Alzheimer's Disease (AD) is a neurodegenerative disorder related with the increase of age and it is the main cause of dementia in the world. AD affects cognitive functions, such as memory, with an ...intensity that leads to several functional losses. The continuous increase of AD incidence demands for an urgent development of effective therapeutic strategies. Despite the extensive research on this disease, only a few drugs able to delay the progression of the disease are currently available. In the last years, several compounds with pharmacological activities isolated from plants, animals and microorganisms, revealed to have beneficial effects for the treatment of AD, targeting different pathological mechanisms. Thus, a wide range of natural compounds may play a relevant role in the prevention of AD and have proven to be efficient in different preclinical and clinical studies. This work aims to review the natural compounds that until this date were described as having significant benefits for this neurological disease, focusing on studies that present clinical trials.
Resveratrol (RES) is a natural polyphenolic non-flavonoid compound present in grapes, mulberries, peanuts, rhubarb and in several other plants. Numerous health effects have been related with its ...intake, such as anti-carcinogenic, anti-inflammatory and brain protective effects. The neuroprotective effects of RES in neurological diseases, such as Alzheimer's (AD) and Parkinson's (PD) diseases, are related to the protection of neurons against oxidative damage and toxicity, and to the prevention of apoptotic neuronal death. In brain cancer, RES induces cell apoptotic death and inhibits angiogenesis and tumor invasion. Despite its great potential as therapeutic agent for the treatment of several diseases, RES exhibits some limitations. It has poor water solubility and it is chemically instable, being degraded by isomerization once exposed to high temperatures, pH changes, UV light, or certain types of enzymes. Thus, RES has low bioavailability, limiting its biological and pharmacological benefits. To overcome these limitations, RES can be delivered by nanocarriers. This field of nanomedicine studies how the drug administration, pharmacokinetics, and pharmacodynamics are affected by the use of nanosized materials. The role of nanotechnology, in the prevention and treatment of neurological diseases, arises from the necessity to mask the physicochemical properties of therapeutic drugs to prolong the half-life and to be able to cross the blood-brain barrier (BBB). This can be achieved by encapsulating the drug in a nanoparticle (NP), which can be made of different kinds of materials. An increasing trend to encapsulate and direct RES to the brain has been observed. RES has been encapsulated in many different types of nanosystems, as liposomes, lipid and polymeric NPs. Furthermore, some of these nanocarriers have been modified with targeting molecules able to recognize the brain areas. Then, this article aims to overview the RES benefits and limitations in the treatment of neurological diseases, as the different nanotechnology strategies to overcome these limitations.
The aggregation of amyloid-β peptide (Aβ) has been linked to the formation of neuritic plaques, which are pathological hallmarks of Alzheimer's disease (AD). Various natural compounds have been ...suggested as therapeutics for AD. Among these compounds, resveratrol has aroused great interest due to its neuroprotective characteristics. Here, we provide evidence that grape skin and grape seed extracts increase the inhibition effect on Aβ aggregation. However, after intravenous injection, resveratrol is rapidly metabolized into both glucuronic acid and sulfate conjugations of the phenolic groups in the liver and intestinal epithelial cells (within less than 2 h), which are then eliminated. In the present study, we show that solid lipid nanoparticles (SLNs) functionalized with an antibody, the anti-transferrin receptor monoclonal antibody (OX26 mAb), can work as a possible carrier to transport the extract to target the brain. Experiments on human brain-like endothelial cells show that the cellular uptake of the OX26 SLNs is substantially more efficient than that of normal SLNs and SLNs functionalized with an unspecific antibody. As a consequence, the transcytosis ability of these different SLNs is higher when functionalized with OX-26.
Intelligence, as a general cognitive ability, shows a substantial inter-subject variation. Because of its impact on our lives, there is great interest in explaining the neural substrates of these ...differences. We used a large set of neuroimaging and behavioral data from 805 subjects, provided by the Human Connectome Project, and applied predictive models based on elastic-net regression using functional connectivity and brain morphometric data to predict general intelligence values. Additionally, we explored the impact of brain spatial distribution of the input connectivity data in the regression model using two strategies: brain parcellation and individual components. Features derived from functional connectivity were considerably more correlated with general intelligence than cortical thickness and surface area. Considering the regularization terms in this particular prediction problem, the best performances were obtained when the impact of all the independent variables was considered in the regresion, i.e. null LASSO sparsity term. Using different parcellation schemes affected predictive performances, which indicates spatial heterogeneity in the regression. We were able to explain 17,5% of the general intelligence variance, in the best performance reached, with a brain parcellation of 25 independent components; by other hand, using only cortical morphometric features the performance reduced to 1,6% for both cortical thickness and surface area. While no component, in particular, was responsible for predicting a large portion of the variance, the spatial components with the best results comprehend parietal, frontal and occipital regions, in agreement with the Parieto-Frontal Integration Theory (P-FIT).
•ICA-based functional connectivity can be used to predict general cognitive ability.•Intelligence functional information is well distributed in the brain.•More important regions for intelligence prediction are in agreement with P-FIT.•FC was considerably more correlated with g than neuroanatomical features.•We show that the ICA model order substantially affects predictive performance.
RESUMO Este artigo explora a história social das duas principais ruas concentradoras de lojas de moda popular de São Paulo: Vinte e Cinco de Março e José Paulino. A partir da recuperação de ...trajetórias de famílias estrangeiras estabelecidas nessas ruas, discute-se como a soma das iniciativas privadas de imigrantes que buscavam a estabilização financeira por meio da abertura do próprio negócio relaciona-se à produção do espaço que ocuparam. Em ambos os casos, a transformação de capital produtivo e comercial (tecidos, armarinhos e roupas) em capital imobiliário (construção de imóveis) foi a principal força motriz do processo de verticalização. As famílias aqui retratadas, a exemplo de outras, são agentes sociais cujas atuações, combinadas a demandas decorrentes da metropolização paulistana e a fatores histórico-geográficos, acarretaram êxito econômico. A produção e a venda de roupas, acessórios, tecidos e armarinhos transformaram a Vinte e Cinco de Março e a José Paulino em eixos de referência na cidade, no estado, no país e na América Latina. Por meio do entrelaçamento de fontes bibliográficas, documentais e orais, buscou-se averiguar e discutir as convergências e as particularidades dos dois territórios. O texto aborda processos que datam das últimas décadas do século XIX e chegam à atualidade. Nesse extenso intervalo, foram realizados os loteamentos e arruamentos originários dos atuais traçados e a construção de grande parte das edificações presentes nas vias, além da chegada de novas comunidades estrangeiras.
ABSTRACT This article explores the social history of the two most important popular fashion streets in São Paulo: Vinte e Cinco de Março and José Paulino. By tracing the trajectories of foreign families fixed on these streets, it discusses how private initiatives of immigrants looking for financial stability through the opening of their own business relates to the creation of the space occupied by them. In both cases, the transformation of commercial and productive capital (fabric, clothes, and sewing supplies of the fashion industry) into real estate capital (building construction) was the main driving force of the verticalization processes. The families here portrayed are social agents whose initiatives, combined with the demands arising from the metropolization process and historic and geographic factors of São Paulo, resulted in economic prosperity. The manufacturing and sales of clothes, fabrics, and sewing supplies transformed Vinte e Cinco de Março and José Paulino into important references in the city, state, country, and Latin America. Through bibliographic, documentary, and oral sources, this study sought to investigate and discuss the convergences and particularities of the two territories, addressing processes that date from the last decade of the 19th century to the present day - a period in which allotments and street layouts were shaped, most buildings were constructed, and new foreign communities arrived to the places.
The interaction of antioxidants with biological membranes is closely related with their efficacy to inhibit the lipid peroxidation, the cause of several pathologies including cancer, ...neurodegenerative and cardiovascular disorders. Despite being pointed as a promising antioxidant agent by some authors, the anti-lipid peroxidation of green tea extract (GTE) has not aroused consensus among the scientific community. Since the interaction of drugs with biological membranes plays a key role on their therapeutic activity, this study aims to evaluate the interaction of GTE with liposomes as in vitro biomembrane models composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine phospholipids in the absence and presence of cholesterol (CHOL) (15 mol%). The affinity of GTE and its main components (−)-epigallocatechin gallate (EGCG) and (−)-epigallocatechin (EGC) to the lipid bilayer, their membrane location as well as their effect on the membrane fluidity was investigated by diverse biophysical techniques. Derivative spectrophotometry results proved that GTE has high affinity to the membrane by establishing hydrophobic interactions with the non-polar region of phospholipids and electrostatic interactions with the polar phospholipid heads. Fluorescence and dynamic light scattering data confirm that GTE is located in both hydrophobic and hydrophilic regions of the lipid membrane, therefore affecting the structure of the biomembrane by increasing its fluidity. However, the increased stiffness and organization of the lipid bilayer caused by CHOL significantly affected the interaction of GTE with the membrane. Moreover, the obtained findings suggest a direct contribution of EGCG and EGC on the GTE-membrane interaction.
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•Green tea extract (GTE) has high affinity for DMPC membranes.•GTE is in both hydrophobic and hydrophilic regions of DMPC membranes.•GTE increased the fluidity of DMPC membranes.•Cholesterol significantly affected the interaction of GTE with the membrane model.•EGCG and EGC have a direct contribution on the GTE-membrane interaction.
Alzheimer's disease (AD) is an incurable neurological illness and the leading cause of dementia, characterized by amyloid β (Aβ) fibril deposits. Caffeic acid (CA) has demonstrated potential value ...for AD therapy due to its anti-amyloidogenic, anti-inflammatory, and antioxidant properties. However, its chemical instability and limited bioavailability limit its therapeutic potential in vivo. Herein, liposomes loading CA were produced by distinct techniques. Taking advantage of the overexpression of transferrin (Tf) receptors in brain endothelial cells, Tf was conjugated to the liposomes’ surface to direct the CA-loaded nanoparticles (NPs) to the blood-brain barrier (BBB). The optimized Tf-modified NPs exhibited a mean size of around 140 nm, a polydispersity index lower than 0.2, and a neutral surface charge, being appropriate for drug delivery. The Tf-functionalized liposomes showed suitable encapsulation efficiency and physical stability for at least 2 months. Furthermore, in simulated physiological settings, the NPs ensured the sustained release of CA for 8 days. The anti-amyloidogenic efficacy of the optimized drug delivery system (DDS) was investigated. The data show that CA-loaded Tf-functionalized liposomes are capable of preventing Aβ aggregation and fibril formation, and disaggregating mature fibrils. Hence, the proposed brain-targeted DDS may be a potential strategy for preventing and treating AD. Future studies in animal models of AD will be valuable to validate the therapeutic efficacy of the optimized nanosystem.
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•Liposomes containing caffeic acid (CA) were produced by various techniques.•Liposomes’ surface was modified with transferrin for improved targeting ability.•Nanoparticles exhibited appropriate physicochemical properties for drug delivery.•CA-loaded liposomes inhibited the aggregation of amyloid β (Aβ) peptides.•CA-loaded liposomes disaggregated mature Aβ fibrils.
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•Lipid membrane models are suitable tools to mimic biological membranes.•Liposomes are one of the most promising in vitro membrane models.•Biophysical techniques provide a full ...understanding of drug-membrane interactions.
The interaction of drugs with biological membranes is a critical factor affecting their pharmacokinetics and pharmacodynamics, so understanding how drugs interact with biomembranes is of valuable interest for the pharmaceutical industry. However, such interactions are difficult to investigate due to the complexity of biological membranes, mainly related to the dynamic structure of membranes that are composed of wide variety of molecules. In this context, in vitro lipid-based membrane models emerged to offer a simple yet useful alternative way of studying drug-membrane interactions. Different lipid models can be used as in vitro biomembrane models, and this review presents a brief overview of the most promising membrane models used in this field. Also, the most used biophysical methodologies to study drugs’ and membranes’ properties using liposomes are reviewed. The significance of using liposomes as lipid membrane models to investigate drug-membrane interactions is discussed and future perspectives are presented.
Molecules inhibiting the amyloid beta (Aβ) peptide aggregation and/or disaggregating mature fibrils are a promising approach for the Alzheimer's disease (AD) therapy, as the Aβ fibrillation is one of ...the key triggers of the disease. Gallic acid (GA) is a phenolic acid with anti-amyloidogenic activity against Aβ in buffered solutions. However, there is still no evidence of these properties in vivo. Given the rate of failures of AD drug development, there is a huge demand of replicating the in vivo environment in in vitro studies, thus allowing to stop earlier the study of molecules with no effect in vivo. Thus, this study aims to evaluate the effect of in vitro neuronal membranes on the GA's ability in preventing Aβ1-42 aggregation and disrupting preformed fibrils. To this end, liposomes were employed to mimic the cell membrane environment. The results reveal that the lipid membranes did not affect the GA's ability in inhibiting Aβ1−42 fibrillation. However, in vitro neuronal membranes modulate the GA-induced Aβ fibrils disaggregation, which may be related with the moderate affinity of the compound for the lipid membrane. Even so, GA presented strong anti-amyloidogenic properties in the cell membrane-like environment. This work highlights the promising value of GA on preventing and treating AD, thus justifying its study in animal models.
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•The GA's anti-amyloidogenic activity was evaluated in a membrane-like environment.•Lipid membranes did not affect the GA's ability in inhibiting Aβ1−42 fibrillation.•Lipid membranes decelerate the GA-induced Aβ fibrils disaggregation.•The partition of GA to the lipid membrane hinders the Aβ fibrils-GA interactions.•GA is a promising molecule to prevent and treat AD.
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