Alzheimer's disease (AD) is a chronic neurodegenerative disease and represents the major cause of dementia worldwide. Currently, there are no available treatments capable to deliver disease-modifying ...effects, and the available drugs can only alleviate the symptoms. The exact pathology of AD is not yet fully understood and several hallmarks such as the presence of amyloid-β (Aβ) senile plaques, neurofibrillary tangles (NFTs) as well as the loss of cholinergic function have been associated to AD. Distinct pharmacological targets have been validated to address AD, with acetylcholinesterase (AChE) and β-secretase-1 (BACE-1) being two of the most explored ones. A great deal of research has been devoted to the development of new AChE and BACE-1 effective inhibitors, tackled separately or in combination of both. The multi-factorial nature of AD conducted to the development of multi-target directed ligands (MTDLs), defined as single molecules capable to modulate more than one biological target, as an alternative approach to the old paradigm one-target one-drug. In this context, this review describes a collection of natural and synthetic compounds with dual-inhibitory properties towards both AChE and BACE-1 in the MTDLs context. Furthermore, this review also provides a critical comprehensive analysis of structure-activity relationships (SAR) of the synthetic compounds.
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•AChE and BACE-1 are the most interesting AD related targets.•Single target AChE or BACE-1 inhibitors do not provide disease modifying effects.•Combining pharmacophores for AChE and BACE-1 inhibition results in well-balanced dual-inhibitors.•AChE and BACE-1 dual-inhibitors can be of both natural or synthetic origin.•BBB permeability should not be disregarded from the very beginning of any design strategy.
In the tropics, highly weathered soils with high phosphorus (P) fixation capacities predominate, reducing the P availability to plants. For this reason, understanding the cycle of P in the soil is ...important to develop management strategies that increase P availability to plants, especially in low-input production systems. The aim of this study was to apply structural equation modeling with latent variables, at an exploratory level, to test hypothetical models of the P cycle using data from the Hedley extraction method. Specifically, we evaluated interactions between the pools of P, and identified which pools act as a sink or source of P in unfertilized soils. The models of the P cycle for the tested soil were able to distinguish between the direct and indirect effects of labile and stable P on the available P pool. This approach led to a proposed distinction of functional P pools in the soil, and identifying the processes of P transformation in the soil between the pools based on a source–sink relationship. Based on these analyses, the organic pool consists of the bicarbonate organic phosphate (Po), hydroxide Po, and sonic Po fractions. The bicarbonate inorganic phosphate (Pi) and hydroxide Pi fractions formed the inorganic pool. The hydrochloride (HCl) Pₕₒₜ and residual P fractions formed the occluded pool, the HCl Pi fraction formed the primary mineral pool, and the resin Pi fraction constituted the most available P pool. Organic P pool was the major source to the available P pool.
Cyperus articulatus L. (Cyperaceae), popularly known in Brazil as “priprioca” or “piriprioca”, is a tropical and subtropical plant used in popular medical practices to treat many diseases, including ...cancer. In this study, C. articulatus rhizome essential oil (EO), collected from the Brazilian Amazon rainforest, was addressed in relation to its chemical composition, induction of cell death in vitro and inhibition of tumor development in vivo, using human hepatocellular carcinoma HepG2 cells as a cell model. EO was obtained by hydrodistillation using a Clevenger-type apparatus and characterized qualitatively and quantitatively by gas chromatography coupled to mass spectrometry (GC-MS) and gas chromatography with flame ionization detection (GC-FID), respectively. The cytotoxic activity of EO was examined against five cancer cell lines (HepG2, HCT116, MCF-7, HL-60 and B16-F10) and one non-cancerous one (MRC-5) using the Alamar blue assay. Cell cycle distribution and cell death were investigated using flow cytometry in HepG2 cells treated with EO after 24, 48 and 72 h of incubation. The cells were also stained with May–Grunwald–Giemsa to analyze the morphological changes. The anti-liver-cancer activity of EO in vivo was evaluated in C.B-17 severe combined immunodeficient (SCID) mice with HepG2 cell xenografts. The main representative substances of this EO sample were muskatone (11.6%), cyclocolorenone (10.3%), α-pinene (8.26%), pogostol (6.36%), α-copaene (4.83%) and caryophyllene oxide (4.82%). EO showed IC50 values for cancer cell lines ranging from 28.5 µg/mL for HepG2 to >50 µg/mL for HCT116, and an IC50 value for non-cancerous of 46.0 µg/mL (MRC-5), showing selectivity indices below 2-fold for all cancer cells tested. HepG2 cells treated with EO showed cell cycle arrest at G2/M along with internucleosomal DNA fragmentation. The morphological alterations included cell shrinkage and chromatin condensation. Treatment with EO also increased the percentage of apoptotic-like cells. The in vivo tumor mass inhibition rates of EO were 46.5–50.0%. The results obtained indicate the anti-liver-cancer potential of C. articulatus rhizome EO.
The present paper describes fundamentals, advantages and limitations of the Box-Behnken design (BBD) for the optimization of analytical methods. It establishes also a comparison between this design ...and composite central, three-level full factorial and Doehlert designs. A detailed study on factors and responses involved during the optimization of analytical systems is also presented. Functions developed for calculation of multiple responses are discussed, including the desirability function
, which was proposed by Derringer and Suich in 1980. Concept and evaluation of robustness of analytical methods are also discussed. Finally, descriptions of applications of this technique for optimization of analytical methods are presented.
A Superconducting Wavelength Shifter (SWLS) capable of achieving a peak magnetic field of 6.6 T is currently being designed for a future hard X-ray beamline of Sirius, the new Brazilian Light Source. ...Due to the machine requirements, a narrow field profile in the central pole region (FWHM < 30 mm) is a constraint to the electromagnetic design. The superconducting racetrack coils, made of NbTi wires, are being designed to be conduction cooled with an operating margin above 20% at 5 K. Two designs are required, the lateral coils with 180 turns and the central coils with 1080 turns, both wound layer by layer with fiberglass insulation and then vacuum impregnated with epoxy resin. The proposed coils design and fabrication route will be presented, as well as the proposed setup for testing them.
Medically approved sterility methods should be a major concern when developing a polymeric scaffold, mainly when commercialization is envisaged. In the present work, poly(lactic acid) (PLA) fiber ...membranes were processed by electrospinning with random and aligned fiber alignment and sterilized under UV, ethylene oxide (EO), and γ-radiation, the most common ones for clinical applications. It was observed that UV light and γ-radiation do not influence fiber morphology or alignment, while electrospun samples treated with EO lead to fiber orientation loss and morphology changing from cylindrical fibers to ribbon-like structures, accompanied to an increase of polymer crystallinity up to 28%. UV light and γ-radiation sterilization methods showed to be less harmful to polymer morphology, without significant changes in polymer thermal and mechanical properties, but a slight increase of polymer wettability was detected, especially for the samples treated with UV radiation. In vitro results indicate that both UV and γ-radiation treatments of PLA membranes allow the adhesion and proliferation of MG 63 osteoblastic cells in a close interaction with the fiber meshes and with a growth pattern highly sensitive to the underlying random or aligned fiber orientation. These results are suggestive of the potential of both γ-radiation sterilized PLA membranes for clinical applications in regenerative medicine, especially those where customized membrane morphology and fiber alignment is an important issue.
The quest to develop materials that enable the manufacture of dimensionally ultra-stable structures for critical-dimension components in spacecraft has led to much research over many decades and the ...evolution of carbon fibre reinforced polymer materials. This has resulted in structural designs that feature a near-zero coefficient of thermal expansion. However, the dimensional instabilities that result from moisture ingression and release remain the fundamental vulnerability of the matrix, which restricts many applications. Here, we address this challenge by developing a space-qualifiable physical surface barrier that blends within the mechanical properties of the composite, thus becoming part of the composite itself. The resulting enhanced composite features mechanical integrity and a strength that is superior to the underlying composite, while remaining impervious to moisture and outgassing. We demonstrate production capability for a model-sized component for the Sentinel-5 mission and demonstrate such capability for future European Space Agency (ESA) and National Aeronautics and Space Administration (NASA) programmes such as Copernicus Extension, Earth Explorer and Science Cosmic Visions.
Abstract
This study sought to assess the feasibility of design, adherence, satisfaction, safety and changes in outcomes followed by a home-based foot–ankle exercise guided by a booklet in individuals ...with diabetic peripheral neuropathy (DPN). 20 participants were allocated usual care control group (CG) or usual care plus home-based foot–ankle exercises intervention group (IG) for 8 weeks. For feasibility, we assessed contact, preliminary screening and recruitment rates, adherence, and using a 5-point Likert scale to satisfaction and safety of the booklet. In the IG, we assessed preliminary changes in DPN symptoms, DPN severity (classified by a fuzzy model) and foot–ankle range of motion between baseline and Week 8. In the first 20 weeks, 1310 individuals were screened for eligibility by phone contact. Contact rate was 89% (contacted participants/20w), preliminary screening success 28% (participants underwent screening/20w), and recruitment rate 1.0 participants/week (eligible participants/20w). The recruitment rate was less than the ideal rate of 5 participants/week. The adherence to the exercises programme was 77%, and the dropout was 11% and 9% for the IG and CG, respectively. In the IG, participants’ median level of satisfaction was 4 (IQR: 4–5) and perceived safety was 3 (IQR: 3–5). IG significantly decreased the DPN severity (p = 0.020), increased hallux relative to forefoot (first metatarsal) range of motion (ROM) (p < 0.001) and decreased maximum forefoot relative to hindfoot (midfoot motion) dorsiflexion during gait (p = 0.029). The home-based programme was feasible, satisfactory, safe and showed preliminary positive changes in DPN severity and foot motion during gait.
Trial Registration
ClinicalTrials.gov, NCT04008745. Registered 02/07/2019.
https://clinicaltrials.gov/ct2/show/NCT04008745
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