International immunopharmacology · 2026
Plasma-activated solutions alleviate intestinal mucosal injury induced by pathogen-host interactions by modulating redox imbalance.
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Peng Yuanchang, Ma Yuyi, Wang Xueni, Ma Rulan, Chen Huan, Deng Xiaoyuan, Min Tianhao, Nan Yanglong, Tong Shiyao, Sun Tuanhe, Wang Wei, Zhang Yong, Hao Nan, Xie Xin, Zhu Kun, Li Kang, Xu Guimin, Zhang Bo, Ren Kaijie, Zhang Hao
Аннотация
BACKGROUND: SARS-CoV-2 spike binds angiotensin-converting enzyme 2 (ACE2), but the mechanisms linking spike exposure to intestinal injury remain incompletely understood. We investigated whether plasma-activated solutions (PAS) alleviate spike-associated intestinal injury by regulating antioxidant signaling.
METHODS: Intestinal injury was induced by recombinant spike receptor-binding domain exposure in humanized ACE2 mice pretreated with dextran sulfate sodium. Caco-2 and HCT116 cells were used for in vitro experiments. PAS was administered orally to mice or applied as plasma-activated culture medium to cells. Reactive oxygen species (ROS) levels, apoptosis, and tissue injury were assessed. Protein stability assays, co-immunoprecipitation, and pathway interventions were used to investigate the underlying mechanism.
RESULTS: Spike exposure increased oxidative stress and epithelial apoptosis and enhanced the association between Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2-related factor 2 (NRF2), accompanied by increased NRF2 ubiquitination, reduced NRF2 stability, and lower heme oxygenase-1 (HO-1) expression. PAS alleviated intestinal injury, reduced ROS accumulation and apoptosis, decreased KEAP1-NRF2 association, and increased NRF2 nuclear accumulation. NRF2 knockdown or pharmacological inhibition of HO-1 attenuated the protective effects of PAS.
CONCLUSION: PAS alleviates spike-associated intestinal injury in the experimental models examined, with the findings supporting a contribution of KEAP1-NRF2/HO-1 signaling to its protective effects.
METHODS: Intestinal injury was induced by recombinant spike receptor-binding domain exposure in humanized ACE2 mice pretreated with dextran sulfate sodium. Caco-2 and HCT116 cells were used for in vitro experiments. PAS was administered orally to mice or applied as plasma-activated culture medium to cells. Reactive oxygen species (ROS) levels, apoptosis, and tissue injury were assessed. Protein stability assays, co-immunoprecipitation, and pathway interventions were used to investigate the underlying mechanism.
RESULTS: Spike exposure increased oxidative stress and epithelial apoptosis and enhanced the association between Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2-related factor 2 (NRF2), accompanied by increased NRF2 ubiquitination, reduced NRF2 stability, and lower heme oxygenase-1 (HO-1) expression. PAS alleviated intestinal injury, reduced ROS accumulation and apoptosis, decreased KEAP1-NRF2 association, and increased NRF2 nuclear accumulation. NRF2 knockdown or pharmacological inhibition of HO-1 attenuated the protective effects of PAS.
CONCLUSION: PAS alleviates spike-associated intestinal injury in the experimental models examined, with the findings supporting a contribution of KEAP1-NRF2/HO-1 signaling to its protective effects.