Next Article in Journal
A New UPLC-MS/MS Method for the Characterization and Discrimination of Polysaccharides from Genus Ephedra Based on Enzymatic Digestions
Previous Article in Journal
Polyphenolics from Albizia harveyi Exhibit Antioxidant Activities and Counteract Oxidative Damage and Ultra-Structural Changes of Cryopreserved Bull Semen
Article Menu
Issue 11 (November) cover image

Export Article

Open AccessArticle
Molecules 2017, 22(11), 1997;

The HMGB1/RAGE Pro-Inflammatory Axis in the Human Placenta: Modulating Effect of Low Molecular Weight Heparin

Department of Surgical Sciences, University of Turin, 10126 Turin, Italy
Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 9 October 2017 / Revised: 10 November 2017 / Accepted: 14 November 2017 / Published: 17 November 2017
(This article belongs to the Section Medicinal Chemistry)
Full-Text   |   PDF [5495 KB, uploaded 17 November 2017]   |  


We evaluated whether physiological and pre-eclamptic (PE) placentae, characterized by exacerbated inflammation, presented alterations in pro-inflammatory High Mobility Group Box 1 (HMGB1) and its Receptor of Advanced Glycation End products (RAGE) expression. Moreover, we investigated, in physiological placental tissue, the ability of Low Molecular Weight Heparin (LMWH) to modify HMGB1 structural conformation thus inhibiting RAGE binding and HMGB1/RAGE axis inflammatory activity. HMGB1, RAGE, IL-6 and TNFα (HMGB1/RAGE targets) mRNA expression were assessed by Real Time PCR. HMGB1, RAGE protein levels were assessed by western blot assay. Physiological term placental explants were treated by 0.5 U LMWH for 24 or 48 h. HMGB1 and RAGE expression and association were evaluated in LMWH explants by RAGE immunoprecipitation followed by HMGB1 immunoblot. HMGB1 spatial localization was evaluated by immuofluorescent staining (IF). HMGB1 expression was increased in PE relative to physiological placentae while RAGE was unvaried. 24 h LMWH treatment significantly up-regulated HMGB1 expression but inhibited HMGB1/RAGE complex formation in physiological explants. RAGE expression decreased in treated relative to untreated explants at 48 h. IF showed HMGB1 localization in both cytoplasm and nucleus of mesenchymal and endothelial cells but not in the trophoblast. IL-6 and TNFα gene expression were significantly increased at 24 h relative to controls, while they were significantly down-regulated in 48 h vs. 24 h LMWH explants. Our data depicted a new molecular mechanism through which LMWH exerts its anti-inflammatory effect on PE placentae, underlying the importance of HMGB1/RAGE axis in PE inflammatory response. View Full-Text
Keywords: heparin; HMGB1; placenta; pre-eclampsia; receptor for advanced glycation end products (RAGE) heparin; HMGB1; placenta; pre-eclampsia; receptor for advanced glycation end products (RAGE)

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material


Share & Cite This Article

MDPI and ACS Style

Zenerino, C.; Nuzzo, A.M.; Giuffrida, D.; Biolcati, M.; Zicari, A.; Todros, T.; Rolfo, A. The HMGB1/RAGE Pro-Inflammatory Axis in the Human Placenta: Modulating Effect of Low Molecular Weight Heparin. Molecules 2017, 22, 1997.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top