Shock (Augusta, Ga.) · 2025
Oridonin Ameliorates Macrophage Oxidative Stress and Pyroptosis In Liver Ischemia-Reperfusion Injury by Inhibiting Mitochondrial ROS/TXNIP/NLRP3.
СтатьяНазвание и аннотация: Перевод в очереди
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Liao Wei, Wu Xinyi, Gong Jianping, Li Shengwei
Аннотация
BACKGROUND: Liver ischemia-reperfusion injury (LIRI) is a main cause of complication development regarding the liver. This study examines how Oridonin mitigates oxidative stress and pyroptosis in macrophages during LIRI by inhibiting the mitochondrial reactive oxygen species (ROS)/thioredoxin-interacting protein (TXNIP)/NOD-like receptor protein 3 (NLRP3) signaling pathway.
METHODS: LIRI mouse models were treated with Oridonin at doses of 1, 5, and 10 mg/kg. Liver damage was evaluated through serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels enzyme linked immunosorbent assay (ELISA), histological analysis (HE staining and Suzuki scoring), and immunofluorescence for NLRP3 and macrophage markers (F4/80, inducible nitric oxide synthase [iNOS]). Inflammatory cytokines (Tumor necrosis factor alpha, interleukin-1beta [IL-1β], IL-18, and IL-6) and oxidative stress markers (malondialdehyde [MDA], total superoxide dismutase [T-SOD], and glutathione peroxidase [GSH-Px]) were measured using ELISA. M1 macrophage markers (iNOS, CD86, and CD80) were assessed via quantitative real-time polymerase chain reaction (qRT-PCR). Primary hepatic macrophages were isolated for flow cytometry, cell-counting kit (CCK)-8 assays, and ROS detection. Protein expression was analyzed using Western Blot and immunohistochemistry.
RESULTS: Oridonin dose-dependently reduced liver damage, lowering ALT/AST levels and improving histological scores. Depletion of Kupffer cells with clodronate liposomes abolished Oridonin's protective effects, indicating macrophage mediation. LIRI increased M1 macrophages, F4/80⁺/iNOS⁺ cells, and inflammatory cytokines, all of which were partially reversed by Oridonin. In vitro, Oridonin reduced oxidative stress and pyroptosis in hypoxia-reoxygenation-exposed hepatic macrophages, evidenced by decreased ROS and lower levels of pyroptosis-related proteins (gasdermin D, Cleaved-Caspase-1, and IL-1β). Mechanistically, Oridonin may ameliorate oxidative stress and pyroptosis in hepatic macrophages of LIRI mice by inhibiting the ROS/TXNIP/NLRP3 pathway.
CONCLUSIONS: Oridonin effectively protects against LIRI by decreasing macrophage M1 polarization, oxidative stress, and pyroptosis through inhibition of the mitochondrial ROS/TXNIP/NLRP3 pathway.
METHODS: LIRI mouse models were treated with Oridonin at doses of 1, 5, and 10 mg/kg. Liver damage was evaluated through serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels enzyme linked immunosorbent assay (ELISA), histological analysis (HE staining and Suzuki scoring), and immunofluorescence for NLRP3 and macrophage markers (F4/80, inducible nitric oxide synthase [iNOS]). Inflammatory cytokines (Tumor necrosis factor alpha, interleukin-1beta [IL-1β], IL-18, and IL-6) and oxidative stress markers (malondialdehyde [MDA], total superoxide dismutase [T-SOD], and glutathione peroxidase [GSH-Px]) were measured using ELISA. M1 macrophage markers (iNOS, CD86, and CD80) were assessed via quantitative real-time polymerase chain reaction (qRT-PCR). Primary hepatic macrophages were isolated for flow cytometry, cell-counting kit (CCK)-8 assays, and ROS detection. Protein expression was analyzed using Western Blot and immunohistochemistry.
RESULTS: Oridonin dose-dependently reduced liver damage, lowering ALT/AST levels and improving histological scores. Depletion of Kupffer cells with clodronate liposomes abolished Oridonin's protective effects, indicating macrophage mediation. LIRI increased M1 macrophages, F4/80⁺/iNOS⁺ cells, and inflammatory cytokines, all of which were partially reversed by Oridonin. In vitro, Oridonin reduced oxidative stress and pyroptosis in hypoxia-reoxygenation-exposed hepatic macrophages, evidenced by decreased ROS and lower levels of pyroptosis-related proteins (gasdermin D, Cleaved-Caspase-1, and IL-1β). Mechanistically, Oridonin may ameliorate oxidative stress and pyroptosis in hepatic macrophages of LIRI mice by inhibiting the ROS/TXNIP/NLRP3 pathway.
CONCLUSIONS: Oridonin effectively protects against LIRI by decreasing macrophage M1 polarization, oxidative stress, and pyroptosis through inhibition of the mitochondrial ROS/TXNIP/NLRP3 pathway.