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1.
Clin Genet ; 105(4): 386-396, 2024 04.
Article in English | MEDLINE | ID: mdl-38151336

ABSTRACT

Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation-Arteriovenous Malformation syndrome 2 and lymphatic-related (non-immune) fetal hydrops (LRHF). Here, we identify two novel variants in EPHB4 that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine-kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development.


Subject(s)
Hydrops Fetalis , Sterile Alpha Motif , Female , Humans , Hydrops Fetalis/diagnostic imaging , Hydrops Fetalis/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Signal Transduction/genetics , Receptor, EphB4/genetics , Receptor, EphB4/metabolism
2.
Mol Biol Rep ; 51(1): 297, 2024 Feb 11.
Article in English | MEDLINE | ID: mdl-38341842

ABSTRACT

BACKGROUND: Erythropoietin-producing hepatocellular (EPH) receptors are the largest known family of receptor tyrosine kinases characterized in humans. These proteins are involved in tissue organization, synaptic plasticity, vascular development and the progression of various diseases including cancer. The Erythropoietin-producing hepatocellular receptor tyrosine kinase member EphB6 is a pseudokinase which has not attracted an equivalent amount of interest as its enzymatically-active counterparts. The aim of this study was to assess the expression of EphB6 in pituitary tumors. METHODS AND RESULTS: Human normal pituitaries and pituitary tumors were examined for EphB6 mRNA expression using real-time PCR and for EphB6 protein by immunohistochemistry and Western blotting. EphB6 was highly expressed in non-functioning pituitary neuroendocrine tumors (NF-PitNETs) versus the normal pituitary and GH-secreting PitNETs. EphB6 mRNA expression was correlated with tumor size. CONCLUSIONS: Our results suggest EphB6 aberrant expression in NF-PitNETs. Future studies are warranted to determine the role and significance of EphB6 in NF-PitNETs tumorigenesis.


Subject(s)
Carcinoma, Hepatocellular , Erythropoietin , Liver Neoplasms , Neuroendocrine Tumors , Pituitary Neoplasms , Humans , Pituitary Neoplasms/genetics , Receptors, Erythropoietin , Neuroendocrine Tumors/genetics , Cell Line, Tumor , Liver Neoplasms/genetics , RNA, Messenger/genetics
3.
Int J Mol Sci ; 25(7)2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38612645

ABSTRACT

Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell-cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell-cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway's intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges.


Subject(s)
Clinical Relevance , Hematologic Neoplasms , Humans , Child , Signal Transduction , Cell Communication , Carcinogenesis , Ephrins , Receptors, Erythropoietin , Tumor Microenvironment
4.
Exp Eye Res ; 226: 109346, 2023 01.
Article in English | MEDLINE | ID: mdl-36529279

ABSTRACT

The posttranscriptional modifications (PTM) of the Histone H3 family play an important role in ocular system differentiation. However, there has been no study on the nature of specific Histone H3 subtype carrying these modifications. Fortuitously, we had previously identified a dominant small-eye mutant Aey69 mouse with a mutation in the H3.2 encoding Hist2h3c1 gene (Vetrivel et al., 2019). In continuation, in the present study, the role of Histone H3.2 with relation to the microphtalmic Aey69 has been elaborated. Foremost, a transgenic mouse line expressing the fusion protein H3.2-GFP was generated using Crispr/Cas9. The approach was intended to confer a unique tag to the Hist2h3c1 gene which is similar in sequence and encoded protein structure to other histones. The GFP tag was then used for ChIP Seq analysis of the genes regulated by H3.2. The approach revealed ocular specific H3.2 targets including Ephrin family genes. Altered enrichment of H3.2 was found in the mutant Aey69 mouse, specifically around the ligand Efna5 and the receptor Ephb2. The effect of this altered enrichment on Ephrin signaling was further analysed by QPCR and immunohistochemistry. This study identifies Hist2h3c1 encoded H3.2 as an important epigenetic player in ocular development. By binding to specific regions of ocular developmental factors Histone H3.2 facilitates the function of these genes for successful early ocular development.


Subject(s)
Histones , Animals , Mice , Histones/genetics , Immunohistochemistry , Mice, Transgenic , Mutation
5.
Semin Cell Dev Biol ; 107: 130-146, 2020 11.
Article in English | MEDLINE | ID: mdl-32600961

ABSTRACT

This chapter discusses our current knowledge on the major segregation events that lead to the individualization of the building blocks of vertebrate organisms, starting with the segregation between "outer" and "inner" cells, the separation of the germ layers and the maintenance of their boundaries during gastrulation, and finally the emergence of the primary axial structure, the notochord. The amphibian embryo is used as the prototypical model, to which fish and mouse development are compared. This comparison highlights a striking conservation of the basic processes. It suggests that simple principles may account for the formation of divergent structures. One of them is based on the non-adhesive nature of the apical domain of epithelial cells, exploited to segregate superficial and deep cell populations as a result of asymmetric division. The other principle involves differential expression of contact cues, such as ephrins and protocadherins, to build up high tension along adhesive interfaces, which efficiently creates sharp boundaries.


Subject(s)
Chromosome Segregation , Embryo, Mammalian/metabolism , Embryo, Nonmammalian/metabolism , Morphogenesis , Vertebrates/embryology , Animals , Biophysical Phenomena
6.
Eur J Neurosci ; 56(9): 5532-5546, 2022 11.
Article in English | MEDLINE | ID: mdl-34989046

ABSTRACT

Erythropoietin-producing hepatoma (Eph) receptors belong to a family of tyrosine kinase receptors that plays a pivotal role in the development of the brain. Eph can be divided broadly into two groups, namely, EphA and EphB, comprising nine and five members, respectively. In recent years, the role of EphA-4 has become increasingly apparent in the onset of Alzheimer's disease (AD). Emerging evidence suggests that EphA-4 results in synaptic dysfunction, which in turn promotes the progression of AD. Moreover, pharmacological or genetic ablation of EphA-4 in the murine model of AD can alleviate the symptoms. The current review summarizes different pathways by which EphA-4 can influence pathogenesis. Since, majority of the studies had reported the protective effect of EphA-4 inhibition during AD, designing therapeutics based on decreasing its enzymatic activity might be necessary for introducing the novel interventions. Therefore, the review described peptide and nanobodies inhibitors of EphA-4 that exhibit the potential to modulate EphA-4 and could be used as lead molecules for the targeted therapy of AD.


Subject(s)
Alzheimer Disease , Animals , Humans , Mice , Alzheimer Disease/drug therapy , Brain/metabolism , Receptors, Eph Family/chemistry , Receptors, Eph Family/metabolism
7.
Proc Natl Acad Sci U S A ; 116(41): 20707-20715, 2019 10 08.
Article in English | MEDLINE | ID: mdl-31548390

ABSTRACT

Cedar virus (CedV) is a bat-borne henipavirus related to Nipah virus (NiV) and Hendra virus (HeV), zoonotic agents of fatal human disease. CedV receptor-binding protein (G) shares only ∼30% sequence identity with those of NiV and HeV, although they can all use ephrin-B2 as an entry receptor. We demonstrate that CedV also enters cells through additional B- and A-class ephrins (ephrin-B1, ephrin-A2, and ephrin-A5) and report the crystal structure of the CedV G ectodomain alone and in complex with ephrin-B1 or ephrin-B2. The CedV G receptor-binding site is structurally distinct from other henipaviruses, underlying its capability to accommodate additional ephrin receptors. We also show that CedV can enter cells through mouse ephrin-A1 but not human ephrin-A1, which differ by 1 residue in the key contact region. This is evidence of species specific ephrin receptor usage by a henipavirus, and implicates additional ephrin receptors in potential zoonotic transmission.


Subject(s)
Ephrin-B1/metabolism , Ephrin-B2/metabolism , Ephrin-B3/metabolism , Henipavirus Infections/virology , Henipavirus/physiology , Receptors, Virus/metabolism , Viral Envelope Proteins/chemistry , Animals , Cell Fusion , Ephrin-B1/genetics , Ephrin-B2/genetics , Ephrin-B3/genetics , Henipavirus Infections/genetics , Henipavirus Infections/metabolism , Humans , Mice , Mutation , Protein Binding , Protein Conformation , Receptors, Virus/genetics , Species Specificity , Viral Envelope Proteins/genetics , Viral Envelope Proteins/metabolism , Virus Internalization
8.
Int J Mol Sci ; 23(7)2022 Mar 24.
Article in English | MEDLINE | ID: mdl-35408909

ABSTRACT

Exosomes are cell-secreted nanoparticles containing various molecules including small vesicles, microRNAs (miRNAs), messenger RNAs or bioactive proteins which are thought to be of paramount importance for intercellular communication. The unique effects of exosomes in terms of cell penetration capacity, decreased immunogenicity and inherent stability, along with their key role in mediating information exchange among tumor cells and their surrounding tumor microenvironment (TME), render them a promising platform for drug targeted delivery. Compared to synthetic drugs, exosomes boast a plethora of advantages, including higher biocompatibility, lower toxicity and increased ability of tissue infiltration. Nevertheless, the use of artificial exosomes can be limited in practice, partly due to their poor targeting ability and partly due to their limited efficacy. Therefore, efforts have been made to engineer stem cell-derived exosomes in order to increase selectiveness and effectivity, which can then become loaded with various active substances depending on the therapeutic approach followed. Erythropoietin-producing human hepatocellular receptors (EPHs), along with their ligands, the EPH family receptor interacting proteins (ephrins), have been extensively investigated for their key roles in both physiology and cancer pathogenesis. EPHs/ephrins exhibit both tumorigenic and tumor suppressing properties, with their targeting representing a promising, novel therapeutic approach in cancer patients' management. In our review, the use of ephrin-loaded exosomes as a potential therapeutic targeted delivery system in cancer will be discussed.


Subject(s)
Exosomes , Neoplasms , Biomarkers , Ephrins/metabolism , Exosomes/metabolism , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Receptors, Eph Family/metabolism , Receptors, Erythropoietin , Tumor Microenvironment
9.
Int J Mol Sci ; 23(6)2022 Mar 17.
Article in English | MEDLINE | ID: mdl-35328669

ABSTRACT

Gynecological cancers represent some of the most common types of malignancy worldwide. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest subfamily of receptor tyrosine kinases, binding membrane-bound proteins called ephrins. EPHs/ephrins exhibit widespread expression in different cell types, playing an important role in carcinogenesis. The aim of the current review was to examine the dysregulation of the EPH/ephrin system in gynecological cancer, clarifying its role in ovarian, endometrial, and cervical carcinogenesis. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms ephrin, ephrin receptor, ovarian cancer, endometrial cancer, and cervical cancer were employed and we were able to identify 57 studies focused on gynecological cancer and published between 2001 and 2021. All researched ephrins seemed to be upregulated in gynecological cancer, whereas EPHs showed either significant overexpression or extensive loss of expression in gynecological tumors, depending on the particular receptor. EPHA2, the most extensively studied EPH in ovarian cancer, exhibited overexpression both in ovarian carcinoma cell lines and patient tissue samples, while EPHB4 was found to be upregulated in endometrial cancer in a series of studies. EPHs/ephrins were shown to exert their role in different stages of gynecological cancer and to influence various clinicopathological parameters. The analysis of patients' gynecological cancer tissue samples, most importantly, revealed the significant role of the EPH/ephrin system in the development and progression of gynecological cancer, as well as overall patient survival. In conclusion, the EPH/ephrin system represents a large family of biomolecules with promising applications in the fields of diagnosis, prognosis, disease monitoring, and treatment of gynecological cancer, with an established important clinical impact.


Subject(s)
Ephrins , Neoplasms , Carcinogenesis , Ephrins/metabolism , Humans , Membrane Proteins/metabolism , Protein Binding , Receptors, Eph Family/metabolism
10.
Int J Mol Sci ; 23(5)2022 Mar 02.
Article in English | MEDLINE | ID: mdl-35269901

ABSTRACT

The EPH/ephrin system constitutes a bidirectional signaling pathway comprised of a family of tyrosine kinase receptors in tandem with their plasma membrane-bound ligand (ephrins). Its significance in a wide variety of physiologic and pathologic processes has been recognized during the past decades. In carcinogenesis, EPH/ephrins coordinate a wide spectrum of pathologic processes, such as angiogenesis, vessel infiltration, and metastasis. Despite the recent advances in colorectal cancer (CRC) diagnosis and treatment, it remains a leading cause of death globally, accounting for 9.2% of all cancer deaths. A growing body of literature has been published lately revitalizing our scientific interest towards the role of EPH/ephrins in pathogenesis and the treatment of CRC. The aim of the present review is to present the recent CRC data which might lead to clinical practice changes in the future.


Subject(s)
Colorectal Neoplasms , Ephrins , Ephrins/metabolism , Humans , Neovascularization, Pathologic , Receptors, Eph Family/metabolism , Signal Transduction/physiology
11.
Int J Mol Sci ; 23(17)2022 Sep 03.
Article in English | MEDLINE | ID: mdl-36077474

ABSTRACT

During orthodontic tooth movement, mechanically induced remodeling occurs in the alveolar bone due to the action of orthodontic forces. The number of factors identified to be involved in mechanically induced bone remodeling is growing steadily. With the uncovering of the functions of neuronal guidance molecules (NGMs) for skeletal development as well as for bone homeostasis, NGMs are now also among the potentially significant factors for the regulation of bone remodeling during orthodontic tooth movement. This narrative review attempts to summarize the functions of NGMs in bone homeostasis and provides insight into the currently sparse literature on the functions of these molecules during orthodontic tooth movement. Presently, four families of NGMs are known: Netrins, Slits, Semaphorins, ephrins and Eph receptors. A search of electronic databases revealed roles in bone homeostasis for representatives from all four NGM families. Functions during orthodontic tooth movement, however, were only identified for Semaphorins, ephrins and Eph receptors. For these, crucial prerequisites for participation in the regulation of orthodontically induced bone remodeling, such as expression in cells of the periodontal ligament and in the alveolar bone, as well as mechanical inducibility, were shown, which suggests that the importance of NGMs in orthodontic tooth movement may be underappreciated to date and further research might be warranted.


Subject(s)
Semaphorins , Tooth Movement Techniques , Axon Guidance , Bone Remodeling/physiology , Ephrins/metabolism , Periodontal Ligament/metabolism , Receptors, Eph Family/metabolism , Semaphorins/metabolism
12.
J Cell Physiol ; 236(3): 2070-2086, 2021 03.
Article in English | MEDLINE | ID: mdl-32740946

ABSTRACT

Intermittent parathyroid hormone (PTH) promotes periodontal repair, but the underlying mechanisms remained unclear. Recent studies found that ephrinB2-EPHB4 forward signaling mediated the anabolic effect of PTH in bone homeostasis. Considering the similarities between cementum and bone, we aimed to examine the therapeutic effect of PTH on resorbed roots and explore the role of forward signaling in this process. In vivo experiments showed that intermittent PTH significantly accelerated the regeneration of root resorption and promoted expression of EPHB4 and ephrinB2. When the signaling was blocked, the resorption repair was also delayed. In vitro studies showed that intermittent PTH promoted the expression of EPHB4 and ephrinB2 in OCCM-30 cells. The effects of PTH on the mineralization capacity of OCCM-30 cells was mediated through the ephrinB2-EPHB4 forward signaling. These results support the premise that the anabolic effects of intermittent PTH on the regeneration of root resorption is via the ephrinB2-EPHB4 forward signaling pathway.


Subject(s)
Cementogenesis/drug effects , Ephrin-B2/metabolism , Parathyroid Hormone/pharmacology , Receptor, EphB4/metabolism , Signal Transduction , Animals , Cell Line , Dental Cementum/drug effects , Dental Cementum/metabolism , Male , Mice , Models, Biological , Parathyroid Hormone/administration & dosage , Rats, Wistar , Regeneration/drug effects , Signal Transduction/drug effects , Tomography, X-Ray Computed , Tooth Root/diagnostic imaging , Tooth Root/drug effects
13.
Int J Mol Sci ; 22(16)2021 Aug 05.
Article in English | MEDLINE | ID: mdl-34445116

ABSTRACT

Erythropoietin-producing human hepatocellular receptors (EPHs) compose the largest known subfamily of receptor tyrosine kinases (RTKs). They bind and interact with the EPH family receptor interacting proteins (ephrins). EPHs/ephrins are implicated in a variety of physiological processes, as well as in cancer pathogenesis. With neoplastic disease remaining a leading cause of death world-wide, the development of novel biomarkers aiding in the field of diagnosis, prognosis, and disease monitoring is of utmost importance. A multitude of studies have proven the association between the expression of members of the EPH/ephrin system and various clinicopathological parameters, including disease stage, tumor histologic grade, and patients' overall survival. Besides their utilization in timely disease detection and assessment of outcome, EPHs/ephrins could also represent possible novel therapeutic targets. The aim of the current review of the literature was to present the existing data regarding the association between EPH/ephrin system expression and the clinical characteristics of malignant tumors.


Subject(s)
Ephrins/metabolism , Neoplasms/metabolism , Receptor, EphA1/metabolism , Biomarkers, Tumor/metabolism , Humans , Signal Transduction/physiology
14.
Int J Mol Sci ; 22(4)2021 Feb 22.
Article in English | MEDLINE | ID: mdl-33671716

ABSTRACT

The effect of the inflammatory response on regenerative processes in the brain is complex. This complexity is even greater when the cause of the tissue damage is an autoimmune response. Multiple sclerosis (MS) is an immune-mediated disease in which demyelination foci are formed in the central nervous system. The degree of repair through oligodendrocyte regeneration and remyelination is insufficient. Ephrins are membrane-bound ligands activating tyrosine kinase signaling proteins that are known to have an inhibitory effect on oligodendrocyte regeneration. In this study, we examined the expression of ephrins on immune cells of 43 patients with relapsing-remitting (RR) MS compared to 27 matched healthy controls (HC). We found an increased expression of ephrin-A2, -A3 and -B3, especially on T cell subpopulations. We also showed overexpression of ephrins on immune cells of patients with RR-MS that increases the forward signaling pathway and that expression of ephrins on immune cells has an inhibitory effect on the differentiation of oligodendrocyte precursor cells (OPCs) in vitro. Our study findings support the concept that the immune activity of T cells in patients with RR-MS has an inhibitory effect on the differentiation capacity of OPCs through the expression and forward signaling of ephrins.


Subject(s)
Ephrins/metabolism , Multiple Sclerosis/immunology , Oligodendroglia/pathology , T-Lymphocyte Subsets/metabolism , Adult , Animals , Case-Control Studies , Cell Differentiation , Cells, Cultured , Female , Humans , Male , Middle Aged , Multiple Sclerosis/pathology , Oligodendrocyte Precursor Cells/metabolism , Oligodendroglia/metabolism , Rats , T-Lymphocyte Subsets/immunology
15.
Molecules ; 25(21)2020 Nov 03.
Article in English | MEDLINE | ID: mdl-33153234

ABSTRACT

In a previous study, EphB4 was demonstrated to be a positive regulator of A375-melanoma growth but a negative regulator of tumor vascularization and perfusion. To distinguish between EphB4 forward and ephrinB2 reverse signaling, we used the commercially available EphB4 kinase inhibitor NVP-BHG712 (NVP), which was later identified as its regioisomer NVPiso. Since there have been reported significant differences between the inhibition profiles of NVP and NVPiso, we compared the influence of NVP and NVPiso on tumor characteristics under the same experimental conditions. Despite the different inhibitory profiles of NVP and NVPiso, the comparative study conducted here showed the same EphB4-induced effects in vivo as in the previous investigation. This confirmed the conclusion that EphB4-ephrinB2 reverse signaling is responsible for increased tumor growth as well as decreased tumor vascularization and perfusion. These results are further substantiated by microarrays showing differences between mock-transfected and EphB4-transfected (A375-EphB4) cells with respect to at least 9 angiogenesis-related proteins. Decreased expression of vascular endothelial growth factor (VEGF), angiotensin 1 (Ang-1), and protein kinase B (Akt/PKB), together with the increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and transforming growth factor beta-2 (TGF-ß2), is consistent with the impaired vascularization of A375-EphB4 xenografts. Functional overexpression of EphB4 in A375-EphB4 cells was confirmed by activation of a variety of signaling pathways, including the Janus kinase/signal transducers and activators of transcription (JAK/STAT), rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen activated protein kinase kinase (Ras/Raf/MEK), and nuclear factor kappa-B (NFkB) pathways.


Subject(s)
Cell Proliferation/drug effects , Melanoma, Experimental , Neoplasm Proteins , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Receptor, EphB4/metabolism , Animals , Cell Hypoxia/drug effects , Cell Line, Tumor , Humans , Melanoma, Experimental/drug therapy , Melanoma, Experimental/enzymology , Melanoma, Experimental/pathology , Mice , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
16.
Pharmacol Res ; 141: 319-330, 2019 03.
Article in English | MEDLINE | ID: mdl-30625359

ABSTRACT

Eph/ephrin interactions and their bidirectional signaling are integral part of the complex communication system between ß-cells, essential for glucose homeostasis. Indeed, Eph/ephrin system was shown to be directly involved in the glucose-stimulated insulin secretion (GSIS) process occurring in the pancreatic islets. Here we tested the Eph antagonist UniPR500 as GSIS enhancer. UniPR500 was validated as EphA5-ephrin-A5 inhibitor in vitro and its efficacy as GSIS enhancer was assessed on EndoC-ßH1 cells. The selectivity of UniPR500 was evaluated by testing this compound on a panel of well-known molecular targets responsible for the regulation of glucose homeostasis. Plasmatic levels of UniPR500 were measured by HPLC/MS approach after oral administration. Finally, UniPR500 was tested as hypoglycemic agent in healthy mice, in a non-genetic mouse model of insulin resistance (IR) and in a non-genetic mouse model of type 1 diabetes (T1D). The compound is an orally bioavailable and selective Eph antagonist, able to increase GSIS from EndoC-ßH1 cells. When tested in vivo UniPR500 showed to improve glucose tolerance in healthy and IR mice. As expected by a GSIS enhancer acting on healthy ß-cells, UniPR500 was ineffective when tested on a non-genetic mouse model of type 1 diabetes, where pancreatic function was severely compromised. In conclusion our findings suggest that Eph targeting is a new and valuable pharmacological strategy in the search of new hypoglycemic agents.


Subject(s)
Ephrins/metabolism , Glucose/metabolism , Hypoglycemic Agents/pharmacology , Insulin Resistance , Insulin Secretion/drug effects , Protein Interaction Maps/drug effects , Animals , Cell Line , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/metabolism , Glucose Tolerance Test , Humans , Insulin/metabolism , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Male , Mice, Inbred C57BL
17.
Curr Rheumatol Rep ; 21(6): 23, 2019 04 12.
Article in English | MEDLINE | ID: mdl-30980212

ABSTRACT

PURPOSE OF REVIEW: Fibrosis is a pathological feature of many human diseases that affect multiple organs. The development of anti-fibrotic therapies has been a difficult endeavor due to the complexity of signaling pathways associated with fibrogenic processes, complicating the identification and modulation of specific targets. Evidence suggests that ephrin ligands and Eph receptors are crucial signaling molecules that contribute to physiological wound repair and the development of tissue fibrosis. Here, we discuss recent advances in the understanding of ephrin and Eph signaling in tissue repair and fibrosis. RECENT FINDINGS: Ephrin-B2 is implicated in fibrosis of multiple organs. Intercepting its signaling may help counteract fibrosis. Ephrins and Eph receptors are candidate mediators of fibrosis. Ephrin-B2, in particular, promotes fibrogenic processes in multiple organs. Thus, therapeutic strategies targeting Ephrin-B2 signaling could yield new ways to treat organ fibrosis.


Subject(s)
Ephrins/metabolism , Receptors, Eph Family/metabolism , Signal Transduction/physiology , Wound Healing/physiology , Animals , Fibrosis/metabolism , Fibrosis/pathology , Humans
18.
Mol Cell Neurosci ; 91: 108-121, 2018 09.
Article in English | MEDLINE | ID: mdl-30031105

ABSTRACT

Synapses are specialized cell-cell junctions that underlie the function of neural circuits by mediating communication between neurons. Both the formation and function of synapses require tight coordination of signaling between pre- and post-synaptic neurons. Trans-synaptic organizing molecules are important mediators of such signaling. Here we discuss how the EphB and ephrin-B families of trans-synaptic organizing proteins direct synapse formation during early development and regulate synaptic function and plasticity at mature synapses. Finally, we highlight recent evidence linking the synaptic organizing role of EphBs and ephrin-Bs to diseases of maladaptive synaptic function and plasticity.


Subject(s)
Ephrins/metabolism , Receptors, Eph Family/metabolism , Synapses/metabolism , Animals , Humans , Neurogenesis , Synapses/physiology , Synaptic Transmission
19.
Stroke ; 49(6): 1479-1487, 2018 06.
Article in English | MEDLINE | ID: mdl-29760276

ABSTRACT

BACKGROUND AND PURPOSE: Detection and localization of the early phase of blood-brain barrier disruption (BBBD) in vivo during cerebral ischemia/reperfusion injury remain a major challenge but may be a relevant outcome parameter in stroke. METHODS: We studied early BBBD in mice after transient middle cerebral artery occlusion by multimodal, high-field (9.4T) in vivo magnetic resonance imaging, including the contrast agent gadofluorineM as an albumin-binding tracer. GadofluorineM contrast-enhanced magnetic resonance imaging was performed to determine BBBD at 2, 6, and 24 hours after reperfusion. BBBD was confirmed and localized along the microvascular tree by using fluorescent gadofluorineM and immunofluorescence stainings (cluster of differentiation 31, ephrin type-B receptor 4, alpha smooth muscle actin, ionized calcium binding adaptor molecule 1). RESULTS: GadofluorineM contrast-enhanced magnetic resonance imaging revealed a multifocal spatial distribution of early BBBD and its close association with the microvasculature at a resolution of 40 µm. GadofluorineM leakage was closely associated with ephrin type-B receptor 4-positive but not alpha smooth muscle actin-positive vessels. The multifocal pattern of early BBBD (already at 2 hours after reperfusion) thus occurred in the distal capillary and venular microvascular bed. These multifocal zones showed distinct imaging signs indicative of early vasogenic edema. The total volume of multifocal early BBBD accurately predicted infarct size at 24 hours after reperfusion. CONCLUSIONS: Early BBBD in focal cerebral ischemia initiates multifocally in the distal capillary and venular bed of the cerebral microvasculature. It is closely associated with perimicrovascular vasogenic edema and microglial activation and predicts the extent of final infarction.


Subject(s)
Blood-Brain Barrier/pathology , Brain Ischemia/pathology , Capillaries/pathology , Stroke/pathology , Animals , Blood-Brain Barrier/metabolism , Brain/blood supply , Brain/pathology , Brain Edema/pathology , Cerebrovascular Circulation/physiology , Infarction, Middle Cerebral Artery/pathology , Magnetic Resonance Imaging/methods , Male , Mice, Inbred C57BL , Reperfusion Injury/pathology
20.
Histochem Cell Biol ; 148(4): 381-394, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28536901

ABSTRACT

Epithelial-free areas, present in both thymic cortex and medulla, have been studied in WT and EphB-deficient mice that have important alterations in the development of thymic epithelium due to the lack of proper thymocyte-thymic epithelial cell interactions. In both WT and mutant thymuses, the number and size of epithelial-free areas are significantly larger in the medulla than in the cortex. The two parameters show a reverse correlation: low numbers of these areas course with large epithelial-free areas and vice versa. However, their structure and cell content are similar in mutant and WT thymuses. Cortical epithelial-free areas just contain DP thymocytes, while the medullary ones consist of SP cells, blood vessels, mesenchyme-derived ER-TR7+ cells and components of the extracellular matrix (i.e., collagen IV, fibronectin, laminin). Other components, such as desmin, αSMA, PDGFRß and Ng2, frequently associated with blood vessel walls, also appear. Vimentin, although present in medullary epithelial-free areas, does not co-express with epithelial cells. Other markers related to epithelial-mesenchymal transitions, such as Snail, Slug or FSP1, are not expressed. These results suggest that alterations in the cell interactions between distinct thymic cell components that induce both increased proportions of apoptotic thymic epithelial cells and altered behavior of the mesenchyme associated with the medullary vasculature could explain the appearance of these areas and their differences in the cortex and medulla.


Subject(s)
Epithelial Cells/metabolism , Receptor, EphB2/metabolism , Receptor, EphB3/metabolism , Thymocytes/metabolism , Thymus Gland/metabolism , Animals , Epithelial Cells/cytology , Epithelial-Mesenchymal Transition , Female , Male , Mice , Mice, Knockout , Receptor, EphB2/deficiency , Receptor, EphB3/deficiency , Thymocytes/cytology , Thymus Gland/cytology
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