Laduviglusib

Androgenetic alopecia (AGA) is a chronic and progressive hair loss disorder marked by follicular miniaturization and a shortened anagen phase. While androgenic and genetic factors contribute to its pathogenesis, increasing evidence highlights the importance of dysregulated molecular signaling in impaired hair follicle (HF) regeneration.This review explores the interconnected signaling pathways that govern HF cycling and regeneration-Wnt/β-catenin, Sonic Hedgehog (Shh), Bone Morphogenetic Protein (BMP), and Notch. Wnt/β-catenin activation initiates anagen by stimulating stem cell proliferation and follicle formation, while Shh supports follicular proliferation and morphogenesis. Notch regulates HF stem cell (HFSC) fate, and BMP enforces quiescence and catagen onset. Crucially, crosstalk between Wnt-BMP and Shh-Notch pathways ensures follicular homeostasis, highlighting the need to view these pathways as an integrated regulatory network.Recent therapeutic innovations focus on modulating these signaling cascades. Small molecules such as valproic acid and CHIR99021 activate Wnt signaling; smoothened agonists target Shh; and Noggin mimetics or BMP-neutralizing antibodies inhibit BMP activity. These approaches have shown promising outcomes in preclinical models, including mouse studies, in vitro HFSC systems, etc. Additionally, emerging gene editing technologies (e.g., CRISPR-Cas9) and stem cell-biomaterial integration offer regenerative strategies that move beyond symptomatic treatments like minoxidil or hair transplantation.Given that AGA is associated with androgen-mediated Wnt suppression and TGF-β activation, targeting these dysregulated networks presents a promising route for long-term management. A deeper understanding of pathway interactions lays the groundwork for precise, durable, and disease-modifying therapies in the evolving landscape of alopecia treatment.

In patients with glaucoma, progressive degeneration of retinal ganglion cells (RGCs) leads to irreversible visual impairments. Despite recent studies indicating that senescence is associated with RGC death, the underlying molecular mechanisms remain unclear.

The chronic ocular hypertension (COH) mouse model was established by infusing a crosslinking hydrogel into the anterior chamber. Cellular senescence was evaluated using Western blot analysis, cell cycle, senescence-associated β-galactosidase (SA-β-gal) staining, enzyme-linked immunosorbent assay, and immunofluorescence. Functional experiments were conducted in retinal precursor (R28) cells through small interfering RNA-mediated knockdown and plasmid-mediated overexpression. Additionally, the role of the protein arginine methyltransferase 5 (PRMT5)-regulated Wnt/β-catenin pathway in RGC senescence was investigated via intravitreal injection of GSK3326595 and CHIR99021 in mice.

We demonstrate that PRMT5 is markedly downregulated in RGC in a COH mouse model, correlating with increased RGC senescence induced by elevated intraocular pressure. Silencing PRMT5 significantly accelerated senescence, as evidenced by increased SA-β-gal activity, cell cycle arrest, and senescence marker upregulation. Cotreatment with GSK3β inhibitor CHIR99021 alleviated hypoxia-induced senescence and reactivated the Wnt/β-catenin pathway, while the antagonist FH535 negated the neuroprotective effects of PRMT5 overexpression. In vivo, the PRMT5 inhibitor GSK3326595 reduced RGC survival and heightened senescence markers, whereas CHIR99021 mitigated RGC loss and restored Wnt/β-catenin signaling.

Taken together, these findings highlight the critical role of the PRMT5-regulated Wnt/β-catenin pathway in RGC senescence and neurodegeneration. Targeting this pathway represents a promising therapeutic strategy for glaucoma.