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1.
Arq, bras psicol ; 73(3)22/08/2022.
Article in Portuguese | LILACS | ID: biblio-1434557

ABSTRACT

O presente texto pretende, a partir de visita à obra clássica de Eça de Queiroz (1880/1963), O mandarim, localizar elementos deste romance fantástico que pos-sam nos oferecer pistas de trabalho, em ato literário, para compreender alguns con-ceitos da teoria psicanalítica freudo-lacaniana. Considerando que a associação entre o desejo inconsciente e a sedução diabólica é desde Freud uma constante, inter-rogamos, a partir do recurso do pacto, utilizado por Queiroz, as implicações e os desdobramentos clínico-teóricos a partir de três pontos conceituais. São eles, em particular, a questão das movimentações narcísicas que marcam um sujeito no inte-rior do par dialético insatisfação e busca de realização; o conceito de gozo como o que se inscreve, além do princípio de prazer; e a dimensão da culpa que se realiza via masoquismo face à não assunção do sujeito pela responsabilidade quanto ao seu desejo e que se localiza no personagem principal do romance no campo do maso-quismo mora


Subject(s)
Pleasure-Pain Principle , Guilt , Literature
2.
Exp Physiol ; 107(8): 933-945, 2022 08.
Article in English | MEDLINE | ID: mdl-35478205

ABSTRACT

NEW FINDINGS: What is the central question of this study? We investigated the effects of intrathecal administration of a novel toxin, CTK 01512-2, in a mouse model of Huntington's disease. We asked whether spinal cord neurons can represent a therapeutic target, given that the spinal cord seems to be involved in motor symptoms of Huntington's disease. Pharmacological approaches focusing on the spinal cord and skeletal muscles might represent a more feasible strategy than a high-risk brain intervention. What is the main finding and its importance? We provided evidence of a novel, local, neuroprotective effect of CTK 01512-2, paving a path for the development of approaches to treat motor symptoms of Huntington's disease beyond the brain. ABSTRACT: Phα1ß is a neurotoxin from the venom of the Phoneutria nigriventer spider, available as CTK 01512-2, a recombinant peptide. Owing to its antinociceptive and analgesic properties, CTK 01512-2 has been described to alleviate neuroinflammatory responses. Despite the diverse actions of CTK 01512-2 on the nervous system, little is known regarding its neuroprotective effect, especially in neurodegenerative conditions such as Huntington's disease (HD), a genetic movement disorder without cure. Here, we investigated whether CTK 01512-2 has a neuroprotective effect in a mouse model of HD. We hypothesized that spinal cord neurons might represent a therapeutic target, because the spinal cord seems to be involved in the motor symptoms of HD (BACHD) mice. We treated BACHD mice with CTK 01512-2 by intrathecal injection and performed in vivo motor behavioural and morphological analyses in the CNS (brain and spinal cord) and muscles. Our data showed that intrathecal injection of CTK 01512-2 significantly improved motor performance in the open field task. CTK 01512-2 protected neurons in the spinal cord (but not in the brain) from death, suggesting a local effect. CTK 01512-2 exerted its neuroprotective effect by inhibiting BACHD neuronal apoptosis, as revealed by a reduction in caspase-3 in the spinal cord. CTK 01512-2 was also able to revert BACHD muscle atrophy. In conclusion, our data suggest a novel role for CTK 01512-2 acting directly in the spinal cord to ameliorate morphofunctional aspects of spinal cord neurons and muscles and improve the performance of BACHD mice in motor behavioural tests. Given that HD shares similar symptoms with many neurodegenerative conditions, the findings presented herein might also be applicable to other disorders.


Subject(s)
Huntington Disease , Neuroprotective Agents , Animals , Disease Models, Animal , Huntington Disease/drug therapy , Huntington Disease/genetics , Mice , Mice, Transgenic , Neurons , Neuroprotective Agents/pharmacology , Spinal Cord
3.
Acta Trop ; 224: 106135, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34536367

ABSTRACT

Neglected for years, Zika virus (ZIKV) has become one of the most relevant arboviruses in current public health. The recent Zika fever epidemic in the Americas generated a worldwide alert due to the association with diseases such as Guillain-Barré syndrome and congenital syndromes. Among the pathogenesis of ZIKV, recent studies suggest that oxidative stress plays an important role during infection and that compounds capable of modulating oxidative stress are promising as therapeutics. Furthermore, so far there are no specific and efficient antiviral drug or vaccine available against ZIKV. Thus, fullerol was evaluated in the context of infection by ZIKV, since it is a carbon nanomaterial known for its potent antioxidant action. In this study, fullerol did not alter cell viability at the concentrations tested, proving to be inert, beyond to presenting high antioxidant power at low concentrations. ZIKV infection of human glioblastoma increased the production of reactive oxygen species by 60% and modulated the Nrf-2 pathway activity negatively. After treatment with fullerol, both conditions were restored to baseline levels. Additionally, fullerol was able to reduce viral production by up to 90%. Therefore, our results suggest that fullerol as a promising candidate in the control of ZIKV infections, presenting both antioxidant and antiviral action.


Subject(s)
Guillain-Barre Syndrome , Zika Virus Infection , Zika Virus , Antioxidants/pharmacology , Antiviral Agents/pharmacology , Humans , Zika Virus Infection/drug therapy
4.
Biomed Pharmacother ; 134: 111120, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33341671

ABSTRACT

Visceral leishmaniasis (VL) is a systemic parasitic disease that leads to high rates of morbidity and mortality in humans worldwide. There is a great need to develop new drugs and novel strategies to make chemotherapy for this disease more efficacious and well tolerated. Recent reports on the immunomodulatory effects and the low toxicity of the spherical carbon nanostructure fullerol led us to investigate in vitro and in vivo antileishmanial activity in free and encapsulated forms in liposomes. When assayed against intramacrophagic Leishmania amastigotes, fullerol showed a dose-dependent reduction of the infection index with IC50 of 0.042 mg/mL. When given daily by i.p. route for 20 days (0.05 mg/kg/d) in a murine model of acute VL, fullerol promoted significant reduction in the liver parasite load. To improve the delivery of fullerol to the infection sites, liposomal formulations were prepared by the dehydration-rehydration method. When evaluated in the acute VL model, liposomal fullerol (Lip-Ful) formulations given i.p. at 0.05 and 0.2 mg/kg with 4-days intervals were more effective than the free form, with significant parasite reductions in both liver and spleen. Lip-Ful at 0.2 mg/kg promoted complete parasite elimination in the liver. The antileishmanial activity of Lip-Ful was further confirmed in a chronic model of VL. Lip-Ful was also found to induce secretion of pro-inflammatory TNF-α, IFN-γ and IL-1ß cytokines. In conclusion, this work reports for the first time the antileishmanial activity of fullerol and introduces an innovative approach for treatment of VL based on the association of this nanostructure with liposomes.


Subject(s)
Fullerenes/pharmacology , Leishmania infantum/drug effects , Leishmania mexicana/drug effects , Leishmaniasis, Visceral/drug therapy , Lipids/chemistry , Liver/parasitology , Macrophages, Peritoneal/parasitology , Trypanocidal Agents/pharmacology , Animals , Cytokines/blood , Disease Models, Animal , Drug Compounding , Female , Fullerenes/chemistry , Inflammation Mediators/blood , Leishmania infantum/growth & development , Leishmania mexicana/growth & development , Leishmaniasis, Visceral/blood , Leishmaniasis, Visceral/parasitology , Liposomes , Liver/metabolism , Mesocricetus , Mice, Inbred BALB C , Nanoparticles , Parasite Load , Trypanocidal Agents/chemistry
5.
Neuropeptides ; 85: 102111, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33333486

ABSTRACT

Abnormal calcium influx and glutamatergic excitotoxicity have been extensively associated with neuronal death in Huntington's disease (HD), a genetic movement disorder. Currently, there is no effective treatment for this fatal condition. The neurotoxin Phα1ß has demonstrated therapeutic effects as a calcium channel blocker, for example during pain control. However, little is known about its neuroprotective effect in HD. Herein, we investigated if Phα1ß is effective in inhibiting neuronal cell death in the BACHD mouse model for HD. We performed intrastriatal injection of Phα1ß in WT and BACHD mice. No side effects or unusual behaviors were observed upon Phα1ß administration. Using three different motor behavior tests, we observed that injection of the toxin in BACHD mice greatly improved the animals' motor-force as seen in the Wire-hang test, and also the locomotor performance, according to the Open field test. NeuN labeling for mature neuron detection revealed that Phα1ß toxin promoted neuronal preservation in the striatum and cortex, when injected locally. Intrastriatal injection of Phα1ß was not able to preserve neurons from the spinal cord and also not revert muscle atrophy in BACHD mice. Finally, we observed that Phα1ß might, at least in part, exert its protective effect by decreasing L-glutamate, measured in cerebrospinal fluid. Our data provide evidence of a novel neuroprotector effect of Phα1ß, paving a path for the development of new approaches to treat HD motor symptoms.


Subject(s)
Huntington Disease/drug therapy , Neuroprotective Agents/administration & dosage , Spider Venoms/administration & dosage , Animals , Disease Models, Animal , Glutamic Acid/metabolism , Huntington Disease/pathology , Mice , Mice, Transgenic , Muscle, Skeletal/drug effects , Muscle, Skeletal/pathology , Neurons/drug effects , Spinal Cord/drug effects , Spinal Cord/pathology
6.
Nanomedicine (Lond) ; 10(15): 2423-50, 2015.
Article in English | MEDLINE | ID: mdl-26244905

ABSTRACT

Graphene and its derivatives, due to a wide range of unique properties that they possess, can be used as starting material for the synthesis of useful nanocomplexes for innovative therapeutic strategies and biodiagnostics. Here, we summarize the latest progress in graphene and its derivatives and their potential applications for drug delivery, gene delivery, biosensor and tissue engineering. A simple comparison with carbon nanotubes uses in biomedicine is also presented. We also discuss their in vitro and in vivo toxicity and biocompatibility in three different life kingdoms (bacterial, mammalian and plant cells). All aspects of how graphene is internalized after in vivo administration or in vitro cell exposure were brought about, and explain how blood-brain barrier can be overlapped by graphene nanomaterials.


Subject(s)
Graphite/chemistry , Nanostructures , Microscopy, Electron, Transmission , Tissue Engineering
7.
Cell Commun Signal ; 12: 78, 2014 Dec 24.
Article in English | MEDLINE | ID: mdl-25539979

ABSTRACT

BACKGROUND: Succinate is an intermediate of the citric acid cycle as well as an extracellular circulating molecule, whose receptor, G protein-coupled receptor-91 (GPR91), was recently identified and characterized in several tissues, including heart. Because some pathological conditions such as ischemia increase succinate blood levels, we investigated the role of this metabolite during a heart ischemic event, using human and rodent models. RESULTS: We found that succinate causes cardiac hypertrophy in a GPR91 dependent manner. GPR91 activation triggers the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), the expression of calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) and the translocation of histone deacetylase 5 (HDAC5) into the cytoplasm, which are hypertrophic-signaling events. Furthermore, we found that serum levels of succinate are increased in patients with cardiac hypertrophy associated with acute and chronic ischemic diseases. CONCLUSIONS: These results show for the first time that succinate plays an important role in cardiomyocyte hypertrophy through GPR91 activation, and extend our understanding of how ischemia can induce hypertrophic cardiomyopathy.


Subject(s)
Heart Diseases/metabolism , Receptors, G-Protein-Coupled/metabolism , Succinic Acid/metabolism , Adult , Animals , Animals, Newborn , Blood Pressure/drug effects , Calcium/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Heart Diseases/pathology , Histone Deacetylases/metabolism , Humans , Liver Cirrhosis/metabolism , Mice, Knockout , Middle Aged , Mitogen-Activated Protein Kinase Kinases/metabolism , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Rats, Wistar , Succinic Acid/blood
8.
PLoS One ; 9(7): e100179, 2014.
Article in English | MEDLINE | ID: mdl-24992197

ABSTRACT

Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i) the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO), and ii) the α2A/α2C-adrenergic receptor knockout (KO) mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. α2A/α2C-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease.


Subject(s)
Cardiotonic Agents/pharmacology , Cholinergic Agents/pharmacology , Cholinesterase Inhibitors/pharmacology , Pyridostigmine Bromide/pharmacology , Animals , Autonomic Nervous System/drug effects , Cells, Cultured , In Vitro Techniques , Isoproterenol/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocytes, Cardiac/drug effects , Rats, Wistar , Signal Transduction/drug effects
9.
J Mol Cell Cardiol ; 53(2): 206-16, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22587993

ABSTRACT

Recent work has provided compelling evidence that increased levels of acetylcholine (ACh) can be protective in heart failure, whereas reduced levels of ACh secretion can cause heart malfunction. Previous data show that cardiomyocytes themselves can actively secrete ACh, raising the question of whether this cardiomyocyte derived ACh may contribute to the protective effects of ACh in the heart. To address the functionality of this non-neuronal ACh machinery, we used cholinesterase inhibitors and a siRNA targeted to AChE (acetylcholinesterase) as a way to increase the availability of ACh secreted by cardiac cells. By using nitric oxide (NO) formation as a biological sensor for released ACh, we showed that cholinesterase inhibition increased NO levels in freshly isolated ventricular myocytes and that this effect was prevented by atropine, a muscarinic receptor antagonist, and by inhibition of ACh synthesis or vesicular storage. Functionally, cholinesterase inhibition prevented the hypertrophic effect as well as molecular changes and calcium transient alterations induced by adrenergic overstimulation in cardiomyocytes. Moreover, inhibition of ACh storage or atropine blunted the anti-hypertrophic action of cholinesterase inhibition. Altogether, our results show that cardiomyocytes possess functional cholinergic machinery that offsets deleterious effects of hyperadrenergic stimulation. In addition, we show that adrenergic stimulation upregulates expression levels of cholinergic components. We propose that this cardiomyocyte cholinergic signaling could amplify the protective effects of the parasympathetic nervous system in the heart and may counteract or partially neutralize hypertrophic adrenergic effects.


Subject(s)
Cardiomegaly/metabolism , Myocytes, Cardiac/metabolism , Acetylcholine/metabolism , Acetylcholinesterase/genetics , Acetylcholinesterase/metabolism , Animals , Atropine/pharmacology , Cell Movement/drug effects , Cells, Cultured , Isoproterenol/pharmacology , Mice , Muscarinic Antagonists/pharmacology , Myocytes, Cardiac/drug effects , Nitrogen Oxides/metabolism , Phenylephrine/pharmacology , RNA, Small Interfering , Rats
10.
Cell Calcium ; 47(1): 37-46, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20018372

ABSTRACT

GPR91 is an orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate, a citric acid cycle intermediate, in several tissues. In the heart, the role of succinate is unknown. We now report that rat ventricular cardiomyocytes express GPR91. We found that succinate, through GPR91, increases the amplitude and the rate of decline of global Ca(2+) transient, by increasing the phosphorylation levels of ryanodine receptor and phospholamban, two well known Ca(2+) handling proteins. The effects of succinate on Ca(2+) transient were abolished by pre-treatment with adenylyl cyclase and cAMP-dependent protein kinase (PKA) inhibitors. Direct PKA activation by succinate was further confirmed using a FRET-based A-kinase activity reporter. Additionally, succinate decreases cardiomyocyte viability through a caspase-3 activation pathway, effect also prevented by PKA inhibition. Taken together, these observations show that succinate acts as a signaling molecule in cardiomyocytes, modulating global Ca(2+) transient and cell viability through a PKA-dependent pathway.


Subject(s)
Calcium Signaling/drug effects , Cell Survival/drug effects , Myocytes, Cardiac/metabolism , Receptors, G-Protein-Coupled/metabolism , Succinic Acid/pharmacology , Animals , Calcium-Binding Proteins/metabolism , Cells, Cultured , Cyclic AMP-Dependent Protein Kinases/metabolism , Male , Microscopy, Confocal , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , RNA, Small Interfering/genetics , Rats , Rats, Wistar , Receptors, G-Protein-Coupled/genetics , Ryanodine Receptor Calcium Release Channel/metabolism
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