Oxidative stress (OS) and endoplasmic reticulum stress (ERS) are at the genesis of placental disorders observed in preeclampsia, intrauterine growth restriction, and maternal hypothyroidism. In this regard, cationic manganese porphyrins (MnPs) comprise potent redox-active therapeutics of high antioxidant and anti-inflammatory potential, which have not been evaluated in metabolic gestational diseases yet. This study evaluated the therapeutic potential of two MnPs, [MnTE-2-PyP] (MnP I) and [MnT(5-Br-3-E-Py)P]5+ (MnP II), in the fetal-placental dysfunction of hypothyroid rats. Hypothyroidism was induced by administration of 6-Propyl-2-thiouracil (PTU) and treatment with MnPs I and II 0.1 mg/kg/day started on the 8th day of gestation (DG). The fetal and placental development, and protein and/or mRNA expression of antioxidant mediators (SOD1, CAT, GPx1), hypoxia (HIF1α), oxidative damage (8-OHdG, MDA), ERS (GRP78 and CHOP), immunological (TNFα, IL-6, IL-10, IL-1β, IL-18, NLRP3, Caspase1, Gasdermin D) and angiogenic (VEGF) were evaluated in the placenta and decidua on the 18th DG using immunohistochemistry and qPCR. ROS and peroxynitrite (PRX) were quantified by fluorometric assay, while enzyme activities of SOD, GST, and catalase were evaluated by colorimetric assay. MnPs I and II increased fetal body mass in hypothyroid rats, and MnP I increased fetal organ mass. MnPs restored the junctional zone morphology in hypothyroid rats and increased placental vascularization. MnPs blocked the increase of OS and ERS mediators caused by hypothyroidism, showing similar levels of expression of HIFα, 8-OHdG, MDA, , GRP78, and to the control. Moreover, MnPs I and/or II increased the protein expression of SOD1, Cat, and GPx1 and restored the expression of IL10, , and in the decidua and/or placenta. However, MnPs did not restore the low placental enzyme activity of SOD, CAT, and GST caused by hypothyroidism, while increased the decidual and placental protein expression of TNFα. The results show that treatment with MnPs improves the fetal-placental development and the placental inflammatory state of hypothyroid rats and protects against oxidative stress and reticular stress caused by hypothyroidism at the maternal-fetal interface.

中文翻译：

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基于锰卟啉的治疗可改善大鼠母体甲状腺功能减退症模型中胎儿胎盘的发育并防止氧化损伤和 NLRP3 炎症小体激活


氧化应激 (OS) 和内质网应激 (ERS) 是先兆子痫、宫内生长受限和母亲甲状腺功能减退症中观察到的胎盘疾病的根源。在这方面，阳离子锰卟啉（MnP）包含具有高抗氧化和抗炎潜力的有效氧化还原活性治疗剂，尚未在代谢性妊娠疾病中进行评估。本研究评估了两种 MnP：[MnTE-2-PyP] (MnP I) 和 [MnT(5-Br-3-E-Py)P]5+ (MnP II) 在胎儿胎盘功能障碍中的治疗潜力甲状腺功能减退大鼠。妊娠第 8 天（DG）开始，给予 6-丙基-2-硫尿嘧啶（PTU）并用 MnPs I 和 II 0.1 mg/kg/天治疗，诱导甲状腺功能减退症。胎儿和胎盘发育，以及抗氧化介质（SOD1、CAT、GPx1）、缺氧（HIF1α）、氧化损伤（8-OHdG、MDA）、ERS（GRP78 和 CHOP）、免疫学（TNFα、使用免疫组织化学和 qPCR 评估第 18 个 DG 的胎盘和蜕膜中的 IL-6、IL-10、IL-1β、IL-18、NLRP3、Caspase1、Gasdermin D）和血管生成 (VEGF)。通过荧光测定法对 ROS 和过氧亚硝酸盐 (PRX) 进行定量，同时通过比色测定法评估 SOD、GST 和过氧化氢酶的酶活性。 MnPs I 和 II 增加了甲状腺功能减退大鼠的胎儿体重，MnP I 增加了胎儿器官质量。 MnPs 恢复了甲状腺功能减退大鼠的交界区形态并增加了胎盘血管化。 MnPs 阻断了甲状腺功能减退引起的 OS 和 ERS ​​介质的增加，显示出与对照相似的 HIFα、8-OHdG、MDA、GRP78 的表达水平。 此外，MnPs I 和/或 II 增加了蜕膜和/或胎盘中 SOD1、Cat 和 GPx1 的蛋白表达，并恢复了 IL10、α、β 和 β 的表达。然而，MnPs并没有恢复甲状腺功能减退引起的SOD、CAT和GST等胎盘酶活性低下，反而增加了蜕膜和胎盘中TNFα的蛋白表达。结果表明，MnPs治疗可改善甲状腺功能减退大鼠的胎儿胎盘发育和胎盘炎症状态，并可防止母胎界面甲状腺功能减退引起的氧化应激和网状应激。