EPH and Ephrins in Pathogenesis and as Drug Target

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (23 December 2023) | Viewed by 4982

Special Issue Editors

Department of Food and Drug, University of Parma, 43124 Parma, Italy
Interests: drug discovery; Eph; ephrin; protein–protein interaction inhibitors (PPI-is); polyphenols; cancer; platelets
Special Issues, Collections and Topics in MDPI journals
Centre Hospitalier de L'Universite de Montreal, University of Montreal, Montreal, QC, Canada
Interests: Eph; ephrin; hypertension; heart rhythm; diabetes; ubiquitin ligase; RNA polymerase II; neural tube defects
Department of Food and Drug, University of Parma, 43124 Parma, Italy
Interests: pharmacology; drug discovery; Eph–ephrin system; cancer; intestinal inflammation

Special Issue Information

Dear Colleagues,

Thirty-five years after the discovery of the first EPH gene by Takaku’s group, Eph receptors and the ephrin ligands are known to constitute a complex and redundant cellular communication network that is mainly involved in adhesion/repulsion responses; these are key processes during embryogenesis, angiogenesis, in the organized cell renewal of the epithelial tissues and in the regeneration/remodeling after injuries. Therefore, it is not surprising that members of this system were shown to be involved in many pathophysiological conditions such as inflammation and atherosclerosis, neurological disorders and cancer, making Eph receptors and ephrin ligands new attractive targets for pharmacologists and pharmaceutical chemists.

At present a plethora of biological techniques and pharmacological tools are available to investigate the roles and the potential benefits of Eph/ephrin targeting in several diseases. Small molecules, peptides and antibodies have shown promising and convincing results in vitro and in preclinical animal models, and some of them have reached clinical trials. Unfortunately, despite these research efforts, drugs targeting this system have not yet reached the market, and the gap between bench and bed still exists.

Taking advantage of the third congress on the Eph/ephrin system (www.ephrins.org), which we recently organized in Montreal after four years of absence due to the pandemic, the present Special Issue of Pharmaceuticals aims to be not only a synthesis of this meeting, but also an opportunity for all scientists in this field. This Special Issue aims to collect the most updated works and to be a valid source of inspiration for future research in the field of Eph/ephrin targeting.

We sincerely hope that you will be able to submit your original contributions to this Special Issue, which aims to be a valuable collection of state-of-the-art works on the Eph/ephrin targeting puzzle.

Dr. Massimiliano Tognolini
Prof. Dr. Jiangping Wu
Dr. Carmine Giorgio
Guest Editors

Manuscript Submission Information

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Keywords

  • Eph–ephrin
  • drug discovery
  • pharmacokinetic
  • kinases
  • signaling
  • PPI inhibitors
  • peptides
  • antibodies
  • small molecules
  • targeting

Published Papers (3 papers)

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Research

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14 pages, 1945 KiB  
Article
The Therapeutic Effects of EFNB2-Fc in a Cell Model of Kawasaki Disease
Pharmaceuticals 2023, 16(4), 500; https://doi.org/10.3390/ph16040500 - 28 Mar 2023
Cited by 1 | Viewed by 1042
Abstract
The EphrinB2/EphB4 signaling pathway involves the regulation of vascular morphogenesis and angiogenesis. However, little is known about EphrinB2/EphB4 in the pathogenesis of Kawasaki disease (KD) and coronary artery aneurysm formation. Hence, this study aimed to explore the role of EphrinB2/EphB4 and the potential [...] Read more.
The EphrinB2/EphB4 signaling pathway involves the regulation of vascular morphogenesis and angiogenesis. However, little is known about EphrinB2/EphB4 in the pathogenesis of Kawasaki disease (KD) and coronary artery aneurysm formation. Hence, this study aimed to explore the role of EphrinB2/EphB4 and the potential therapeutic effect of EphrinB2-Fc in the coronary arterial endothelial injury of KD. The levels of EphB4 were compared between KD patients and healthy children. Human coronary artery endothelial cells (HCAECs) were stimulated with sera from acute KD patients to establish the KD cell model. The overexpression of EphB4 or treatment with EphrinB2-Fc was found to intervene in the cell model. The cell migration, angiogenesis, and proliferation ability were assessed, and the expression of inflammation-related factors was measured. Our study showed that EphB4 showed low expression in both KD patients and the cell model of KD. The EphB4 protein levels in the CECs of CAA+ KD patients were much lower than those in healthy children. EphrinB2-Fc treatment of KD sera-activated HCAECs suppressed cell proliferation, reduced the expression of inflammation-related factors (such as IL-6 and P-selectin), and elevated cell angiogenesis ability. The results reveal that EphrinB2-Fc has a protective function in endothelial cells and has promising clinical applications for protecting vascular endothelium in patients with KD. Full article
(This article belongs to the Special Issue EPH and Ephrins in Pathogenesis and as Drug Target)
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Review

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12 pages, 1681 KiB  
Review
EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in Humans
Pharmaceuticals 2023, 16(2), 165; https://doi.org/10.3390/ph16020165 - 23 Jan 2023
Cited by 3 | Viewed by 2036
Abstract
Ephrin receptors constitute a large family of receptor tyrosine kinases in mammals that through interaction with cell surface-anchored ephrin ligands regulate multiple different cellular responses in numerous cell types and tissues. In the cardiovascular system, studies performed in vitro and in vivo have [...] Read more.
Ephrin receptors constitute a large family of receptor tyrosine kinases in mammals that through interaction with cell surface-anchored ephrin ligands regulate multiple different cellular responses in numerous cell types and tissues. In the cardiovascular system, studies performed in vitro and in vivo have pointed to a critical role for Ephrin receptor B4 (EPHB4) as a regulator of blood and lymphatic vascular development and function. However, in this role, EPHB4 appears to act not as a classical growth factor receptor but instead functions to dampen the activation of the Ras-mitogen activated protein signaling (MAPK) pathway induced by other growth factor receptors in endothelial cells (EC). To inhibit the Ras-MAPK pathway, EPHB4 interacts functionally with Ras p21 protein activator 1 (RASA1) also known as p120 Ras GTPase-activating protein. Here, we review the evidence for an inhibitory role for an EPHB4–RASA1 interface in EC. We further discuss the mechanisms by which loss of EPHB4–RASA1 signaling in EC leads to blood and lymphatic vascular abnormalities in mice and the implications of these findings for an understanding of the pathogenesis of vascular anomalies in humans caused by mutations in EPHB4 and RASA1 genes. Last, we provide insights into possible means of drug therapy for EPHB4- and RASA1-related vascular anomalies. Full article
(This article belongs to the Special Issue EPH and Ephrins in Pathogenesis and as Drug Target)
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Other

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9 pages, 1957 KiB  
Case Report
Cooccurring Type 1 Diabetes Mellitus and Autoimmune Thyroiditis in a Girl with Craniofrontonasal Syndrome: Are EFNB1 Variants Associated with Autoimmunity?
Pharmaceuticals 2022, 15(12), 1535; https://doi.org/10.3390/ph15121535 - 10 Dec 2022
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Abstract
Craniofrontonasal syndrome (CFNS), also known as craniofrontonasal dysplasia, is an X-linked inherited developmental malformation caused by mutations in the ephrin B1 (EFNB1) gene. The main phenotypic features of the syndrome are coronal synostosis, hypertelorism, bifid nasal tip, dry and curly hair, [...] Read more.
Craniofrontonasal syndrome (CFNS), also known as craniofrontonasal dysplasia, is an X-linked inherited developmental malformation caused by mutations in the ephrin B1 (EFNB1) gene. The main phenotypic features of the syndrome are coronal synostosis, hypertelorism, bifid nasal tip, dry and curly hair, and longitudinal splitting of nails. A 9-year-and-11-month-old girl with CFNS was admitted due to polyuria, polydipsia, fatigue, and abdominal pain. On physical examination, she had the classical phenotypical features of CFNS. Genetic tests revealed a c.429_430insT (p.Gly144TrpfsTer31) heterozygote variant in the EFNB1 coding region. The patient was diagnosed with type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis based on laboratory findings and symptoms. The mother of the patient, who had the same CFNS phenotype and EFNB1 variant, was screened for autoimmune diseases and was also with autoimmune thyroiditis. This is the first report describing the association of CFNS with T1DM and autoimmune thyroiditis in patients with EFNB1 mutation. Full article
(This article belongs to the Special Issue EPH and Ephrins in Pathogenesis and as Drug Target)
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