右美托咪定通过抑制TLR-4/NF-κB通路改善压力应激小鼠的乳腺肿瘤治疗效果OA

[Objective]This study aimed to investigate whether dexmedetomidine(Dex)alleviates stress-induced mammary tumor progression in mice by inhibiting the TLR4/NF-κB signaling pathway,and to examine its effects on anxiety-depression-like behaviors and stress hormone levels.[Methods]An orthotopic EMT6 mammary tumor model was established in mice,and chronic mild stress(CMS)was applied to induce anxiety-depression-like states.The mice were divided into six groups:naive,tumor,CMS,CMS+tumor,CMS+tumor+Dex,and CMS+tumor+Vehicle groups.Behavioral changes were evaluated using the open field test and tail suspension test.Plasma stress hormone levels were measured by high-performance liquid chromatography.Western blot and RT-qPCR were performed to detect the expression of TLR4,p-NF-κB p65,p-IκBα,and inflammatory cytokines(IL-6,IL-1β,TNF-α)in tumor tissues.In vitro,EMT6 cells were treated with cortisol to mimic the stress-related microenvironment,and the effects of Dex on the TLR4/NF-κB pathway were assessed by CCK-8,Western blot,and RT-qPCR.[Results]Tumor-bearing mice exhibited significant anxiety-depression-like behaviors(P＜0.05),along with markedly elevated plasma levels of norepinephrine,epinephrine,and cortisol(P＜0.05).Chronic stress further aggravated these behavioral abnormalities and promoted tumor growth(P＜0.05).Dexmedetomidine intervention significantly improved anxiety-depression-like behaviors(P＜0.05)and lowered peripheral stress hormone levels(P＜0.05)in stress-exposed tumor-bearing mice.In vitro experiments demonstrated that cortisol treatment activated the TLR4/NF-κB pathway(P＜0.001)and upregulated the expression of inflammatory cytokines(P＜0.05 in EMT6 cells,whereas dexmedetomidine effectively suppressed this activation(P＜0.001).In the in vivo model,dexmedetomidine treatment downregulated the expression of TLR4,p-NF-κB p65,p-IκBα,and pro-inflammatory cytokines in tumor tissues(P＜0.001)and significantly inhibited tumor growth(P＜0.05).[Conclusion]Dexmedetomidine inhibits the TLR4/NF-κB signaling pathway,alleviates stress-induced inflammatory responses,improves anxiety-and depression-like behaviors,reduces stress hormone levels,and suppresses mammary tumor progression.These findings provide an experimental basis for understanding anxiety-and depression-associated breast tumor progression and suggest that Dexmedetomidine and the TLR4/NF-κB pathway may serve as potential therapeutic targets.