RESUMO
Preeclampsia (PE) is a life-threatening pregnancy-specific complication with controversial mechanisms and no effective treatment except delivery is available. Currently, increasing researchers suggested that PE shares pathophysiologic features with protein misfolding/aggregation disorders, such as Alzheimer disease (AD). Evidences have proposed defective autophagy as a potential source of protein aggregation in PE. Endoplasmic reticulum-selective autophagy (ER-phagy) plays a critical role in clearing misfolded proteins and maintaining ER homeostasis. However, its roles in the molecular pathology of PE remain unclear. We found that lncRNA DUXAP8 was upregulated in preeclamptic placentae and significantly correlated with clinical indicators. DUXAP8 specifically binds to PCBP2 and inhibits its ubiquitination-mediated degradation, and decreased levels of PCBP2 reversed the activation effect of DUXAP8 overexpression on AKT/mTOR signaling pathway. Function experiments showed that DUXAP8 overexpression inhibited trophoblastic proliferation, migration, and invasion of HTR-8/SVneo and JAR cells. Moreover, pathological accumulation of swollen and lytic ER (endoplasmic reticulum) was observed in DUXAP8-overexpressed HTR8/SVneo cells and PE placental villus trophoblast cells, which suggesting that ER clearance ability is impaired. Further studies found that DUXAP8 overexpression impaired ER-phagy and caused protein aggregation medicated by reduced FAM134B and LC3II expression (key proteins involved in ER-phagy) via activating AKT/mTOR signaling pathway. The increased level of FAM134B significantly reversed the inhibitory effect of DUXAP8 overexpression on the proliferation, migration, and invasion of trophoblasts. In vivo, DUXAP8 overexpression through tail vein injection of adenovirus induced PE-like phenotypes in pregnant rats accompanied with activated AKT/mTOR signaling, decreased expression of FAM134B and LC3-II proteins and increased protein aggregation in placental tissues. Our study reveals the important role of lncRNA DUXAP8 in regulating trophoblast biological behaviors through FAM134B-mediated ER-phagy, providing a new theoretical basis for understanding the pathogenesis of PE.
Assuntos
Autofagia , Retículo Endoplasmático , Pré-Eclâmpsia , Proteínas Proto-Oncogênicas c-akt , RNA Longo não Codificante , Transdução de Sinais , Serina-Treonina Quinases TOR , Trofoblastos , Adulto , Animais , Feminino , Humanos , Gravidez , Ratos , Autofagia/genética , Linhagem Celular , Movimento Celular/genética , Proliferação de Células/genética , Retículo Endoplasmático/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Serina-Treonina Quinases TOR/metabolismo , Trofoblastos/metabolismo , Trofoblastos/patologia , MasculinoRESUMO
BACKGROUND: The recent COVID-19 outbreak in Wuhan, China, has quickly spread throughout the world. In this study, we systematically reviewed the clinical features and outcomes of pregnant women with COVID-19. METHODS: PubMed, Web of Science, EMBASE and MEDLINE were searched from January 1, 2020, to April 16, 2020. Case reports and case series of pregnant women infected with SARS-CoV-2 were included. Two reviewers screened 366 studies and 14 studies were included. Four reviewers independently extracted the features from the studies. We used a random-effects model to analyse the incidence (P) and 95% confidence interval (95% CI). Heterogeneity was assessed using the I2 statistic. RESULTS: The meta-analysis included 236 pregnant women with COVID-19. The results were as follows: positive CT findings (71%; 95% CI, 0.49-0.93), caesarean section (65%; 95% CI, 0.42-0.87), fever (51%; 95% CI, 0.35-0.67), lymphopenia (49%; 95% CI, 0.29-0.70), coexisting disorders (33%; 95% CI, 0.21-0.44), cough (31%; 95% CI, 0.23-0.39), fetal distress (29%; 95% CI, 0.08-0.49), preterm labor (23%; 95% CI, 0.14-0.32), and severe case or death (12%; 95% CI, 0.03-0.20). The subgroup analysis showed that compared with non-pregnant patients, pregnant women with COVID-19 had significantly lower incidences of fever (pregnant women, 51%; non-pregnant patients, 91%; P < 0.00001) and cough (pregnant women, 31%; non-pregnant patients, 67%; P < 0.0001). CONCLUSIONS: The incidences of fever, cough and positive CT findings in pregnant women with COVID-19 are less than those in the normal population with COVID-19, but the rate of preterm labor is higher among pregnant with COVID-19 than among normal pregnant women. There is currently no evidence that COVID-19 can spread through vertical transmission.
