首页> 美国卫生研究院文献>International Journal of Biological Sciences >Differential Expression Patterns of Glycolytic Enzymes and Mitochondria-Dependent Apoptosis in PCOS Patients with Endometrial Hyperplasia an Early Hallmark of Endometrial Cancer In Vivo and the Impact of Metformin In Vitro
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Differential Expression Patterns of Glycolytic Enzymes and Mitochondria-Dependent Apoptosis in PCOS Patients with Endometrial Hyperplasia an Early Hallmark of Endometrial Cancer In Vivo and the Impact of Metformin In Vitro

机译:子宫内膜增生子宫内膜癌的早期标志体内和二甲双胍的体外影响的PCOS患者糖酵解酶和线粒体依赖性细胞凋亡的差异表达模式。

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摘要

The underlying mechanisms of polycystic ovarian syndrome (PCOS)-induced endometrial dysfunction are not fully understood, and although accumulating evidence shows that the use of metformin has beneficial effects in PCOS patients, the precise regulatory mechanisms of metformin on endometrial function under PCOS conditions have only been partially explored. To address these clinical challenges, this study aimed to assess the protein expression patterns of glycolytic enzymes, estrogen receptor (ER), and androgen receptor (AR) along with differences in mitochondria-dependent apoptosis in PCOS patients with and without endometrial hyperplasia in vivo and to investigate the effects of metformin in PCOS patients with endometrial hyperplasia in vitro. Here, we showed that compared to non-PCOS patients and PCOS patients without hyperplasia, the endometria from PCOS patients with hyperplasia had a distinct protein expression pattern of glycolytic enzymes, including pyruvate kinase isozyme M2 isoform (PKM2) and pyruvate dehydrogenase (PDH), and mitochondrial transcription factor A (TFAM). In PCOS patients with endometrial hyperplasia, increased glandular epithelial cell secretion and infiltrated stromal cells in the glands were associated with decreased PDH immunoreactivity in the epithelial cells. Using endometrial tissues from PCOS patients with hyperplasia, we found that in response to metformin treatment in vitro, hexokinase 2 (HK2) expression was decreased, whereas phosphofructokinase (PFK), PKM2, and lactate dehydrogenase A (LDHA) expression was increased compared to controls. Although there was no change in PDH expression, metformin treatment increased the expression of TFAM and cleaved caspase-3. Moreover, our in vivo study showed that while endometrial ERβ expression was no different between non-PCOS and PCOS patients regardless of whether or not hyperplasia was present, ERα and AR protein expression was gradually increased in women with PCOS following the onset of endometrial hyperplasia. Our in vitro study showed that treatment with metformin inhibited ERα expression without affecting ERβ expression. Our findings suggest that decreased glycolysis and increased mitochondrial activity might contribute to the onset of ERα-dependent endometrial hyperplasia and that metformin might directly reverse impaired glycolysis and normalize mitochondrial function in PCOS patients with endometrial hyperplasia.
机译:多囊卵巢综合征(PCOS)引起的子宫内膜功能障碍的潜在机制尚未完全了解,尽管越来越多的证据表明二甲双胍对PCOS患者有有益作用,但在PCOS条件下二甲双胍对子宫内膜功能的精确调节机制仅被部分探索。为应对这些临床挑战,本研究旨在评估体内和非体外膜内膜增生的PCOS患者中糖酵解酶,雌激素受体(ER)和雄激素受体(AR)的蛋白质表达模式以及线粒体依赖性凋亡的差异。研究二甲双胍对PCOS子宫内膜增生患者的影响。在这里,我们发现,与非PCOS患者和没有增生的PCOS患者相比,患有增生的PCOS患者的子宫内膜具有独特的糖酵解蛋白表达模式,包括丙酮酸激酶同工酶M2亚型(PKM2)和丙酮酸脱氢酶(PDH),和线粒体转录因子A(TFAM)。在患有子宫内膜增生的PCOS患者中,腺体上皮细胞分泌增加和基质细胞浸润与上皮细胞PDH免疫反应性降低有关。使用PCOS增生患者的子宫内膜组织,我们发现在体外对二甲双胍治疗的反应中,己糖激酶2(HK2)的表达降低,而磷酸果糖激酶(PFK),PKM2和乳酸脱氢酶A(LDHA)的表达高于对照组。 。尽管PDH表达没有变化,但是二甲双胍治疗增加了TFAM的表达并切割了caspase-3。此外,我们的体内研究表明,尽管非PCOS和PCOS患者无论是否存在增生,子宫内膜ERβ的表达无差异,但子宫内膜增生开始后,患有PCOS的女性的ERα和AR蛋白表达逐渐增加。我们的体外研究表明,用二甲双胍治疗可抑制ERα表达而不会影响ERβ表达。我们的发现表明糖酵解的减少和线粒体活性的增加可能会导致ERα依赖性子宫内膜增生的发作,二甲双胍可能直接逆转糖酵解受损,并使患有子宫内膜增生的PCOS患者的线粒体功能正常化。

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