Wei Zhang,Chengcheng Fan,Zhongxue Yi,Tao Du,Nana Wang,Weizhu Tian,Qian Pan,Xiande Ma,Zhe Wang
Background Cerebral ischemia/reperfusion injury (CIRI) is still a complicated disease with high fatality rates worldwide. Transmembrane Protein 79 (TMEM79) regulates inflammation and oxidative stress in some other diseases.Methods CIRI mouse model was established using C57BL/6J mice through middle cerebral artery occlusion-reperfusion (MCAO/R), and BV2 cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R) to simulate CIRI. Brain tissue or BV2 cells were transfected or injected with lentivirus-carried TMEM79 overexpression vector. The impact of TMEM79 on CIRI-triggered oxidative stress was ascertained by dihydroethidium (DHE) staining and examination of oxidative stress indicators. Regulation of TMEM79 in neuronal apoptosis and inflammation was determined using TUNEL staining and ELISA.Results TMEM79 overexpression mitigated neurological deficit induced by MCAO/R and decreased the extent of cerebral infarct. TMEM79 prevented neuronal death in brain tissue of MCAO/R mouse model and suppressed inflammatory response by reducing inflammatory cytokines levels. Moreover, TMEM79 significantly attenuated inflammation and oxidative stress caused by OGD/R in BV2 cells. TMEM79 facilitated the activation of Nrf2 and inhibited NLRP3 and caspase-1 expressions. Rescue experiments indicated that the Nrf2/NLRP3 signaling pathway mediated the mitigative effect of TMEM79 on CIRI in vivo and in vitro.Conclusion Overall, TMEM79 was confirmed to attenuate CIRI via regulating the Nrf2/NLRP3 signaling pathway.
Wilson's disease (WD), as a typical disease of excessive Cu 2+ deposition, is characterized by disorders of copper metabolism in the brain and thereby damaging the reproductive system. Conventional interventions using copper chelators can temporarily reduce intracellular copper (in-copper), but continuous re-entry of extracellular copper (ex-copper) into cells results in suboptimal therapy. Effective therapy requires multipronged copper metabolism management. Here, an orally administered, engineered Ganoderma-derived extracellular vesicle (CZGE) is developed for synergistic in/ex-copper regulation. Specifically, CZGE is designed by co-fusing Ganoderma-derived extracellular vesicle (GEVs) and targeted nanomicelles containing zinc-curcumin (Zn-Cur) complex (ZCNs). CZGE, with β -glucan-enriched GEVs and kisspeptin-10-modified ZCNs, can effectively penetrate intestinal and brain barriers after oral administration to target hypothalamic neurons.After internalization, Zn-Cur released from CZGE replaces excess Cu 2+ to form copper-curcumin (Cu-Cur) and release Zn 2+ via ion exchange. Cu-Cur reduces in-copper and neuroinflammation via the Nrf2/NLRP3 pathway, while Zn 2+ inhibits ex-copper influx by activating zinc transporter 1. In WD mice, CZGE alleviates hypothalamic copper deposition, activates ERK1/2 phosphorylation, and repairs reproductive dysfunction by modulating the hypothalamic-pituitary-testicular axis. It first reveals a targeted nanomedicine based on ion exchange that multipronged management in-copper and ex-copper, offering a promising therapeutic strategy for addressing WD with reproductive dysfunction.
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