Daidzein-rich isoflavone aglycones inhibit cell growth and inflammation in endometriosis
Daidzein-rich isoflavone aglycones inhibit cell growth and inflammation in endometriosis
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DOI：
10.1016/j.jsbmb.2018.04.004
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发表时间：
2018-07-01
影响因子：
4.1
通讯作者：
Kitawaki, J.
中科院分区：
文献类型：
--
作者：
Takaoka, O.;Mori, T.;Kitawaki, J.
子宫内膜异位症是一种雌激素依赖性疾病，异黄酮与雌激素受体相互作用。本研究的目的是研究富含大豆黄酮苷元 (DRIA) 的膳食补充剂对子宫内膜异位症细胞增殖的体外和体内影响。从卵巢子宫内膜瘤 (OESC) 和正常子宫内膜 (NESC) 中分离的基质细胞与 DRIA 一起培养，即每种 DRIA 成分（黄豆苷元、金雀异黄素或黄豆黄素）或异黄酮糖苷（IG；DRIA 前体）。通过将供体小鼠子宫碎片移植到受体小鼠体内建立子宫内膜异位症小鼠模型。我们的结果表明，DRIA (0.2-20 μM) 抑制 OESC 的增殖（0.2 μM 时 P < 0.05；2 和 20 μM 时 P < 0.01），但不抑制 NESC 的增殖。然而，大豆黄酮、金雀异黄素、黄豆黄素和IG并不抑制它们的增殖。 DRIA 诱导的抑制可通过拮抗剂 PHTPP 或 ER β siRNA 抑制雌激素受体 (ER)β 来逆转 (P < 0.05)，但不能通过 ER α 拮抗剂 MPP 来逆转。在 OESC 中，DRIA 导致 IL-6、IL-8、COX-2 和芳香酶表达降低，以及芳香酶活性、血清糖皮质激素调节激酶水平和 PGE(2) 水平降低 (P < 0.05)。蛋白质印迹和免疫荧光测定表明，DRIA 抑制 TNF-α 诱导的 I kappa B 磷酸化和 p65 摄取到 OESC 的细胞核中。在小鼠模型中，与饲喂含 IG 饲料和对照饲料的小鼠相比，含 DRIA 的饲料显着降低了子宫内膜异位症样病变的数量、重量和 Ki-67 增殖活性 (P < 0.01)。总之，DRIA 抑制子宫内膜异位症的细胞增殖，因此代表了子宫内膜异位症治疗的潜在治疗选择。
Endometriosis is an estrogen-dependent disease, and isoflavones interact with estrogen receptors. The purposes of this study are to investigate the in vitro and in vivo effects of daidzein-rich isoflavone aglycones (DRIAs), dietary supplements, on cellular proliferation in endometriosis. Strornal cells isolated from ovarian endometrioma (OESCs) and normal endometrium (NESCs) were cultured with DRIAs, i.e., each of the DRIA components (daidzein, genistein, or glycitein), or isoflavone glycosides (IG; DRIA precursors). A mouse model of endometriosis was established by transplanting donor-mouse uterine fragments into recipient mice. Our results showed that DRIAs (0.2-20 mu M) inhibited the proliferation of OESCs (P < 0.05 for 0.2 mu M; P < 0.01 for 2 and 20 mu M) but not of NESCs. However, daidzein, genistein, glycitein, and IG did not inhibit their proliferation. DRIA-induced suppression was reversed by inhibition of the estrogen receptor (ER)beta by an antagonist, PHTPP, or by ER beta siRNA (P < 0.05), but not by MPP, an ER alpha antagonist. In OESCs, DRIAs led to reduced expression of IL-6, IL-8, COX-2, and aromatase, as well as reduced aromatase activity, serum glucocorticoid-regulated kinase levels, and PGE(2) levels (P < 0.05). Western blot and immunofluorescence assays revealed that DRIAs inhibited TNF-alpha-induced I kappa B phosphorylation and p65 uptake into the nuclei of OESCs. In the mouse model, a DRIA-containing feed significantly decreased the number, weight, and Ki-67 proliferative activity of endometriosis-like lesions compared to in mice fed with an IG-containing feed and the control feed (P < 0.01). In conclusion, DRIAs inhibit cellular proliferation in endometriosis, thus representing a potential therapeutic option for the management of endometriosis.