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1.
Eur J Med Chem ; 182: 111628, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472473

RESUMO

Dengue fever is a mosquito-borne viral disease that has become a major public health concern worldwide. This disease presents with a wide range of clinical manifestations, from a mild cold-like illness to the more serious hemorrhagic dengue fever and dengue shock syndrome. Currently, neither an approved drug nor an effective vaccine for the treatment are available to fight the disease. The envelope protein (E) is a major component of the virion surface. This protein plays a key role during the viral entry process, constituting an attractive target for the development of antiviral drugs. The crystal structure of the E protein reveals the existence of a hydrophobic pocket occupied by the detergent n-octyl-ß-d-glucoside (ß-OG). This pocket lies at the hinge region between domains I and II and is important for the low pH-triggered conformational rearrangement required for the fusion of the virion with the host's cell. Aiming at the design of novel molecules which bind to E and act as virus entry inhibitors, we undertook a de novo design approach by "growing" molecules inside the hydrophobic site (ß-OG). From more than 240000 small-molecules generated, the 2,4 pyrimidine scaffold was selected as the best candidate, from which one synthesized compound displayed micromolar activity. Molecular dynamics-based optimization was performed on this hit, and thirty derivatives were designed in silico, synthesized and evaluated on their capacity to inhibit dengue virus entry into the host cell. Four compounds were found to be potent antiviral compounds in the low-micromolar range. The assessment of drug-like physicochemical and in vitro pharmacokinetic properties revealed that compounds 3e and 3h presented acceptable solubility values and were stable in mouse plasma, simulated gastric fluid, simulated intestinal fluid, and phosphate buffered saline solution.


Assuntos
Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Desenho de Drogas , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas do Envelope Viral/antagonistas & inibidores , Células A549 , Animais , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Vírus da Dengue/metabolismo , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Solubilidade , Relação Estrutura-Atividade , Proteínas do Envelope Viral/metabolismo
2.
Cell Mol Immunol ; 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243359

RESUMO

Evidence supports a possible role of BANK1 in innate immune signaling in B cells. In the present study, we investigated the interaction of BANK1 with two key mediators in interferon and inflammatory cytokine production, TRAF6 and MyD88. We revealed by coimmunoprecipitation (CoIP) analyses the binding of BANK1 with TRAF6 and MyD88, which were mediated by the BANK1 Toll/interleukin-1 receptor (TIR) domain. In addition, the natural BANK1-40C variant showed increased binding to MyD88. Next, we demonstrated in mouse splenic B cells that BANK1 colocalized with Toll-like receptor (TLR) 7 and TLR9 and that after stimulation with TLR7 and TLR9 agonists, the number of double-positive BANK1-TLR7, -TLR9, -TRAF6, and -MyD88 cells increased. Furthermore, we identified five TRAF6-binding motifs (BMs) in BANK1 and confirmed by point mutations and decoy peptide experiments that the C-terminal domain of BANK1-full-length (-FL) and the N-terminal domain of BANK1-Delta2 (-D2) are necessary for this binding. Functionally, we determined that the absence of the TIR domain in BANK1-D2 is important for its lysine (K)63-linked polyubiquitination and its ability to produce interleukin (IL)-8. Overall, our study describes a specific function of BANK1 in MyD88-TRAF6 innate immune signaling in B cells, clarifies functional differences between the two BANK1 isoforms and explains for the first time a functional link between autoimmune phenotypes including SLE and the naturally occurring BANK1-40C variant.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30873119

RESUMO

A major consequence of the world industrialized lifestyle is the increasing period of unnatural light in environments during the day and artificial lighting at night. This major change disrupts endogenous homeostasis with external circadian cues, which has been associated to higher risk of diseases affecting human health, mainly cancer among others. Circadian disruption promotes tumor development and accelerate its fast progression. The dysregulation mechanisms of circadian genes is greatly affected by the genetic variability of these genes. To date, several core circadian genes, also called circadian clock genes, have been identified, comprising the following: ARNTL, CLOCK, CRY1, CRY2, CSNK1E, NPAS2, NR1D1, NR1D2, PER1, PER2, PER3, RORA, and TIMELESS. The polymorphic variants of these circadian genes might contribute to an individual's risk to cancer. In this short review, we focused on clock circadian clock-related genes, major contributors of the susceptibility to endocrine-dependent cancers through affecting circadian clock, most likely affecting hormonal regulation. We examined polymorphisms affecting breast, prostate and ovarian carcinogenesis, in addition to pancreatic and thyroid cancer. Further study of the genetic composition in circadian clock-controlled tumors will be of great importance by establishing the foundation to discover novel genetic biomarkers for cancer prevention, prognosis and target therapies.

4.
J Zoo Wildl Med ; 49(3): 824-827, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30212325

RESUMO

A free-ranging juvenile California sea lion ( Zalophus californianus) stranded on the coast of Vancouver, British Columbia, with signs of lethargy and emaciation in April 2016. An asymmetrical skull with a prominent superficial cervical lymph node was found on initial assessment. Fine-needle aspirates and biopsies of the lymph node were consistent with neoplasia and the animal was humanely euthanized and presented for necropsy. A metastatic parotid gland adenocarcinoma was diagnosed with regional lymph node and pulmonary metastases. Local invasion of contiguous skeletal muscle, bone, ear, and tonsils was extensive and likely accounted for the unilateral craniofacial deformity. Neoplasia of nonurogenital origin in juvenile California sea lions are reported infrequently. This is the first case of a parotid carcinoma in a California sea lion.


Assuntos
Carcinoma/veterinária , Neoplasias Parotídeas/veterinária , Leões-Marinhos , Animais , Animais Selvagens , Carcinoma/patologia , Masculino , Neoplasias Parotídeas/patologia
5.
Sci Rep ; 8(1): 11577, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30068967

RESUMO

Mass strandings of sperm whales (Physeter macrocephalus) are rare in the Mediterranean Sea. Nevertheless, in 2014 a pod of 7 specimens stranded alive along the Italian coast of the Central Adriatic Sea: 3 individuals died on the beach after a few hours due to internal damages induced by prolonged recumbency; the remaining 4 whales were refloated after great efforts. All the dead animals were genetically related females; one was pregnant. All the animals were infected by dolphin morbillivirus (DMV) and the pregnant whale was also affected by a severe nephropathy due to a large kidney stone. Other analyses ruled out other possible relevant factors related to weather conditions or human activities. The results of multidisciplinary post-mortem analyses revealed that the 7 sperm whales entered the Adriatic Sea encountering adverse weather conditions and then kept heading northward following the pregnant but sick leader of the pod, thereby reaching the stranding site. DMV infection most likely played a crucial role in impairing the health condition and orientation abilities of the whales. They did not steer back towards deeper waters, but eventually stranded along the Central Adriatic Sea coastline, a real trap for sperm whales.


Assuntos
Comportamento Animal , Infecções por Morbillivirus/veterinária , Morbillivirus/isolamento & purificação , Cachalote , Animais , Itália , Mar Mediterrâneo , Infecções por Morbillivirus/patologia
6.
Methods Mol Biol ; 1604: 351-370, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28986848

RESUMO

Host restriction factors are cellular components that interfere with viral multiplication. They are up-regulated and expressed upon viral infection and in consequence their activity is specific. So far several important restriction factors have been described against diverse viruses. The cellular antiviral mechanisms defined include proteins with the ability to interfere with early steps of viral replication and others that have been shown to block viral morphogenesis. However, other strategies by which the antiviral action is exerted still remain elusive. An additional interesting matter is how viruses also developed ways to by-pass these host-specific obstacles. Thus, unusual cell localization or re-localization represents a frequent virus choice to evade the cellular surveillance. In the present chapter, we summarize methods to identify cell restriction factors, their antiviral activity, and possible subcellular locations where their activity can take place.


Assuntos
Febre Hemorrágica com Síndrome Renal/metabolismo , Animais , Dengue/virologia , Vírus da Dengue/metabolismo , Humanos , Vírus Junin/metabolismo , RNA Interferente Pequeno
7.
Virology ; 514: 216-229, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29202415

RESUMO

Junín arenavirus infections are associated with high levels of interferons in both severe and fatal cases. Upon Junín virus (JUNV) infection a cell signaling cascade initiates, that ultimately attempts to limit viral replication and prevent infection progression through the expression of host antiviral proteins. The interferon stimulated gene (ISG) viperin has drawn our attention as it has been highlighted as an important antiviral protein against several viral infections. The studies of the mechanistic actions of viperin have described important functional domains relating its antiviral and immune-modulating actions through cellular lipid structures. In line with this, through silencing and overexpression approaches, we have identified viperin as an antiviral ISG against JUNV. In addition, we found that lipid droplet structures are modulated during JUNV infection, suggesting its relevance for proper virus multiplication. Furthermore, our confocal microscopy images, bioinformatics and functional results also revealed viperin-JUNV protein interactions that might be participating in this antiviral pathway at lipid droplet level. Altogether, these results will help to better understand the factors mediating innate immunity in arenavirus infection and may lead to the development of pharmacological agents that can boost their effectiveness thereby leading to new treatments for this viral disease.


Assuntos
Febre Hemorrágica Americana/imunologia , Vírus Junin/fisiologia , Gotículas Lipídicas/virologia , Proteínas/imunologia , Febre Hemorrágica Americana/genética , Febre Hemorrágica Americana/virologia , Humanos , Interferons/genética , Interferons/imunologia , Vírus Junin/química , Vírus Junin/genética , Vírus Junin/imunologia , Gotículas Lipídicas/imunologia , Nucleoproteínas/química , Nucleoproteínas/genética , Nucleoproteínas/imunologia , Domínios Proteicos , Proteínas/química , Proteínas/genética , Replicação Viral
8.
Dis Aquat Organ ; 127(1): 57-63, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29256428

RESUMO

Peribullar sinuses of harbour porpoises Phocoena phocoena are parasitized with high prevalence by the nematode Stenurus minor. The effect of S. minor on the hearing ability of this species is still undetermined. Here, we review the occurrence of S. minor in the inner ear of harbour porpoises recovered from strandings in the North and Baltic Seas. In particular, we present the results from ears collected in German and Danish waters from 2002 to 2016 and from Dutch waters from 2010 to 2016. While the prevalence of S. minor in pterygoid and peribullar sinuses and tympanic cavity was high in harbour porpoises (66.67% in our cases), its prevalence in the cochlea was rare. Only 1 case out of 129 analysed by either histology, electron microscopy or immunofluorescence showed the presence of a nematode parasite morphologically consistent with S. minor at the most basal portion of the right cochlea. This individual also had severe haemorrhage along the right cochlear spiral, which was likely caused by ectopic S. minor migration. Although this animal might have had impaired hearing in the right ear, it was otherwise in good body condition with evidence of recent feeding. These findings highlight the need to study the effect of parasites on hearing, and other pathological changes that might impair appropriate processing of acoustic information.


Assuntos
Doenças do Labirinto/veterinária , Infecções por Nematoides/veterinária , Phocoena/parasitologia , Animais , Orelha Interna/parasitologia , Orelha Interna/ultraestrutura , Doenças do Labirinto/epidemiologia , Doenças do Labirinto/parasitologia , Nematoides/classificação , Nematoides/isolamento & purificação , Infecções por Nematoides/epidemiologia , Infecções por Nematoides/parasitologia , Mar do Norte/epidemiologia
9.
Clin Rev Allergy Immunol ; 53(2): 198-218, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28528521

RESUMO

Systemic autoimmune diseases (SADs) encompass a wide spectrum of clinical signs as a reflection of their complex physiopathology. A variety of mechanisms related with the innate immune system are in the origin of the loss of self-tolerance in these diseases, and for most of them, the myeloid leukocytes are key actors. Monocytes, macrophages, dendritic cells, and neutrophils are first-line immune effectors located in the interface between innate and adaptive immunity. They are crucial in the organization of the local and systemic responses to damage-associated molecular patterns (DAMPs) and determine the intensity, orientation, and duration of the local immune response through the expression of chemokines, costimulatory or protolerogenic factors. In this review, we summarize the current knowledge about the role of the main myeloid populations in the induction and maintenance of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary antiphospholipid antibody syndrome (PAPS), systemic sclerosis (SSc), and Sjögren's syndrome (SjS), based on the data from both mouse preclinical models and patients. According to these data, our challenge in the next few years is to better dissect the fine mechanisms underlying the pathological role of myeloid cells in these diseases in order to define specific cell subsets or proteins that can be potential targets for drug development.


Assuntos
Autoanticorpos/metabolismo , Doenças Autoimunes/imunologia , Células Mieloides/imunologia , Imunidade Adaptativa , Animais , Apresentação do Antígeno , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Imunidade Inata , Camundongos , Tolerância a Antígenos Próprios
10.
Sci Rep ; 7: 46444, 2017 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-28406244

RESUMO

Atherosclerosis is a chronic inflammatory cardiovascular disease that is responsible of high mortality worldwide. Evidence indicates that maladaptive autoimmune responses in the arterial wall play critical roles in the process of atherosclerosis. Cortistatin is a neuropeptide expressed in the vascular system and atherosclerotic plaques that regulates vascular calcification and neointimal formation, and inhibits inflammation in different experimental models of autoimmune diseases. Its role in inflammatory cardiovascular disorders is largely unexplored. The aim of this study is to investigate the potential therapeutic effects of cortistatin in two well-established preclinical models of atherosclerosis, and the molecular and cellular mechanisms involved. Systemic treatment with cortistatin reduced the number and size of atherosclerotic plaques in carotid artery, heart, aortic arch and aorta in acute and chronic atherosclerosis induced in apolipoprotein E-deficient mice fed a high-lipid diet. This effect was exerted at multiple levels. Cortistatin reduced Th1/Th17-driven inflammatory responses and increased regulatory T cells in atherosclerotic arteries and lymphoid organs. Moreover, cortistatin reduced the capacity of endothelial cells to bind and recruit immune cells to the plaque and impaired the formation of foam cells by enhancing cholesterol efflux from macrophages. Cortistatin emerges as a new candidate for the treatment of the clinical manifestations of atherosclerosis.


Assuntos
Anti-Inflamatórios/administração & dosagem , Células Espumosas/efeitos dos fármacos , Hiperlipidemias/complicações , Neuropeptídeos/administração & dosagem , Placa Aterosclerótica/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Células Espumosas/metabolismo , Hiperlipidemias/genética , Camundongos , Camundongos Knockout para ApoE , Neuropeptídeos/farmacologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
11.
Sci Rep ; 7: 41848, 2017 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-28165504

RESUMO

Assessment of the impact of noise over-exposure in stranded cetaceans is challenging, as the lesions that lead to hearing loss occur at the cellular level and inner ear cells are very sensitive to autolysis. Distinguishing ante-mortem pathology from post-mortem change has been a major constraint in diagnosing potential impact. Here, we outline a methodology applicable to the detection of noise-induced hearing loss in stranded cetaceans. Inner ears from two mass strandings of long-finned pilot whales in Scotland were processed for scanning electron microscopy observation. In one case, a juvenile animal, whose ears were fixed within 4 hours of death, revealed that many sensory cells at the apex of the cochlear spiral were missing. In this case, the absence of outer hair cells would be compatible with overexposure to underwater noise, affecting the region which transduces the lowest frequencies of the pilot whales hearing spectrum. Perfusion of cochlea with fixative greatly improved preservation and enabled diagnostic imaging of the organ of Corti, even 30 hours after death. This finding supports adopting a routine protocol to detect the pathological legacy of noise overexposure in mass stranded cetaceans as a key to understanding the complex processes and implications that lie behind such stranding events.


Assuntos
Orelha Interna/ultraestrutura , Perda Auditiva Provocada por Ruído/patologia , Baleias/fisiologia , Animais , Orelha Interna/diagnóstico por imagem , Microscopia Eletrônica de Varredura/métodos
12.
Br J Pharmacol ; 174(3): 267-280, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27922195

RESUMO

BACKGROUND AND PURPOSE: Myocarditis is an inflammatory and autoimmune cardiovascular disease that causes dilated myocardiopathy and is responsible for high morbidity and mortality worldwide. Cortistatin is a neuropeptide produced by neurons and cells of the immune and vascular systems. Besides its action in locomotor activity and sleep, cortistatin inhibits inflammation in different experimental models of autoimmune diseases. However, its role in inflammatory cardiovascular disorders is unexplored. Here, we investigated the therapeutic effects of cortistatin in a well-established preclinical model of experimental autoimmune myocarditis (EAM). EXPERIMENTAL APPROACH: We induced EAM by immunization with a fragment of cardiac myosin in susceptible Balb/c mice. Cortistatin was administered i.p. starting 7, 11 or 15 days after EAM induction. At day 21, we evaluated heart hypertrophy, myocardial injury, cardiac inflammatory infiltration and levels of serum and cardiac inflammatory cytokines, cortistatin and autoantibodies. We determined proliferation and cytokine production by heart draining lymph node cells in response to cardiac myosin restimulation. KEY RESULTS: Systemic injection of cortistatin during the effector phase of the disease significantly reduced its prevalence and signs of heart hypertrophy and injury (decreased the levels of brain natriuretic peptide) and impaired myocardial inflammatory cell infiltration. This effect was accompanied by a reduction in self-antigen-specific T-cell responses in lymph nodes and in the levels of cardiomyogenic antibodies and inflammatory cytokines in serum and myocardium. Finally, we found a positive correlation between cardiac and systemic cortistatin levels and EAM severity. CONCLUSIONS AND IMPLICATIONS: Cortistatin emerges as a new candidate to treat inflammatory dilated cardiomyopathy.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Cardiomiopatia Dilatada/tratamento farmacológico , Miocardite/tratamento farmacológico , Neuropeptídeos/farmacologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Cardiomiopatia Dilatada/imunologia , Cardiomiopatia Dilatada/fisiopatologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Linfonodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Miocardite/imunologia , Miocardite/fisiopatologia , Neuropeptídeos/administração & dosagem , Índice de Gravidade de Doença , Linfócitos T/imunologia , Fatores de Tempo
13.
Stem Cell Res ; 17(2): 238-247, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27591480

RESUMO

Over-expression of the early neural inducer, Noggin, in nestin positive subventricular zone (SVZ), neural stem cells (NSC) promotes proliferation and neuronal differentiation of neural progenitors and inhibits the expression of a CNS-enriched microRNA-410 (miR-410) (Morell et al., 2015). When expressed in neurospheres derived from the adult SVZ, miR-410 inhibits neuronal and oligodendrocyte differentiation, and promotes astrocyte differentiation. miR-410 also reverses the increase in neuronal differentiation and decreased astroglial differentiation caused by Noggin over-expression. Conversely, inhibition of miR-410 activity promotes neuronal and decreases astroglial differentiation of NSC. Using computer prediction algorithms and luciferase reporter assays we identified multiple neurogenic genes including Elavl4 as downstream targets of miR-410 via the canonical miRNA-3'UTR interaction. Over-expression of Elavl4 transcripts without the endogenous 3'UTR rescued the decrease in neuronal differentiation caused by miR-410 overexpression. Interestingly, we also observed that miR-410 affected neurite morphology; over-expression of miR-410 resulted in the formation of short, unbranched neurites. We conclude that miR-410 expression provides a new link between BMP signaling and the crucial lineage choice of adult neural stem cells via its ability to bind and control the expression of neurogenic gene transcripts.


Assuntos
Ventrículos Laterais/citologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Técnicas de Cultura de Células , Diferenciação Celular , Linhagem Celular , Proteína Semelhante a ELAV 4/antagonistas & inibidores , Proteína Semelhante a ELAV 4/genética , Proteína Semelhante a ELAV 4/metabolismo , Imuno-Histoquímica , Ventrículos Laterais/metabolismo , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Nestina/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese , Oligodendroglia/citologia , Oligodendroglia/metabolismo
14.
J Comp Neurol ; 523(3): 431-48, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25269663

RESUMO

The morphological study of the Odontocete organ of Corti, together with possible alterations associated with damage from sound exposure, represents a key conservation approach to assess the effects of acoustic pollution on marine ecosystems. By collaborating with stranding networks from several European countries, 150 ears from 13 species of Odontocetes were collected and analyzed by scanning (SEM) and transmission (TEM) electron microscopy. Based on our analyses, we first describe and compare Odontocete cochlear structures and then propose a diagnostic method to identify inner ear alterations in stranded individuals. The two species analyzed by TEM (Phocoena phocoena and Stenella coeruleoalba) showed morphological characteristics in the lower basal turn of high-frequency hearing species. Among other striking features, outer hair cell bodies were extremely small and were strongly attached to Deiters cells. Such morphological characteristics, shared with horseshoe bats, suggest that there has been convergent evolution of sound reception mechanisms among echolocating species. Despite possible autolytic artifacts due to technical and experimental constraints, the SEM analysis allowed us to detect the presence of scarring processes resulting from the disappearance of outer hair cells from the epithelium. In addition, in contrast to the rapid decomposition process of the sensory epithelium after death (especially of the inner hair cells), the tectorial membrane appeared to be more resistant to postmortem autolysis effects. Analysis of the stereocilia imprint pattern at the undersurface of the tectorial membrane may provide a way to detect possible ultrastructural alterations of the hair cell stereocilia by mirroring them on the tectorial membrane.


Assuntos
Células Ciliadas Auditivas/ultraestrutura , Microscopia Eletrônica de Transmissão , Órgão Espiral/ultraestrutura , Animais , Orelha/anatomia & histologia , Microscopia Eletrônica de Varredura , Toninhas , Especificidade da Espécie
15.
Saúde Soc ; 23(2): 677-688, apr-jun/2014.
Artigo em Português | LILACS | ID: lil-718555

RESUMO

A intervenção interdisciplinar universitária em regiões de alta vulnerabilidade da Baixada Santista, além de contribuir para o fortalecimento do Sistema Único de Saúde (SUS), evidencia o sofrimento enfrentado pelo agente comunitário de saúde (ACS) em seu dia a dia, advindo de solicitações dos munícipes. Estas resultantes da exclusão e violência social em que vivem acrescidas de condições de trabalho insalubres e baixa remuneração. O objetivo deste artigo é apresentar a sistematização de uma experiência de intervenção por meio de um projeto de extensão universitária, trazendo elementos que potencializem as ações dos agentes comunitários de saúde da Estratégia Saúde da Família (ESF) na Baixada Santista. Para este estudo qualitativo, foram analisados os diários de campo dos encontros semanais, a partir da percepção de professores e alunos, referentes ao período de agosto de 2010 a junho de 2011. A organização e análise dos dados tiveram como referência a Teoria Fundamentada nos dados. Os resultados indicaram a necessidade de acolhimento de experiências dos ACSs, ampliando a compreensão dos dilemas vividos por estes profissionais e consequentemente dos impasses de implementação do SUS e da ESF. Além disso, o incentivo ao processo de educação continuada baseada em uma práxis que promova os projetos de vida pessoais e profissionais dos ACSs...


The interdisciplinary intervention by the university in areas of high vulnerability of Santos, besides contributing to the strengthening of the Brazilian National Health System (SUS), highlights the suffering faced by community health agents (CHA) in their routines, coming from requests from citizens. These result from social exclusion and the violence in which they live, as well as unhealthy working conditions and low pay. The purpose of this article is to present an experience of systematic intervention through a university extension project, bringing elements that enhance the actions of community health agents of the Family Health Strategy (FHS) in Santos. For this qualitative study we analyzed the field diaries of weekly meetings, from the perspective of teachers and students, for the period from August 2010 to June 2011. Data’s organization and analysis were based on the Grounded Theory. The results indicated the need of gathering the CHA experiences, broadening the understanding of the dilemmas faced by these professionals and consequently the impasses of implementing SUS and the FHS. Moreover, continued education should be encouraged, based upon a praxis able to promote CHA’s personal and professional projects...


Assuntos
Humanos , Masculino , Feminino , Agentes Comunitários de Saúde/educação , Educação Continuada , Saúde da Família , Estratégia Saúde da Família , Sistema Único de Saúde , Acolhimento , Condições de Trabalho , Pesquisa Qualitativa
16.
Saúde Soc ; 23(2): 677-688, apr-jun/2014.
Artigo em Português | CidSaúde - Cidades saudáveis | ID: cid-66853

RESUMO

A intervenção interdisciplinar universitária em regiões de alta vulnerabilidade da Baixada Santista, além de contribuir para o fortalecimento do Sistema Único de Saúde (SUS), evidencia o sofrimento enfrentado pelo agente comunitário de saúde (ACS) em seu dia a dia, advindo de solicitações dos munícipes. Estas resultantes da exclusão e violência social em que vivem acrescidas de condições de trabalho insalubres e baixa remuneração. O objetivo deste artigo é apresentar a sistematização de uma experiência de intervenção por meio de um projeto de extensão universitária, trazendo elementos que potencializem as ações dos agentes comunitários de saúde da Estratégia Saúde da Família (ESF) na Baixada Santista. Para este estudo qualitativo, foram analisados os diários de campo dos encontros semanais, a partir da percepção de professores e alunos, referentes ao período de agosto de 2010 a junho de 2011. A organização e análise dos dados tiveram como referência a Teoria Fundamentada nos dados. Os resultados indicaram a necessidade de acolhimento de experiências dos ACSs, ampliando a compreensão dos dilemas vividos por estes profissionais e consequentemente dos impasses de implementação do SUS e da ESF. Além disso, o incentivo ao processo de educação continuada baseada em uma práxis que promova os projetos de vida pessoais e profissionais dos ACSs.(AU)


Assuntos
Saúde da Família , Condições de Trabalho , Educação Continuada , Estratégias , Agentes Comunitários de Saúde , Sistema Único de Saúde , Pesquisa Qualitativa
17.
Brain Behav Immun ; 37: 152-63, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24321213

RESUMO

Adrenomedullin is a neuropeptide known for its cardiovascular activities and anti-inflammatory effects. Here, we investigated the effect of adrenomedullin in a model of experimental autoimmune encephalomyelitis (EAE) that mirrors chronic progressive multiple sclerosis. A short-term systemic treatment with adrenomedullin reduced clinical severity and incidence of EAE, the appearance of inflammatory infiltrates in spinal cord and the subsequent demyelination and axonal damage. This effect was exerted at multiple levels affecting both early and late events of the disease. Adrenomedullin decreased the presence/activation of encephalitogenic Th1 and Th17 cells and down-regulated several inflammatory mediators in peripheral lymphoid organs and central nervous system. Noteworthy, adrenomedullin inhibited the production by encephalitogenic cells of osteopontin and of Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), two critical cytokines in the development of EAE. At the same time, adrenomedullin increased the number of IL-10-producing regulatory T cells with suppressive effects on the progression of EAE. Furthermore, adrenomedullin generated dendritic cells with a semi-mature phenotype that impaired encephalitogenic responses in vitro and in vivo. Finally, adrenomedullin regulated glial activity and favored an active program of neuroprotection/regeneration. Therefore, the use of adrenomedullin emerges as a novel multimodal therapeutic approach to treat chronic progressive multiple sclerosis.


Assuntos
Adrenomedulina/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Doença Crônica , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Feminino , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Baço/efeitos dos fármacos , Baço/imunologia
18.
Neurobiol Dis ; 63: 141-54, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24333694

RESUMO

Clinical pain, as a consequence of inflammation or injury of peripheral organs (inflammatory pain) or nerve injury (neuropathic pain), represents a serious public health issue. Treatment of pain-related suffering requires knowledge of how pain signals are initially interpreted and subsequently transmitted and perpetuated. To limit duration and intensity of pain, inhibitory signals participate in pain perception. Cortistatin is a cyclic-neuropeptide that exerts potent inhibitory actions on cortical neurons and immune cells. Here, we found that cortistatin is a natural analgesic component of the peripheral nociceptive system produced by peptidergic nociceptive neurons of the dorsal root ganglia in response to inflammatory and noxious stimuli. Moreover, cortistatin is produced by GABAergic interneurons of deep layers of dorsal horn of spinal cord. By using cortistatin-deficient mice, we demonstrated that endogenous cortistatin critically tunes pain perception in physiological and pathological states. Furthermore, peripheral and spinal injection of cortistatin potently reduced nocifensive behavior, heat hyperalgesia and tactile allodynia in experimental models of clinical pain evoked by chronic inflammation, surgery and arthritis. The analgesic effects of cortistatin were independent of its anti-inflammatory activity and directly exerted on peripheral and central nociceptive terminals via Gαi-coupled somatostatin-receptors (mainly sstr2) and blocking intracellular signaling that drives neuronal plasticity including protein kinase A-, calcium- and Akt/ERK-mediated release of nociceptive peptides. Moreover, cortistatin could modulate, through its binding to ghrelin-receptor (GHSR1), pain-induced sensitization of secondary neurons in spinal cord. Therefore, cortistatin emerges as an anti-inflammatory factor with potent analgesic effects that offers a new approach to clinical pain therapy, especially in inflammatory states.


Assuntos
Analgésicos/uso terapêutico , Neuropeptídeos/metabolismo , Dor/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Células Cultivadas , Modelos Animais de Doenças , Vias de Administração de Medicamentos , Feminino , Gânglios Espinais/citologia , Inflamação/complicações , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neuropeptídeos/deficiência , Nitrobenzenos/uso terapêutico , Dor/etiologia , Dor/genética , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Medula Espinal/citologia , Sulfonamidas/uso terapêutico , Fatores de Tempo
19.
Saúde Soc ; 22(3): 903-915, jul.-set. 2013. tab
Artigo em Português | LILACS | ID: lil-694136

RESUMO

Neste estudo quantitativo e de base populacional objetivou-se identificar as intenções reprodutivas de mulheres com cinco ou mais filhos, residentes em Curitiba, Paraná. Foram entrevistadas 441 mulheres em seus domicílios entre os anos de 2006 a 2008. Calcularam-se frequências, e o teste t de Student e o coeficiente de Spearman para algumas variáveis. Para análise das perguntas abertas utilizou-se a análise de conteúdo e se elaboraram tabelas com as categorias e as respectivas frequências. O estudo revelou que para 51 por cento das mulheres o número ideal de filhos seria dois; 10 por cento tiveram o número de filhos que desejavam. Em 113 casos (40,4 por cento) o marido preferia ter um número maior de filhos do que as mulheres. Identificaram-se dificuldades na definição e na conquista da fecundidade desejada, falhas na assistência à saúde reprodutiva e desigualdades sociais e de gênero. O monitoramento pelos gestores de saúde dos diferenciais de fecundidade é necessário para o alcance da justiça social e a garantia dos direitos humanos, sexuais e reprodutivos, no Brasil.


This quantitative and population-based study aimed to identify reproductive intentions of women with five or more children living in Curitiba, Paraná. 441 women were interviewed in their homes between the years 2006 to 2008. Frequencies were calculated, as well as Student's t test and Spearman coefficient for some variables. To analyse the open questions it was used content analysis and worked out tables with categories , their frequencies and percentages. The study revealed that for 51% of women the ideal number of children would have been two children; 10% had the number of children they wanted. In 113 cases (40.4%) the husbands would rather have a larger number of children than women. Difficulties were identified in the definition and achievement of desired fertility, besides failures in reproductive health care and social and gender inequalities. Health managers should monitor the differentials in fertility rates in order to pursue social justice and ensure human rights, as well as sexual and reproductive rights in Brazil.


Assuntos
Humanos , Feminino , Anticoncepção , Comportamento Reprodutivo , Medicina Reprodutiva , Condições Sociais , População Urbana , Mulheres , Estudos Transversais , Demografia , Pesquisa Qualitativa
20.
J Immunol ; 191(5): 2144-54, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23918980

RESUMO

Cortistatin is a cyclic-neuropeptide produced by brain cortex and immune cells that shows potent anti-inflammatory activity. In this article, we investigated the effect of cortistatin in two models of experimental autoimmune encephalomyelitis (EAE) that mirror chronic and relapsing-remitting multiple sclerosis. A short-term systemic treatment with cortistatin reduced clinical severity and incidence of EAE, the appearance of inflammatory infiltrates in spinal cord, and the subsequent demyelination and axonal damage. This effect was associated with a reduction of the two deleterious components of the disease, namely, the autoimmune and inflammatory response. Cortistatin decreased the presence/activation of encephalitogenic Th1 and Th17 cells in periphery and nervous system, and downregulated various inflammatory mediators, whereas it increased the number of regulatory T cells with suppressive effects on the encephalitogenic response. Moreover, cortistatin regulated glial activity and favored an active program of neuroprotection/regeneration. We further used cortistatin-deficient mice to investigate the role of endogenous cortistatin in the control of immune responses. Surprisingly, cortistatin-deficient mice were partially resistant to EAE and other inflammatory disorders, despite showing competent inflammatory/autoreactive responses. This unexpected phenotype was associated with elevated circulating glucocorticoids and an anxiety-like behavior. Our findings provide a powerful rationale for the assessment of the efficacy of cortistatin as a novel multimodal therapeutic approach to treat multiple sclerosis and identify cortistatin as a key endogenous component of neuroimmune system.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Neuropeptídeos/metabolismo , Linfócitos T/efeitos dos fármacos , Animais , Encefalomielite Autoimune Experimental/patologia , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropeptídeos/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/imunologia , Medula Espinal/patologia , Linfócitos T/imunologia
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