Sestrin2 alleviates palmitate-induced endoplasmic reticulum stress, apoptosis, and defective invasion of human trophoblast cells.
- 作者列表："Lee S","Shin J","Hong Y","Shin SM","Shin HW","Shin J","Lee SK","Park HW
:Problem Maternal obesity induces elevated saturated fatty acid palmitate levels in the blood and causes pregnancy complications such as gestational diabetes, pre-eclampsia, fetal growth abnormalities, and stillbirth. Sestrin2, a highly conserved stress-inducible protein, is involved in the cellular responses of various stress conditions and homeostatic regulation. However, the effects of Sestrin2 on trophoblast cells have not yet been investigated. Here, we investigated the role of Sestrin2 in palmitate-induced lipotoxicity and its underlying mechanisms in human first-trimester trophoblast cells (Sw.71). Method of study Mouse placental tissues were obtained from low-fat diet-fed mice (n = 14) and high-fat diet-fed mice (n = 14) at gestation day 17.5. Sw.71 cells were treated with palmitate or bovine serum albumin as vehicle controls. The role of Sestrin2 in palmitate-induced lipotoxicity were examined by immunocytochemistry, immunoblot analysis, quantitative real-time PCR, and invasion assay. Results Expression of placental Sestrin2 was elevated in high-fat diet-fed dams compared to that of low-fat diet-fed dams. Prolonged treatment of Sw.71 cells with palmitate induced endoplasmic reticulum (ER) stress-dependent expressions of Sestrin2 protein and mRNA, and the treatment also triggered apoptosis. Knockdown of Sestrin2 increased palmitate-mediated ER stress, inflammatory signaling, and apoptosis. Furthermore, Sestrin2 suppressed impaired trophoblast invasion caused by palmitate, and attenuated palmitate-induced ER stress and inflammation via AMPK/mTORC1 pathways. Conclusion Our study provides the relationship between Sestrin2, AMPK/mTORC1 pathway, and trophoblast function, suggesting that Sestrin2 may be a novel potential therapeutic target for the prevention of pregnancy complications.
: 孕妇肥胖导致血液中饱和脂肪酸棕榈酸水平升高，并引起妊娠并发症，如妊娠糖尿病、先兆子痫、胎儿生长异常和死胎。Sestrin2 是一种高度保守的应激诱导蛋白，参与各种应激条件的细胞反应和稳态调节。然而，Sestrin2 对滋养层细胞的影响尚未被研究。在这里，我们研究了 Sestrin2 在棕榈酸诱导的脂肪毒性中的作用及其在人妊娠早期滋养层细胞 (Sw.71) 中的潜在机制。研究方法小鼠胎盘组织来自低脂饮食喂养的小鼠 (n = 14) 和高脂饮食喂养的小鼠 (n = 14)，在妊娠 17.5 天。Sw.71 细胞用棕榈酸盐或牛血清白蛋白处理作为溶剂对照。通过免疫细胞化学、免疫印迹分析、定量实时 PCR 和侵袭试验检测 Sestrin2 在棕榈酸诱导的脂毒性中的作用。结果与低脂饲料喂养的水坝相比，高脂饲料喂养的水坝胎盘 Sestrin2 的表达升高。棕榈酸盐延长处理 Sw.71 细胞诱导内质网 (ER) 应激依赖性 Sestrin2 蛋白和 mRNA 表达，处理也引发细胞凋亡。敲除 Sestrin2 增加了棕榈酸介导的内质网应激、炎症信号和细胞凋亡。此外，Sestrin2 抑制棕榈酸盐引起的滋养层侵袭受损，并通过 AMPK/mTORC1 通路减弱棕榈酸盐诱导的 ER 应激和炎症。结论我们的研究提供了 Sestrin2 、 AMPK/mTORC1 通路与滋养细胞功能的关系，提示 Sestrin2 可能是预防妊娠并发症的一个新的潜在治疗靶点。
METHODS::Maternal lifestyle affects both mother health and pregnancy outcome in humans. Several studies have demonstrated that interventions oriented towards reducing stress and anxiety have positive effects on pregnancy complications such as preeclampsia, excessive gestational weight, gestational diabetes and preterm birth. In this work, we showed that the environmental enrichment (EE), defined as a noninvasive and biological significant stimulus of the sensory pathway combined with voluntary physical activity, prevented preterm birth (PTB) rate in a 41% in an inflammatory mouse model induced by the systemic administration of bacterial lipopolysaccharide (LPS). Furthermore, we found that EE modulates maternal metabolism and produces an anti-inflammatory environment that contributes to pregnancy maintenance. In pregnant mice uterus, EE reduces the expression of TLR4 and CD14 (the LPS receptor and its coactivator protein), preventing the LPS-induced increase in PGE2 and PGF2α release and nitric oxide synthase (NOS) activity. In cervical tissue, EE inhibits cervical ripening events, such as PGE2 release, matrix metalloproteinase (MMP)-9 increased activity and neutrophil recruitment, therefore conserving cervical function. It seems that EE exposure could mimic the stress and anxiety-reducing techniques mentioned above, explaining, at least partially, the beneficial effects of having a healthy lifestyle before and during gestation. Furthermore, we propose that designing an EE protocol for humans could be a noninvasive and preventive therapy for pregnancy complications, averting pre-term birth occurrence and dreaded sequelae that are present in the offspring born to soon.
METHODS:PROBLEM:We aimed to investigate the main causes of recurrent miscarriage (RM) in patients with losses after spontaneous gestation (SG) and after in vitro fertilization (IVF). METHOD OF STUDY:A prospective case-control study was conducted. The eligible patients were women who had experienced two or more consecutive abortions after less than 12 weeks gestation, two consecutive losses after SG or two consecutive losses after IVF. All patients were subjected to the following evaluations: karyotyping of the aborted material, alloimmune and autoimmune marker testing, and acquired and hereditary thrombophilia marker testing. RESULTS:In total, 58 patients were eligible: 32 patients with RM after SG and 26 patients with RM after IVF. The factors associated with RM were genetic (29%), immune (14%), thrombophilic (21%), and thrombophilic and immune (24%), and only 12% of the cases were idiopathic. Comparing the two study groups (SG and IVF), all studied factors were similar, except for a higher ANA positivity observed in the SG group (SG 30.4% versus IVF 5.3%, OR 8.6 (CI 1.1 - 21.1, P 0.048). CONCLUSIONS:Our study identified the possibly factors associated with recurrent miscarriage in 86% of the cases, and these factors appear to be similar in patients with recurrent miscarriage after spontaneous gestation and IVF. This study demonstrates that IVF with PGT-A with euploid embryo transfer could reduce abortions by up to 29%, but other factors needs to be investigated even in patients undergoing in vitro fertilization.
METHODS:OBJECTIVES:To evaluate the impact of pre-operative Music Therapy (MT) on pain in first-trimester abortion under local anaesthesia (ALA). DESIGN:Randomised controlled trial comparing patients undergoing a first-trimester ALA with or without a pre-operative MT session. SETTING:University hospital of Angers from November 2016 to August 2017. POPULATION:Patients who underwent first-trimester abortion under ALA. METHODS:Patients allocated to MT group underwent a pre-operative 20 minutes session of MT. MAIN OUTCOME MEASURES:Pain was assessed using a visual analogue scale (VAS) just before the procedure, during the procedure, at the end of the procedure and upon returning to the ward. RESULTS:159 patients were randomised (80 in MT group, and 79 in the control group). 2 patients were excluded from the control group and 6 from the MT group. Therefore, 77 patients were analysed in the control group and 74 in the MT group. The intensity of pain were similar in both the MT group and the Control group just before the procedure (VAS: 4.0±2.9 vs. 3.6±2.5, p=0.78), during the procedure (VAS: 5.3±2.5 vs. 4.9±2.9, p=0.78), at the end of the procedure (VAS: 2.7±2.4 vs. 2.6±2.4, p=0.43) and upon returning to the ward (VAS:1.8±2.0 vs. 1.5±2.0, p=0.84). The difference in pain between entering the department and returning to the room after the procedure was similar between the MT and Control groups (0.3±2.5 vs. 0.3±2.4 VAS levels difference; p=0.92). CONCLUSION:Music therapy session before an ALA procedure resulted in no improvement in patient perception of pain during a first-trimester abortion.