5-雄烯二醇(ADIOL)作为选择性雌激素受体β(ERβ)配体,对许多疾病具有保护作用。所以,我们对其在乙酸(AA)诱导的结肠炎中的作用进行了新的研究,并研究了其对TLR4介导的PI3K/Akt和NF-κB通路的影响以及ERβ作为贡献机制的潜在作用.
方法:大鼠随机分为5组;对照组,结肠炎,结肠炎+美沙拉嗪(MLZ),结肠炎+ADIOL,结肠炎+ADIOL+PHTPP(ER-β拮抗剂)。在第8天通过乙酸(AA)的直肠灌肠诱发结肠炎。在治疗结束时,收集结肠进行宏观评估。丙二醛(MDA)的组织水平,超氧化物歧化酶(SOD),核因子κB(NF-κB),toll样受体(TLR4),并测定磷酸化蛋白激酶B(pAKT)。此外,白细胞介素-1β(IL-1β)基因表达,金属蛋白酶9(Mmp9),肌醇3磷酸激酶(PI3K),中性粒细胞明胶酶相关脂质运载蛋白(NGAL),评估ERβ和NLRP6。还研究了组织病理学和免疫组织化学研究。
结果:与未治疗的AA组相比,注射ADIOL后,疾病活动指数(DAI)和宏观评估指标显著下降.的确,ADIOL显著降低结肠组织MDA水平,TLR4,pAKT,和NF-κB免疫染色,同时增加SOD活性和βcatenin免疫染色。ADIOL减轻了IL1β的高基因表达,NGAL,MMP9和PI3K同时增加ERβ和NLRP6基因表达。此外,ADIOL可明显改善AA组的病理变化。特异性ERβ拮抗剂,PHTPP,ADIOL的这些保护作用大大降低。
结论:ADIOL主要通过激活ERβ对AA诱导的结肠炎有益。
5-
androstenediol (ADIOL) functions as a selective estrogen receptor β (ERβ) ligand with a protective effect against many diseases. So, we conducted a novel insight into its role in acetic acid (AA)-induced colitis and investigated its effect on TLR4-Mediated PI3K/Akt and NF-κB Pathways and the potential role of ERβ as contributing mechanisms.
METHODS: Rats were randomized into 5 Groups; Control, Colitis, Colitis + mesalazine (MLZ), Colitis + ADIOL, and Colitis + ADIOL + PHTPP (ER-β antagonist). The colitis was induced through a rectal enema of acetic acid (AA) on the 8th day. At the end of treatment, colons were collected for macroscopic assessment. Tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), nuclear factor kappa b (NF-κB), toll-like receptor (TLR4), and phosphorylated Protein kinase B (pAKT) were measured. Besides, Gene expression of interleukin-1beta (IL-1β), metalloproteases 9 (Mmp9), inositol 3 phosphate kinase (PI3K), Neutrophil gelatinase-associated lipocalin (NGAL), ERβ and NLRP6 were assessed. Histopathological and immunohistochemical studies were also investigated.
RESULTS: Compared to the untreated AA group, the disease activity index (DAI) and macroscopic assessment indicators significantly decreased with ADIOL injections. Indeed, ADIOL significantly decreased colonic tissue levels of MDA, TLR4, pAKT, and NF-κB immunostainig while increased SOD activity and β catenin immunostainig. ADIOL mitigated the high genetic expressions of IL1β, NGAL, MMP9, and PI3K while increased ERβ and NLRP6 gene expression. Also, the pathological changes detected in AA groups were markedly ameliorated with ADIOL. The specific ERβ antagonist, PHTPP, largely diminished these protective effects of ADIOL.
CONCLUSIONS: ADIOL could be beneficial against AA-induced colitis mostly through activating ERβ.