Regulation of hypoxia-inducible factor-1α, regulated in development and DNA damage response-1 and mammalian target of rapamycin in human placental BeWo cells under hypoxia

Zhang, Fan; Guan, Li-li; Yu, Pin; Wang, X.D.; Hu, Yayi

doi:10.1016/j.placenta.2016.07.003

Cited by 9 publications

(5 citation statements)

References 37 publications

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“…The possible neuropharmacological mechanisms of action of the rapamycin and axitinib synergy should note. Thus, rapamycin reduces the production of HIF-1α [20,21] and abolishes insulin-induced HIF-1 activation in retinal pigment epithelial cells [22]. Hence, mTOR upstream is considered a way of HIF-1α activation and HIF-1-dependent gene expression [20].…”

Section: Discussionmentioning

confidence: 99%

“…Hence, mTOR upstream is considered a way of HIF-1α activation and HIF-1-dependent gene expression [20]. Besides, HIF-mediated transcription of angiogenic factors [21] causes vascularization-targeted mTOR signalling [23]. It should stress that tyrosine kinase inhibitors decrease VEGF expression by hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms [24,25].…”

Section: Discussionmentioning

confidence: 99%

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Immunohistochemical neuroinflammatory markers in the hippocampus of PTZ-kindled rats under conditions of rapamycin and axitinib treatment

Poshyvak

Pinyazhko

Godlevsky

et al. 2023

SR: PS

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The aim of the study is to determine the level of HIF-1α, TNF-α, and NF-kB in the hippocampus of kindled rats treated with rapamycin and axitinib. Materials and methods. Kindling was produced in 29 rats by administration of three-week pentylenetetrazole (PTZ, 35.0 mg/kg, i.p.). Treatment with rapamycin (0.5 mg/kg, i.p.) and axitinib (2.5 mg/kg, i.p.) was performed for ten days in fully kindled rats. The avidin-biotin-peroxidase method was used for hippocampal slice staining. For negative control, staining was performed using only secondary antibodies. Results. The HIF-1α expression increased in kindled rats raised by 1.77 times compared to the control (p<0.001). Axitinib treatment resulted in of HIF-1α level of 16.7 % (p<0.05) compared with kindled animals, while combined treatment with rapamycin and axitinib reduced HIF-1α by 33.8 % (p<0.01). In kindled rats, TNF-α expression was 3.74 times greater than in control (p<0.001). Rapamycin treatment reduced TNF-α by 31.0 % (p<0.01). Axitinib treatment caused a reduction of TNF-α by 21.1 % (p<0.05). Combined treatment with rapamycin and axitinib reduced TNF-α by 48.0 % (p<0.001) but still exceeded the TNF-α in control by 1.95 times (p<0.01). NF-kB level in kindled rats exceeded the control by three times (p<0.001). Rapamycin caused a reduction of 19.3 % (p>0.05), while axitinib – by 26.5 % (p<0.05) compared with kindled rats. Combined treatment with rapamycin and axitinib resulted in NF-kB reduction by 56.7 % compared with kindled rats (p<0.001). Conclusions. PTZ-kindling resulted in an increase in the immunoreactivity of HIF-1α, TNF-α, and NF-kB in the hippocampus. Combined treatment with rapamycin and axitinib engendered prevention of generalized seizures and normalized the level of HIF-1α and NF-kB with a significant reduction of TNF-α. Effects of treatment favours of synergy action of rapamycin and axitinib

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immunohistochemical neuroinflammatory markers in the hippocampus of PTZ-kindled rats under conditions of rapamycin and axitinib treatment

Poshyvak

Pinyazhko

Godlevsky

et al. 2023

SR: PS

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“…Active trophoblast cell growth, differentiation, and migration are important to placental development and may be restricted by hypoxia [ 50 , 51 ]. HIF-1 α and mTOR are key mediators of many metabolic processes that occur in response to cell hypoxia [ 52 ]. The present study HIF-1 α and mTOR are key mediators of many metabolic processes that occur in response to cell hypoxia [ 52 ], and consistent with the changes in miR-373-3p and SLC38A1, we uncovered higher mTOR activity and HIF-1 α levels in the placental tissues of smaller sIUGR fetuses.…”

Section: Discussionmentioning

confidence: 99%

“…HIF-1 α and mTOR are key mediators of many metabolic processes that occur in response to cell hypoxia [ 52 ]. The present study HIF-1 α and mTOR are key mediators of many metabolic processes that occur in response to cell hypoxia [ 52 ], and consistent with the changes in miR-373-3p and SLC38A1, we uncovered higher mTOR activity and HIF-1 α levels in the placental tissues of smaller sIUGR fetuses. Likewise, HIF-1 α downregulation enhanced the proliferation and migration of trophoblast cells and the expression of SLC38A1, while the altered miR-373-3p and SLC38A1 levels influenced both their own functions and the activities of mTOR and HIF-1 α in trophoblast cells, suggesting an interplay between the miR-373-3p/SLC38A1 axis and mTOR/HIF1 α signaling.…”

Section: Discussionmentioning

confidence: 99%

miR-373-3p Regulates the Proliferative and Migratory Properties of Human HTR8 Cells via SLC38A1 Modulation

et al. 2022

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The genetic pathogenesis of selective intrauterine growth restriction (sIUGR) remains elusive, with evidence suggesting an important role of epigenetic factors such as microRNAs. In this study, we explored the relevance of miR-373-3p to the occurrence of sIUGR. Hypoxia enhanced the levels of miR-373-3p and hypoxia-inducible factor (HIF)-1α, while HIF-1α knockdown not only boosted the migration and proliferation of HTR8 cells but also suppressed the hypoxia-induced upregulation of miR-373-3p and SLC38A1. By contrast, HIF-1α overexpression induced miR-373-3p downregulation and SLC38A1 upregulation, reducing cell growth and migration, which could be reversed by a miR-373-3p inhibitor. Importantly, the miR-373-3p inhibitor and mimic reproduced phenomena similar to those induced by HIF-1α downregulation and overexpression, respectively (including altered SLC38A1 expression, mTOR activation, cell growth, and migration). Mechanistically, the miRNA regulated cell behaviors and related mTOR signaling by targeting SLC38A1 expression through an interaction with the 3 ′ -untranslated region of SLC38A1. The placental tissues of smaller sIUGR fetuses exhibited miR-373-3p and HIF-1α upregulation, SLC38A1 downregulation, and activated mTOR. Overall, miR-373-3p appears to restrict the growth and migration of HTR8 trophoblast cells by targeting SLC38A1, as observed in the placental tissues associated with smaller sIUGR fetuses, and it could have utility in the diagnosis and treatment of this disorder.

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“…During the first trimester of human pregnancy, extravillous cytotrophoblast cells invade basal decidua, which temporarily occlude the uterine spiral arteries and lead to placental hypoperfusion, thereby decrease nutrient and gas exchange between the mother and fetus or even placental hypoxia (Baumann et al, 2007; Zhou et al, 2016; Zhu et al, 2017). It is widely believed that placental hypoxia has been implicated in pregnancy‐specific disorders, including pre‐eclampsia (PE) and intrauterine growth restriction (IUGR; Caniggia & Winter, 2002; Gagnon, 2003; Granger et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia‐induced SPOP attenuates the mobility of trophoblast cells through inhibition of the PI3K/AKT/GSK3β pathway

Dong

Yang

Chen

et al. 2021

Cell Biology International

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Placental hypoxia has been implicated in pregnancy pathologies such as pre‐eclampsia and intrauterine growth restriction. However, the underlying mechanism by which the trophoblasts respond to hypoxia remains unclear. Speckle‑type POZ protein (SPOP), an E3 ubiquitin ligase adapter, was previously reported to play important roles in various physiological and pathological processes. This study aims to investigate the expression and biological functions of SPOP after exposure to cobalt chloride (CoCl2)‐mimicked hypoxia conditions using human trophoblast‐derived choriocarcinoma cell lines and extravillous cytotrophoblast. These data showed that SPOP protein was directly induced by CoCl2‐mimicked hypoxia and regulated by HIF‐1α at the posttranscription level. CoCl2 treatment could dramatically influence the localization of SPOP in trophoblasts, especially the accumulation of SPOP into the nucleus. In addition, both CoCl2‐mimicked hypoxia and induction of endogenous SPOP expression by lentivirus transfection attenuated the migration and invasion abilities of trophoblasts. Furthermore, we demonstrated that SPOP was involved in CoCl2‐induced the inhibition of the PI3K/AKT/GSK3β pathway in placental trophoblasts. Taken together, these data indicate that accumulation of HIF‐1α augments the expression of SPOP in trophoblasts, which impairs trophoblastic mobility by targeting the PI3K/AKT/GSK3β pathway. This potentially leads to insufficient uterine spiral artery remodeling and suboptimal placental perfusion, and thus the development of pregnancy‐related complication.

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Regulation of hypoxia-inducible factor-1α, regulated in development and DNA damage response-1 and mammalian target of rapamycin in human placental BeWo cells under hypoxia

Cited by 9 publications

References 37 publications

Immunohistochemical neuroinflammatory markers in the hippocampus of PTZ-kindled rats under conditions of rapamycin and axitinib treatment

Immunohistochemical neuroinflammatory markers in the hippocampus of PTZ-kindled rats under conditions of rapamycin and axitinib treatment

miR-373-3p Regulates the Proliferative and Migratory Properties of Human HTR8 Cells via SLC38A1 Modulation

Hypoxia‐induced SPOP attenuates the mobility of trophoblast cells through inhibition of the PI3K/AKT/GSK3β pathway

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