Neurotrophin receptors expression and JNK pathway activation in human astrocytomas

<p>Abstract</p> <p>Background</p> <p>Neurotrophins are growth factors that regulate cell growth, differentiation and apoptosis in the nervous system. Their diverse actions are mediated through two different transmembrane – receptor signaling systems: Trk receptor tyrosine kinases (TrkA, TrkB, TrkC) and p75^NTRneurotrophin receptor. Trk receptors promote cell survival and differentiation while p75^NTRinduces, in most cases, the activity of JNK-p53-Bax apoptosis pathway or suppresses intracellular survival signaling cascades. Robust Trk activation blocks p75^NTR-induced apoptosis by suppressing the JNK-p53-Bax pathway. The aim of this exploratory study was to investigate the expression levels of neurotrophin receptors, Trks and p75^NTR, and the activation of JNK pathway in human astrocytomas and in adjacent non-neoplastic brain tissue.</p> <p>Methods</p> <p>Formalin-fixed paraffin-embedded serial sections from 33 supratentorial astrocytomas (5 diffuse fibrillary astrocytomas, WHO grade II; 6 anaplastic astrocytomas, WHO grade III; 22 glioblastomas multiforme, WHO grade IV) were immunostained following microwave pretreatment. Polyclonal antibodies against TrkA, TrkB, TrkC and monoclonal antibodies against p75^NTRand phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were used. The labeling index (LI), defined as the percentage of positive (labeled) cells out of the total number of tumor cells counted, was determined.</p> <p>Results</p> <p>Moderate to strong, granular cytoplasmic immunoreactivity for TrkA, TrkB and TrkC receptors was detected in greater than or equal to 10% of tumor cells in the majority of tumors independently of grade; on the contrary, p75^NTRreceptor expression was found in a small percentage of tumor cells (~1%) in some tumors. The endothelium of tumor capillaries showed conspicuous immunoreactivity for TrkB receptor. Trk immunoreactivity seemed to be localized in some neurons and astrocytes in non-neoplastic tissue. Phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were significantly co-expressed in a tumor grade-dependent manner (p < 0.05). Interestingly, a statistically significant (p < 0.05) reverse relationship between Trk receptors LIs and pc-Jun/pJNK LIs was noted in some glioblastomas multiforme.</p> <p>Conclusion</p> <p>In the context of astrocytomas, Trk receptors (TrkA, TrkB, TrkC) expression may promote tumor growth independently of grade. Furthermore, activation of JNK pathway may contribute to progression towards malignancy. Considering the fact that regional tumor heterogeneity may be a limiting factor for immunohistochemical studies, the significance of the reverse relationship between Trk receptors and pc-Jun/pJNK LIs with respect to biological behavior of human astrocytomas requires further evaluation.</p

NGF and proNGF Regulate Functionally Distinct mRNAs in PC12 Cells: An Early Gene Expression Profiling

The biological activities of NGF and of its precursor proNGF are quite distinct, due to different receptor binding profiles, but little is known about how proNGF regulates gene expression. Whether proNGF is a purely pro-apoptotic molecule and/or simply a “less potent NGF” is still a matter of debate. We performed experiments to address this question, by verifying whether a proNGF specific transcriptional signature, distinct from that of NGF, could be identified. To this aim, we studied gene expression regulation by proNGF and NGF in PC12 cells incubated for 1 and 4 hours with recombinant NGF and proNGF, in its wild-type or in a furin-cleavage resistant form. mRNA expression profiles were analyzed by whole genome microarrays at early time points, in order to identify specific profiles of NGF and proNGF. Clear differences between the mRNA profiles modulated by the three neurotrophin forms were identified. NGF and proNGF modulate remarkably distinct mRNA expression patterns, with the gene expression profile regulated by NGF being significantly more complex than that by proNGF, both in terms of the total number of differentially expressed mRNAs and of the gene families involved. Moreover, while the total number of genes modulated by NGF increases dramatically with time, that by proNGFs is unchanged or reduced. We identified a subset of regulated genes that could be ascribed to a “pure proNGF” signalling, distinct from the “pure NGF” one. We also conclude that the composition of mixed NGF and proNGF samples, when the two proteins coexist, influences the profile of gene expression. Based on this comparison of the gene expression profiles regulated by NGF and its proNGF precursor, we conclude that the two proteins activate largely distinct transcriptional programs and that the ratio of NGF to proNGF in vivo can profoundly influence the pattern of regulated mRNAs

Neuroregeneration in neurodegenerative disorders

<p>Abstract</p> <p>Background</p> <p>Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and neurorestoration - implantation of viable cells as a therapeutical approach.</p> <p>Discussion</p> <p>Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer's Disease or Parkinson's Disease and correlate with low endogenous protection, as a result of a diminished growth factors expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a "neuroregenerative reserve", that could be exploited by growth factors or stem cells-neurorestoration therapies.</p> <p>Summary</p> <p>In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer's Disease and Parkinson's Disease.</p

The L 98-59 System: Three Transiting, Terrestrial-Size Planets Orbiting A Nearby M Dwarf

We report the Transiting Exoplanet Survey Satellite (TESS) discovery of three terrestrial-size planets transiting L 98-59 (TOI-175, TIC 307210830)—a bright M dwarf at a distance of 10.6 pc. Using the Gaia-measured distance and broadband photometry, we find that the host star is an M3 dwarf. Combined with the TESS transits from three sectors, the corresponding stellar parameters yield planet radii ranging from 0.8 R⊕ to 1.6 R⊕. All three planets have short orbital periods, ranging from 2.25 to 7.45 days with the outer pair just wide of a 2:1 period resonance. Diagnostic tests produced by the TESS Data Validation Report and the vetting package DAVE rule out common false-positive sources. These analyses, along with dedicated follow-up and the multiplicity of the system, lend confidence that the observed signals are caused by planets transiting L 98-59 and are not associated with other sources in the field. The L 98-59 system is interesting for a number of reasons: the host star is bright (V = 11.7 mag, K = 7.1 mag) and the planets are prime targets for further follow-up observations including precision radial-velocity mass measurements and future transit spectroscopy with the James Webb Space Telescope; the near-resonant configuration makes the system a laboratory to study planetary system dynamical evolution; and three planets of relatively similar size in the same system present an opportunity to study terrestrial planets where other variables (age, metallicity, etc.) can be held constant. L 98-59 will be observed in four more TESS sectors, which will provide a wealth of information on the three currently known planets and have the potential to reveal additional planets in the system

The L 98-59 System: Three Transiting, Terrestrial-size Planets Orbiting a Nearby M Dwarf

We report the Transiting Exoplanet Survey Satellite (TESS) discovery of three terrestrial-size planets transiting L 98-59 (TOI-175, TIC 307210830)—a bright M dwarf at a distance of 10.6 pc. Using the Gaia-measured distance and broadband photometry, we find that the host star is an M3 dwarf. Combined with the TESS transits from three sectors, the corresponding stellar parameters yield planet radii ranging from 0.8 R ⊕ to 1.6 R ⊕. All three planets have short orbital periods, ranging from 2.25 to 7.45 days with the outer pair just wide of a 2:1 period resonance. Diagnostic tests produced by the TESS Data Validation Report and the vetting package DAVE rule out common false-positive sources. These analyses, along with dedicated follow-up and the multiplicity of the system, lend confidence that the observed signals are caused by planets transiting L 98-59 and are not associated with other sources in the field. The L 98-59 system is interesting for a number of reasons: the host star is bright (V = 11.7 mag, K = 7.1 mag) and the planets are prime targets for further follow-up observations including precision radial-velocity mass measurements and future transit spectroscopy with the James Webb Space Telescope; the near-resonant configuration makes the system a laboratory to study planetary system dynamical evolution; and three planets of relatively similar size in the same system present an opportunity to study terrestrial planets where other variables (age, metallicity, etc.) can be held constant. L 98-59 will be observed in four more TESS sectors, which will provide a wealth of information on the three currently known planets and have the potential to reveal additional planets in the system

Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)

This work has been supported by Bristol Research into Alzheimer’s and Care of the Elderly (BRACE), the Sigmund Gestetner Trust Fund (University of Bristol), the Alzheimer’s Society and the Alumni of the University of Bristol. K.C. and D.J.W. were supported by UK Wellcome Trust-MRC Neurodegenerative Disease Initiative Programme. J.H.Y. was supported by the Korea-UK Alzheimer’s Research Consortium Programme under the Korean Ministry of Health and Welfare. T.M.P. and S.C. were supported by Bristol-Chonnam Frontier Programme under the Chonnam National University Hospital. K.C. was supported by the Wolfson Research Merit Award and Royal Society, London.This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging.Publisher PDFPeer reviewe

Preparation and electrochemical properties of nanoporous transparent antimony-doped tin oxide (ATO) coatings

Nanoporous antimony-doped tin oxide (ATO) coatings with high surface area, optical transparency and electron transfer properties have been prepared using an interpenetrating inorganic–organic hybrid sol–gel approach. UV-Vis and X-ray photoelectron spectroscopic studies were carried out on the prepared materials in addition to the characterization of their microstructures with scanning electron microscopy, transmission electron microscopy, and nitrogen sorption experiments. Cyclic voltammetry (CV) and impedance spectroscopy were employed to characterize the electrochemical and electron transfer properties of the coatings in both acidic and neutral media with an Fe3+/Fe2+ redox couple. The material had a specific surface area of over 90 m2 g−1 with a bimodal pore distribution with two distinctive peaks at ca. 8 and 40 nm. The electrochemical capacitance of the material was about 100 times as high as the value obtained for a commercially available nonporous fluorine-doped tin oxide (FTO) electrode. The estimated electron transfer rate of the former was three times larger than that of the FTO. The optical transparency, high surface area and high electron transfer rate of the nanoporous ATO coatings make the material well suited for diverse photoelectrochemical applications.by Sudhanshu Sharma et al.

Characterization and functional significance of glucocorticoid receptors in patients with major depression: Modulation by antidepressant treatment

Hyperactivity of the hypothalamic pituitary adrenal (HPA) axis in patients with major depression is one of the most consistent findings in biological psychiatry. Experimental data support the idea that glucocorticoid-mediated feedback via glucocorticoid receptors (GR) is impaired in major depression. The aim of the present work was to assess the putative changes in GR density of peripheral blood mononuclear cells (PBMCs) in a group of patients with major depression and to determine modulation of these GR sites by antidepressant treatment. In addition, susceptibility of PBMCs to glucocorticoid effects was also studied using a functional end-point analysis in vitro, such as cortisol inhibition of mitogen-induced lymphocyte proliferation. Cortisol levels were also measured before and after dexamethasone suppression test (DST). The results showed a decrease in GR density in depressed patients compared with healthy subjects, mainly in those patients that showed basal cortisol levels in the upper normal range and were refractory to DST. Regarding the functional significance of this variation, two representative groups emerged from our study: a) free-medication patients with GR function comparable to healthy controls, and b) patients showing diminished GR activity. These results suggest a lack of relationship between GR density and cortisol-induced inhibition of lymphocyte proliferation. Patients treated with different antidepressant drugs showed a marked increase in the number of GR sites per cell compared to non-treated. Interestingly, this increase was even higher than in normal subjects. Hence, restoration of GR density after an efficient antidepressant treatment could be an index of an effective modulatory action of drugs on GR expression and highlights the possibility that GR levels might be used as markers of a successful treatment. © 2003 Elsevier Science Ltd. All rights reserved.Fil: Calfa, Gaston Diego. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; ArgentinaFil: Kademian, S.. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; ArgentinaFil: Ceschin, Danilo Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; ArgentinaFil: Vega, G.. PSIQUE; ArgentinaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Volosin, M.. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentin