The protective role of Cordyceps cicadae and its active ingredient myriocin against sodium iodate-induced age-related macular degeneration via an anti-necroptotic TNF-RIPK1/3 pathway

Ethnopharmacological relevance Cordyceps cicadae ( C.cicadae ), named “Chan Hua”, an anamorph of Isaria cicadae Miquel , is an entomogenous complex formed by fungi parasitizing on the larvae of cicadas and belongs to the Claviciptaceae family and the genus Codyceps , which traditionally holds a significant place in Chinese ethnopharmacology, specifically for eye clarity and as a remedy for age-related ocular conditions. The underlying mechanisms contributing to its eyesight enhancement and potential effectiveness against Age-related macular degeneration (AMD) remain unexplored. Aim of the study This study aims to elucidate the protective role of C.cicadae and its active ingredient, Myriocin (Myr), against AMD. Materials and methods A chemical inducer was employed to make retinal pigment epithelium (RPE) damag e in vitro and in vivo . The key ingredients of C.cicadae and their related mechanisms for anti-AMD were studied through bioinformatic analysis and molecular biological approaches. Results Myr was identified through high-performance liquid chromatography (HPLC) as an active ingredient in C.cicadae , and demonstrated a protective effect on RPE cells, reducing the structural damage and cell death induced by sodium iodate (SI). Further, Myr reduced eyelid secretions in AMD mice and restored their retinal structure and function. The differentially expressed genes (DEGs) in Myr treatment are primarily associated with TNF and Necroptosis signaling pathways. Molecular docking indicated a strong affinity between TNF and Myr. Myr inhibited the TNF signaling pathway thereby reducing the expression of inflammatory factors in ARPE-19?cells. Additionally, Myr had consistent action with the necroptosis inhibitor Necrostatin-1 (Nec-1), inhibited the RIPK1/RIPK3/MLKL pathway thereby protecting ARPE-19?cells. Conclusion The findings present Myr, as a potent protector against SI-induced AMD, predominantly through modulation of the TNF-RIPK1/RIPK3/MLKL signaling pathway, offering the insights of therapeutic C.cicadae as viable candidates for AMD treatment.

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