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1.
Biomédica (Bogotá) ; 43(1): 51-60, mar. 2023. graf
Artigo em Espanhol | LILACS | ID: biblio-1533919

RESUMO

Hay muchos factores implicados en la incidencia de la enfermedad de Alzheimer que, en combinación, terminan por impedir o dificultar las funciones neuronales normales. Actualmente, poco se conoce sobre la regulación del calcio, antes de la enfermedad y durante la misma. La inestabilidad interna de los niveles de calcio se asocia a un mayor riesgo vascular, condición prevalente en un gran número de individuos ya comprometidos por la enfermedad de Alzheimer. Esta revisión proporciona una reevaluación de los mecanismos moleculares de la ATPasa dependiente de Ca2+ del retículo sarcoendoplásmico (SERC-A) en la enfermedad y analiza los aspectos más destacados de la función de los canales de calcio dependientes de voltaje; de esta manera, se podrán abrir nuevas alternativas de tratamiento. Estos mecanismos de regulación son clínicamente relevantes, ya que se ha implicado la función irregular de SERC-A en diversas alteraciones de la función cerebral.


There are many factors involved in the incidence of Alzheimer's disease that, in combination, impede or hinder normal neuronal functions. Little is currently known about calcium regulation before and during the disease. Internal instability of calcium levels is associated with increased vascular risk, a prevalent condition in a high number of individuals already compromised by Alzheimer's disease. This review provides a reevaluation of the molecular mechanism of the sarcoendoplasmic reticulum calcium ATPase (SERC-A) in the disease and discusses salient aspects of voltage-gated calcium channel function; in these way new alternatives could be open for its treatment. These regulation mechanisms are clinically relevant since the irregular functions of SERC+A has been implicated in pathologies of brain function.


Assuntos
Distúrbios do Metabolismo do Cálcio , Doença de Alzheimer , Receptores de N-Metil-D-Aspartato , ATPases Transportadoras de Cálcio , Retículo Endoplasmático
2.
Rev. Méd. Inst. Mex. Seguro Soc ; 60(2): 211-223, abr. 2022. ilus, tab
Artigo em Espanhol | LILACS | ID: biblio-1367402

RESUMO

El retículo endoplásmico es un organelo abundante, dinámico y sensor de energía. Sus abundantes membranas, rugosa y lisa, se encuentran distribuidas en diferentes proporciones dependiendo del linaje y requerimiento celular. Su función es llevar a cabo la síntesis de proteínas y lípidos, y es el almacén principal de Ca2+ intracelular. La sobrecarga calórica y la glucolipotoxicidad generada por dietas hipercalóricas provoca la alteración del retículo endoplásmico, activando la respuesta a proteínas mal plegadas (UPR, Unfolded Protein Response, por sus siglas en inglés) como reacción al estrés celular relacionado con el retículo endoplásmico y cuyo objetivo es restablecer la homeostasis del organelo al disminuir el estrés oxidante, la síntesis de proteínas y la fuga de Ca2+. Sin embargo, durante un estrés crónico, la UPR induce formación de especies reactivas de oxígeno, inflamación y apoptosis, exacerbando el estado del retículo endoplásmico y propagando un efecto nocivo para los demás organelos. Es por ello que el estrés del retículo endoplásmico se ha considerado un inductor del inicio y desarrollo de enfermedades metabólicas, incluido el agravamiento de COVID-19. Hasta el momento, existen pocas estrategias para reestablecer la homeostasis del retículo endoplásmico, las cuales son dirigidas a los sensores que desencadenan la UPR. Por tanto, se justifica con urgencia la identificación de nuevos mecanismos y terapias novedosas relacionadas con mitigar el impacto del estrés del retículo endoplásmico y las complicaciones asociadas.


The endoplasmic reticulum is an abundant, dynamic and energy-sensing organelle. Its abundant membranes, rough and smooth, are distributed in different proportions depending on the cell lineage and requirement. Its function is to carry out protein and lipid synthesis, and it is the main intracellular Ca2+ store. Caloric overload and glycolipotoxicity generated by hypercaloric diets cause alteration of the endoplasmic reticulum, activating the Unfolded Protein Response (UPR) as a reaction to cellular stress related to the endoplasmic reticulum and whose objective is to restore the homeostasis of the organelle by decreasing oxidative stress, protein synthesis and Ca2+ leakage. However, during chronic stress, the UPR induces reactive oxygen species formation, inflammation and apoptosis, exacerbating the state of the endoplasmic reticulum and propagating a deleterious effect on the other organelles. This is why endoplasmic reticulum stress has been considered an inducer of the onset and development of metabolic diseases, including the aggravation of COVID-19. So far, few strategies exist to reestablish endoplasmic reticulum homeostasis, which are targeted to sensors that trigger UPR. Therefore, the identif ication of new mechanisms and novel therapies related to mitigating the impact of endoplasmic reticulum stress and associated complications is urgently warranted.


Assuntos
Humanos , Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , COVID-19/complicações , Doenças Metabólicas/etiologia , COVID-19/terapia , Homeostase
3.
Mem. Inst. Oswaldo Cruz ; 116: e200443, 2021. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1154874

RESUMO

BACKGROUND The coronaviruses (CoVs) called the attention of the world for causing outbreaks of severe acute respiratory syndrome (SARS-CoV), in Asia in 2002-03, and respiratory disease in the Middle East (MERS-CoV), in 2012. In December 2019, yet again a new coronavirus (SARS-CoV-2) first identified in Wuhan, China, was associated with a severe respiratory infection, known today as COVID-19. This new virus quickly spread throughout China and 30 additional countries. As result, the World Health Organization (WHO) elevated the status of the COVID-19 outbreak from emergency of international concern to pandemic on March 11, 2020. The impact of COVID-19 on public health and economy fueled a worldwide race to approve therapeutic and prophylactic agents, but so far, there are no specific antiviral drugs or vaccines available. In current scenario, the development of in vitro systems for viral mass production and for testing antiviral and vaccine candidates proves to be an urgent matter. OBJECTIVE The objective of this paper is study the biology of SARS-CoV-2 in Vero-E6 cells at the ultrastructural level. METHODS In this study, we documented, by transmission electron microscopy and real-time reverse transcription polymerase chain reaction (RT-PCR), the infection of Vero-E6 cells with SARS-CoV-2 samples isolated from Brazilian patients. FINDINGS The infected cells presented cytopathic effects and SARS-CoV-2 particles were observed attached to the cell surface and inside cytoplasmic vesicles. The entry of the virus into cells occurred through the endocytic pathway or by fusion of the viral envelope with the cell membrane. Assembled nucleocapsids were verified inside rough endoplasmic reticulum cisterns (RER). Viral maturation seemed to occur by budding of viral particles from the RER into smooth membrane vesicles. MAIN CONCLUSIONS Therefore, the susceptibility of Vero-E6 cells to SARS-CoV-2 infection and the viral pathway inside the cells were demonstrated by ultrastructural analysis.


Assuntos
Humanos , Animais , Células Vero/virologia , Vesículas Citoplasmáticas/virologia , Efeito Citopatogênico Viral , SARS-CoV-2/fisiologia , Chlorocebus aethiops , Nucleocapsídeo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Microscopia Eletrônica de Transmissão , Endocitose , Retículo Endoplasmático/virologia , Internalização do Vírus , Reação em Cadeia da Polimerase em Tempo Real
4.
Rev. méd. Chile ; 148(2): 216-223, feb. 2020. graf
Artigo em Espanhol | LILACS | ID: biblio-1115779

RESUMO

The clinical features of Alzheimer's disease (AD), for example the progressive memory loss, are produced by neuronal loss and synaptic dysfunction. These events have been associated with histopathological alterations in AD brain, including the presence of amyloid plaques and neurofibrillary tangles. Recent studies suggest that cellular stress produced by the aggregation of misfolded proteins leads to alterations in protein homeostasis, that is regulated for the most part by endoplasmic reticulum (ER). The ER is the main compartment involved in the folding and secretion of proteins and is drastically affected in AD neurons. Recent evidence implicates the participation of adaptive responses to stress within the ER in the disease process through a signaling pathway known as the Unfolded Protein Response (UPR) which alleviates the protein aggregation and ER stress. Based on the involvement of ER stress in several diseases, efforts are being done to identify small molecules that can inhibit or activate selective UPR components. Here, we review the findings suggesting a functional role of ER stress in the etiology of AD. Possible therapeutic strategies to mitigate ER stress in the context of AD are discussed.


Assuntos
Humanos , Doença de Alzheimer , Transdução de Sinais , Retículo Endoplasmático , Resposta a Proteínas não Dobradas , Estresse do Retículo Endoplasmático
5.
Motriz (Online) ; 23(spe): e101605, 2017. graf
Artigo em Inglês | LILACS | ID: biblio-841849

RESUMO

Abstract AIMS knowing the relationship between endoplasmic reticulum (ER) stress and inflammation and based on the fact that downhill running-based overtraining (OT) model increases hypothalamus levels of some pro-inflammatory cytokines, we verified the effects of three OT protocols on the levels of BiP, pIRE-1 (Ser734), pPERK (Thr981), pelF2alpha (Ser52), ATF-6 and GRP-94 proteins in the mouse hypothalamus after two weeks of recovery. METHODS the mice were randomized into control (CT), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up) and overtrained by running without inclination (OTR) groups. After 2-week total recovery period (i.e., week 10), hypothalamus was removed and used for immunoblotting. RESULTS the OTR/down group exhibited high levels of BiP and ATF6. The other OT protocols showed higher levels of pPERK (Th981) and pelf-2alpha (Ser52) when compared with the CT group. CONCLUSION the current results suggest that after a 2-week total recovery period, the overtrained groups increased partially their ER stress protein levels, but without hypothalamic inflammation, which characterizes a physiological condition related to an adaptation mechanism.(AU)


Assuntos
Animais , Masculino , Camundongos , Adaptação Fisiológica , Retículo Endoplasmático , Exercício Físico , Hipotálamo , Camundongos Endogâmicos C57BL
7.
Dental press j. orthod. (Impr.) ; 20(2): 68-75, Mar-Apr/2015. tab, graf
Artigo em Inglês | LILACS | ID: lil-745863

RESUMO

OBJECTIVE: The aim of this cross sectional study was to assess serum insulin-like growth factor-1 (IGF-1) levels in female and male subjects at various cervical vertebral maturation (CVM) stages. MATERIAL AND METHODS: The study sample consisted of 60 subjects, 30 females and 30 males, in the age range of 8-23 years. For all subjects, serum IGF-1 level was estimated from blood samples by means of chemiluminescence immunoassay (CLIA). CVM was assessed on lateral cephalograms using the method described by Baccetti. Serum IGF-1 level and cervical staging data of 30 female subjects were included and taken from records of a previous study. Data were analyzed by Kruska-Wallis and Mann Whitney test. Bonferroni correction was carried out and alpha value was set at 0.003. RESULTS: Peak value of serum IGF-1 was observed in cervical stages CS3 in females and CS4 in males. Differences between males and females were observed in mean values of IGF-1 at stages CS3, 4 and 5. The highest mean IGF-1 levels in males was observed in CS4 followed by CS5 and third highest in CS3; whereas in females the highest mean IGF-1 levelswas observed in CS3 followed by CS4 and third highest in CS5. Trends of IGF-1 in relation to the cervical stages also differed between males and females. The greatest mean serum IGF-1 value for both sexes was comparable, for females (397 ng/ml) values were slightly higher than in males (394.8 ng/ml). CONCLUSIONS: Males and females showed differences in IGF-1 trends and levels at different cervical stages. .


OBJETIVO: o objetivo do presente estudo transversal foi avaliar os níveis do fator de crescimento semelhante à insulina-1 (IGF-1 sérico) em pacientes de ambos os sexos e em diferentes estágios de maturação das vértebras cervicais (MVC). MÉTODOS: a amostra consistiu de 60 pacientes, sendo 30 do sexo masculino e 30 do sexo feminino, com idades entre 8 e 23 anos. Amostras de sangue foram colhidas de todos os pacientes, cujos níveis de IGF-1 sérico foram avaliados por meio do método de imunoensaio quimioluminescente (CLIA). O estágio de MVC foi avaliado por meio de radiografias cefalométricas de perfil por meio do método descrito por Baccetti. O nível de IGF-1 sérico e o estágio de maturação das vertebras cervicais de 30 pacientes do sexo feminino foram avaliados e os dados retirados dos registros de um estudo prévio. Os dados foram submetidos aos testes de Kruskal-Wallis e de Mann-Whitney. A correção de Bonferroni foi calculada e o valor de alfa foi de 0,003. RESULTADOS: o valor de pico do IGF-1 sérico foi encontrado no estágio CS3, para mulheres, e CS4, para homens. Foram encontradas diferenças entre as médias dos valores de IGF-1 entre homens e mulheres nos estágios CS3, 4 e 5. O valor médio mais alto para os níveis de IGF-1 nos homens foi observado no estágio CS4, seguido do estágio CS5 e CS3. Nas mulheres, o valor médio mais alto foi observado em CS3, seguido do estágio CS4 e CS5. Diferenças também foram encontradas quanto à curva do IGF-1, em relação ao estágio de maturação das vértebras cervicais nos pacientes de ambos os sexos. O valor médio de IGF-1 sérico mais alto foi comparado. As pacientes do sexo feminino apresentaram valores ligeiramente mais altos (397ng/ml) em comparação aos pacientes do sexo masculino (394.8ng/ml). CONCLUSÕES: homens e mulheres apresentam valores de IGF-1 diferentes em estágios de maturação das vértebras cervicais diferentes. .


Assuntos
Animais , Camundongos , Retículo Endoplasmático/metabolismo , Mediadores da Inflamação/metabolismo , Macrolídeos/metabolismo , Mycobacterium ulcerans/patogenicidade , Úlcera de Buruli/metabolismo , Úlcera de Buruli/microbiologia , Úlcera de Buruli/patologia , Linhagem Celular , Moléculas de Adesão Celular , Retículo Endoplasmático/patologia , Lipopolissacarídeos/toxicidade , Mycobacterium ulcerans/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Fator de Necrose Tumoral alfa
8.
Rev. bras. cir. cardiovasc ; 30(1): 24-32, Jan-Mar/2015. tab, graf
Artigo em Inglês | LILACS | ID: lil-742904

RESUMO

Objective: A retrospective cohort study was preformed aiming to verify the presence of transient dysfunction of gas exchange in the postoperative period of cardiac surgery and determine if this disorder is linked to cardiorespiratory events. Methods: We included 942 consecutive patients undergoing cardiac surgery and cardiac procedures who were referred to the Intensive Care Unit between June 2007 and November 2011. Results: Fifteen patients had acute respiratory distress syndrome (2%), 199 (27.75%) had mild transient dysfunction of gas exchange, 402 (56.1%) had moderate transient dysfunction of gas exchange, and 39 (5.4%) had severe transient dysfunction of gas exchange. Hypertension and cardiogenic shock were associated with the emergence of moderate transient dysfunction of gas exchange postoperatively (P=0.02 and P=0.019, respectively) and were risk factors for this dysfunction (P=0.0023 and P=0.0017, respectively). Diabetes mellitus was also a risk factor for transient dysfunction of gas exchange (P=0.03). Pneumonia was present in 8.9% of cases and correlated with the presence of moderate transient dysfunction of gas exchange (P=0.001). Severe transient dysfunction of gas exchange was associated with patients who had renal replacement therapy (P=0.0005), hemotherapy (P=0.0001), enteral nutrition (P=0.0012), or cardiac arrhythmia (P=0.0451). Conclusion: Preoperative hypertension and cardiogenic shock were associated with the occurrence of postoperative transient dysfunction of gas exchange. The preoperative risk factors included hypertension, cardiogenic shock, and diabetes. Postoperatively, pneumonia, ventilator-associated pneumonia, renal replacement therapy, hemotherapy, and cardiac arrhythmia were associated with the appearance of some degree of transient dysfunction of gas exchange, which was a risk factor for reintubation, pneumonia, ventilator-associated pneumonia, and renal replacement therapy in the postoperative period ...


Objetivo: Estudo de coorte retrospectivo com objetivo de verificar a presença de disfunção transitória da troca gasosa no pós-operatório de cirurgia cardíaca e determinar se esse transtorno está relacionado a eventos cardiorrespiratórios. Métodos: Foram incluídos 942 pacientes consecutivos submetidos à cirurgia cardíaca e procedimentos cardíacos, encaminhados para a Unidade de Terapia Intensiva, entre junho de 2007 e novembro de 2011. Resultados: A síndrome do desconforto respiratório agudo foi observada em 15 (2%) pacientes, 199 (27,75%) pacientes apresentaram disfunção transitória da troca gasosa leve, disfunção transitória da troca gasosa moderada foi observada em 402 (56,1%) pacientes e disfunção transitória da troca gasosa grave em 39 (5,4%). A presença de hipertensão arterial sistêmica e choque cardiogênico foi associada ao surgimento de disfunção transitória da troca gasosa moderada no período pós-operatório (P=0,02 e P=0,019, respectivamente) e foram considerados fatores de risco para essa disfunção (P=0,0023 e P=0,0017, respectivamente). A presença de diabetes mellitus também foi considerada um fator de risco para disfunção transitória da troca gasosa (P=0,03). Houve correlação entre a presença de pneumonia e a presença de disfunção transitória da troca gasosa moderada em 8,9% dos casos (P=0,001). A presença de disfunção transitória da troca gasosa grave foi associada a pacientes que necessitaram de hemodiálise (P=0,0005), hemoterapia (P=0,0001), nutrição enteral (P=0,0012), ou arritmia cardíaca (P=0,0451). Conclusão: A presença de hipertensão arterial sistêmica pré-operatória e choque cardiogênico foi associada à ocorrência de disfunção transitória da troca gasosa pós-operatória. Os fatores de risco pré-operatórios foram hipertensão arterial sistêmica, choque cardiogênico e diabetes. No pós-operatório, pneumonia, pneumonia associada à ventilação, hemodiálise, hemoterapia e arritmia cardíaca foram associadas com certo grau de ...


Assuntos
Animais , Humanos , Ratos , Oxirredutases do Álcool/metabolismo , Células Endoteliais/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fenantrenos/metabolismo , Aldeído Redutase , Fator de Ligação a CCAAT/metabolismo , Caspases/metabolismo , Retículo Endoplasmático/metabolismo , Leupeptinas/farmacologia , Oxirredução , Estresse Oxidativo , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo
10.
São Paulo; s.n; 2015. [109] p. ilus, tab, graf.
Tese em Português | LILACS | ID: biblio-870942

RESUMO

Dissulfeto isomerase protéica (PDIA1 ou PDI) é uma chaperona e ditiol-dissulfeto oxido-redutase residente do reticulo endoplasmático (RE). PDI é essencial à regulação da proteostase por ter função no enovelamento oxidativo de proteínas e na via de degradação associada ao RE (ERAD). Além disso, PDI interage fisicamente e regula a atividade de NADPH oxidases, e fora da célula é um regulador redox essencial à atividade de proteínas extracelulares. Este pool epi/pericelular da PDI (pecPDI) regula função de proteínas de membrana/secretadas, como integrinas, glicoproteínas gp120 do virus HIV e outras, com múltiplas funções que incluem: trombose, ativação plaquetária, adesão celular, infecção viral e remodelamento vascular. A rota de externalização da PDI permanece obscura, e seu conhecimento pode indicar mecanismos dos efeitos (fisio)patológicos da PDI. A secreção da PDI pela rota RE-Golgi foi sugerida em células endoteliais infectadas pelo vírus da dengue, células pancreáticas e tireoideanas. No entanto, uma varredura sistemática das possíveis rotas de externalização da PDI não foi previamente realizada. Neste estudo, mostramos que células endoteliais (EC) externalizam constitutivamente, por rotas distintas, dois pools de PDI, de superfície celular e solúvel, enquanto na EC não estimulada PDI não foi detectada significativamente em micropartículas. PDI externalizada corresponde a ca.1,4% do pool total de PDI celular. Tanto a PDI de superfície celular como a solúvel foram majoritariamente secretadas pela via de secreção não-convencional do tipo IV independente de GRASP. Contudo, a via de secreção clássica também contribui para externalização basal da PDI de superfície celular, mas não da solúvel basal ou estimulada por PMA, ATP e trombina indicando que todas envolvem escape do Golgi. Além disso, a externalização constitutiva da PDI de superfície em célula muscular lisa vascular também ocorre por via independente de Golgi. Externalização...


Protein disulfide isomerase (PDIA1 or PDI) is dithiol-disulfide oxireductase chaperone resident in the endoplasmic reticulum (ER). PDI is essential for proteostasis, due to its support of oxidative protein folding and ER-associated protein degradation (ERAD). In addition, PDI associates with NADPH oxidase(s) and regulate its activity, while outside of the cell, PDI redox-dependently modulates extracellular proteins. This epi/pericellular PDI (pecPDI) pool is known to regulate membrane/secreted proteins such as integrins, HIV glycoprotein gp120 and others, with functions that involve thrombosis, platelet function, cell adhesion, viral infection and vascular remodeling. PDI externalization route remains enigmatic and its elucidation can help understand some (patho)physiological PDI effects. An ER-Golgi route for PDI secretion has been as described on dengue virus-infected endothelial cells pancreatic and thyroid) cells. However, none of these papers addressed PDI secretion routes in a systematic fashion. Here, we show that endothelial cells (EC) constitutively externalize, through different routes, two PDI pools, a cell-surface and a secreted one, while in nonstimulated ECs PDI was not significantly detected in microparticles. Externalized PDI corresponds to < 2% of total cellular PDI pool. Both cell-surface and soluble PDI were predominantly externalized through unconventional type IV GRASP-independent pathway(s). However, the classical secretory pathway also contributes to basal cell-surface, but not soluble, PDI externalization, as PMA, ATP or thrombin-stimulated secretion also involve Golgi bypass. Furthermore, constitutive cell-surface PDI externalization in vascular smooth muscle cells also occurs in a Golgi-independent way. PDI externalization was not detectably mediated by non-conventional type I, II and III secretion routes, secretory lysosomes, recycling endosomes and ATP dependent active transport in EC. Since chaperones are essential for cellular...


Assuntos
Animais , Masculino , Coelhos , Ratos , Biologia Celular , Retículo Endoplasmático , Células Endoteliais , Espaço Extracelular , Músculo Liso Vascular , Isomerases de Dissulfetos de Proteínas
11.
Biol. Res ; 48: 1-5, 2015. graf
Artigo em Inglês | LILACS | ID: biblio-950819

RESUMO

BACKGROUND: In the central nervous system, interleukin-10 (IL-10) provides trophic and survival effects directly on neurons, modulates neurite plasticity, and has a pivotal importance in the neuronal regeneration in neurodegenerative and neuroinflammatory conditions. This cytokine is primarily produced by glial cells and has beneficial effects on the neuronal viability. However, the mechanisms of IL-10-elicited neuroprotection are not clear. RESULTS: Membrane preparations, isolated from wild-type (Wt) and IL-10 knockout (KO) mice brain were used in this study. It has been shown that compared to wild-type mice, in IL-10 KO mice brain, the amount of immunoglobulin binding protein (BiP) is greatly increased, whereas the content of sigma receptor-1 (SigR1) is not changed significantly. Co-immunoprecipitation experiments have shown that the association of SigR1 with small GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1), NR2B subunit of NMDA-receptor (NMDAR) and inositol-3-phosphate receptor (IP3R) is higher in the IL-10 KO mice brain than in the Wt mice brain. Besides, we have found that either glutamate or sigma ligands, separately or together, do not change glutamate-induced NADPH-oxidase (NOX) activity in Wt-type mice brain membrane preparations, whereas in IL-10 KO mice high concentration of glutamate markedly increases the NOX-dependent production of reactive oxygen species (ROS). Glutamate-dependent ROS production was decreased to the normal levels by the action of sigma-agonists. CONCLUSIONS: It has been concluded that IL-10 deprivation, at least in part, can lead to the induction of ER-stress, which causes BiP expression and SigR1 redistribution between components of endoplasmic reticulum (ER) and plasma membrane. Moreover, IL-10 deficiency can change the specific organization of NMDAR, increasing the surface expression of SigR1-sensitive NR2B-containing NMDAR. In these conditions, glutamate-dependent ROS production is greatly increased leading to the initiation of apoptosis. In this circumstances, sigma-ligands could play a preventive role against NMDA receptor-mediated excitotoxicity.


Assuntos
Animais , Masculino , Camundongos , Encéfalo/metabolismo , Interleucina-10/genética , Receptores sigma/metabolismo , Ácido Glutâmico/metabolismo , NADPH Oxidases/metabolismo , Membrana Celular/metabolismo , Receptores sigma/classificação , Receptores sigma/agonistas , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Receptores de N-Metil-D-Aspartato/classificação , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Imunoprecipitação , Retículo Endoplasmático/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico/metabolismo , Camundongos Endogâmicos C57BL , Neurônios/metabolismo
12.
Int. j. morphol ; 32(3): 839-843, Sept. 2014. ilus
Artigo em Inglês | LILACS | ID: lil-728276

RESUMO

Metformin, an oral biguanide approved for the treatment of type II diabetes is widely prescribed for other clinical conditions. Currently, metformin is being investigated as potential anti-tumor agent. However, there have been recent concerns about hepatotoxicity associated with the use of metformin. This study, by means of high resolution transmission electron microscopy (TEM) and morphometry, investigated potential ultrastructural changes induced by metformin treatment on the hepatocytes of spontaneously hypertensive rats (SHR). Morphometric analysis was carried out on images of randomly selected cells from sectioned gluteraldehyde-osmium-fixed, Epon embedded liver tissue. One-way analysis of variance (ANOVA) on morphometric data showed statistically significant differences in the mean volume density (MVD) of lipid bodies (F=136.48, P<0.0001)and mean surface density (MSD) of endoplasmic reticulum (ER) (F=12.45, P<0.003) between hepatocytes of control (n=8) and metformin-treated (MT) (n=8) animals. MVD for control group was 5.42% (±0.36 SEM) but decreased significantly in the MT group (1.13%, ±0.04 SEM). Similarly, MSD of ER for control was 24.7 µm2/µm3 (±1.64 SEM) but decreased for MT animals (18.90 µm2/µm3, ±0.28 SEM). These data are most likely consistent with the effects of metformin on lipid metabolism, and may not reflect on hepatotoxicity induced by the drug, in SHRs.


La metformina, una biguanida oral aprobada para el tratamiento de la diabetes tipo II, es también ampliamente prescrita para otros cuadros clínicos. Actualmente, la metformina está siendo investigada como posible agente anti-tumoral. Sin embargo, ha habido recientes preocupaciones acerca de la hepatotoxicidad asociada con el uso de metformina. En este estudio, por medio de la microscopía electrónica de transmisión (MET) de alta resolución y morfometría, se investigaron los posibles cambios ultraestructurales, inducidos por el tratamiento con metformina, en los hepatocitos de ratas espontáneamente hipertensas (REH). El análisis morfométrico se llevó a cabo en imágenes de células seleccionadas al azar a partir de tejido hepático seccionado, fijado con glutaraldehído-osmio e inmerso en Epon. El análisis de la varianza (ANOVA) de los datos morfométricos mostró diferencias significativas en la densidad de volumen medio (DVM) de cuerpos lipídicos (F=136,48, P<0,0001) y la densidad de superficie media (DSM) del retículo endoplasmático (RE) (F=12,45, P<0,003) entre los hepatocitos control (n=8) y los animales tratados con metformina (MT) (n=8). La DVM para el grupo control fue de 5,42% (±0,36 EEM), pero disminuyó significativamente en el grupo MT (1,13%, ±0,04 EEM). Del mismo modo, la DSM del RE para el grupo control fue de 24,7 µm2/µm3 (±1,64 EEM), pero disminuyó para los animales MT (18,90 µm2/µm3, ±0,28 EEM). Estos datos están probablemente más relacionados con los efectos de la metformina sobre el metabolismo de los lípidos, y no se relacionarían con la hepatotoxicidad por inducción de la droga, en REH.


Assuntos
Animais , Ratos , Hepatócitos/efeitos dos fármacos , Hipertensão/metabolismo , Metformina/administração & dosagem , Análise de Variância , Hepatócitos/ultraestrutura , Microscopia Eletrônica de Transmissão , Retículo Endoplasmático/efeitos dos fármacos , Lipídeos/análise , Metformina/farmacologia
13.
Arq. bras. endocrinol. metab ; 58(6): 600-609, 08/2014. graf
Artigo em Inglês | LILACS | ID: lil-721396

RESUMO

Overall excess of fat, usually defined by the body mass index, is associated with metabolic (e.g. glucose intolerance, type 2 diabetes mellitus (T2DM), dyslipidemia) and non-metabolic disorders (e.g. neoplasias, polycystic ovary syndrome, non-alcoholic fat liver disease, glomerulopathy, bone fragility etc.). However, more than its total amount, the distribution of adipose tissue throughout the body is a better predictor of the risk to the development of those disorders. Fat accumulation in the abdominal area and in non-adipose tissue (ectopic fat), for example, is associated with increased risk to develop metabolic and non-metabolic derangements. On the other hand, observations suggest that individuals who present peripheral adiposity, characterized by large hip and thigh circumferences, have better glucose tolerance, reduced incidence of T2DM and of metabolic syndrome. Insulin resistance (IR) is one of the main culprits in the association between obesity, particularly visceral, and metabolic as well as non-metabolic diseases. In this review we will highlight the current pathophysiological and molecular mechanisms possibly involved in the link between increased VAT, ectopic fat, IR and comorbidities. We will also provide some insights in the identification of these abnormalities. Arq Bras Endocrinol Metab. 2014;58(6):600-9.


Excesso de gordura, geralmente definido pelo índice de massa corporal, está associado a distúrbios metabólicos (p. ex., intolerância à glicose, diabetes melito tipo 2 (DM2), dislipidemia) e não metabólicos (p. ex., neoplasias, síndrome dos ovários policísticos, esteatose hepática não alcoólica, glomerulopatia, fragilidade óssea etc.). No entanto, mais do que sua quantidade total, a forma da distribuição corporal de tecido adiposo constitui-se em um melhor indicador de risco para o desenvolvimento de tais doenças. O acúmulo de gordura na região abdominal e em tecido não adiposo (gordura ectópica), por exemplo, está associado ao aumento de risco para distúrbios metabólicos e não metabólicos. Por outro lado, observações sugerem que os indivíduos que apresentam adiposidade periférica, caracterizada por aumento das circunferências dos quadris e da coxas, têm melhor tolerância à glicose, redução das incidências de DM2 e da síndrome metabólica. Uma das alterações subjacentes na relação entre a obesidade, particularmente a visceral, e os distúrbios citados é a resistência à insulina. Nesta revisão, enfatizaremos os mecanismos fisiopatológicos e moleculares possivelmente implicados na ligação entre o aumento das gorduras visceral e ectópica, IR e comorbidades. Também mencionaremos os métodos diagnósticos mais frequentemente usados na identificação dessas anormalidades. Arq Bras Endocrinol Metab. 2014;58(6):600-9.


Assuntos
Animais , Humanos , Tecido Adiposo/fisiopatologia , Hiperinsulinismo/complicações , Resistência à Insulina , Obesidade/complicações , Apoptose , Tecido Adiposo/patologia , Distribuição da Gordura Corporal , Retículo Endoplasmático/metabolismo , Hiperinsulinismo/metabolismo , Mitocôndrias/metabolismo , Oxirredução , Estresse Oxidativo , Obesidade/metabolismo , Obesidade/fisiopatologia , Medição de Risco
14.
Rio de Janeiro; s.n; 2014. xi,96 p. ilus, graf, mapas.
Tese em Português | LILACS | ID: lil-781865

RESUMO

T. gondii é parasito intracelular obrigatório, agente etiológico datoxoplasmose, doença com ampla distribuição mundial. Os transtornos mais severos(fase aguda) acometem pacientes imunocomprometidos. Hospedeirosimunologicamente sadios, uma vez infectados, apresentam cistos teciduais (fasecrônica) de modo perene. Estudos sugerem que por possuírem um eficientemetabolismo energético, os principais tecidos eleitos para a cistogênese do T.gondii, são o nervoso e o muscular esquelético. O presente trabalho dedicou-se aoestudo das associações de mitocôndrias e do retículo endoplasmßtico (RE) àmembrana do vacúolo parasitóforo (MVP) e à parede cística. Para tanto, foramutilizados bradizoítos e taquizoítos da cepa ME49 (tipo II) e culturas primßrias decélula muscular esquelética (CME) e da linhagem C2C12. Nossas estratégiasmetodológicas contemplaram microscopia de fluorescência, microscopia eletrônicade transmissão, respirometria de alta resolução e ensaios de efeito de um inibidor dafosforilação oxidativa (ISA-34) sobre a cistogênese. Os dados obtidos apontam aocorrência de: (i) associações entre mitocôndrias com a parede cística; (ii) aspectospeculiares ultraestruturais decorrentes de associações entre mitocôndrias e RE(rugoso e liso) da CME com a MVP de vacúolos contendo bradizoítos; (iii)manutenção do metabolismo mitocondrial da CME pelo T. gondii, durante a fasecrônica; (iv) efeito inibitório do composto ISA-34 sobre o desenvolvimento de cistosteciduais. Estes resultados, além de iniciarem uma linha de pesquisa inédita arespeito das respostas do metabolismo energético da CME frente à cistogênese deT. gondii, também abrem novas perspectivas para uma terapia alternativa voltadapara a fase crônica da toxoplasmose...


Toxoplasma gondii is an obligatory intracellular parasite, agent oftoxoplasmosis, disease with a worldwide distribution. The most severe disorders(acute phase) affect immunocompromised patients. Immunologically healthyindividuals, once infected, develop tissue cysts (chronic phase) that can persist forthe host life span. Studies suggest that an efficient energetic metabolism, as innervous and skeletal muscle tissues, leads to the development of T. gondiicystogenesis. The present work aims the study of the association of skeletal musclecell (SkMC) mitochondria and endoplasmic reticulum (ER) to the parasitophorousvacuole membrane (PVM) and to the cyst wall (CW). Bradyzoites and tachyzoitesfrom ME49 strain (type II) of T. gondii and SkMC cultures and C2C12 cell line wereused. The methodological strategies employed were fluorescence microscopy,transmission electron microscopy, high-resolution respirometry and assay using ISA-34, an inhibitor of oxidative phosphorylation. Our data point out: (i) associationsbetween mitochondria and CW; (ii) ultrastructural aspects of the association of SkMCmitochondria and ER (rough and smooth) with PVM of bradyzoite-containingvacuoles; (iii) maintenance of SkMC mitochondrial metabolism by T. gondii and, (iv)inhibitory effect of ISA-34 on the tissue cysts development. These results stimulatefurther investigation concerning the response of SkMC energy metabolism duringcystogenesis of T. gondii and also open novel perspectives for an alternative therapyagainst toxoplasmosis chronic phase...


Assuntos
Camundongos , Fibras Musculares Esqueléticas/metabolismo , Mitocôndrias , Toxoplasma/citologia , Toxoplasmose/diagnóstico , Retículo Endoplasmático
15.
Mem. Inst. Oswaldo Cruz ; 107(2): 262-272, Mar. 2012. ilus, graf
Artigo em Inglês | LILACS | ID: lil-617074

RESUMO

The flaviviral envelope proteins, E protein and precursor membrane protein, are mainly associated with the endoplasmic reticulum (ER) through two transmembrane (TM) domains that are exposed to the luminal face of this compartment. Their retention is associated with the viral assembly process. ER-retrieval motifs were mapped at the carboxy terminus of these envelope proteins. A recombinant yellow fever (YF) 17D virus expressing the reporter green fluorescent protein (GFP) with the stem-anchor (SA) region of E protein fused to its carboxy terminus was subjected to distinct genetic mutations in the SA sequence to investigate their effect on ER retention. Initially, we introduced progressive deletions of the stem elements (H1, CS and H2). In a second set of mutants, the effect of a length increase for the first TM anchor region was evaluated either by replacing it with the longer TM of human LAMP-1 or by the insertion of the VALLLVA sequence into its carboxy terminus. We did not detect any effect on the GFP localisation in the cell, which remained associated with the ER. Further studies should be undertaken to elucidate the causes of the ER retention of recombinant proteins expressed at the intergenic E/NS1 region of the YF 17D virus polyprotein.


Assuntos
Animais , DNA Intergênico/genética , Retículo Endoplasmático/virologia , Proteínas de Fluorescência Verde/genética , Mutagênese Insercional/genética , Vírus da Febre Amarela/genética , Chlorocebus aethiops , Proteínas de Membrana , Células Vero
16.
J. bras. med ; 99(3): 13-19, Out.-Dez. 2011.
Artigo em Português | LILACS | ID: lil-612614

RESUMO

O íon cálcio funciona como um segundo mensageiro que regula um amplo espectro de processos celulares. A diminuição ou perda do controle dos mecanismos que regulam a concentração intracelular desse íon está associada, respectivamente, ao envelhecimento dos neurônios e a doenças neurodegenerativas. A gênese dessas modificações é desconhecida. Entretanto, estudos recentes apontam para uma provável correlação entre expressão gênica alterada, estresse do retículo endoplasmático e os processos patológicos associados à disfunção na concentração intracelular de cálcio. O esclarecimento dessas questões poderá trazer novos alvos terapêuticos capazes de frear ou reverter tais alterações, combatendo, dessa forma, tanto o envelhecimento neuronal quanto as doenças neurodegenerativas.


Calcium is a second messenger that regulates a lot of cellular functions. The following mechanisms regulate the intracellular concentrations of the ion: influx, release, extrusion and storage. Decrease or loss in control of these mechanisms is related to aging of neurons and neurodegenerative diseases, respectively. The genesis of these alterations is unknown. However, recent studies point to a correlation between calcium dysfunction and altered gene expression. There is also a correlation between endoplasmic reticulum stress and pathological processes. Further investigations may reveal new therapeutical targets that can block or revert these alterations.


Assuntos
Humanos , Masculino , Feminino , Sinalização do Cálcio , Cálcio/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doenças Neurodegenerativas/fisiopatologia , Senescência Celular/fisiologia , Expressão Gênica/genética , Neurônios , Neurônios/metabolismo , Retículo Endoplasmático/metabolismo
17.
Braz. j. morphol. sci ; 28(2): 120-128, Apr.-June 2011. tab, ilus
Artigo em Inglês | LILACS | ID: lil-644141

RESUMO

Heart autonomic ganglia play an important role in cardiac rhythm control, protecting against certainarrhythmias due to their parasympathetic activity. Starvation during pregnancy may cause cardiac disorders andhinder optimal cardiac performance. Also, morphology of subepicardial neuron is subjected to the influenceof extrinsic factors. We studied the influence of protein deprivation on subepicardic neurons in rats at earlydevelopment stages and the effect of restoration of a normal diet.: Three groups of pregnant Wistar rats weresubmitted to different diets according to its protein content: normal (NN group) and 5% casein (DD group),until 42 days after delivery and low protein for 21 days with refeeding for a further 21 days (RN group).All animal were weighed. The number and area of neuronal profiles were measured. The neurons werestained by histochemical methods â-nicotinamide adenine dinucleotide (NADH) and â-nicotinamide adeninedinucleotide phosphate diaphorase (NADPH-d) and their ultra structure were observed.Group DD and RNanimals weighed less than those from group NN. The number of neurons and the cellular profile area didnot show significant differences among groups for both techniques. Endoplasmatic reticulum ribosomes inneurons of undernourished animals showed decreased electron density. Protein deprivation in early stages ofdevelopment produces ultra structural changes but does not alter the number and profile area of nerve cellbodies in rats.


Assuntos
Animais , Feminino , Gravidez , Ratos , Retículo Endoplasmático , Dieta , Neurônios , Ribossomos/metabolismo , Distúrbios Nutricionais , Ratos Wistar/anatomia & histologia
18.
Biol. Res ; 44(1): 17-23, 2011. ilus
Artigo em Inglês | LILACS | ID: lil-591860

RESUMO

Neurons are highly polarized, but the trafficking mechanisms that operate in these cells and the topological organization of their secretory organelles are still poorly understood. Particularly incipient is our knowledge of the role of the neuronal endoplasmic reticulum. Here we review the current understanding of the endoplasmic reticulum in neurons, its structure, composition, dendritic distribution and dynamics. We also focus on the trafficking of proteins through the dendritic endoplasmic reticulum, emphasizing the relevance of transport, retention, assembly of multi-subunit protein complexes and export. We additionally discuss the roles of the dendritic endoplasmic reticulum in synaptic plasticity.


Assuntos
Humanos , Permeabilidade da Membrana Celular/fisiologia , Dendritos/fisiologia , Retículo Endoplasmático/fisiologia , Proteínas de Membrana/fisiologia , Plasticidade Neuronal/fisiologia , Dendritos/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/metabolismo , Transporte Proteico/fisiologia
19.
Biol. Res ; 44(1): 75-80, 2011. ilus
Artigo em Inglês | LILACS | ID: lil-591867

RESUMO

Unfolded protein response (UPR) is a signaling mechanism activated by misfolded protein accumulation in the endoplasmic reticulum. It is a widespread process that has been described in organisms ranging from yeasts to mammals. In recent years, our understanding of UPR signaling pathway in plants has advanced. Two transcription factors from Arabidopsis thaliana have been reported to function as the sensor/ transducer of this response (AtbZIP60 and AtbZIP28). They seem to be involved in both heat and biotic stress. Furthermore, overexpression of one of them (AtbZIP60) produces plants with a higher tolerance for salt stress, suggesting that this transcription factor may play a role in abiotic stress. Furthermore, some data suggest that crosstalk between genes involved in abiotic stress and UPR may also exist in plants. On the other hand, UPR is related to programmed cell death (PCD) in plants given that that triggering UPR results in induction of PCD-related genes. This article reviews the latest progress in understanding UPR signaling in plants and analyzes its relationship to key processes in plant physiology.


Assuntos
Arabidopsis/fisiologia , Retículo Endoplasmático/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/fisiologia , Resposta a Proteínas não Dobradas/fisiologia , Estresse Fisiológico/fisiologia
20.
Mem. Inst. Oswaldo Cruz ; 105(1): 79-85, Feb. 2010. ilus, tab
Artigo em Inglês | LILACS | ID: lil-539299

RESUMO

Alpha 1,2-mannosidases from glycosyl hydrolase family 47 participate in N-glycan biosynthesis. In filamentous fungi and mammalian cells, á1,2-mannosidases are present in the endoplasmic reticulum (ER) and Golgi complex and are required to generate complex N-glycans. However, lower eukaryotes such Saccharomyces cerevisiae contain only one á1,2-mannosidase in the lumen of the ER and synthesise high-mannose N-glycans. Little is known about the N-glycan structure and the enzyme machinery involved in the synthesis of these oligosaccharides in the dimorphic fungus Sporothrix schenckii. Here, a membrane-bound á-mannosidase from S. schenckii was solubilised using a high-temperature procedure and purified by conventional methods of protein isolation. Analytical zymograms revealed a polypeptide of 75 kDa to be responsible for enzyme activity and this purified protein was recognised by anti-á1,2-mannosidase antibodies. The enzyme hydrolysed Man9GlcNAc2 into Man8GlcNAc2 isomer B and was inhibited preferentially by 1-deoxymannojirimycin. This á1,2-mannosidase was localised in the ER, with the catalytic domain within the lumen of this compartment. These properties are consistent with an ER-localised á1,2-mannosidase of glycosyl hydrolase family 47. Our results also suggested that in contrast to other filamentous fungi, S. schenckii lacks Golgi á1,2-mannosidases and therefore, the processing of N-glycans by á1,2-mannosidases is similar to that present in lower eukaryotes.


Assuntos
Retículo Endoplasmático/enzimologia , Manosidases/isolamento & purificação , Sporothrix/enzimologia , Manosidases/química , Sporothrix/classificação , Sporothrix/citologia
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