genetic structure analysis revealed that the YFC could be divided into 3 plumage color populations, with the yellow-feathered chickens showing the highest genetic diversity, whereas the black-feathered chickens exhibited the strongest signatures of artificial selection. Further, detection of selection signals through Fst, ROD, XPCLR indicated that 59 overlapping genes (including MC1R, CDH1, TCF25, and ZFHX3), 19 overlapping genes (including GRM5, TYR, CTSC, and RAB38), and 17 overlapping genes (including PTCH1, FBP1, and FBP2) were significantly associated with black, white, and yellow plumage color in YFC, respectively. GO annotation and KEGG pathway analysis indicated that the plumage color regulation primarily involved in cell adhesion and signal transduction, regulation and synthesis of melanin, and synthesis of biological molecules. Moreover, GWAS and Sanger sequencing revealed that the rs317806696 in the CDH1 gene was relevant to the black plumage color of YFC, while the rs317372610 and rs741501156 in the TYR gene was associated with the white plumage color. Hence, the objective of this study is to provide comprehensive genomic insights into the genetic diversity and plumage color regulation in YFC, which provide the foundation for protection of YFC genetic resources and selection of chicken breeding program for different plumage colors.