Hyperglycemia in Pregnancy-Associated Oxidative Stress Augments Altered Placental Glucose Transporter 1 Trafficking via AMPKα/p38MAPK Signaling Cascade

Wang, Shuxian; Ning, Jie; Huai, Jing; Yang, Huixia

doi:10.3390/ijms23158572

Cited by 4 publications

(9 citation statements)

References 64 publications

(76 reference statements)

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“…Mechanistically, hyperglycemia upregulates GLUT1 in the trophoblasts via the AMPKα-p38MAPK signaling cascade, thereby regulating placental transport function. 192 Several studies confirmed increased expression and activity of GLUT1 in the placental basement membrane but not the syncytial microvillous in women with GDM. [194][195][196] However, certain studies confirmed altered GLUT1 expression in patients with pregestational diabetes mellitus (PGDM) but not GDM.…”

Section: Gestational Diabetes Mellitusmentioning

confidence: 96%

“…Wang et al. confirmed that D‐glucose 6‐phosphate, Beta‐D‐Fructose 6‐phosphate, and D‐Fructose 1,6‐bisphosphate were significantly increased in the insulin‐controlled GDM group 192 . However, Zhang et al.…”

Section: Glycolysis In Pathological Pregnancymentioning

confidence: 97%

“…Several studies confirmed increased expression and activity of GLUT1 in the placental basement membrane but not the syncytial microvillous in women with GDM 194–196 . However, certain studies confirmed altered GLUT1 expression in patients with pregestational diabetes mellitus (PGDM) but not GDM 192,197–200 . Furthermore, GDM‐associated hyperglycemia inhibited AMPK activation, impaired GLUT3 distribution, suppressed cell viability in the placenta, and led to excessive fetal growth 201 .…”

Section: Glycolysis In Pathological Pregnancymentioning

confidence: 99%

“…[189][190][191] Increased glycolysis/gluconeogenesis and decreased fatty acid metabolism are generally accepted as characteristics of GDM. 192,193 Hyperglycemia during GDM leads to altered placental glucose uptake. Recently, Wang et al demonstrated GLUT1 upregulation in the hyperglycemia in pregnancy group.…”

Section: Gestational Diabetes Mellitusmentioning

confidence: 99%

“…demonstrated GLUT1 upregulation in the hyperglycemia in pregnancy group. Mechanistically, hyperglycemia upregulates GLUT1 in the trophoblasts via the AMPKα‐p38MAPK signaling cascade, thereby regulating placental transport function 192 . Several studies confirmed increased expression and activity of GLUT1 in the placental basement membrane but not the syncytial microvillous in women with GDM 194–196 .…”

Section: Glycolysis In Pathological Pregnancymentioning

confidence: 99%

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Glycolysis: A fork in the path of normal and pathological pregnancy

Gou,

Zhang

2023

The FASEB Journal

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Glucose metabolism is vital to the survival of living organisms. Since the discovery of the Warburg effect in the 1920s, glycolysis has become a major research area in the field of metabolism. Glycolysis has been extensively studied in the field of cancer and is considered as a promising therapeutic target. However, research on the role of glycolysis in pregnancy is limited. Recent evidence suggests that blastocysts, trophoblasts, decidua, and tumors all acquire metabolic energy at specific stages in a highly similar manner. Glycolysis, carefully controlled throughout pregnancy, maintains a dynamic and coordinated state, so as to maintain the homeostasis of the maternal–fetal interface and ensure normal gestation. In the present review, we investigate metabolic remodeling and the selective propensity of the embryo and placenta for glycolysis. We then address dysregulated glycolysis that occurs in the cellular interactive network at the maternal–fetal interface in miscarriage, preeclampsia, fetal growth restriction, and gestational diabetes mellitus. We provide new insights into the field of maternal–fetal medicine from a metabolic perspective, thus revealing the mystery of human pregnancy.

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Section: Gestational Diabetes Mellitusmentioning

confidence: 96%

Section: Glycolysis In Pathological Pregnancymentioning

confidence: 97%

Section: Glycolysis In Pathological Pregnancymentioning

confidence: 99%

Section: Gestational Diabetes Mellitusmentioning

confidence: 99%

Section: Glycolysis In Pathological Pregnancymentioning

confidence: 99%

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Glycolysis: A fork in the path of normal and pathological pregnancy

Gou,

Zhang

2023

The FASEB Journal

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Studying the O-GlcNAcome of human placentas using banked tissue samples

Luna,

Malard,

Pereckas

et al. 2024

Glycobiology

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O-GlcNAcylation is a dynamic modulator of signaling pathways, equal in magnitude to the widely studied phosphorylation. With the rapid development of tools for its detection at the single protein level, the O-GlcNAc modification rapidly emerged as a novel diagnostic and therapeutic target in human diseases. Yet, mapping the human O-GlcNAcome in various tissues is essential for generating relevant biomarkers. In this study, we used human banked tissue as a sample source to identify O-GlcNAcylated protein targets relevant to human diseases. Using human term placentas, we propose (1) a method to clean frozen banked tissue of blood proteins; (2) an optimized protocol for the enrichment of O-GlcNAcylated proteins using immunoaffinity purification; and (3) a bioinformatic workflow to identify the most promising O-GlcNAc targets. As a proof-of-concept, we used 45 mg of banked placental samples from two pregnancies to generate intracellular protein extracts depleted of blood protein. Then, antibody-based O-GlcNAc enrichment on denatured samples yielded over 2000 unique HexNAc PSMs and 900 unique sites using 300 μg of protein lysate. Due to efficient sample cleanup, we also captured 82 HexNAc proteins with high placental expression. Finally, we provide a bioinformatic tool (CytOVS) to sort the HexNAc proteins based on their cellular localization and extract the most promising O-GlcNAc targets to explore further. To conclude, we provide a simple 3-step workflow to generate a manageable list of O-GlcNAc proteins from human tissue and improve our understanding of O-GlcNAcylation’s role in health and diseases.

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METTL3 regulates glucose transporter expression in placenta exposed to hyperglycemia through the mTOR signaling pathway

Ning,

Huai,

Wang

et al. 2023

Chinese Medical Journal

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Background: Alterations in the placental expression of glucose transporters (GLUTs), the crucial maternal–fetal nutrient transporters, have been found in women with hyperglycemia in pregnancy (HIP). However, there is still uncertainty about the underlying effect of the high-glucose environment on placental GLUTs expression in HIP. Methods: We quantitatively evaluated the activity of mammalian target of rapamycin (mTOR) and expression of GLUTs (GLUT1, GLUT3, and GLUT4) in the placenta of women with normal pregnancies (CTRL, n = 12) and pregnant women complicated with poorly controlled type 2 diabetes mellitus (T2DM, n = 12) by immunohistochemistry. In addition, BeWo cells were treated with different glucose concentrations to verify the regulation of hyperglycemia. Then, changes in the expression of GLUTs following the activation or suppression of the mTOR pathway were also assessed using MHY1485/rapamycin (RAPA) treatment or small interfering RNA (siRNA)-mediated silencing approaches. Moreover, we further explored the alteration and potential upstream regulatory role of methyltransferase-like 3 (METTL3) when exposed to hyperglycemia. Results: mTOR, phosphorylated mTOR (p-mTOR), and GLUT1 protein levels were upregulated in the placenta of women with T2DM compared with those CTRL. In BeWo cells, mTOR activity increased with increasing glucose concentration, and the expression of GLUT1, GLUT3, and GLUT4 as well as GLUT1 cell membrane translocation were upregulated by hyperglycemia to varying degrees. Both the drug-mediated and genetic depletion of mTOR signaling in BeWo cells suppressed GLUTs expression, whereas MHY1485-induced mTOR activation upregulated GLUTs expression. Additionally, high glucose levels upregulated METTL3 expression and nuclear translocation, and decreasing METTL3 levels suppressed GLUTs expression and mTOR activity and vice versa. Furthermore, in METTL3 knockdown BeWo cells, the inhibitory effect on GLUTs expression was eliminated by activating the mTOR signaling pathway using MHY1485. Conclusion: High-glucose environment-induced upregulation of METTL3 in trophoblasts regulates the expression of GLUTs through mTOR signaling, contributing to disordered nutrient transport in women with HIP.

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Hyperglycemia in Pregnancy-Associated Oxidative Stress Augments Altered Placental Glucose Transporter 1 Trafficking via AMPKα/p38MAPK Signaling Cascade

Cited by 4 publications

References 64 publications

Glycolysis: A fork in the path of normal and pathological pregnancy

Glycolysis: A fork in the path of normal and pathological pregnancy

Studying the O-GlcNAcome of human placentas using banked tissue samples

METTL3 regulates glucose transporter expression in placenta exposed to hyperglycemia through the mTOR signaling pathway

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