Quercetin antagonized advanced glycated end products induced apoptosis and functional inhibition of fibroblasts from the prolapsed uterosacral ligament.

IF 1.9 Q3 PHARMACOLOGY & PHARMACY Drug Discoveries and Therapeutics Pub Date : 2024-01-12 Epub Date: 2023-12-03 DOI:10.5582/ddt.2023.01047
Yizhen Sima, Junwei Li, Leimei Xu, Chengzhen Xiao, Lisha Li, Ling Wang, Yisong Chen
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Abstract

The altered behaviors and functions of pelvic floor fibroblasts are pathophysiological changes of pelvic organ prolapse (POP). Our previous study showed that advanced glycated end products (AGEs) accumulated in the pelvic tissues of POP and induced fibroblast apoptosis. The study was designed to investigate whether quercetin antagonize AGEs-induced apoptosis and functional inhibition of fibroblasts. The uptake of 5-ethynyl-2'-deoxyuridine (EdU) was evaluated for cell proliferation. Flow cytometric analysis was applied for cell apoptosis. Intracellular reactive oxygen species (ROS) content was determined by the fluorescence of dichlorofluorescein (DCF). The contractility of fibroblasts was measured by collagen gel contraction assay. The expressions of extracellular matrix (ECM) related genes and the expression of miR-4429 and caspase-3 were quantified by qPCR. The expressions of phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), serine-threonine kinase (Akt), and phosphorylated Akt (p-Akt) were analyzed by Western Blot. The down-regulation of miR-4429 was achieved by cell transfection. Quercetin antagonized AGEs-induced apoptosis, proliferation inhibition, and ROS increase in fibroblasts. Quercetin did not alleviate AGEs-induced contractile impairment of fibroblasts. Quercetin reduced the gene expressions of lysyl oxidase like protein 1 (LOXL1)and matrix metallopeptidase 1 (MMP1), and increased the gene expressions of lysyl oxidase (LOX) and fibrillin 2 (FBN2) in fibroblasts. Quercetin reversed AGEs-induced upregulation of PTEN and downregulation of PI3K, P-Akt, and miR-4429 in fibroblasts. The inhibitory effect of quercetin on AGEs-induced fibroblast apoptosis was inhibited by downregulating the expression of miR-4429. In conclusion, quercetin antagonized AGEs-induced apoptosis and functional inhibition of fibroblasts from the prolapsed uterosacral ligament. And inhibiting AGEs-induced down-regulation of miR-4429/PTEN/PI3K/Akt pathway was the mechanism underlying the antagonistic effect of quercetin on AGEs-induced apoptosis.

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槲皮素拮抗晚期糖基化终产物诱导子宫骶韧带脱垂成纤维细胞凋亡和功能抑制。
盆底成纤维细胞行为和功能的改变是盆腔器官脱垂(POP)的病理生理改变。我们之前的研究表明,晚期糖基化终产物(AGEs)在POP的盆腔组织中积累并诱导成纤维细胞凋亡。研究槲皮素对衰老诱导的成纤维细胞凋亡和功能抑制的拮抗作用。评估5-乙基-2'-脱氧尿苷(EdU)的摄取对细胞增殖的影响。流式细胞术检测细胞凋亡。采用二氯荧光素(DCF)荧光法测定细胞内活性氧(ROS)含量。采用胶原凝胶收缩法测定成纤维细胞的收缩能力。采用qPCR定量检测细胞外基质(extracellular matrix, ECM)相关基因的表达以及miR-4429、caspase-3的表达。Western Blot法分析磷酸酶及紧张素同源物(PTEN)、磷酸肌肽3-激酶(PI3K)、丝氨酸-苏氨酸激酶(Akt)、磷酸化Akt (p-Akt)的表达。通过细胞转染实现miR-4429的下调。槲皮素可拮抗ages诱导的成纤维细胞凋亡、增殖抑制和ROS增加。槲皮素不能减轻ages诱导的成纤维细胞收缩损伤。槲皮素降低了成纤维细胞中赖氨酸氧化酶样蛋白1 (LOXL1)和基质金属肽酶1 (MMP1)的基因表达,增加了赖氨酸氧化酶(LOX)和纤维蛋白2 (FBN2)的基因表达。槲皮素逆转了ages诱导的成纤维细胞中PTEN的上调和PI3K、P-Akt和miR-4429的下调。槲皮素通过下调miR-4429的表达抑制ages诱导的成纤维细胞凋亡。槲皮素可拮抗ages诱导的子宫骶韧带脱垂成纤维细胞凋亡和功能抑制。槲皮素抑制衰老诱导的miR-4429/PTEN/PI3K/Akt通路下调是槲皮素抑制衰老诱导的细胞凋亡的机制。
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来源期刊
Drug Discoveries and Therapeutics
Drug Discoveries and Therapeutics PHARMACOLOGY & PHARMACY-
CiteScore
3.20
自引率
3.20%
发文量
51
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