PLGA-PVA-PEG Single Emulsion Method as a Candidate for Aminolevulinic Acid (5-ALA) Encapsulation: Laboratory Scaling Up and Stability Evaluation.

One of the most widely used molecules used for photodynamic therapy (PDT) is 5-aminolevulinic acid (5-ALA), a precursor in the synthesis of tetrapyrroles such as chlorophyll and heme. The 5-ALA skin permeation is considerably reduced due to its hydrophilic characteristics, decreasing its local bioavailability and therapeutic effect. For this reason, five different systems containing polymeric particles of poly [D, L-lactic-co-glycolic acid (PLGA)] were developed to encapsulate 5-ALA based on single and double emulsions methodology. All systems were standardized (according to the volume of reagents and mass of pharmaceutical ingredients) and compared in terms of laboratory scaling up, particle formation and stability over time. UV-VIS spectroscopy revealed that particle absorption/adsorption of 5-ALA was dependent on the method of synthesis. Different size distribution was observed by DLS and NTA techniques, revealing that 5-ALA increased the particle size. The contact angle evaluation showed that the system hydrophobicity was dependent on the surfactant and the 5-ALA contribution. The FTIR results indicated that the type of emulsion influenced the particle formation, as well as allowing PEG functionalization and interaction with 5-ALA. According to the 1H-NMR results, the 5-ALA reduced the T1 values of polyvinyl alcohol (PVA) and PLGA in the double emulsion systems due to the decrease in molecular packing in the hydrophobic region. The results indicated that the system formed by single emulsion containing the combination PVA-PEG presented greater stability with less influence from 5-ALA. This system is a promising candidate to successfully encapsulate 5-ALA and achieve good performance and specificity for in vitro skin cancer treatment.

Mefloquine synergism with anti-tuberculosis drugs and correlation to membrane effects: Biologic, spectroscopic and molecular dynamics simulations studies.

Studies displaying the combination of mefloquine (MFL) with anti-tuberculosis (TB) substances are limited in the literature. In this work, the effect of MFL-association with two first-line anti-TB drugs and six fluoroquinolones was evaluated against Mycobacterium tuberculosis drug resistant strains. MFL showed synergistic interaction with isoniazid, pyrazinamide, and several fluoroquinolones, reaching fractional inhibitory concentration indexes (FICIs) ranging from 0.03 to 0.5. In order to better understand the observed results, two approaches have been explored: (i) spectroscopic responses attributed to the effect of MFL on physicochemical properties related to a liposomal membrane model composed by soybean asolectin; (ii) molecular dynamics (MD) simulation data regarding MFL interaction with a membrane model based on PIM2, a lipid constituent of the mycobacterial cell wall. FTIR and NMR data showed that MFL affects expressively the region between the phosphate and the first methylene groups of soybean asolectin membranes, disordering these regions. MD simulations results detected high MFL density in the glycolipid interface and showed that the drug increases the membrane lateral diffusion, enhancing its permeability. The obtained results suggest that synergistic activities related to MFL are attributed to its effect of lipid disorder and membrane permeability enhancement.

Simultaneous Application of Mixotrophic Culture and Magnetic Fields as a Strategy to Improve Spirulina sp. LEB 18 Phycocyanin Synthesis.

Spirulina is a filamentous microalga which is considered a promising alternative source of essential nutrients and active biomolecules. High production cost and the space required to install a photobioreactor are two of the greatest challenges in the industrial application of microalga-based products. Thus, this study aimed to improve Spirulina sp. LEB 18 biomass and phycocyanin content by combining the application of mixotrophic culture and magnetic fields (MF). Zarrouk medium was modified with 1 and 3 g/L liquid molasses and the application of 30 mT for 1·h/d was investigated. Mixotrophic culture with 1 g/L molasses showed the highest biomass concentration (1.62 g/L), carbohydrate content (25.6%), and lipid contents (8.7%) after 15 days. Although the combination of 30 mT and 1 g/L liquid molasses decreased biomass production (1.44 g/L), there was increase in protein yield (76.9%) and protein productivity (73.8 mg/L·d). The proposed method increased phycocyanin production by 145% and its purity from 0.584 in the control culture to 0.627. Data described by this study show that the combination of mixotrophic culture and MF application is a promising alternative to increase microalga protein and phycocyanin production.

Proton transfer in fluorescent secondary amines: synthesis, photophysics, theoretical calculation and preparation of photoactive phosphatidylcholine-based liposomes.

In this article, new fluorescent lipophilic based benzazoles were synthesized from the reaction between photoactive formyl derivatives and aliphatic amines followed by NaBH4 reduction with good yields. The photophysics of the benzazoles was investigated experimentally and theoretically. These compounds present absorption maxima in the UV region (∼339 nm) and fluorescence emission maxima in the cyan to green region with a large Stokes shift (∼175 nm) due to a proton transfer process in the excited state. Two fluorophores were successfully used as a proof of concept to produce stable photoactive liposomes prepared from phosphatidylcholine (PC) and were characterized by zeta potential, small angle X-ray scattering (SAXS), FTIR and UV-Vis experiments (turbidity). The scattering data indicate that the presence of compounds 20 and 23 reduces the overall surface charge of the PC vesicles, possibly due to the partial neutralization of phosphatidic acid and/or phosphatidylinositol phosphate by the amine groups, and they also modify the structural features of the assemblies, leading, in particular, to a reduction in the thickness of the hydrophobic inner segment (tt) of the liposomes. DFT and TD-DFT calculations were performed with the ωB97XD functional. Geometric analyses show that the 2-(2'-hydroxyphenyl)benzazolic planar portion allows an effective ππ* electronic transition. Additionally, the calculations indicate a small energy barrier to proton transfer. The results of the absorption and emission maxima show a slight solvent influence on the wavelengths.

In Vitro Anti/Pro-oxidant Activities of R. ferruginea Extract and Its Effect on Glioma Cell Viability: Correlation with Phenolic Compound Content and Effects on Membrane Dynamics.

Rapanea ferruginea antioxidant and antitumoral properties were not explored before in literature. This study aimed to investigate these biological activities for the R. ferruginea leaf extract and correlate them with its phenolic content and influence in biological membrane dynamics. Thus, in this study, anti/pro-oxidative properties of R. ferruginea leaf extract by in vitro DPPH and TBARS assays, with respect to the free radical reducing potential and to its activity regarding membrane free radical-induced peroxidation, respectively. Furthermore, preliminary tests related to the extract effect on in vitro glioma cell viability were also performed. In parallel, the phenolic content was detected by HPLC-DAD and included syringic and trans-cinnamic acids, quercetrin, catechin, quercetin, and gallic acid. In an attempt to correlate the biological activity of R. ferruginea extract and its effect on membrane dynamics, the molecular interaction between the extract and a liposomal model with natural-sourced phospholipids was investigated. Location and changes in vibrational, rotational, and translational lipid motions, as well as in the phase state of liposomes, induced by R. ferruginea extract, were monitored by Fourier-transform infrared spectroscopy, nuclear magnetic resonance, differential scanning calorimetry, and UV-visible spectroscopy. In its free form, the extract showed promising in vitro antioxidant properties. Free-form extract (at 1000µ g/mL) exposure reduced glioma cell in vitro viability in 40%, as evidenced by MTT tests. Pro-oxidant behavior was observed when the extract was loaded into liposomes. A 70.8% cell viability reduction was achieved with 500 µg/mL of liposome-loaded extract. The compounds of R. ferruginea extract ordered liposome interface and disorder edits a polar region. Phenolic content, as well as membrane interaction and modulation may have an important role in the oxidative and antitumoral activities of the R. ferruginea leaf extract.

Lipid-based nanocarrier for quercetin delivery: system characterization and molecular interactions studies.

The flavonoid quercetin (QU) is a naturally occurring compound with several biological activities. However, the oral bioavailability of this compound is very low due to the high pre-systemic metabolism in the colon and liver and its low water solubility. In this context, the development of QU-loaded nanocarriers (NEs) is a promising approach to improve the drug oral bioavailability. This study investigates the variation of the concentration of 12-hydroxystearic acid-polyethylene glycol copolymer, lecithin and castor oil (CO) as to increase the amount of QU encapsulated while maintaining physicochemical characteristics described in previous studies. To better understand the ability to load and release the drug, we investigated the molecular interactions between QU and NE. Lipid-based NEs were prepared using CO as oily phase and PEG 660-stearate and lecithin as surfactants. Hot solvent diffusion and phase inversion temperature were methods employed to produce NEs. The QU-NEs were investigated for physicochemical characteristics and in vitro drug release. Molecular interactions between QU and the NEs were monitored through the complementary infrared (Fourier transform infrared) and NMR. The results revealed that it was possible to incorporate higher amounts of QU in a lipid-based NE with a reduced size (20 nm). The system developed allow a sustained release of QU probably due to the shell formed by the surfactants around the NE and the flavonoid ordering effect in the emulsion hydrophobic regions, which may reduce the system permeability.

Benzohydroxamate and nitrobenzohydroxamate affect membrane order: Correlations between spectroscopic and molecular dynamics to approach tuberculosis.

This work correlates the effects of benzohydroxamate (BH) and nitrobenzohydroxamate (NBH) anions in two membrane models which may be used for anti-tuberculosis (anti-TB) spectroscopic studies and/or computational studies. Firstly, the BH and NBH influence in the physico-chemical properties of soy asolectin (ASO)-based large multilamellar vesicles (MLVs) were evaluated by spectroscopic and calorimetric studies. In parallel, the BH and NBH interaction with a Mycobacterium tuberculosis (Mtb) inner membrane model, composed of phosphatidyl-myo-inositol-dimannoside (PIM2), was investigated by molecular dynamics (MD) simulations. Spectroscopic data showed a localization of BH close to the lipid phosphate group, while NBH was found close to the choline region. The BH ordered the ASO choline, phosphate and carbonyl regions and disrupted the acyl methylenes, reducing the membrane packing of the lipid hydrophobic region. On the other hand, NBH showed an ordering effect in all the lipid groups (polar, interface and hydrophobic ones). By MD studies, it was found that NBH enhanced the stability of the PIM2 membrane more than BH, while also being positioned closer to its mannosyl oxygens. As in ASO MLVs, BH was localized close to the PIM2 phosphate group and disrupted its acyl chains. However, higher values of lateral diffusion were observed for NBH than BH. Despite this, BH and NBH increased the membrane thickness by 35 %, which suggests a global ordering effect of both drugs. Findings of this work reinforce the accordance and complementarity between MLVs based on ASO and the PIM2 MD model results to study the drug effects in Mtb membrane properties.

Effects of α-eleostearic acid on asolectin liposomes dynamics: relevance to its antioxidant activity.

In this study, the effect of α-eleostearic acid (α-ESA) on the lipid peroxidation of soybean asolectin (ASO) liposomes was investigated. This effect was correlated to changes caused by the fatty acid in the membrane dynamics. The influence of α-ESA on the dynamic properties of liposomes, such as hydration, mobility and order, were followed by horizontal attenuated total reflection Fourier transform infrared spectroscopy (HATR-FTIR), nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC) and UV-vis techniques. The α-ESA showed an in vitro antioxidant activity against the damage induced by hydroxyl radical (OH) in ASO liposomes. The analysis of HATR-FTIR frequency shifts and bandwidths and (1)H NMR spin-lattice relaxation times, related to specific lipid groups, showed that α-ESA causes an ordering effect on the polar and interfacial regions of ASO liposomes, which may restrict the OH diffusion in the membrane. The DSC enthalpy variation analysis suggested that the fatty acid promoted a disordering effect on lipid hydrophobic regions, which may facilitate interactions between the reactive specie and α-ESA. Turbidity results showed that α-ESA induces a global disordering effect on ASO liposomes, which may be attributed to a change in the lipid geometry and shape. Results of this study may allow a more complete view of α-ESA antioxidant mode of action against OH, considering its influence on the membrane dynamics.

Effect of transcranial direct current stimulation combined with gait and mobility training on functionality in children with cerebral palsy: study protocol for a double-blind randomized controlled clinical trial.

BACKGROUND: The project proposes three innovative intervention techniques (treadmill training, mobility training with virtual reality and transcranial direct current stimulation that can be safely administered to children with cerebral palsy. The combination of transcranial stimulation and physical therapy resources will provide the training of a specific task with multiple rhythmic repetitions of the phases of the gait cycle, providing rich sensory stimuli with a modified excitability threshold of the primary motor cortex to enhance local synaptic efficacy and potentiate motor learning. METHODS/DESIGN: A prospective, double-blind, randomized, controlled, analytical, clinical trial will be carried out.Eligible participants will be children with cerebral palsy classified on levels I, II and III of the Gross Motor Function Classification System between four and ten years of age. The participants will be randomly allocated to four groups: 1) gait training on a treadmill with placebo transcranial stimulation; 2) gait training on a treadmill with active transcranial stimulation; 3) mobility training with virtual reality and placebo transcranial stimulation; 4) mobility training with virtual reality and active transcranial stimulation. Transcranial direct current stimulation will be applied with the anodal electrode positioned in the region of the dominant hemisphere over C3, corresponding to the primary motor cortex, and the cathode positioned in the supraorbital region contralateral to the anode. A 1 mA current will be applied for 20 minutes. Treadmill training and mobility training with virtual reality will be performed in 30-minute sessions five times a week for two weeks (total of 10 sessions). Evaluations will be performed on four occasions: one week prior to the intervention; one week following the intervention; one month after the end of the intervention;and 3 months after the end of the intervention. The evaluations will involve three-dimensional gait analysis, analysis of cortex excitability (motor threshold and motor evoked potential), Six-Minute Walk Test, Timed Up-and-Go Test, Pediatric Evaluation Disability Inventory, Gross Motor Function Measure, Berg Balance Scale, stabilometry, maximum respiratory pressure and an effort test. DISCUSSION: This paper offers a detailed description of a prospective, double-blind, randomized, controlled, analytical, clinical trial aimed at demonstrating the effect combining transcranial stimulation with treadmill and mobility training on functionality and primary cortex excitability in children with Cerebral Palsy classified on Gross Motor Function Classification System levels I, II and III. The results will be published and will contribute to evidence regarding the use of treadmill training on this population. TRIAL REGISTRATION: ReBEC RBR-9B5DH7.

How does shading mitigates the water deficit in young Hymenaea courbaril L. plants?

Information on tolerance to isolated or combined abiotic stresses is still scarce for tree species, although such stresses are normal in nature. The interactive effect of light availability and water stress has been reported for some native tree species in Brazil but has not been widely investigated. To test the hypothesis that shading can mitigate the stressful effect of water deficit on the photosynthetic and antioxidant metabolism and on the growth of young Hymenaea courbaril L. plants, we evaluated the following two water regimes: a) continuous irrigation - control (I) - 75% field capacity. and b) water deficit (S), characterized by irrigation suspension associated the two following periods of evaluation: P0 - when the photosynthetic rate of plants subjected to irrigation suspension reached values ​​close to zero, with the seedlings being re-irrigated at that moment, and REC - when the photosynthetic rate of the re-irrigated plants of each shading levels reached values ​​similar to those of plants in the control treatment, totaling four treatments: IP0, SP0, IREC, and SREC. The plants of these four treatments were cultivated under the four following shading levels: 0, 30, 50, and 70%, constituting 16 treatments. Intermediate shading of 30 and 50% mitigates the water deficit and accelerates the recovery of H. courbaril. Water deficit associated with cultivation without shading (0%) should not be adopted in the cultivation or transplantation of H. courbaril. After the resumption of irrigation in the REC, the other characteristics presented a recovery under all cultivation conditions. Key message: Intermediate shading of 30 and 50% mitigates the water deficit and accelerates the recovery of H. courbaril.

Structure and interaction roles in the release profile of chalcone-loaded liposomes.

The structures and molecular interactions of established synthetic chalcones were correlated with their release profiles from asolectin liposomes. The effects of chalcones on the properties of liposomes were evaluated by dynamic light scattering (DLS), ultraviolet-visible spectroscopy (UV-VIS), horizontal attenuated total reflection Fourier transform infrared (HATR-FTIR), 31P nuclear magnetic resonance (31P NMR), zeta (ζ) potential and differential scanning calorimetry (DSC). The profiles and mechanisms of release were accessed according to the Korsmeyer-Peppas model. Results obtained allowed the establishment of a relationship between the chalcone release profile and 1) the ordering effects of chalcones in different membrane regions, 2) their polar or interfacial location in the lipid layer, 3) the influence of hydroxy and methoxy substituents, 4) their effect on reorientation of lipid choline-phosphate regions. The obtained data may improve the development of chalcone-based systems to be used in the therapy of chronic and acute diseases.

Neuromodulation: A combined-therapy protocol for speech rehabilitation in a child with cerebral palsy.

INTRODUCTION: Transcranial direct current stimulation (tDCS) modulates cortical activity and potentiates functional gains achieved during therapeutic protocols. The aim of Integrative Speech Therapy Protocol is to rehabilitate speech in patients with impairments regarding neuropyschomotor development by combining oral motor stimuli, specific articulatory production, and the stimulation of phonological aspects of language. OBJECTIVE: Investigate the effect of transcranial direct current stimulation combined to integrative speech therapy in a child with cerebral palsy. METHODS: We performed a case study with tDCS and speech therapy in a patient with cerebral palsy and apraxia of speech. To assess the patient's speech, we used a parameterized test for the Brazilian Portuguese speech - ABFW. The CFCS and Vicking Speech Scales presented level IV and III, respectively. The patient underwent two periods with ten stimulation sessions each: first with anodal stimulation over Broca's area; and second over the left dorsolateral prefrontal cortex. Two indices were calculated: the percentage of consonants correct; and percentage of consonants correct-revised. Descriptive statistics were employed for the clinical data. For the outcomes, changes in each score were calculated as the difference in pre-intervention and post-intervention using Wilcoxon-Mann-Whitney test. RESULTS: Increases were found in percentage of correct consonants indices as well as to produce two-syllable and three-syllable words after both types of stimulation, characterized mainly by correct vowels that marked the presence of the syllable. Number of phonemes increased 0 to 4 at first the stimulation and 4 to 10 at the second. CONCLUSION: The combined-therapy program contributed to improve the speech rehabilitation results in a patient with cerebral palsy.

Spirulina sp. LEB 18-extracted phycocyanin: Effects on liposomes' physicochemical parameters and correlation with antiradical/antioxidant properties.

This study describes the physicochemical properties of soybean asolectin (ASO) liposomes loaded with phycocyanin (Phy) extracted from Spirulina sp. LEB 18. The effects of Phy in the liposomes' properties were investigated by Fourier transform infrared spectroscopy (FTIR), 1H and 31P nuclear magnetic resonance (NMR), zeta (ζ)-potential, dynamic light scattering (DLS) and ultraviolet-visible (UV-vis) techniques. Phy restricted the motion of ASO polar and interface groups and disrupted the package arrangement of the lipid hydrophobic regions, as a likely effect of dipolar and π interactions related to its amino acid residues and pyrrole portions. These interactions were correlated to antiradical/antioxidant Phy responses obtained by 2,2-diphenyl-1-picrylhidrazil (DPPH) assay, thiobarbituric acid reactive substances (TBARS) and ferric reducing antioxidant power (FRAP) methods, and discussed to bring new chemical perspectives about Phy-loaded liposomes-related nutraceutical applications in inflammatory and viral infection processes.

Physico-chemical interactions of a new rod-coil-rod polymer with liposomal system: Approaches to applications in tryptophan-related therapies.

This work describes the synthesis of the new supramolecular rod-coil-rod polymer, designated as cholesterol-PEO1000-tryptophan (Chl-PEO-Trp), as well as its effects on the physico-chemical properties of phosphatidylcholine (PC)-based liposomes. The molecular interactions between the Chl-PEO-Trp and PC were characterized by HATR-FTIR, DSC, NMR, DLS and zeta (ζ) potential techniques. The Chl-PEO-Trp polymer yield was 75 %. FTIR and DSC data showed that the motion of almost all PC groups was restricted by the polymer, and it promoted a decrease of the trans-gauche isomerization of the PC methylene, restricting the mobility of the hydrophobic region of the liposomes. NMR analyses indicated a Chl-PEO-Trp-induced restriction in the rotation of the PC phosphorus and a discreet increase of the hydrogen mobility of the choline. Despite this increase in the rotation of the choline, DLS and ζ-potential analyses suggested a reorientation of the choline group toward the system surface, which contributed, along with the other physico-chemical effects, to a globally packed membrane arrangement and reduced liposome size. Data described in this work were correlated to possible applications of the Chl-PEO-Trp in its free or PC liposome-loaded forms in the diagnosis and therapy of cancer, SARS caused by coronaviruses, and central nervous system-related diseases.

A large epidemic of a necrotic skin infection in the Democratic Republic of São Tomé and Principe: an epidemiological study.

INTRODUCTION: In 2016-18, the Democratic Republic of São Tomé and Príncipe suffered a necrotic skin infection epidemic. METHODS: A surveillance system was established after increased hospitalisations for this infection. Microbiology results were available for samples analysed in December 2016 and March 2017 using whole genome sequencing and metagenomics. Negative binomial regression was used to study the association of weather conditions with monthly case counts in a time-series analysis. RESULTS: From October 2016 to October 2018, the epidemic cumulative attack rate was 1.5%. The first peak lasted 5 months, accounting for one-third of total cases. We could not conclusively identify the aetiological agent(s) due to the country's lack of microbiology capacity. Increased relative humidity was associated with increased monthly cases (incidence rate ratio (IRR) 1.05, 95% CI 1.02-1.09), and higher precipitation in the previous month with a higher number of cases in the following month (months with 0-49 mm rainfall compared with months with 50-149 mm and ≥150 mm: IRR 1.44, 95 % CI 1.13-1.78 and 1.50, 95% CI 1.12-1.99, respectively). DISCUSSION: This epidemic was favoured by increased relative humidity and precipitation, potentially contributing to community-based transmission of ubiquitous bacterial strains superinfecting skin wounds. FUNDING: World Health Organization Regional Office for Africa, Ministry of Health.

Hesperidin and hesperetin membrane interaction: understanding the role of 7-O-glycoside moiety in flavonoids.

Citrus species contain various typical flavonoids. However, absorption and metabolism of flavonoids are complex processes that determine its bioavailability which remain not clear until now. The aim of this study was to investigate the interactions among dimyristoyl-phosphatidyl choline (DMPC) liposomes and the flavanones hesperidin (glycoside) and hesperetin (aglycone). The results describe the molecular details of these interactions and the consequences for the membranes properties, by using differential scanning calorimetry (DSC), atomic force microscopy (AFM), fluorescence (using MC540 as probe), X-ray diffraction and theoretical study. The results show that hesperetin interacts with membranes stronger than hesperidin. It is possible to hypostatize that hesperidin, due to its rutinoside moiety, is located at the level of polar head whereas hesperetin interacts better with acyl chains and adopts a more planar conformation. The findings of this work may contribute to explain the high bioavailability of aglycones due to better membrane interaction.

Influence of melatonin on the order of phosphatidylcholine-based membranes.

The effect of melatonin was evaluated on three phosphatidylcholine-based membrane models. Changes in liposome dynamics were monitored by fluorescence, following the response of the probe merocyanine-540, as well as by differential scanning calorimetry (DSC). Langmuir monolayers were investigated using molecular area measurements, as well as by Brewster angle microscopy (BAM). Mica-supported bilayers were observed via atomic force microscopy (AFM). Fluorescence results demonstrating that melatonin increases the affinity between MC-540 and lipid molecules possibly because of an increase in the membrane fluidity in liposomes. DSC analyses showed that melatonin promoted a reduction in enthalpy in the lipid nonpolar chains. Melatonin also promoted an increase in the molecular area of Langmuir monolayers, as well as a decrease in membrane thickness. Consequently, melatonin appeared to induce re-ordering effects in liposome and Langmuir monolayers. AFM images of bilayers immobilized on mica suggested that melatonin induced a gel state predominance or a delay in the main phase transition. At experimental conditions, melatonin interacted actively with all membranes models tested and induced changes in their physico-chemical properties. The data presented here may contribute to the understanding of melatonin physiologic properties, as well as the development of therapeutic advanced systems, such as drug delivery systems and biosensors.

A systematic review of transcranial direct current stimulation effects in attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) stands out as the most prevalent neurodevelopmental disorder of childhood, with global prevalence ranging from 3.4% to 7•2%. Its cognitive symptoms result from the combination of complex etiological processes encompassing genetic and environmental components. Available therapeutic approaches are associated with significant challenges such as modest efficacy or side effects. Transcranial direct current stimulation (tDCS) is a promising tool for enhancing cognitive performance in neuropsychiatric disorders. Trials investigating its applicability in ADHD have showed propitious, however, still preliminary findings. METHODS: We performed a systemic review by searching on Medline, Cochrane Library, Web of Science, ScienceDirect and Embase using the descriptors: "attention-deficit/hyperactivity disorder" or "ADHD"; and "transcranial direct current stimulation" or "tDCS"; following PRISMA guidelines. RESULTS: A total of 383 articles were identified. After removing duplicates, 45 studies were assessed for eligibility, and after careful review, 11 manuscripts applying tDCS in ADHD were included. Significant improvements in attention, inhibitory control and working memory were reported, in addition to increased brain connectivity following use of active tDCS. LIMITATIONS: The main limitation was the small number of trials investigating use of tDCS in ADHD. Study methods and outcome measures were quite variable, and generally did not include long-term follow-up. CONCLUSIONS: Although the extent literature indicates promising findings, the available data remains highly preliminary. Further trials evaluating the efficacy of tDCS for ADHD, with longer follow-up, are necessary. These studies will be needed to determine the optimal protocol for clinical efficacy.

Dimiristoylphosphatidylcholine/genistein molecular interactions: A physico-chemical approach to anti-glioma drug delivery systems.

Regarding free genistein small delivery to the central nervous system, physico-chemical parameters of dimiristoylphosphatidylcholine liposome-loaded genistein were investigated, as well as its in vitro activity against the DPPH radical and glioma cells. Data obtained by UV-vis spectroscopy, Fourier Transform Infrared Spectroscopy, Nuclear Magnetic Resonance, Differential Scanning Calorimetry and Dynamic Light Scattering were used to characterize the liposomal system with respect to motion restriction, hydration degree, trans-gauche isomerization and phase state. In vitro antitumoral effects were monitored through conting and viability assays. Genistein hydroxyl group and lipid hydrogen bonds may have important role in dimiristoylphosphatidylcholine phosphate and choline motion restriction. Genistein-induced choline restriction may be also related to a decrease in the group rotation rate. Genistein: dimiristoylphosphatidylcholine system showed higher molecular package at the acyl chains region compaired to empty liposomes, and it may be related to a decrease in gauche bonds quantity and system size. Lipid acyl chain length seems to influence different genistein effects on membranes, due to the presence of gauche conformers. Genistein: dimiristoylphosphatidylcholine liposome was more efficient as DPPH reducting system than the free-Gen. Liposomal system, at genistein 100 µM, was so efficient as the correspondent free-form genistein, probably showing higher stability to cross the blood-brain barrier. Genistein and the lipid did not show an additive activity against glioma cells. Antioxidant and anti-glioma genistein-loaded liposome potential may be related to the isoflavone location and its restriction effect in the lipid molecular motion. Anti-glioma activity may also be related to a decrease of system size and trans-gauche isomerization.

Molecular interactions and physico-chemical characterization of quercetin-loaded magnetoliposomes.

The bioflavonoid quercetin may prevent magnetoliposomes oxidation, preserving their stability. In this work, the interaction between quercetin and asolectin-based magnetoliposomes was investigated by monitoring the hydration degree, vibrational, rotational and translational mobility parameters of the system as well as its thermodynamic properties. The efficiency of the encapsulation of maghemite magnetic nanoparticles was detected by high resolution-continuum source flame atomic absorption spectrometry (HR-CS FAAS). The magnetic behavior of the system was studied by vibrating sample magnetometry (VSM) technique. The size and surface charge of magnetoliposomes were detected by dynamic light scattering (DLS) and zeta potential (ζ-potential) measurements. The influence of quercetin on the physico-chemical parameters of the magnetoliposomes was evaluated by Fourier transform infrared spectroscopy (FTIR), 31P and 1H nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC) techniques. In vitro antioxidant and antitumoral assays were also performed for the magnetoliposomes. An insertion of quercetin into magnetoliposomes reduced the efficiency of the encapsulation of maghemite nanoparticles by 11%, suggesting a significant interaction between flavonoid and nanoparticles in a specific region of the system. Quercetin discreetly decreased the saturation magnetization of magnetoliposomes, but did not affect the superparamagnetic behavior of the system. 31P and 1H NMR results showed that quercetin did not alter the inverted hexagonal system phase state but decreased lipid polar head mobility. The flavonoid also seems to reorient the choline group above the bilayer phosphate membrane plane, as indicated by ζ-potential system values. FTIR, NMR and DSC responses showed that quercetin disordered the carbonyl and the methylene regions of the magnetoliposomes. Quercetin, as the nanoparticles, seems to be located in the polar head regions of magnetoliposomes, ordering it and diminishing the lipid intermolecular communication in the membrane carbonyl and non-polar regions. The lipid peroxidation of the magnetoliposomes was prevented 8-fold by the presence of quercetin in the system. Also, the flavonoid was responsible for a 45% reduction in the viability of glioma cells. Location and interactions between quercetin and magnetoliposomes components were discussed in order to be correlated with the results of biological activity, contributing to the design of more stable and efficient magnetoliposomes to be applied as contrast and antitumoral agents.