The incidence of acute ischemic stroke (AIS) has shown a persistent upward trend in recent years. External factors, including chemical and plastic exposures, have been shown to worsen the prognosis of cerebrovascular diseases, especially AIS. Hexafluoropropylene oxide dimer acid (HFPO-DA), a prevalent plastic additive, is globally distributed. However, its bioaccumulation potential and neurovascular toxicity remain poorly understood. Using a mixed subchronic-acute aggravation model in middle cerebral artery occlusion/reperfusion (MCAO/R) rats, we found that HFPO-DA exposure dose-dependently exacerbated neurological deficits, enlarged infarct volumes, and intensified reactive microgliosis. Computationally, we prioritized the CSNK2A1/GSK3B/NF-κB signaling axis as a key mechanistic candidate, with bindings predicted by molecular docking. In vitro cellular thermal shift assays (CETSA) coupled with targeted siRNA knockdown in BV2 cells supported a direct physical interaction between HFPO-DA and CSNK2A1. Moreover, in vivo CSNK2A1 inhibition with CX-4945 partially reversed the HFPO-DA-induced aggravation of ischemic injury. Collectively, our results suggest that HFPO-DA might be a potent environmental driver of post-ischemic neuroinflammation, likely acting in part via the CSNK2A1/GSK3B/NF-κB signaling pathway. These results provide novel insights into the specific neurotoxic mechanisms of HFPO-DA, highlighting its potential health risks in susceptible populations.
Cisplatin, a frontline chemotherapeutic agent against cancer, faces challenges in clinical application due to significant toxicities and suboptimal efficacy. Renal toxicity, a dose-limiting factor of cisplatin, results from multifactorial processes including cisplatin-induced cellular pyroptosis, oxidative damage, and inflammatory responses. Our findings reveal that Tea Polyphenols Nanoparticles (TPNs) derived from Epigallocatechin gallate (EGCG) effectively could address these diverse mechanisms, comprehensively alleviating cisplatin-induced nephrotoxicity. Leveraging TPNs as carriers, chemical conjugation enables the encapsulation of tetravalent cisplatin prodrug, extending its systemic half-life, enhancing tumor tissue accumulation, while simultaneously mitigating renal toxicity. Concurrently, employing a CRISPR/Cas9 kinase library, we identified CSNK2A1 as a target sensitizing tumor cells to cisplatin, enabling specific siRNA sequences to augment cisplatin susceptibility, thereby minimizing the dosage requirement. Benefiting from the versatile carrier properties of TPNs to codeliver cisplatin prodrug and anti-CSNK2A1 siRNA, we developed a codelivery system, Pt-TPNs/siRNA. Pt-TPNs/siRNA not only enhances the anticancer effects but also mitigates cisplatin-induced renal toxicity, achieving efficacy while reducing toxicity. Mechanistic and safety assessments of these nanoparticles were conducted at both cellular and animal levels, opening new avenues for improved clinical utilization of cisplatin.
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