142 research outputs found
Lithocholic Acid Is an Eph-ephrin Ligand Interfering with Eph-kinase Activation
Eph-ephrin system plays a central role in a large variety of human cancers. In
fact, alterated expression and/or de-regulated function of Eph-ephrin system
promotes tumorigenesis and development of a more aggressive and metastatic
tumour phenotype. In particular EphA2 upregulation is correlated with tumour
stage and progression and the expression of EphA2 in non-trasformed cells
induces malignant transformation and confers tumorigenic potential. Based on
these evidences our aim was to identify small molecules able to modulate
EphA2-ephrinA1 activity through an ELISA-based binding screening. We identified
lithocholic acid (LCA) as a competitive and reversible ligand inhibiting
EphA2-ephrinA1 interaction (Ki = 49 µM). Since each
ephrin binds many Eph receptors, also LCA does not discriminate between
different Eph-ephrin binding suggesting an interaction with a highly conserved
region of Eph receptor family. Structurally related bile acids neither inhibited
Eph-ephrin binding nor affected Eph phosphorylation. Conversely, LCA inhibited
EphA2 phosphorylation induced by ephrinA1-Fc in PC3 and HT29 human prostate and
colon adenocarcinoma cell lines (IC50 = 48 and
66 µM, respectively) without affecting cell viability or other receptor
tyrosine-kinase (EGFR, VEGFR, IGFR1β, IRKβ) activity. LCA did not
inhibit the enzymatic kinase activity of EphA2 at 100 µM (LANCE method)
confirming to target the Eph-ephrin protein-protein interaction. Finally, LCA
inhibited cell rounding and retraction induced by EphA2 activation in PC3 cells.
In conclusion, our findings identified a hit compound useful for the development
of molecules targeting ephrin system. Moreover, as ephrin signalling is a key
player in the intestinal cell renewal, our work could provide an interesting
starting point for further investigations about the role of LCA in the
intestinal homeostasis
Diverse and Active Roles for Adipocytes During Mammary Gland Growth and Function
The mammary gland is unique in its requirement to develop in close association with a depot of adipose tissue that is commonly referred to as the mammary fat pad. As discussed throughout this issue, the mammary fat pad represents a complex stromal microenvironment that includes a variety of cell types. In this article we focus on adipocytes as local regulators of epithelial cell growth and their function during lactation. Several important considerations arise from such a discussion. There is a clear and close interrelationship between different stromal tissue types within the mammary fat pad and its adipocytes. Furthermore, these relationships are both stage- and species-dependent, although many questions remain unanswered regarding their roles in these different states. Several lines of evidence also suggest that adipocytes within the mammary fat pad may function differently from those in other fat depots. Finally, past and future technologies present a variety of opportunities to model these complexities in order to more precisely delineate the many potential functions of adipocytes within the mammary glands. A thorough understanding of the role for this cell type in the mammary glands could present numerous opportunities to modify both breast cancer risk and lactation performance
Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU)
GABA Expression and Regulation by Sensory Experience in the Developing Visual System
The developing retinotectal system of the Xenopus laevis tadpole is a model of choice for studying visual experience-dependent circuit maturation in the intact animal. The neurotransmitter gamma-aminobutyric acid (GABA) has been shown to play a critical role in the formation of sensory circuits in this preparation, however a comprehensive neuroanatomical study of GABAergic cell distribution in the developing tadpole has not been conducted. We report a detailed description of the spatial expression of GABA immunoreactivity in the Xenopus laevis tadpole brain at two key developmental stages: stage 40/42 around the onset of retinotectal innervation and stage 47 when the retinotectal circuit supports visually-guided behavior. During this period, GABAergic neurons within specific brain structures appeared to redistribute from clusters of neuronal somata to a sparser, more uniform distribution. Furthermore, we found that GABA levels were regulated by recent sensory experience. Both ELISA measurements of GABA concentration and quantitative analysis of GABA immunoreactivity in tissue sections from the optic tectum show that GABA increased in response to a 4 hr period of enhanced visual stimulation in stage 47 tadpoles. These observations reveal a remarkable degree of adaptability of GABAergic neurons in the developing brain, consistent with their key contributions to circuit development and function
Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS
Protein network analysis reveals selectively vulnerable regions and biological processes in FTD
Exophthalmos in a young woman with no Graves’ disease – a case report of IgG4-related orbitopathy
Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies
Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia
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