Enhancement of the FGFR1 signaling in the FGFR1-5-HT1A heteroreceptor complex in midbrain raphe 5-HT neuron systems. Relevance for neuroplasticity and depression

New findings show existence of FGFR1-5-HT1A heteroreceptor complexes in 5-HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus. Synergistic receptor-receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity. The existence of FGFR1-5-HT1A heteroreceptor complexes also in midbrain raphe 5-HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5-HT levels can cause an activation of the FGF-2/FGFR1 mechanism in these nerve cells as well. Therefore, the agonist modulation of the FGFR1-5-HT1A heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5-HT nerve cells. The combined i.c.v. treatment with FGF-2 and the 5-HT1A agonist 8-OHDPAT synergistically increased FGFR1 and ERK1/2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells. Cotreatment with FGF2 and the 5-HT1A agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5-HT immunoreactivity. These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the 5-HT1A receptor. Taken together, the 5-HT1A autoreceptors by being part of a FGFR1-5-HT1A heteroreceptor complex in the midbrain raphe 5-HT nerve cells appears to have also a trophic role in the central 5-HT neuron systems besides playing a key role in reducing the firing of these neurons

Electrochemical preparation and characterization of magnetic core–shell nanowires for biomedical applications

Magnetic CoNi@Au coreshell nanorods have been electrochemically synthesized, characterized and functionalized to test their inherent cytotoxicity in order to assess their potential use for biomedical applications. The initially electrodeposited CoNi nanorods have been covered with a gold layer bymeans of galvanic displacement to minimize the nanowires toxicity and their aggregation, and favour the functionalization. The presence of a gold layer on the nanorod surface slightlymodifies themagnetic behaviour of the asdeposited nanorods, maintaining their softmagnetic behaviour and high magnetization of saturation. The complete covering of the nanorodswith the gold shell favours a good functionalization with a layer of (11Mercaptoundecyl) hexa(ethylene glycol)molecules, in order to create a hydrophilic coating to avoid the aggregation of nanorods, keeping themin suspension and give them stability in biological media. The presence of the organic layer incorporated was detected by means of electrochemical probe experiments. A cytotoxicity test of functionalized coreshell nanorods, carried out with adherent HeLa cells, showed that cell viability was higher than 80% for amounts of nanorods up to 10 μgmL−1. These results make functionalized nanorods promising vehicles for targeted drug delivery inmedicine, which gives a complementary property to the magnetic nanoparticles. © 2015 Elsevier B.V. All rights reserved

Evidence for the existence of FGFR1–5-HT1A heteroreceptor complexes in the midbrain raphe 5-HT system

The ascending midbrain 5-HT neurons known to contain 5-HT1A autoreceptors may be dysregulated in depression due to a reduced trophic support. With in situ proximity ligation assay (PLA) and supported by co-location of the FGFR1 and 5-HT1A immunoreactivities in midbrain raphe 5-HT cells, evidence for the existence of FGFR1–5-HT1A heteroreceptor complexes were obtained in the dorsal and median raphe nuclei of the Sprague–Dawley rat. Their existence in the rat medullary raphe RN33B cell cultures was also established. After combined FGF-2 and 8-OH-DPAT treatment, a marked and significant increase in PLA positive clusters was found in the RN33B cells. Similar results were reached upon coactivation by agonists in HEK293T cells using the Fluorescent Resonance Energy Transfer (FRET) technique resulting in increased FRETmax and reduced FRET50 values. The heteroreceptor complex formation was dependent on TMV of the 5-HT1A receptor since it was blocked by incubation with TMV but not with TMII. Taken together, the 5-HT1A autoreceptors by being recruited into a FGFR1–5-HT1A heteroreceptor complex in the midbrain raphe 5-HT nerve cells may develop a novel function, namely a trophic role in many midbrain 5-HT neuron systems originating from the dorsal and medianus raphe nuclei

Fibroblast growth factor receptor 1- 5-hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity.

BACKGROUND: The hippocampus and its 5-hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity. METHODS: The analysis was made with bioluminescence resonance energy transfer, co-immunoprecipitation, in situ proximity ligation assay, binding assay, in cell western and the forced swim test. RESULTS: Using bioluminescence resonance energy transfer analysis, fibroblast growth factor receptor 1 (FGFR1)-5-hydroxytryptamine 1A (5-HT1A) receptor complexes have been demonstrated and their specificity and agonist modulation characterized. Their presence based on co-immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location. In vitro assays on extracellular signal-regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 (FGF2) and a 5-HT1A agonist, and dependent on the heteroreceptor interface. In vitro and in vivo studies also revealed a 5-HT1A agonist induced phosphorylation of FGFR1 and extracellular signal-regulated kinase 1/2 in rat hippocampus without changing FGF2 levels. Co-activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface. The combined acute and repeated intracerebroventricular treatment with FGF2 and 8-OH-DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test. CONCLUSIONS: The findings indicate that neurotrophic and antidepressant effects of 5-HT in brain may, in part, be mediated by activation of the 5-HT1A receptor protomer in the hippocampal FGFR1-5-HT1A receptor complex enhancing the FGFR1 signaling

pi-Donor/pi-Acceptor Interactions for the Encapsulation of Neurotransmitters on Functionalized Polysilicon-Based Microparticles

Bipyridinium salts, commonly known as viologens, are π-acceptor molecules that strongly interact with π-donor compounds, such as porphyrins or amino acids, leading their self-assembling. These properties have promoted us to functionalize polysilicon microparticles with bipyridinium salts for the encapsulation and release of π-donor compounds such as catecholamines and indolamines. In this work, the synthesis and characterization of four gemini-type amphiphilic bipyridinium salts (1·4PF6-4·4PF6), and their immobilization either non-covalently or covalently on polysilicon surfaces and microparticles have been achieved. More importantly, they act as hosts for the subsequent incorporation of π-donor neurotransmitters such as dopamine, serotonin, adrenaline or noradrenaline. Ultraviolet-visible absorption and fluorescence spectroscopies and high-performance liquid chromatography were used to detect the formation of the complex in solution. The immobilization of bipyridinium salts and neurotransmitter incorporation on polysilicon surfaces was corroborated by contact angle measurements. The reduction in the bipyridinium moiety and the subsequent release of the neurotransmitter was achieved using ascorbic acid, or Vitamin C, as a triggering agent. Quantification of neurotransmitter encapsulated and released from the microparticles was performed using high-performance liquid chromatography. The cytotoxicity and genotoxicity studies of the bipyridinium salt 1·4PF6, which was selected for the non-covalent functionalization of the microparticles, demonstrated its low toxicity in the mouse fibroblast cell line (3T3/NIH), the human liver carcinoma cell line (HepG2) and the human epithelial colorectal adenocarcinoma cell line (Caco-2). View Full

ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment

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Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors

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