Effects of Different Inflammatory Factors on Hepatocyte Kinase Receptors and Ligands in Human Periodontal Ligament Fibroblasts / 中国医学科学院学报

Objective To investigate the effects of different inflammatory factors on hepatocyte kinase receptor(Eph)and ligand(ephrin)in human periodontal ligament fibroblasts(hPDLFs).Methods hPDLFs were stimulated with either 10 ng/ml tumor necrosis factor-α(TNF-α)or 10 ng/ml interleukin(IL)-1β,and then the expressions of Eph and ephrin at both mRNA and protein levels were determined at 0,1,2,6,12,and 24 hours.Results The levels of Eph receptors and ephrin ligand changed in a time-dependent manner in human periodontal ligament fibroblasts after treatment with TNF-α or IL-1β. The expression of ephrinA2 significantly increased in both groups within 24 hours(all <0.05). In the TNF-α group,the mRNA expression of ephrinA2 significantly increased at 1 h and was significant higher that in the IL-1β group at 24 h(<0.05). EphB4 showed a time-dependent decline after a short period of high expression.Conclusions Both TNF-α and IL-1β can cause changes in the expressions of Eph receptors and ephrin ligands in hPDLFs. The changes induced by both are consistent,although the effect of TNF-α is more pronounced.

Axon Guidance Molecules Guiding Neuroinflammation

Axon guidance molecules (AGMs), such as Netrins, Semaphorins, and Ephrins, have long been known to regulate axonal growth in the developing nervous system. Interestingly, the chemotactic properties of AGMs are also important in the postnatal period, such as in the regulation of immune and inflammatory responses. In particular, AGMs play pivotal roles in inflammation of the nervous system, by either stimulating or inhibiting inflammatory responses, depending on specific ligand-receptor combinations. Understanding such regulatory functions of AGMs in neuroinflammation may allow finding new molecular targets to treat neurodegenerative diseases, in which neuroinflammation underlies aetiology and progression.

An integrated review on new targets in the treatment of neuropathic pain

Neuropathic pain is a complex chronic pain state caused by the dysfunction of somatosensory nervous system, and it affects the millions of people worldwide. At present, there are very few medical treatments available for neuropathic pain management and the intolerable side effects of medications may further worsen the symptoms. Despite the presence of profound knowledge that delineates the pathophysiology and mechanisms leading to neuropathic pain, the unmet clinical needs demand more research in this field that would ultimately assist to ameliorate the pain conditions. Efforts are being made globally to explore and understand the basic molecular mechanisms responsible for somatosensory dysfunction in preclinical pain models. The present review highlights some of the novel molecular targets like D-amino acid oxidase, endoplasmic reticulum stress receptors, sigma receptors, hyperpolarization-activated cyclic nucleotide-gated cation channels, histone deacetylase, Wnt/β-catenin and Wnt/Ryk, ephrins and Eph receptor tyrosine kinase, Cdh-1 and mitochondrial ATPase that are implicated in the induction of neuropathic pain. Studies conducted on the different animal models and observed results have been summarized with an aim to facilitate the efforts made in the drug discovery. The diligent analysis and exploitation of these targets may help in the identification of some promising therapies that can better manage neuropathic pain and improve the health of patients.

Bidirectional ephrin signaling in bone

The interaction between ephrin ligands (efn) and their receptors (Eph) is capable of inducing forward signaling, from ligand to receptor, as well as reverse signaling, from receptor to ligand. The ephrins are widely expressed in many tissues, where they mediate cell migration and adherence, properties that make the efn-Eph signaling critically important in establishing and maintaining tissue boundaries. The efn-Eph system has also received considerable attention in skeletal tissues, as ligand and receptor combinations are predicted to mediate interactions between the different types of cells that regulate bone development and homeostasis. This review summarizes our current understanding of efn-Eph signaling with a particular focus on the expression and functions of ephrins and their receptors in bone.

Research progress in cytokines and signaling pathways for promoting pulmonary angiogenesis and vascular development / 中国当代儿科杂志

With the advances in pre- and post-natal medical care, the incidence of bronchopulmonary dysplasia (BPD) is on the rise, while its pathogenesis remains not clear. New BPD theory shows that the core pathogenesis of BPD is simple alveolar structure and pulmonary microvascular abnormalities that eventually lead to reduced pulmonary gas exchange, so the research on pulmonary microvascular development was gradually taken seriously. Pulmonary angiogenesis and vascular development require the participation of various cytokines and signaling pathways, the most important of which include VEGF/VEGFR pathway, Ang/Tie pathway, Ephrins/Eph pathway, and Notch/Jagged1 pathway. These cytokines and signaling pathways play important roles in pulmonary vascular development.

Brain-Region Specific Apoptosis Triggered by Eph/ephrin Signaling

Eph receptors and their ligands, ephrins, are abundantly expressed in neuroepithelial cells of the early embryonic brain. Overstimulation of Eph signaling in vivo increases apoptotic cell death of neuroepithelial cells, whereas null mutation of the Eph gene leads to the development of a larger brain during embryogenesis. Thus, it appears that Eph-ephrin signaling plays a role in regulating apoptotic cell death of neuroepithelial cells, thereby influencing brain size during embryonic development. Interestingly, Eph-ephrin signaling is bi-directional, with forward signaling from ephrin- to Eph-expressing cells and reverse signaling from Eph- to ephrin-expressing cells. However, it is not clear whether this forward or reverse signaling plays a role in regulating the size of the neuroepithelial cell population during early brain development. Also, Eph receptors and their corresponding ligands are mutually exclusive in their expression domains, and they encounter each other only at interfaces between their expression domains. This expression pattern may be a critical mechanism for preventing overstimulation of Eph-ephrin signaling. Nevertheless, Eph receptors are co-expressed with their corresponding ligands in certain brain regions. Recently, two studies demonstrated that brain region-specific apoptosis may be triggered by the overlapping expression of Eph and ephrin, a theme that will be explored in this mini-review.

Papel das interações mediadas pelo receptor EphB2 sobre a migração de precursores de células T / Role of EphB2 receptor-mediated interactions in migration of T-cell precursors

A colonização do timo por precursores hematopoéticos representa um evento crucial para o desenvolvimento deste próprio órgão, assim como garante a diferenciação e a formação do repertório de células T maduras. Entretanto, os mecanismos moleculares que dirigem este processo não são totalmente conhecidos. A entrada destes precursores depende da ativação de uma cascata de sinalizações intermoleculares, onde participam algumas moléculas, como as integrinas e as quimiocinas. Os receptores Eph, que compõem a maior família de receptores tirosina-quinase, representam importantes moléculas reguladoras do desenvolvimento de sistemas e órgãos, sendo encontrados também no tecido linfóide. Mais recentemente, essa família de receptores, juntamente com seus ligantes, efrinas, foi descrita como moléculas co-estimulatórias de sinais transmitidos em linfócitos T pelo receptor de antígeno, por quimiocinas e integrinas. Neste contexto, o objetivo central deste trabalho foi o de avaliar as possíveis funções dos receptores Eph, em particular EphB2, em modular a atividade migratória de precursores T durante os processos de colonização do timo e maturação intratímica de linfócitos. Nossos resultados demonstram a expressão dos receptores EphB2 no timo de camundongos e a sua participação tanto nos processos iniciais da organogênese do timo, quanto na diferenciação intratímica de timócitos. Este receptor, assim como seus principais ligantes, também é expresso em células precursoras derivadas da medula óssea de camundongos e é capaz de modular a migração e a capacidade de entrada destes precursores em lóbulos tímicos alinfóides. Além disso, vimos que a falta deste receptor, ou de seu domínio catalítico tirosina-quinase, promove uma redução na deposição de proteínas da matriz extracelular e de quimiocinas no timo, assim como resulta em importante inibição da entrada dos precursores hematopoiéticos neste órgão. De igual maneira, o desequilíbrio dos sinais transmitidos pelo complexo EphB2/efrina-B impede o correto posicionamento intratímico destes precursores, possivelmente levando a um bloqueio na maturação dos timócitos. Finalmente, demonstramos que a ausência do receptor ou dos sinais EphB2 não modifica os níveis de expressão de outros receptores como integrinas e receptores de quimiocina nos precursores hematopoiéticos e timócitos, mas possivelmente modula sua atividade e, desta forma, a atividade migratória destas células frente a estímulos hapto e quimiotáticos. Em conjunto, nossos resultados apontam uma importante participação dos sinais desencadeados pelo complexo Eph/efrina e sua co-regulação com outros receptores que modulam o processo de migração dos precursores de células T, desde sua entrada no timo, até o seu correto desenvolvimento e migração dentro deste órgão.