Biomedical subjects

Mariana S Silveira

Publications and source records attributed to Mariana S Silveira.

6 recordsLinked to original sources

PubMed2006

A conserved domain of the gp85/trans-sialidase family activates host cell extracellular signal-regulated kinase and facilitates Trypanosoma cruzi infection.

Chagas' disease is a chronic, debilitating and incapacitating illness, caused by the protozoan parasite Trypanosoma cruzi when infective trypomastigotes invade host cells. Although the mechanism of trypomastigotes interaction with mammalian cells has been intensively studied, a final and integrated picture of the signal transduction mechanisms involved still remains to be elucidated. Our group has previously shown that the conserved FLY domain (VTVXNVFLYNR), present in all members of the gp85/trans-sialidase glycoprotein family coating the surface of trypomastigotes, binds to cytokeratin 18 (CK18) on the surface of LLC-MK(2) epithelial cells, and significantly increases parasite entry into mammalian cells. Now it is reported that FLY, present on the surface of trypomastigotes or on latex beads binds to CK18, promotes dephosphorylation and reorganization of CK18 and activation of the ERK1/2 signaling cascade culminating in an increase of approximately 9-fold in the number of parasites/cell. Inhibition of ERK1/2 phosphorylation completely blocks the adhesion of FLY to cells and blocks by 57% the host cell infection by T. cruzi. Taken together our results indicate that the conserved FLY domain is an important tool that trypomastigotes have evolved to specific exploit the host cell machinery and guarantee a successful infection.

Amino Acid Sequence↗

PubMed2006

Neuroprotection by cAMP: Another brick in the wall.

Programmed cell death occurs in the nervous system both in normal development as well as in pathologic conditions, and is a key issue related to both brain repair and neurodegenerative diseases. Modulation of cell death in the nervous system may involve neurotrophic factors and other peptides, neurotransmitters and neuromodulators, that activate various signal transduction pathways, which in turn interact with the cell death execution machinery. Here we discuss the role of the second messenger cyclic adenosine 3'5'-monophosphate (cAMP) in cell death, and summarize current evidence that cAMP is a nodal point of neuroprotective signaling pathways.

Animals↗

PubMed2005

Neuritogenesis and neuronal differentiation promoted by 2,4-dinitrophenol, a novel anti-amyloidogenic compound.

Neurite outgrowth is a critical event in neuronal development, formation, and remodeling of synapses, response to injury, and regeneration. We examined the effects of 2,4-dinitrophenol (DNP), a recently described blocker of the aggregation and neurotoxicity of the beta-amyloid peptide, on neurite elongation of central neurons. Morphometric analysis of rat embryo hippocampal and cortical neuronal cultures showed that neurite outgrowth was stimulated by DNP. This effect was accompanied by increases in the neuronal levels of the microtubule-associated protein tau and of cyclic adenosine 3',5' monophosphate (cAMP). DNP also promoted cAMP accumulation, increased tau level, neurite outgrowth, and neuronal differentiation in the mouse neuroblastoma cell line N2A. We show that DNP-induced differentiation requires activation of the extracellular signal-regulated kinase (ERK). The finding that DNP promotes neuritogenesis and neuronal differentiation suggests that, in addition to its anti-amyloidogenic actions, it may be a useful lead compound in the development of novel therapeutic approaches targeting neurite dystrophy and synaptic dysfunction in neurodegenerative pathologies such as Alzheimer's disease.

2,4-Dinitrophenol↗

PubMed2005

NMDA receptor activation modulates programmed cell death during early post-natal retinal development: a BDNF-dependent mechanism.

Glutamate is a classical excitotoxin of the central nervous system (CNS), but extensive work demonstrates neuroprotective roles of this neurotransmitter in developing CNS. Mechanisms of glutamate-mediated neuroprotection are still under scrutiny. In this study, we investigated mediators of glutamate-induced neuroprotection, and tested whether this neurotransmitter controls programmed cell death in the developing retina. The protective effect of N-methyl-d-aspartate (NMDA) upon differentiating cells of retinal explants was completely blocked by a neutralizing antibody to brain-derived neurotrophic factor (BDNF), but not by an antibody to neurotrophin-4 (NT-4). Consistently, chronic activation of NMDA receptor increased the expression of BDNF and trkB mRNA, as well as BDNF protein content, but did not change the content of NT-4 mRNA in retinal tissue. Furthermore, we showed that in vivo inactivation of NMDA receptor by intraperitoneal injections of MK-801 increased natural cell death of specific cell populations of the post-natal retina. Our results show that chronic activation of NMDA receptors in vitro induces a BDNF-dependent neuroprotective state in differentiating retinal cells, and that NMDA receptor activation controls programmed cell death of developing retinal neurons in vivo.

Aging↗

PubMed2004

Control of programmed cell death by neurotransmitters and neuropeptides in the developing mammalian retina.

It has long been known that a barrage of signals from neighboring and connecting cells, as well as components of the extracellular matrix, control cell survival. Given the extensive repertoire of retinal neurotransmitters, neuromodulators and neurotrophic factors, and the exhuberant interconnectivity of retinal interneurons, it is likely that various classes of released neuroactive substances may be involved in the control of sensitivity to retinal cell death. The aim of this article is to review evidence that neurotransmitters and neuropeptides control the sensitivity to programmed cell death in the developing retina. Whereas the best understood mechanism of execution of cell death is that of caspase-mediated apoptosis, current evidence shows that not only there are many parallel pathways to apoptotic cell death, but non-apoptotic programs of execution of cell death are also available, and may be triggered either in isolation or combined with apoptosis. The experimental data show that many upstream signaling pathways can modulate cell death, including those dependent on the second messengers cAMP-PKA, calcium and nitric oxide. Evidence for anterograde neurotrophic control is provided by a variety of models of the central nervous system, and the data reviewed here indicate that an early function of certain neurotransmitters, such as glutamate and dopamine, as well as neuropeptides such as pituitary adenylyl cyclase-activating polypeptide and vasoactive intestinal peptide is the trophic support of cell populations in the developing retina. This may have implications both regarding the mechanisms of retinal organogenesis, as well as pathological conditions leading to retinal dystrophies and to dysfunctional cellular behavior.

Animals↗

PubMed2002

Pituitary adenylyl cyclase-activating polypeptide prevents induced cell death in retinal tissue through activation of cyclic AMP-dependent protein kinase.

Multiple neuroactive substances are secreted by neurons and/or glial cells and modulate the sensitivity to cell death. In the developing retina, it has been shown that increased intracellular levels of cAMP protect cells from degeneration. We tested the hypothesis that the neuroactive peptide pituitary adenylyl cyclase-activating polypeptide (PACAP) has neuroprotective effects upon the developing rat retina. PACAP38 prevented anisomycin-induced cell death in the neuroblastic layer (NBL) of retinal explants, and complete inhibition of induced cell death was obtained with 1 nm. A similar protective effect was observed with PACAP27 and with the specific PAC1 receptor agonist maxadilan but not with glucagon. Photoreceptor cell death induced by thapsigargin was also prevented by PACAP38. The neuroprotective effect of PACAP38 upon the NBL could be reverted by the competitive PACAP receptor antagonist PACAP6-38 and by the specific PAC1 receptor antagonist Maxd.4. Molecular and immunohistochemical analysis demonstrated PAC1 receptors, and treatment with PACAP38 induced phospho-cAMP-response element-binding protein immunoreactivity in the anisomycin-sensitive undifferentiated postmitotic cells within the NBL. PACAP38 produced an increase in cAMP but not inositol triphosphate, and treatment with the cAMP-dependent protein kinase inhibitor R(p)-cAMPS blocked the protective effect of PACAP38. The results indicate that activation of PAC1 receptors by PACAP38 modulates cell death in the developing retina through the intracellular cAMP/cAMP-dependent protein kinase pathway.

Animals↗