RESUMEN
Alzheimer's disease (AD) is the main cause of dementia in the world and its etiology is not yet fully understood. The pathology of AD is primarily characterized by intracellular neurofibrillary tangles and extracellular amyloid-ß plaques. Unfortunately, few treatment options are available, and most treat symptoms, as is the case of acetylcholinesterase inhibitors (IAChE) and N-methyl-d-aspartate receptor antagonists. For more than 20 years pharmaceutical research has targeted the "amyloid cascade hypothesis," but this has not produced meaningful results, leading researchers to focus now on other characteristics of the disease and on multitarget approaches. This review aims to evaluate some new treatments that are being developed and studied. Among these are new treatments based on peptides, which have high selectivity and low toxicity; however, these compounds have a short half-life and encounter challenges when crossing the blood-brain barrier. The present review discusses up-and-coming peptides tested as treatments and explores some nanotechnological strategies to overcome the downsides. These compounds are promising, as they not only act on the symptoms but also aim to prevent progressive neuronal loss.
Asunto(s)
Enfermedad de Alzheimer , Nanopartículas , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Acetilcolinesterasa/uso terapéutico , Péptidos beta-Amiloides , Inhibidores de la Colinesterasa/uso terapéutico , Nanopartículas/uso terapéuticoRESUMEN
Exercise training reduces renin-angiotensin system (RAS) activation, decreases plasma and tissue oxidative stress and inflammation in hypertension. However, the temporal nature of these phenomena in response to exercise is unknown. We sought to determine in spontaneously hypertensive rats (SHR) and age-matched WKY controls the weekly effects of training on blood pressure (BP), plasma and left ventricle (LV) Ang II and Ang-(1-7) content (HPLC), LV oxidative stress (DHE staining), gene and protein expression (qPCR and WB) of pro-inflammatory cytokines, antioxidant enzymes and their consequence on hypertension-induced cardiac remodeling. SHR and WKY were submitted to aerobic training (T) or maintained sedentary (S) for 8 weeks; measurements were made at weeks 0, 1, 2, 4 and 8. Hypertension-induced cardiac hypertrophy was accompanied by acute plasma Ang II increase with amplified responses during the late phase of LV hypertrophy. Similar pattern was observed for oxidative stress markers, TNF alpha and interleukin-1ß, associated with cardiomyocytes' diameter enlargement and collagen deposition. SHR-T exhibited prompt and marked decrease in LV Ang II content (T1 vs T4 in WKY-T), normalized oxidative stress (T2), augmented antioxidant defense (T4) and reduced both collagen deposition and inflammatory profile (T8), without changing cardiomyocytes' diameter and LV hypertrophy. These changes were accompanied by decreased plasma Ang II content (T2-T4) and reduced BP (T8). SHR-T and WKY-T showed parallel increases in LV and plasma Ang-(1-7) content. Our data indicate that early training-induced downregulation of LV ACE-AngII-AT1 receptor axis is a crucial mechanism to reduce oxidative/pro-inflammatory profile and improve antioxidant defense in SHR-T, showing in addition this effect precedes plasma RAS deactivation.
Asunto(s)
Angiotensina II/metabolismo , Hipertensión/fisiopatología , Inflamación/metabolismo , Miocardio/metabolismo , Estrés Oxidativo , Condicionamiento Físico Animal , Remodelación Ventricular , Animales , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
We explored the impact of Nox-2 in modulating inflammatory-mediated microglial responses in the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model. Nox1 and Nox2 gene expression were found to increase in striatum, whereas a marked increase of Nox2 expression was observed in substantia nigra (SN) of wild-type (wt) mice after PD induction. Gp91(phox-/-) 6-OHDA-lesioned mice exhibited a significant reduction in the apomorphine-induced rotational behavior, when compared to wt mice. Immunolabeling assays indicated that striatal 6-OHDA injections reduced the number of dopaminergic (DA) neurons in the SN of wt mice. In gp91(phox-/-) 6-OHDA-lesioned mice the DA degeneration was negligible, suggesting an involvement of Nox in 6-OHDA-mediated SN degeneration. Gp91(phox-/-) 6-OHDA-lesioned mice treated with minocycline, a tetracycline derivative that exerts multiple anti-inflammatory effects, including microglial inhibition, exhibited increased apomorphine-induced rotational behavior and degeneration of DA neurons after 6-OHDA injections. The same treatment also increased TNF-α release and potentiated NF-κB activation in the SN of gp91(phox-/-)-lesioned mice. Our results demonstrate for the first time that inhibition of microglial cells increases the susceptibility of gp91(phox-/-) 6-OHDA lesioned mice to develop PD. Blockade of microglia leads to NF-κB activation and TNF-α release into the SN of gp91(phox-/-) 6-OHDA lesioned mice, a likely mechanism whereby gp91(phox-/-) 6-OHDA lesioned mice may be more susceptible to develop PD after microglial cell inhibition. Nox2 adds an essential level of regulation to signaling pathways underlying the inflammatory response after PD induction.
Asunto(s)
Microglía/patología , NADPH Oxidasas/genética , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/patología , Oxidopamina/farmacología , Enfermedad de Parkinson/patología , Animales , Apomorfina/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Inflamación/genética , Inflamación/patología , Masculino , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/efectos de los fármacos , Microglía/metabolismo , Minociclina/farmacología , NADH NADPH Oxidorreductasas/genética , NADPH Oxidasa 1 , NADPH Oxidasa 2 , FN-kappa B/genética , Degeneración Nerviosa/genética , Enfermedad de Parkinson/genética , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Ocular enucleation produces significant morphological and physiological changes in central visual areas. However, our knowledge of the molecular events resulting from eye enucleation in visual brain areas remains elusive. We characterized here the transcription nuclear factor kappa-B (NF-κB) activation induced by ocular enucleation in the rat superior colliculus (SC). We also tested the effectiveness of the synthetic glucocorticoid dexamethasone in inhibiting its activation. Electrophoretic mobility shift assays to detect NF-κB indicated that this transcription factor is activated in the SC from 1h to day 15 postlesion. The expression of p65 and p50 proteins in the nuclear extracts was also increased. Dexamethasone treatment was able to significantly inhibit NF-κB activation. These findings suggest that this transcriptional factor is importantly involved in the visual system short-term processes that ensue after retinal lesions in the adult brain.
Asunto(s)
Enucleación del Ojo , FN-kappa B/metabolismo , Colículos Superiores/metabolismo , Animales , Glucemia/metabolismo , Dexametasona/farmacología , Ensayo de Cambio de Movilidad Electroforética , Glucocorticoides/farmacología , Immunoblotting , Masculino , Ratas , Ratas WistarRESUMEN
To detect orthopoxvirus in the Brazilian Amazon, we conducted a serosurvey of 344 wild animals. Neutralizing antibodies against orthopoxvirus were detected by plaque-reduction neutralizing tests in 84 serum samples. Amplicons from 6 monkey samples were sequenced. These amplicons identified vaccinia virus genetically similar to strains from bovine vaccinia outbreaks in Brazil.
Asunto(s)
Enfermedades de los Monos/epidemiología , Virus Vaccinia/aislamiento & purificación , Vaccinia/veterinaria , Alouatta , Animales , Armadillos , Brasil/epidemiología , Cebus , Chlorocebus aethiops , ADN Viral/análisis , ADN Viral/genética , Zorros , Hemaglutininas Virales/análisis , Hemaglutininas Virales/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular , Datos de Secuencia Molecular , Enfermedades de los Monos/inmunología , Enfermedades de los Monos/virología , Pruebas de Neutralización , Zarigüeyas , Péptidos/análisis , Péptidos/genética , Filogenia , Prevalencia , Procyonidae , Roedores , Análisis de Secuencia de ADN , Vaccinia/epidemiología , Vaccinia/inmunología , Vaccinia/virología , Virus Vaccinia/genética , Virus Vaccinia/inmunología , Células VeroRESUMEN
BACKGROUND: Despite the fact that smallpox eradication was declared by the World Health Organization (WHO) in 1980, other poxviruses have emerged and re-emerged, with significant public health and economic impacts. Vaccinia virus (VACV), a poxvirus used during the WHO smallpox vaccination campaign, has been involved in zoonotic infections in Brazilian rural areas (Bovine Vaccinia outbreaks - BV), affecting dairy cattle and milkers. Little is known about VACV's natural hosts and its epidemiological and ecological characteristics. Although VACV was isolated and/or serologically detected in Brazilian wild animals, the link between wildlife and farms has not yet been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we describe for the first time, to our knowledge, the isolation of a VACV (Mariana virus - MARV) from a mouse during a BV outbreak. Genetic data, in association with biological assays, showed that this isolate was the same etiological agent causing exanthematic lesions observed in the cattle and human inhabitants of a particular BV-affected area. Phylogenetic analysis grouped MARV with other VACV isolated during BV outbreaks. CONCLUSION/SIGNIFICANCE: These data provide new biological and epidemiological information on VACV and lead to an interesting question: could peridomestic rodents be the link between wildlife and BV outbreaks?
Asunto(s)
Enfermedades de los Bovinos/virología , Virus Vaccinia/aislamiento & purificación , Vaccinia/veterinaria , Zoonosis/epidemiología , Secuencia de Aminoácidos , Animales , Animales Domésticos , Animales Salvajes , Bioensayo , Brasil/epidemiología , Bovinos , Enfermedades de los Bovinos/genética , Ecología , Humanos , Ratones , Datos de Secuencia Molecular , Filogenia , Ratas , Homología de Secuencia de Aminoácido , Vaccinia/transmisión , Vaccinia/virología , Virus Vaccinia/clasificación , Virus Vaccinia/genéticaRESUMEN
BACKGROUND: Orthopoxvirus (OPV) and Parapoxvirus (PPV) have been associated with worldwide exanthematic outbreaks. Some species of these genera are able to infect humans and domestic animals, causing serious economic losses and public health impact. Rapid, useful and highly specific methods are required to detect and epidemiologically monitor such poxviruses. In the present paper, we describe the development of a nested-multiplex PCR method for the simultaneous detection of OPV and PPV species directly from exanthematic lesions, with no previous viral isolation or DNA extraction. METHODS AND RESULTS: The OPV/PPV nested-multiplex PCR was developed based on the evaluation and combination of published primer sets, and was applied to the detection of the target pathogens. The method showed high sensitivity, and the specificity was confirmed by amplicon sequencing. Exanthematic lesion samples collected during bovine vaccinia or contagious ecthyma outbreaks were submitted to OPV/PPV nested-multiplex PCR and confirmed its applicability. CONCLUSION: These results suggest that the presented multiplex PCR provides a highly robust and sensitive method to detect OPV and PPV directly from clinical samples. The method can be used for viral identification and monitoring, especially in areas where OPV and PPV co-circulate.
Asunto(s)
Orthopoxvirus/aislamiento & purificación , Parapoxvirus/aislamiento & purificación , Reacción en Cadena de la Polimerasa/métodos , Infecciones por Poxviridae/veterinaria , Infecciones por Poxviridae/virología , Animales , Bovinos , Enfermedades de los Bovinos/virología , Cartilla de ADN/genética , Enfermedades de las Cabras/virología , Cabras , Humanos , Datos de Secuencia Molecular , Orthopoxvirus/genética , Parapoxvirus/genética , Ovinos , Enfermedades de las Ovejas/virologíaRESUMEN
Cocaine is a worldwide used drug and its abuse is associated with physical, psychiatric and social problems. The mechanism by which cocaine causes neurological damage is very complex and involves several neurotransmitter systems. For example, cocaine increases extracellular levels of dopamine and free radicals, and modulates several transcription factors. NF-kappaB is a transcription factor that regulates gene expression involved in cellular death. Our aim was to investigate the toxicity and modulation of NF-kappaB activity by cocaine in PC 12 cells. Treatment with cocaine (1 mM) for 24 hours induced DNA fragmentation, cellular membrane rupture and reduction of mitochondrial activity. A decrease in Bcl-2 protein and mRNA levels, and an increase in caspase 3 activity and cleavage were also observed. In addition, cocaine (after 6 hours treatment) activated the p50/p65 subunit of NF-kappaB complex and the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, attenuated the NF-kappaB activation. Inhibition of NF-kappaB activity by using PDTC and Sodium Salicilate increased cell death caused by cocaine. These results suggest that cocaine induces cell death (apoptosis and necrosis) and activates NF-kappaB in PC12 cells. This activation occurs, at least partially, due to activation of D1 receptors and seems to have an anti-apoptotic effect on these cells.