目的 篩選與潰瘍性結(jié)腸炎（ulcerative colitis，UC）和雷公藤多苷（Tripterygium wilfordii polycoride，TWP）治療應(yīng)答均相關(guān)的核心基因，探討TWP在緩解UC炎癥中的潛在機(jī)制。方法 構(gòu)建2,4,6-三硝基苯磺酸（2,4,6-trinitrobenzenesulfonic acid，TNBS）/乙醇誘導(dǎo)的UC大鼠模型，利用Affymetrix GeneChip^® Rat Genome 230 2.0芯片，開展表達(dá)譜芯片分析以明確與UC炎癥及TWP治療應(yīng)答均相關(guān)的核心基因，并利用富集分析和和IPA分析發(fā)現(xiàn)與核心基因高度相關(guān)的通路，利用慢病毒轉(zhuǎn)染進(jìn)行驗(yàn)證，通過qRT-PCR和免疫熒光檢測核心基因的表達(dá)。結(jié)果 大鼠結(jié)腸表達(dá)譜芯片檢測結(jié)果表明，TWP可顯著下調(diào)模型組中上調(diào)的1 056個差異表達(dá)基因，其中S100鈣結(jié)合蛋白A8（S100 calcium binding protein A8，S100A8）的表達(dá)變化最為顯著，提示其可能是TWP調(diào)控UC炎癥的核心靶基因。富集分析、IPA網(wǎng)絡(luò)分析及慢病毒轉(zhuǎn)染結(jié)果進(jìn)一步表明，S100A8主要通過調(diào)控核因子-κB（nuclear factor-κB，NF-κB）信號通路及相關(guān)炎癥因子發(fā)揮作用。免疫熒光與qRT-PCR結(jié)果也證實(shí)，TWP干預(yù)可顯著降低S100A8在UC模型中的表達(dá)，抑制作用呈劑量相關(guān)性。結(jié)論 S100A8可能是TWP調(diào)控UC炎癥的關(guān)鍵靶點(diǎn)，其調(diào)控機(jī)制可能與NF-κB通路相關(guān)，為UC的藥物干預(yù)提供了新的分子靶點(diǎn)和潛在的治療策略。

ObjectiveTo identify core genes associated with ulcerative colitis (UC) pathogenesis and Tripterygium wilfordii polycoride (TWP) therapeutic response, while elucidating the molecular pathways through which TWP mitigates intestinal inflammation.Methods A 2,4,6-trinitrobenzenesulfonic acid (TNBS)/ethanol-induced UC rat model was established. Genome-wide transcriptomic profiling was performed using the Affymetrix GeneChip^® Rat Genome 230 2.0 microarray to identify inflammation-related differentially expressed genes (DEGs) modulated by TWP. Enrichment analysis and IPA were employed to delineate critical signaling pathways. Key findings were validated via qRT-PCR and immunofluorescence assays.Results Microarray analysis revealed that TWP treatment significantly down-regulated 1 056 inflammation-associated DEGs up-regulated in UC rats, with S100 calcium binding protein A8 (S100A8) exhibiting the most prominent suppression. Functional enrichment and IPA network modeling implicated S100A8 in nuclear factor-κB (NF-κB) signaling pathway modulation and inflammatory cytokine regulation. Lentiviral transduction experiments further confirmed this pathway association. Both immunofluorescence and qRT-PCR analysis demonstrated that TWP dose-dependently inhibited S100A8 expression in colonic tissues of UC rats.Conclusion S100A8 serves as a pivotal therapeutic target through which TWP ameliorates UC-associated inflammation, primarily via NF-κB pathway inhibition. This study unveils novel molecular targets and mechanistic insights for developing UC therapeutics.

R285.5

國家自然科學(xué)基金面上項(xiàng)目（81273903）；國家自然科學(xué)基金面上項(xiàng)目（81673798）；國家自然科學(xué)基金面上項(xiàng)目（81973617）