miR-146a-5p improves the decidual cytokine microenvironment by regulating the toll-like receptor signaling pathway in unexplained spontaneous abortion

Ye, Hongxia; Li, Lan; Dong, Ya-Jun; Li, Penghao; Su, Qin; Guo, Yanhua; Lu, Yanrong; Zhang, Ying; Jia, Yan; Cheng, Jun

doi:10.1016/j.intimp.2020.107066

Cited by 9 publications

(13 citation statements)

References 42 publications

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“…Previous studies documented that MiR-520 upregulation in both placenta and maternal circulation is highly linked to placental pathologies, such as IUGR [ 38 ] and our records of declined fetal weight supports this fact. Concerning MiR-146a, its up-regulation is highly associated with balanced micro-environment of pregnancy, and its downregulation was involved in unexplained spontaneous abortion [ 39 ] in agreement with our data.…”

Section: Discussionsupporting

confidence: 89%

Mentha pulegium L. (Pennyroyal, Lamiaceae) Extracts Impose Abortion or Fetal-Mediated Toxicity in Pregnant Rats; Evidenced by the Modulation of Pregnancy Hormones, MiR-520, MiR-146a, TIMP-1 and MMP-9 Protein Expressions, Inflammatory State, Certain Related Signaling Pathways, and Metabolite Profiling via UPLC-ESI-TOF-MS

El-Gazar

Emad

Ragab

et al. 2022

Toxins

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Pregnant women usually turn to natural products to relieve pregnancy-related ailments which might pose health risks. Mentha pulegium L. (MP, Lamiaceae) is a common insect repellent, and the present work validates its abortifacient capacity, targeting morphological anomalies, biological, and behavioral consequences, compared to misoprostol. The study also includes untargeted metabolite profiling of MP extract and fractions thereof viz. methylene chloride (MecH), ethyl acetate (EtOAc), butanol (But), and the remaining liquor (Rem. Aq.) by UPLC-ESI-MS-TOF, to unravel the constituents provoking abortion. Administration of MP extract/fractions, for three days starting from day 15th of gestation, affected fetal development by disrupting the uterine and placental tissues, or even caused pregnancy termination. These effects also entailed biochemical changes where they decreased progesterone and increased estradiol serum levels, modulated placental gene expressions of both MiR-(146a and 520), decreased uterine MMP-9, and up-regulated TIMP-1 protein expression, and empathized inflammatory responses (TNF-α, IL-1β). In addition, these alterations affected the brain's GFAP, BDNF, and 5-HT content and some of the behavioral parameters escorted by the open field test. All these incidences were also perceived in the misoprostol-treated group. A total of 128 metabolites were identified in the alcoholic extract of MP, including hydroxycinnamates, flavonoid conjugates, quinones, iridoids, and terpenes. MP extract was successful in terminating the pregnancy with minimal behavioral abnormalities and low toxicity margins.

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Section: Discussionsupporting

confidence: 89%

Mentha pulegium L. (Pennyroyal, Lamiaceae) Extracts Impose Abortion or Fetal-Mediated Toxicity in Pregnant Rats; Evidenced by the Modulation of Pregnancy Hormones, MiR-520, MiR-146a, TIMP-1 and MMP-9 Protein Expressions, Inflammatory State, Certain Related Signaling Pathways, and Metabolite Profiling via UPLC-ESI-TOF-MS

El-Gazar

Emad

Ragab

et al. 2022

Toxins

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“…Among them, miR-449a has been previously identified in oviductal EVs 17 , 66 and their predicted target genes have been associated to embryo development, oxytocin pathway, and estrogen signaling pathway, suggesting a potential role in MRP in the mare. The microRNA miR-146a-5p, which showed highest levels on P10, has been found to improve the decidual cytokine microenvironment by regulating the TOLL-like receptor pathway in human endometrium 67 , indicating a role in the uterus in modulating the maternal immune system.…”

Section: Discussionmentioning

confidence: 99%

Uterine extracellular vesicles as multi-signal messengers during maternal recognition of pregnancy in the mare

Vegas

Hamdi

Podico

et al. 2022

Sci Rep

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In contrast to other domestic mammals, the embryo-derived signal(s) leading to maternal recognition of pregnancy (MRP) are still unknow in the mare. We hypothesize that these embryonic signals could be packed into uterine extracellular vesicles (uEVs), acting as multi-signal messengers between the conceptus and the maternal tract, and contributing to MRP. To unveil these signals, the RNA and protein cargos of uEVs isolated from uterine lavages collected from pregnant mares (P; day 10, 11, 12 and 13 after ovulation) and cyclic control mares (C; day 10 and 13 after ovulation) were analyzed. Our results showed a fine-tuned regulation of the uEV cargo (RNAs and proteins), by the day of pregnancy, the estrous cycle, and even the size of the embryo. A particular RNA pattern was identified with specific increase on P12 related to immune system and hormonal response. Besides, a set of proteins as well as RNAs was highly enriched in EVs on P12 and P13. Differential abundance of miRNAs was also identified in P13-derived uEVs. Their target genes were linked to down- or upregulated genes in the embryo and the endometrium, exposing their potential origin. Our study identified for first time specific molecules packed in uEVs, which were previously associated to MRP in the mare, and thus bringing added value to the current knowledge. Further integrative and functional analyses will help to confirm the role of these molecules in uEVs during MRP in the mare.

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“…Zhao et al showed that miR146a-5p is downregulated in the deciduae of RSM patients compared with healthy controls [ 55 ]. Moreover, it has been established that miR146a improves the decidual cytokine microenvironment through modulating the Toll-like receptor (TLR) pathway and other possible mechanisms of RSM pathogenesis [ 57 ]. Furthermore, Chen et al proposed that miR146a downregulates TLR4 , tumor necrosis factor receptor-associated factor-6 ( TRAF6 ), and IL-1 receptor-associated kinase 1 ( IRAK1 ) and phosphorylates NF- κ B. Consequently, suppressing TLR4/TRAF6/JNK and TLR4/NF- κ B pathways inhibits proinflammatory cytokine production [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Association of Polymorphisms in miR146a, an Inflammation-Associated MicroRNA, with the Risk of Idiopathic Recurrent Spontaneous Miscarriage: A Case-Control Study

et al. 2022

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It has been established that microRNAs (miRNAs) are involved in the regulation of immune responses and serve as biomarkers of inflammatory diseases as well as recurrent spontaneous miscarriage (RSM). Herein, we aimed to study the relationship between three functional miR146a gene polymorphisms with idiopathic RSM (IRSM) susceptibility. We recruited 161 patients with IRSM and 177 healthy women with at least one live birth and without a history of abortion. Genotyping was performed using RFLP-PCR and ARMS-PCR methods. We found that the rs6864584 T/C decreased the risk of IRSM under dominant TT+TC vs. CC ( OR = 0.029 ) and allelic C vs. T ( OR = 0.028 ) contrast models. Regarding rs2961920 A/C and rs57095329 A/G polymorphisms, the enhanced risk of IRSM was observed under different genetic contrasted models, including the codominant CC vs. AA ( OR = 2.81 for rs2961920) and codominant GG vs. AA ( OR = 2.36 for rs57095329). After applying a Bonferroni correction, haplotype analysis revealed a 51% decreased risk of IRSM regarding the ACA genotype combination. This is the first study reporting that miR146a rs57095329 A/G, rs2961920A/C, and rs6864584 T/C polymorphisms are associated with the risk of IRSM in a southern Iranian population. Performing replicated case-control studies on other ethnicities is warranted to outline the precise effects of the studied variants on the risk of gestational trophoblastic disorders.

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miR-146a-5p improves the decidual cytokine microenvironment by regulating the toll-like receptor signaling pathway in unexplained spontaneous abortion

Cited by 9 publications

References 42 publications

Uterine extracellular vesicles as multi-signal messengers during maternal recognition of pregnancy in the mare

Association of Polymorphisms in miR146a, an Inflammation-Associated MicroRNA, with the Risk of Idiopathic Recurrent Spontaneous Miscarriage: A Case-Control Study

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