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Overexpression of MD1 ameliorates pathological myocardial remodeling in diabetic cardiomyopathy by TLR4/STAT3 signaling pathway 过表达 MD1 可通过 TLR4/STAT3 信号通路改善糖尿病心肌病的病理性心肌重塑。
IF 4.1 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-13 DOI: 10.1016/j.mce.2024.112315
Caijie Shen , Shuwen Yang , Nan Wu , Wang Jian , Tingsha Du , Huimin Chu , Weiping Du

Diabetic cardiomyopathy (DCM) is characterized by oxidative damage and inflammatory responses. Myeloid differentiation protein 1 (MD1) exhibits antioxidant and anti-inflammatory properties. However, the specific role of MD1 in DCM has yet to be elucidated. This study aims to investigate the role of MD1 in DCM and to elucidate the underlying mechanisms. We utilized a gain-of-function approach to explore the involvement of MD1 in DCM. Diabetes was induced in MD1-transgenic (MD1-TG) mice and their wild-type (WT) counterparts via streptozotocin (STZ) injection. Additionally, a diabetes cell model was established using H9c2 cells exposed to high glucose levels. We conducted comprehensive evaluations, including pathological analyses, echocardiography, electrocardiography, and molecular assessments, to elucidate the underlying mechanisms of MD1 in DCM. Notably, MD1 expression was reduced in the hearts of STZ-induced diabetic mice. Overexpression of MD1 significantly improved cardiac function and markedly inhibited ventricular pathological hypertrophy and fibrosis in these mice. Furthermore, MD1 overexpression resulted in a substantial decrease in myocardial reactive oxygen species (ROS) accumulation, mitigating myocardial oxidative stress and reducing the levels of inflammation-related markers such as IL-1β, IL-6, and TNF-α. Mechanistically, MD1 overexpression inhibited the activation of the TLR4/STAT3 signaling pathway, as demonstrated in both in vivo and in vitro experiments. The overexpression of MD1 significantly impeded pathological cardiac remodeling and improved cardiac function in STZ-induced diabetic mice. This effect was primarily attributed to a reduction in ROS accumulation and mitigation of myocardial oxidative stress and inflammation, facilitated by the inhibition of the TLR4/STAT3 signaling pathway.

糖尿病心肌病(DCM)的特点是氧化损伤和炎症反应。髓系分化蛋白 1(MD1)具有抗氧化和抗炎特性。然而,MD1 在 DCM 中的具体作用仍有待阐明。本研究旨在探讨 MD1 在 DCM 中的作用并阐明其潜在机制。我们采用功能增益法来探讨 MD1 在 DCM 中的参与。通过注射链脲佐菌素(STZ)诱导 MD1 转基因(MD1-TG)小鼠及其野生型(WT)小鼠患糖尿病。此外,我们还利用暴露于高葡萄糖水平的 H9c2 细胞建立了糖尿病细胞模型。我们进行了全面的评估,包括病理分析、超声心动图、心电图和分子评估,以阐明 MD1 在 DCM 中的潜在机制。值得注意的是,MD1在STZ诱导的糖尿病小鼠心脏中表达减少。过表达 MD1 能显著改善这些小鼠的心功能,并明显抑制心室病理性肥厚和纤维化。此外,MD1 的过表达导致心肌活性氧(ROS)积累大幅减少,减轻了心肌氧化应激,降低了炎症相关标志物(如 IL-1β、IL-6 和 TNF-α)的水平。从机理上讲,MD1的过表达抑制了TLR4/STAT3信号通路的激活,这在体内和体外实验中均得到了证实。在 STZ 诱导的糖尿病小鼠体内,MD1 的过表达能显著抑制病理性心脏重塑并改善心脏功能。这种效应主要归因于抑制 TLR4/STAT3 信号通路减少了 ROS 的积累,减轻了心肌氧化应激和炎症反应。
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引用次数: 0
Fundamentals and recent advances in the evaluation and management of medullary thyroid carcinoma 甲状腺髓样癌评估和管理的基础与最新进展。
IF 3.8 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-12 DOI: 10.1016/j.mce.2024.112295
Benjamin J. Gigliotti , Jennifer A. Brooks , Lori J. Wirth

Medullary thyroid carcinoma (MTC) is a rare primary neuroendocrine thyroid carcinoma that is distinct from other thyroid or neuroendocrine cancers. Most cases of MTC are sporadic, although MTC exhibits a high degree of heritability as part of the multiple endocrine neoplasia syndromes. REarranged during Transfection (RET) mutations are the primary oncogenic drivers and advances in molecular profiling have revealed that MTC is enriched in druggable alterations. Surgery at an early stage is the only chance for cure, but many patients present with or develop metastases. C-cell-specific calcitonin trajectory and structural doubling times are critical biomarkers to inform prognosis, extent of surgery, likelihood of residual disease, and need for additional therapy. Recent advances in the role of active surveillance, regionally directed therapies for localized disease, and systemic therapy with multi-kinase and RET-specific inhibitors for progressive/metastatic disease have significantly improved outcomes for patients with MTC.

甲状腺髓样癌(MTC)是一种罕见的原发性神经内分泌甲状腺癌,与其他甲状腺癌或神经内分泌癌不同。大多数 MTC 病例为散发性,但作为多发性内分泌肿瘤综合征的一部分,MTC 具有高度遗传性。RET突变是主要的致癌驱动因素,分子图谱分析的进展显示,MTC富含可药物治疗的改变。早期手术是治愈的唯一机会,但许多患者会出现或发展为转移瘤。C细胞特异性降钙素轨迹和结构倍增时间是重要的生物标志物,可为预后、手术范围、残留疾病的可能性以及是否需要额外治疗提供依据。最近,积极监测、针对局部疾病的区域定向疗法以及针对进展性/转移性疾病的多激酶和 RET 特异性抑制剂全身疗法的作用都取得了进展,从而显著改善了 MTC 患者的预后。
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引用次数: 0
Knockdown of type 2 orexin receptor in adult mouse testis potentiates testosterone production and germ cell proliferation 敲除成年小鼠睾丸中的 2 型奥曲肽受体可促进睾酮生成和生殖细胞增殖。
IF 4.1 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-10 DOI: 10.1016/j.mce.2024.112312
Pratikshya Sahoo , Debarshi Sarkar , Shubhangi Sharma , Arpit Verma , Suraj Kumar Naik , Vikash Prashar , Jyoti Parkash , Shio Kumar Singh

Orexins (OXs) are neuropeptides which regulate various physiological processes. OXs exist in two different forms, mainly orexin A (OXA) and orexin B (OXB) and their effects are mediated via OX1R and OX2R. Presence of OXB and OX2R in mouse testis is also reported. However, the role of OXB/OX2R in the male gonad remains unexplored. Herein we investigated the role of OXB/OX2R system in testicular physiology under in vivo and ex vivo conditions. Adult mice were given a single dose of bilateral intratesticular injection of siRNA targeting OX2R and were sacrificed 96 h post-injection. OX2R-knockdown potentiated serum and intratesticular testosterone levels with up-regulation in the expressions of major steroidogenic proteins. Germ cell proliferation also increased in siRNA-treated mice. Results of the ex vivo experiment also supported the findings of the in vivo study. In conclusion, OX2R may regulate testosterone production and thereby control the fine-tuning between steroidogenesis and germ cell dynamics.

奥曲肽是一种神经肽,可调节各种生理过程。OXs 以两种不同的形式存在,主要是 OXin A(OXA)和 OXin B(OXB),其作用通过 OX1R 和 OX2R 介导。也有报道称小鼠睾丸中存在 OXB 和 OX2R。然而,OXB/OX2R在雄性性腺中的作用仍未得到探索。在此,我们研究了体内和体外条件下 OXB/OX2R 系统在睾丸生理中的作用。成年小鼠接受单剂量双侧睾丸内注射靶向 OX2R 的 siRNA,注射后 96 小时处死。OX2R敲除可提高血清和睾丸内睾酮水平,并上调主要类固醇生成蛋白的表达。经 siRNA 处理的小鼠生殖细胞增殖也有所增加。体内外实验的结果也支持了体内研究的发现。总之,OX2R 可调节睾酮的产生,从而控制类固醇生成和生殖细胞动态之间的微调。
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引用次数: 0
Angiotensin II: Role in oxidative stress, endothelial dysfunction, and diseases 血管紧张素 II:在氧化应激、内皮功能障碍和疾病中的作用
IF 4.1 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-08 DOI: 10.1016/j.mce.2024.112309
Amir Ajoolabady , Domenico Pratico , Jun Ren

Angiotensin II (Ang II) is a protein hormone capable of physiologically regulating blood pressure through diverse mechanisms. Ang II is mainly produced by the liver at homeostatic levels. However, excessive production of Ang II is closely associated with a series of pathological events in the body. The endothelial dysfunction is one of these pathological events that can drive vascular anomalies. The excessive exposure of endothelial cells (ECs) to Ang II may induce endothelial dysfunction via diverse mechanisms. One of these mechanisms is Ang II-mediated mitochondrial oxidative stress. In this mini-review, we aimed to discuss the molecular mechanisms of Ang II-mediated endothelial dysfunction through mitochondrial oxidative stress and the protective role of nitric oxide in ECs. Deciphering these mechanisms may disclose novel therapeutic strategies to prevent endothelial dysfunction and associated diseases induced by elevated leves of Ang II in the blood.

血管紧张素 II(Ang II)是一种蛋白质激素,能够通过多种机制对血压进行生理调节。血管紧张素 II 主要由肝脏产生,处于平衡状态。然而,Ang II 的过量产生与体内一系列病理事件密切相关。内皮功能障碍就是其中一种可导致血管异常的病理事件。内皮细胞(ECs)过度暴露于 Ang II 可通过多种机制诱发内皮功能障碍。其中一种机制是 Ang II 介导的线粒体氧化应激。在这篇微型综述中,我们旨在讨论 Ang II 通过线粒体氧化应激介导的内皮功能障碍的分子机制以及一氧化氮在 EC 中的保护作用。破译这些机制可能会发现新的治疗策略,以预防血液中 Ang II 浓度升高引起的内皮功能障碍和相关疾病。
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引用次数: 0
Corrigendum to “Polypeptide N-Acetylgalactosaminyl transferase 14 is a novel mediator in pancreatic β-cell function and growth” [Mol. Cell. Endocrinol., 591(2024) 112269-112278, 0303–7207] 多肽 N-乙酰半乳糖氨基转移酶 14 是胰腺 β 细胞功能和生长的新型介质》[Mol.Cell.Endocrinol.,591(2024) 112269-112278, 0303-7207] 更正
IF 4.1 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-04 DOI: 10.1016/j.mce.2024.112291
Tingting Shu , Yan Zhang , Tong Sun , Yunxia Zhu
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引用次数: 0
Melatonin changes energy metabolism and reduces oncogenic signaling in ovarian cancer cells 褪黑激素改变卵巢癌细胞的能量代谢并减少致癌信号传导
IF 4.1 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-04 DOI: 10.1016/j.mce.2024.112296
Henrique Spaulonci Silveira , Roberta Carvalho Cesário , Renan Aparecido Vígaro , Leticia Barbosa Gaiotte , Maira Smaniotto Cucielo , Fernando Guimarães , Fábio Rodrigues Ferreira Seiva , Debora Aparecida P.C. Zuccari , Russel J. Reiter , Luiz Gustavo de Almeida Chuffa

Ovarian cancer (OC) adjusts energy metabolism in favor of its progression and dissemination. Because melatonin (Mel) has antitumor actions, we investigated its impact on energy metabolism and kinase signaling in OC cells (SKOV-3 and CAISMOV-24). Cells were divided into control and Mel-treated groups, in the presence or absence of the antagonist luzindole. There was a decrease in the levels of HIF-1α, G6PDH, GAPDH, PDH, and CS after Mel treatment even in the presence of luzindole in both OC cells. Mel treatment also reduced the activity of OC-related enzymes including PFK-1, G6PDH, LDH, CS, and GS whereas PDH activity was increased. Lactate and glutamine levels dropped after Mel treatment. Mel further promoted a reduction in the concentrations of CREB, JNK, NF-kB, p-38, ERK1/2, AKT, P70S6K, and STAT in both cell lines. Mel reverses Warburg-type metabolism and possibly reduces glutaminolysis, thereby attenuating various oncogenic molecules associated with OC progression and invasion.

卵巢癌(OC)会调整能量代谢以促进其发展和扩散。由于褪黑激素(Mel)具有抗肿瘤作用,我们研究了它对卵巢癌细胞(SKOV-3 和 CAISMOV-24)能量代谢和激酶信号转导的影响。细胞被分为对照组和 Mel 处理组,在有或没有拮抗剂吕吲哚的情况下。即使在有吕吲哚存在的情况下,两种 OC 细胞中的 HIF-1α、G6PDH、GAPDH、PDH 和 CS 水平在经 Mel 处理后都有所下降。梅尔处理还降低了与 OC 相关的酶的活性,包括 PFK-1、G6PDH、LDH、CS 和 GS,而 PDH 的活性则有所增加。经 Mel 处理后,乳酸和谷氨酰胺水平下降。Mel 进一步促进了两种细胞系中 CREB、JNK、NF-kB、p-38、ERK1/2、AKT、P70S6K 和 STAT 浓度的降低。Mel能逆转沃伯格型新陈代谢,并可能减少谷氨酰胺溶解,从而抑制与OC进展和侵袭相关的各种致癌分子。
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引用次数: 0
Multiple androgen pathways contribute to the steroid signature of adrenarche 多种雄激素途径促成了肾上腺皮质发育的类固醇特征
IF 4.1 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-03 DOI: 10.1016/j.mce.2024.112293
Jani Liimatta , Therina du Toit , Clarissa D. Voegel , Jarmo Jääskeläinen , Timo A. Lakka , Christa E. Flück

Context

Adrenarche is a normal developmental event in mid-childhood characterized by increasing adrenal androgen secretion. The role of the classic androgen pathway has been well described in adrenarche, but the role of newer active androgens and additional androgen pathways is less clear.

Objective

To study the contribution of novel androgens and related steroid biosynthesis pathways to the development of adrenarche, and to identify additional steroid biomarkers of adrenarche.

Design

A longitudinal study of children aged 6–8 years at baseline, followed up at ages 8–10 and 14–16 years. A total of 34 children (20 girls) with clinical and/or biochemical signs of adrenarche (cases) and 24 children (11 girls) without these signs (controls) at age 8–10 years were included. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry.

Main outcome measures

Thirty-two steroids compartmentalized in progestagens, gluco- and mineralocorticoid pathways, and four androgen related pathways, including the classic, backdoor, 11-oxy, and 11-oxy backdoor pathways.

Results

The classic and 11-oxy androgen pathways were more active, and serum concentrations of main androgens in the classic (dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione and androsterone) and 11-oxy (11β-hydroxyandrostenedione, 11β-hydroxytestosterone, 11-ketoandrostenedione, and 11-ketotestosterone) pathways were higher in cases at ages 6–8 and 8–10 years. Pregnenolone concentrations at adrenarchal age (8–10 years) and cortisol concentrations at adolescence (14–16 years) were higher in cases. 11β-hydroxyandrosterone and 11-ketoandrosterone tended to be higher in cases with clinical signs compared to cases who had only biochemical evidence of adrenarche, albeit they were detected at low levels. In biomarker analyses, calculated steroid ratios with cortisol, cortisone, or 11-deoxycortisone as dividers were better classifiers for adrenarche than single steroids. Among these ratios, androstenedione/cortisone was the best.

Conclusions

The classic and 11-oxy androgen pathways are active in adrenarche. Children with earlier timing of adrenarche have higher serum cortisol levels at late pubertal age, suggesting that early adrenarche might have long-term effects on adrenal steroidogenesis by increasing the activity of the glucocorticoid pathway. Future studies should employ comprehensive steroid profiling to define novel classifiers and biomarkers for adrenarche and premature adrenarche.

背景肾上腺初潮是儿童中期的正常发育过程,其特点是肾上腺雄激素分泌增加。研究新型雄激素和相关类固醇生物合成途径对肾上腺皮质发育的作用,并确定肾上腺皮质发育的其他类固醇生物标志物。设计对基线年龄为 6-8 岁的儿童进行纵向研究,并在 8-10 岁和 14-16 岁时进行随访。研究共纳入了 34 名(20 名女孩)8-10 岁时有肾上腺皮质激素临床和/或生化征兆的儿童(病例)和 24 名(11 名女孩)无这些征兆的儿童(对照组)。血清类固醇分析采用液相色谱高分辨质谱法进行。主要结果指标32种类固醇分为孕激素、糖皮质激素和矿皮质激素途径,以及四种雄激素相关途径,包括经典途径、后门途径、11-氧途径和11-氧后门途径。结果 6-8岁和8-10岁的病例中,经典雄激素途径和11-氧雄激素途径更为活跃,血清中经典途径(脱氢表雄酮、硫酸脱氢表雄酮、雄烯二酮和雄甾酮)和11-氧途径(11β-羟基雄烯二酮、11β-羟基睾酮、11-酮雄烯二酮和11-酮睾酮)的主要雄激素浓度较高。病例在肾上腺年龄(8-10 岁)的孕烯醇酮浓度和青春期(14-16 岁)的皮质醇浓度较高。有临床症状的病例中,11β-羟基雄酮和 11-酮基雄酮的含量往往高于仅有肾上腺皮质发育生化证据的病例,尽管这两种激素的检测水平较低。在生物标志物分析中,以皮质醇、可的松或 11-脱氧可的松为分界线计算出的类固醇比率比单一类固醇更能对肾上腺皮质发育不良进行分类。在这些比率中,雄烯二酮/可的松是最好的。肾上腺初潮时间较早的儿童在青春期晚期的血清皮质醇水平较高,这表明肾上腺初潮过早可能会增加糖皮质激素途径的活性,从而对肾上腺类固醇的生成产生长期影响。未来的研究应采用全面的类固醇分析方法来确定肾上腺皮质激素初潮和过早肾上腺皮质激素初潮的新型分类指标和生物标志物。
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引用次数: 0
Dopamine-mediated autocrine inhibition of insulin secretion 多巴胺介导的胰岛素分泌自分泌抑制。
IF 4.1 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-03 DOI: 10.1016/j.mce.2024.112294
Edoardo Ferrero , Matilde Masini , Marco Carli , Stefania Moscato , Pascale Beffy , Francesca Vaglini , Letizia Mattii , Alessandro Corti , Marco Scarselli , Michela Novelli , Vincenzo De Tata

The aim of the present research was to explore the mechanisms underlying the role of dopamine in the regulation of insulin secretion in beta cells. The effect of dopamine on insulin secretion was investigated on INS 832/13 cell line upon glucose and other secretagogues stimulation. Results show that dopamine significantly inhibits insulin secretion stimulated by both glucose and other secretagogues, while it has no effect on the basal secretion. This effect requires the presence of dopamine during incubation with the various secretagogues. Both electron microscopy and immunohistochemistry indicate that in beta cells the D2 dopamine receptor is localized within the insulin granules. Blocking dopamine entry into the insulin granules by inhibiting the VMAT2 transporter with tetrabenazine causes a significant increase in ROS production. Our results confirm that dopamine plays an important role in the regulation of insulin secretion by pancreatic beta cells through a regulated and precise compartmentalization mechanisms.

本研究旨在探索多巴胺在调节β细胞胰岛素分泌中的作用机制。研究人员在 INS 832/13 细胞系上研究了多巴胺在葡萄糖和其他促泌剂刺激下对胰岛素分泌的影响。结果表明,多巴胺能明显抑制葡萄糖和其他促泌剂刺激下的胰岛素分泌,而对基础分泌没有影响。这种作用需要在与各种分泌物一起孵育期间多巴胺的存在。电子显微镜和免疫组化都表明,在β细胞中,D2多巴胺受体位于胰岛素颗粒内。用四苯巴嗪抑制 VMAT2 转运体,阻止多巴胺进入胰岛素颗粒,会导致 ROS 生成显著增加。我们的研究结果证实,多巴胺通过调节和精确的分区机制在调节胰岛β细胞分泌胰岛素的过程中发挥着重要作用。
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引用次数: 0
YTHDF2 regulates MSS51 expression contributing to mitochondria dysfunction of granulosa cells in polycystic ovarian syndrome patients YTHDF2调节MSS51的表达,导致多囊卵巢综合征患者颗粒细胞线粒体功能障碍
IF 3.8 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-01 DOI: 10.1016/j.mce.2024.112292
Yun-Yun Jiao , Ning Song , Xing-Yu Fang , Xiao-Tong Lu, Ning Sun, Hai-Xia Jin, Lei Chen, Xian-Ju Huang, Shuang Wen, Zhao-Ting Wu, Xiao-Peng Wang, Ting-Ting Cheng, Gui-Dong Yao, Wen-Yan Song

Research question

Granulosa cells (GCs) dysfunction plays a crucial role in the pathogenesis of polycystic ovary syndrome (PCOS). It is reported that YTH domain-containing family protein 2 (YTHDF2) is upregulated in mural GCs of PCOS patients. What effect does the differential expression of YTHDF2 have in PCOS patients?

Design

Mural GCs and cumulus GCs from 15 patients with PCOS and 15 ovulatory controls and 4 cases of pathological sections in each group were collected. Real-time PCR, Western Blot, immunohistochemistry, and immunofluorescence experiments were conducted to detect gene and protein expression. RNA immunoprecipitation assay was performed to evaluate the binding relationship between YTHDF2 and MSS51. Mitochondrial morphology, cellular ATP and ROS levels and glycolysis-related gene expression were detected after YTHDF2 overexpression or MSS51 inhibition.

Results

In the present study, we found that YTHDF2 was upregulated in GCs of PCOS patients while MSS51 was downregulated. YTHDF2 protein can bind to MSS51 mRNA and affect MSS51 expression. The reduction of MSS51 expression or the increase in YTHDF2 expression can lead to mitochondrial damage, reduced ATP levels, increased ROS levels and reduced expression of LDHA, PFKP and PKM.

Conclusions

YTHDF2 may regulate the expression of MSS51, affecting the structure and function of mitochondria in GCs and interfering with cellular glycolysis, which may disturb the normal biological processes of GCs and follicle development in PCOS patients.

研究问题颗粒细胞(GCs)功能障碍在多囊卵巢综合征(PCOS)的发病机制中起着至关重要的作用。据报道,含YTH结构域的家族蛋白2(YTHDF2)在多囊卵巢综合征患者的壁层GC中上调。设计收集15例多囊卵巢综合征患者和15例排卵对照组的壁细胞和积液细胞,每组4例病理切片。采用实时 PCR、Western Blot、免疫组织化学和免疫荧光实验检测基因和蛋白质的表达。通过 RNA 免疫沉淀实验评估 YTHDF2 与 MSS51 的结合关系。结果 在本研究中,我们发现 YTHDF2 在 PCOS 患者的 GC 中上调,而 MSS51 则下调。YTHDF2蛋白可与MSS51 mRNA结合并影响MSS51的表达。结论YTHDF2可能调控MSS51的表达,影响GCs中线粒体的结构和功能,干扰细胞糖酵解,从而干扰PCOS患者GCs的正常生物学过程和卵泡发育。
{"title":"YTHDF2 regulates MSS51 expression contributing to mitochondria dysfunction of granulosa cells in polycystic ovarian syndrome patients","authors":"Yun-Yun Jiao ,&nbsp;Ning Song ,&nbsp;Xing-Yu Fang ,&nbsp;Xiao-Tong Lu,&nbsp;Ning Sun,&nbsp;Hai-Xia Jin,&nbsp;Lei Chen,&nbsp;Xian-Ju Huang,&nbsp;Shuang Wen,&nbsp;Zhao-Ting Wu,&nbsp;Xiao-Peng Wang,&nbsp;Ting-Ting Cheng,&nbsp;Gui-Dong Yao,&nbsp;Wen-Yan Song","doi":"10.1016/j.mce.2024.112292","DOIUrl":"10.1016/j.mce.2024.112292","url":null,"abstract":"<div><h3>Research question</h3><p>Granulosa cells (GCs) dysfunction plays a crucial role in the pathogenesis of polycystic ovary syndrome (PCOS). It is reported that YTH domain-containing family protein 2 (YTHDF2) is upregulated in mural GCs of PCOS patients. What effect does the differential expression of YTHDF2 have in PCOS patients?</p></div><div><h3>Design</h3><p>Mural GCs and cumulus GCs from 15 patients with PCOS and 15 ovulatory controls and 4 cases of pathological sections in each group were collected. Real-time PCR, Western Blot, immunohistochemistry, and immunofluorescence experiments were conducted to detect gene and protein expression. RNA immunoprecipitation assay was performed to evaluate the binding relationship between YTHDF2 and MSS51. Mitochondrial morphology, cellular ATP and ROS levels and glycolysis-related gene expression were detected after YTHDF2 overexpression or MSS51 inhibition.</p></div><div><h3>Results</h3><p>In the present study, we found that YTHDF2 was upregulated in GCs of PCOS patients while MSS51 was downregulated. YTHDF2 protein can bind to MSS51 mRNA and affect MSS51 expression. The reduction of MSS51 expression or the increase in YTHDF2 expression can lead to mitochondrial damage, reduced ATP levels, increased ROS levels and reduced expression of <em>LDHA, PFKP</em> and <em>PKM</em>.</p></div><div><h3>Conclusions</h3><p>YTHDF2 may regulate the expression of MSS51, affecting the structure and function of mitochondria in GCs and interfering with cellular glycolysis, which may disturb the normal biological processes of GCs and follicle development in PCOS patients.</p></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"592 ","pages":"Article 112292"},"PeriodicalIF":3.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141235621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dual inhibition of AKT and ERK1/2 pathways restores the expression of progesterone Receptor-B in endometriotic lesions through epigenetic mechanisms 通过表观遗传机制双重抑制 AKT 和 ERK1/2 通路可恢复子宫内膜异位症病灶中孕酮受体-B 的表达
IF 3.8 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-05-31 DOI: 10.1016/j.mce.2024.112290
Sudipta Dutta , JeHoon Lee , Sakhila K. Banu, Joe A. Arosh

Endometriosis is an estrogen-dependent and progesterone-resistant gynecological inflammatory disease of reproductive-age women. Progesterone resistance, loss of progesterone receptor -B (PR-B) in the stromal cells of the endometrium, is one of the hallmarks of endometriosis and a major contributing factor for infertility in endometriosis patients. Loss of PR-B in the stromal cells of the endometriotic lesions poses resistance to the success of progesterone-based therapy. The working hypothesis is that PR-B is hypermethylated and epigenetically silenced, and inhibition of AKT and ERK1/2 pathways will decrease the hypermethylation, reverse the epigenetic silencing, and restore the expression of PR-B via DNA methylation and histone modification mechanisms in the endometriotic lesions. The objectives are to (i) determine the effects of dual inhibition of AKT and ERK1/2 pathways on the expression of PR-B and DNA methylation and histone modification protein machinery in the endometriotic lesions and (ii) identify the underlying epigenetic mechanisms of PR-B restoration in the endometriotic lesions. The results indicate that dual inhibition of AKT and ERK1/2 pathways decreases the hypermethylation, reverses the epigenetic silencing, and restores the expression of PR-B via DNA methylation and H3K9 and H3K27 methylation mechanisms in the endometriotic lesions or endometriotic stromal cells of human origin. These results support the novel concept that restored expression of PR-B in the endometriotic lesions and endometrium may improve the clinical outcome of progesterone therapy in endometriosis patients.

子宫内膜异位症是育龄妇女的一种雌激素依赖性和孕激素抵抗性妇科炎症。孕激素抵抗,即子宫内膜基质细胞中孕激素受体-B(PR-B)的缺失,是子宫内膜异位症的特征之一,也是导致子宫内膜异位症患者不孕的主要因素。子宫内膜异位症病灶基质细胞中 PR-B 的缺失对孕激素治疗的成功构成了阻力。研究假设 PR-B 存在高甲基化和表观遗传沉默,而抑制 AKT 和 ERK1/2 通路将减少高甲基化,逆转表观遗传沉默,并通过 DNA 甲基化和组蛋白修饰机制恢复 PR-B 在子宫内膜异位症病灶中的表达。研究目的是:(i) 确定 AKT 和 ERK1/2 通路双重抑制对子宫内膜异位症病灶中 PR-B 的表达以及 DNA 甲基化和组蛋白修饰蛋白机制的影响;(ii) 找出子宫内膜异位症病灶中 PR-B 恢复的潜在表观遗传学机制。结果表明,双重抑制 AKT 和 ERK1/2 通路可降低高甲基化,逆转表观遗传沉默,并通过 DNA 甲基化、H3K9 和 H3K27 甲基化机制恢复 PR-B 在子宫内膜异位症病灶或人源子宫内膜异位症基质细胞中的表达。这些结果支持了一个新概念,即恢复 PR-B 在子宫内膜异位症病灶和子宫内膜中的表达可改善子宫内膜异位症患者接受黄体酮治疗的临床效果。
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引用次数: 0
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Molecular and Cellular Endocrinology
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