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Tytuł:
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Excess glucose induce trophoblast inflammation and limit cell migration through HMGB1 activation of Toll-Like receptor 4.
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Autorzy:
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Heim KR; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, New Haven, Connecticut.
Mulla MJ; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, New Haven, Connecticut.
Potter JA; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, New Haven, Connecticut.
Han CS; Department of Obstetrics & Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California.
Guller S; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, New Haven, Connecticut.
Abrahams VM; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, New Haven, Connecticut.
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Źródło:
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American journal of reproductive immunology (New York, N.Y. : 1989) [Am J Reprod Immunol] 2018 Nov; Vol. 80 (5), pp. e13044. Date of Electronic Publication: 2018 Sep 02.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Copenhagen : Wiley-Blackwell
Original Publication: New York : Alan R. Liss, Inc., c1989-
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MeSH Terms:
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Alarmins/*metabolism
HMGB1 Protein/*metabolism
Hyperglycemia/*immunology
Inflammation/*immunology
Pre-Eclampsia/*immunology
Toll-Like Receptor 4/*metabolism
Trophoblasts/*immunology
Cell Line ; Cell Movement ; Female ; Glycyrrhizic Acid/pharmacology ; HMGB1 Protein/antagonists & inhibitors ; Humans ; Interleukin-1beta/metabolism ; Interleukin-8/metabolism ; Pregnancy ; Risk ; Signal Transduction ; Trophoblasts/pathology ; Vascular Endothelial Growth Factor Receptor-1/metabolism
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Grant Information:
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Albert McKern Scholar Award for Perinatal Research International Yale School of Medicine; Paul Titus Fellowship International Yale School of Medicine
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Contributed Indexing:
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Keywords: diabetes; immunology; placenta; preeclampsia; pregnancy; trophoblast
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Substance Nomenclature:
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0 (Alarmins)
0 (HMGB1 Protein)
0 (Interleukin-1beta)
0 (Interleukin-8)
0 (TLR4 protein, human)
0 (Toll-Like Receptor 4)
6FO62043WK (Glycyrrhizic Acid)
EC 2.7.10.1 (FLT1 protein, human)
EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1)
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Entry Date(s):
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Date Created: 20180904 Date Completed: 20191028 Latest Revision: 20191028
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Update Code:
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20240104
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DOI:
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10.1111/aji.13044
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PMID:
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30175447
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Problem: Hyperglycemia increases the risk of preeclampsia. Hyperglycemia induces a placental trophoblast inflammatory (IL-1β, IL-6, IL-8), antiangiogenic (sFlt-1, sEndoglin), and anti-migratory profile. The IL-1β response is mediated via inflammasome activation by the damage-associated molecular pattern (DAMP), uric acid. The objective of this study was to determine the role of high-mobility group box-1 (HMGB1), a DAMP that activates Toll-like receptor 4 (TLR4), in human first trimester trophoblast responses to hyperglycemia. The trophoblast response to excess glucose under different oxygen tensions was also investigated.
Method of Study: The human first trimester trophoblast cell line (Sw.71) was exposed to glucose mimicking normoglycemia (5 mmol/L) and hyperglycemia (10 mmol/L), either alone or with the TLR4 antagonist, LPS-RS; or the HMGB1 inhibitor, glycyrrhizin. Cells were also treated with glucose under hyperoxic (21% O 2 ), normoxic (8% O 2 ), and hypoxic (2% O 2 ) conditions. Cell-free supernatants were assayed by ELISA and bioassays for inflammatory: IL-1β, IL-6, and IL-8; inflammasome-associated: uric acid and caspase-1; angiogenic: sEndoglin, sFlt-1, and PlGF; and the DAMP, HMGB1. Cell migration was measured using a two-chamber colormetric assay.
Results: Excess glucose triggered a trophoblast sterile inflammatory IL-8 and antimigratory response through HMGB1 activation of TLR4. The IL-1β and sFlt-1/PlGF response was TLR4-mediated, but HMGB1-independent, suggesting another DAMP may be involved. Hyperoxia rather than normoxia or hypoxia was a major driver of trophoblast dysfunction in response to excess glucose.
Conclusion: The findings from this study indicate a novel mechanism by which hyperglycemia may impact trophoblast function, early placentation, and ultimately, pregnancy outcome.
(© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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