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[Display omitted] Triple negative breast cancer (TNBC), a particularly aggressive breast cancer subtype without estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2) expression, possesses highly invasive capacity, uncontrolled proliferative phenotype and poor clinical prognosis. Sesamol enriched in sesame seeds has been widely reported as a metabolic modulator due to its anti-aging, anti-hepatotoxic and cardio-protective properties. In this study, we found that sesamol significantly inhibited proliferation, migration and invasion of TNBC cells via attenuating PCNA, CyclinD1 expression and reversion of epithelial-mesenchymal transition (EMT) characterized by increased epithelial marker E-cadherin and decreased mesenchymal marker N-cadherin, Vimentin, Snail expression. Moreover, sesamol inactivated Wnt/β-catenin signaling and Wnt agonist 1 AMBMP application reversed the inhibition of proliferation, migration and invasion of TNBC by sesamol administration. Subsequently, our data showed that sesamol induced Wnt inhibitory factor 1 (WIF1), an endogenous inhibitor of Wnt/β-catenin pathway, expression and WIF1 artificial knockdown abrogated the inactivation of Wnt/β-catenin signaling by sesamol exposure in TNBC cells. And we found that promoter region de-methylation was responsible for WIF1 up-regulation by sesamol administration. Finally, with the xenograft assay using nude mice, we also found that sesamol inhibited proliferation and metastasis of TNBC via WIF1-induced inactivation of Wnt/β-catenin signaling in vivo. Collectively, these data added novel understandings and evidences to the anti-cancer properties of sesamol. [ABSTRACT FROM AUTHOR]

Rationale: Photoreceptor loss is a primary pathological feature of retinal degeneration (RD) with limited treatment strategies. RNA interference (RNAi) has emerged as a promising method of gene therapy in regenerative medicine. However, the transfer of RNAi therapeutics to photoreceptors and the deficiency of effective therapeutic targets are still major challenges in the treatment of RD. Methods: In this study, photoreceptor-derived extracellular vesicles (PEVs) conjugated with photoreceptor-binding peptide MH42 (PEVs MH42 ) were prepared using the anchoring peptide CP05. Transcriptome sequencing was applied to investigate the potential therapeutic target of RD. We then engineered PEVs MH42 with specific small-interfering RNAs (siRNAs) through electroporation and evaluated their therapeutic efficacy in N-methyl-N-nitrosourea (MNU)-induced RD mice and Pde6β rd1/rd1 mutant mice. Results: PEVs MH42 were selectively accumulated in photoreceptors after intravitreal injection. Cullin-7 (Cul7) was identified as a novel therapeutic target of RD. Taking advantage of the established PEVs MH42 , siRNAs targeting Cul7 (siCul7) were efficiently delivered to photoreceptors and consequently blocked the expression of Cul7. Moreover, suppression of Cul7 effectively protected photoreceptors to alleviate RD both in MNU-induced mouse model and Pde6β rd1/rd1 mutant mouse model. Mechanistically, PEVs MH42 loaded with siCul7 (PEVs MH42 -siCul7)-induced Cul7 downregulation was responsible for preventing Cul7-mediated glutathione peroxidase 4 (Gpx4) ubiquitination and degradation, resulting in the inhibition of photoreceptor ferroptosis. Conclusions: In summary, PEVs MH42 -siCul7 attenuate photoreceptor ferroptosis to treat RD by inhibiting Cul7-induced ubiquitination of Gpx4. Our study develops a PEVs-based platform for photoreceptor-targeted delivery and highlights the potential of PEVs MH42 -siCul7 as effective therapeutics for RD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)