Alpha 1 Antitrypsin Regulates Trophoblast Syncytialization and Inflammatory Factor Expression

Yoshida, Kanoko; Yano, Aruto; Kusama, Kaoru; Ishikawa, Gen; Tamura, Kazuhiro

doi:10.3390/ijms23041955

Cited by 5 publications

(7 citation statements)

References 35 publications

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“…On the other hand, ER stress may regulate the invasion of extravillous trophoblast cells and relate to the pathogenesis of HDP 29 . Previous study showed that the ER stress inducers tunicamycin and thapsigargin inhibited trophoblast fusion.…”

Section: Discussionmentioning

confidence: 99%

Quercetin stimulates trophoblast fusion via the mitochondrial function

Yoshida,

Kusama,

Shinohara

et al. 2024

Sci Rep

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The fusion of mononuclear trophoblasts into multinucleate syncytiotrophoblasts is the critical event in the process of syncytialization, and its dysregulation can lead to pregnancy complications, notably hypertensive disorders of pregnancy (HDP). Oxidative stress may disrupt trophoblast syncytialization in HDP. Specifically, placentas with HDP exhibit impaired mitochondria, giving rise to the generation of reactive oxygen species (ROS) and subsequent oxidative stress. Quercetin, a bioflavonoid known for its antioxidant and anti-aging properties, has the potential to mitigate oxidative stress during trophoblast syncytialization. However, the precise mechanism underlying the action of quercetin in these processes remains to be elucidated. To explore the impact of quercetin on syncytialization, mitochondrial function, and ROS generation, cyclic AMP-stimulated BeWo cells were treated with quercetin. The expression of markers associated with cell fusion, mitochondrial function, and oxidative stress was determined using qPCR and western blotting. Additionally, morphological syncytialization and mitophagy (mitochondrial degradation) were assessed by immunofluorescence analysis. Our results revealed that quercetin increased the expression of syncytialization markers and promoted cell fusion. Furthermore, this compound also upregulated markers associated with mitophagy and mitochondrial fusion, which are corroborated by visual evidence of mitophagy through the fluorescence microscope. Cell fusion naturally stimulated ROS generation, which was attenuated by quercetin. Quercetin downregulated the expression of NRF2 and HO-1 during syncytialization, while increasing the expression of sirtuin1/3/6, which are known to play essential roles in antioxidant responses. In conclusion, quercetin effectively regulates mitochondrial function through its antioxidant properties and the suppression of ROS generation, ultimately promoting trophoblast fusion, suggesting that the flavonoid has the potential to ameliorate pregnancy-related disorder stemming from placental dysplasia.

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Section: Discussionmentioning

confidence: 99%

Quercetin stimulates trophoblast fusion via the mitochondrial function

Yoshida,

Kusama,

Shinohara

et al. 2024

Sci Rep

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“…ESCs cells were transfected with either a non-targeting control, or with SERPINA1 (EHU090971, Sigma-Aldrich), TLR3 (EHU019541, Sigma-Aldrich), or TLR4 siRNA (EHU086621, Sigma-Aldrich) using Lipofectamine RNAiMAX (Thermo Fisher Scientific) ( 22 ).…”

Section: Methodsmentioning

confidence: 99%

“…Immunoreactive bands were detected using an enhanced chemiluminescence kit (Merck Millipore, Burlingame, MA, USA) after incubation with horseradish peroxidase-labeled goat anti-rabbit or anti-mouse IgG (1:5,000; Vector Laboratories, Burlingame, CA, USA). Signals were detected using a C-DiGit Blot Scanner (LI-COR, Lincoln, NE, USA) ( 22 ).…”

Section: Methodsmentioning

confidence: 99%

“…By contrast, treatment with purified SERPINA1 inhibits the production of proinflammatory cytokines in human endometrial cells in vitro ( 6 ), and improves the survival rate of mice with peritonitis and sepsis ( 19 ). Furthermore, SERPINA1 reduces organ damage in a serine protease activity-independent fashion ( 17 , 18 , 20 – 22 ); However, the molecular mechanism(s) by which SERPINA1 affects expression of inflammatory factors likely linked to development of endometriotic lesions has not been characterized fully. Here, to investigate the physiological role of SERPINA1 in endometrial stromal cells (ESCs), we extracted RNA from ESCs in which SERPINA1 was knocked down and then performed RNA sequence analysis.…”

Section: Introductionmentioning

confidence: 99%

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Toll-like receptor signaling pathway triggered by inhibition of serpin A1 stimulates production of inflammatory cytokines by endometrial stromal cells

et al. 2022

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Endometriosis is characterized by the presence of inflamed and fibrotic endometrial tissue outside the uterine cavity. Previously, we found decreased SERPINA1 (alpha-1 antitrypsin) expression in endometriosis-like lesions in a mouse model of endometriosis, suggesting that it exacerbated inflammation in these lesions. However, the molecular mechanism(s) by which SERPINA1 affects expression of inflammatory factors and development of endometriotic lesions have not been fully characterized. To investigate the role of intracellular SERPINA1 in endometrial stromal cells (ESCs), we performed RNA sequence analysis using RNA extracted from ESCs in which SERPINA1 was knocked down. The analysis identified several toll-like receptor (TLR)-related factors as being upregulated. Silencing of SERPINA1 increased expression of TLR3 and TLR4 in ESCs, as well as several TLR signaling pathway components, including MYD88, IRAK1/4, interleukin (IL)-1β, and interferon (IFN)-β. TLR3 or TLR4 agonists increased expression of inflammatory factors in SERPINA1-knockdown ESCs, whereas TLR3 or TLR4 inhibitors decreased expression. In addition, treatment with recombinant IL-1β or IFN-β increased expression of MYD88 and inflammatory factors in ESCs. Immunohistochemical analysis of endometriotic tissues showed that TLR3, TLR4, and MYD88 were localized in endometriosis lesions. Taken together, the data suggest that reduced expression of SERPINA1 induces expression of inflammatory factors by ESCs, which in turn are associated with TLR3/4, IL-1β, and IFN-β signaling. Regulation of intracellular SERPINA1 levels in ESCs may be a strategy to inhibit inflammatory responses in endometriotic lesions.

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“…In addition, maternal factors such as obesity, hypertension, and autoimmune diseases increase the risk of developing HDP. Furthermore, the degree of inflammation of maternal blood vessels before pregnancy may contribute to the onset of HDP [ 136 , 137 , 138 ]. In recent years, it has been reported that autophagy is involved in placental hypoxia and that autophagy failure is associated with the onset of PE [ 139 , 140 ].…”

Section: Diseases Involving Placental Dysfunctionmentioning

confidence: 99%

Human Chorionic Villous Differentiation and Placental Development

Kojima

Ono

Kuji

et al. 2022

IJMS

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In humans, the placenta provides the only fetomaternal connection and is essential for establishing a pregnancy as well as fetal well-being. Additionally, it allows maternal physiological adaptation and embryonic immunological acceptance, support, and nutrition. The placenta is derived from extra-embryonic tissues that develop rapidly and dynamically in the first weeks of pregnancy. It is primarily composed of trophoblasts that differentiate into villi, stromal cells, macrophages, and fetal endothelial cells (FEC). Placental differentiation may be closely related to perinatal diseases, including fetal growth retardation (FGR) and hypertensive disorders of pregnancy (HDP), and miscarriage. There are limited findings regarding human chorionic villous differentiation and placental development because conducting in vivo studies is extremely difficult. Placental tissue varies widely among species. Thus, experimental animal findings are difficult to apply to humans. Early villous differentiation is difficult to study due to the small tissue size; however, a detailed analysis can potentially elucidate perinatal disease causes or help develop novel therapies. Artificial induction of early villous differentiation using human embryonic stem (ES) cells/induced pluripotent stem (iPS) cells was attempted, producing normally differentiated villi that can be used for interventional/invasive research. Here, we summarized and correlated early villous differentiation findings and discussed clinical diseases.

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Alpha 1 Antitrypsin Regulates Trophoblast Syncytialization and Inflammatory Factor Expression

Cited by 5 publications

References 35 publications

Quercetin stimulates trophoblast fusion via the mitochondrial function

Quercetin stimulates trophoblast fusion via the mitochondrial function

Toll-like receptor signaling pathway triggered by inhibition of serpin A1 stimulates production of inflammatory cytokines by endometrial stromal cells

Human Chorionic Villous Differentiation and Placental Development

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