Instituto de Ciências Ambientais, Químicas e Farmacêuticas

Nanotechnology refers to the control, manipulation, study and manufacture of structures and devices at the nanometer size range. The small size, customized surface, improved solubility and multi-functionality of nanoparticles will continue to create new biomedical applications, as nanoparticles allow to dominate stability, solubility and bioavailability, as well controlled release of drugs. The type of a nanoparticle, and its related chemical, physical and morphological properties influence its interaction with living cells, as well as determine the route of clearance and possible toxic effects. This field requires cross-disciplinary research and gives opportunities to design and develop multifunctional devices, which allow the diagnosis and treatment of devastating diseases. Over the past few decades, biodegradable polymers have been studied for the fabrication of drug delivery systems. There was extensive development of biodegradable polymeric nanoparticles for drug delivery and tissue engineering, in view of their applications in controlling the release of drugs, stabilizing labile molecules from degradation and site-specific drug targeting. The primary aim is to reduce dosing frequency and prolong the therapeutic outcomes. For this purpose, inert excipients should be selected, being biopolymers, e.g. sodium alginate, commonly used in controlled drug delivery. Nanoparticles composed of alginate (known as anionic polysaccharide widely distributed in the cell walls of brown algae which, when in contact with water, forms a viscous gum) have emerged as one of the most extensively characterized biomaterials used for drug delivery and targeting a set of administration routes. Their advantages include not only the versatile physicochemical properties, which allow chemical modifications for site-specific targeting but also their biocompatibility and biodegradation profiles, as well as mucoadhesiveness. Furthermore, mechanical strength, gelation, and cell affinity can be modulated by combining alginate nanoparticles with other polymers, surface tailoring using specific targeting moieties and by chemical or physical cross-linking. However, for every physicochemical modification in the macromolecule/ nanoparticles, a new toxicological profile may be obtained. In this paper, the different aspects related to the use of alginate nanoparticles for drug delivery and targeting have been revised, as well as how their toxicological profile will determine the therapeutic outcome of the drug delivery system.

Sequence capture of ultraconserved elements (UCEs) associated with massively parallel sequencing has become a common source of nuclear data for studies of animal systematics and phylogeography. However, mitochondrial and microsatellite variation are still commonly used in various kinds of molecular studies, and probably will complement genomic data in years to come. Here we show that besides providing abundant genomic data, UCE sequencing is an excellent source of both sequences for microsatellite loci design and complete mitochondrial genomes with high sequencing depth. Identification of dozens of microsatellite loci and assembly of complete mitogenomes is exemplified here using three species of Poospiza warbling finches from southern and southeastern Brazil. This strategy opens exciting opportunities to simultaneously analyze genome-wide nuclear datasets and traditionally used mtDNA and microsatellite markers in non-model amniotes at no additional cost.

This paper aims to put constraints on the transition redshift $z_t$, which determines the onset of cosmic acceleration, in cosmological-model independent frameworks. In order to do that, we use the non-parametric Gaussian Process method with $H(z)$ and SNe Ia data. The deceleration parameter reconstruction from $H(z)$ data yields $z_t=0.59^{+0.12}_{-0.11}$. The reconstruction from SNe Ia data assumes spatial flatness and yields $z_t=0.683^{+0.11}_{-0.082}$. These results were found with a Gaussian kernel and we show that they are consistent with two other kernel choices.

Mutations in the quinolone resistance-determining regions (QRDR) in chromosomal gyrA and parC genes and fluoroquinolone susceptibility profiles were investigated in quinolone-resistant Enterobacteriaceae isolated from community and hospitalized patientsin the Brazilian Southeast region. A total of 112 nalidixic acid-resistant enterobacterial isolates collected from 2000 to 2005 were investigated for mutations in the topoisomerases genes gyrA and parC by amplifying and sequencing the QRDR regions. Susceptibility to fluoroquinolones was tested by the agar dilution method. Amongst the 112 enterobacterial isolates, 81 (72.3%) were resistant to ciprofloxacin and 5 (4.5%) showed reduced susceptibility. Twenty-six (23.2%) were susceptible to ciprofloxacin. Several alterations were detected in gyrA and parC genes. Escherichia coli isolates (47.7%) showed double mutations in the gyrA gene and a single one in the parC gene. Two unusual aminoacid substitutions are reported, an Asp87-Asn in a Citrobacter freundii isolate with reduced susceptibility to fluoroquinolones and a Glu84-Ala in one E. coli isolate.Only a parC gene mutation was found in fluoroquinolone-susceptible Enterobacter aerogenes. None of the isolates susceptible to ciprofloxacin presented mutations in topoisomerase genes. This comprehensive analysis of QRDRs in gyrA and parC genes, covering commonly isolated Enterobacteriaceae in Brazil is the largest reported up to now.

Manipulation techniques of materials at nanoscale level have been pointed in the last decades as a promising tool to develop a new class of modified electrodes applicable in biosensors. Also, the high control of material properties is crucial to detect single events at molecular and atomic level. For instance, nanostructured thin films obtained by Langmuir-Blodgett (LB) and Layer-by-layer (LbL) techniques has been reported as an interesting approach to obtain more selective and sensitive modified electrodes and in addition to nanostructured materials are promising strategies for the fabrication of electrochemical biodevices. Thus, our main focus in this review paper is to show an overview on recent trends in the utilization of manipulation techniques applied to the development of electrochemical biosensors. Emphasis will be given in the utilization of different techniques utilized on the modification of electrodes to enhance electrochemical biosensing performance of enzyme-, protein- and DNA-based biosensors and nano-based electrochemical biosensors for diagnosis.

Molecular dynamics simulations were performed for ionic liquids based on the bis(trifluoromethylsulfonyl)imide anion, [NTf(2)], and ammonium cations with increasing length of the alkyl chain and ether functionalized chain. The signature of charge ordering is a sharp peak in the charge-charge structure factor, S(qq)(k), whose intensity is barely affected for longer carbon chain in tetraalkylammonium systems, but decreases in ether functionalized ionic liquids. The first sharp diffraction peak (FSDP) and the corresponding intermediate range order (IRO) are observed in the total S(k) of ionic liquids containing ammonium cations with relatively long chains. The intensity of the FSDP is lower in the total S(k) of the ether derivative in comparison with the tetraalkylammonium counterpart of the same chain length. It is shown that the nature of the IRO is structural heterogeneity of polar and non-polar domains, even though domains defined by chain interactions in the ether derivatives become more polar. Charge correlation in the ether derivative is modified because cations can be coordinated by oxygen atoms of the ether functionalized chain of neighboring cations.

Introduction: T helper 17 (Th17) has been implicated in a variety of inflammatory lung and immune system diseases. However, little is known about the expression and biological role of IL 17 in acute lung injury (ALI). We investigated the mechanisms involved in the effect of anti-IL17 in a model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Methods: Mice were pre-treated with anti-IL17, 1h before saline/LPS intratracheal administration alongside non-treated controls and levels of exhaled nitric oxide (eNO), cytokine expression, extracellular matrix remodeling and oxidative stress, as well as immune cell counts in bronchoalveolar lavage fluid (BALF), and respiratory mechanics were assessed in lung tissue. Results: LPS instillation led to an increase in multiple cytokines, proteases, nuclear factor-κB and Forkhead box P3 (FOXP3), eNO and regulators of the actomyosin cytoskeleton, the number of CD4+ and iNOS-positive cells as well as the number of neutrophils and macrophages in BALF, resistance and elastance of the respiratory system, ARG-1 gene expression, collagen fibers, and actin and 8-iso-PGF2α volume fractions. Pre-treatment with anti-IL17 led to a significant reduction in the level of all assessed factors. Conclusions: Anti-IL17 can protect the lungs from the inflammatory effects of LPS-induced ALI, primarily mediated by the reduced expression of cytokines and oxidative stress. This suggests that further studies using anti-IL17 in a treatment regime would be highly worthwhile.

This study investigated soil clay mineralogy of mangrove forests along the Brazilian coast in eight regions of different environmental characteristics, with a focus on the crystallochemical features and genesis of 2:1 phyllosilicates. Samples from two different depths (0–30 and 60–90 cm) and two clay size fractions (<2 and <0.2 μm) were studied. The analytical tools used were X-ray diffraction, Fourier-transform infrared spectroscopy, and transmission electron microscopy–energy dispersive spectroscopy (TEM-EDS). A complex assemblage was found in both fractions, including high proportions of kaolinite, illite (Fe-illite/glauconite), and smectite (Fe-beidellite, Fe-montmorillonite), minor amounts of gibbsite and quartz, and traces of K-feldspar, halloysite, and amphibole crystals (TEM-EDS data). Evidence of illite–smectite and possibly kaolinite–smectite mixed-layer phases was found in the <0.2-μm fraction. An authigenic transformation process likely taking place, from kaolinite to Fe-illite/glauconite, through transitory kaolinite–smectite and illite–smectite phases. The reaction is triggered by high Fe activity in solution generated by dissolution of Fe oxides and pyrite present in the sediment, at approximately neutral pH and high salt content in the water. Smectite illitization takes place by substitution of Al3+ for Si4+ in the tetrahedral sheet, of Fe and Mg2+ for Al3+ in the octahedral sheet, and progressive Fe reduction, all of which produces an increase in the layer charge and K uptake. The sequential nature of the transformation (kaolinite–smectite–illite) suggests a solid-state transformation process. Two unusual kaolinite-rich mangroves were found, indicating low reactivity or high deposition rate of continental sediments of soils derived from the Barreiras Group, dominated by kaolinite.

Carbapenem-resistant Acinetobacter baumannii (CRAB) are emerging worldwide. In South America, clinical isolates presenting such a phenotype usually do not belong to the globally distributed international clone 2 (IC2). The majority of these isolates are also resistant to multiple other antimicrobials and are often designated extremely drug-resistant (XDR). The aim of this study was to characterize the resistance mechanisms presented by 18 carbapenem-resistant A. baumannii isolates from five different Brazilian hospitals. Species identification was determined by rpoB sequencing, and antimicrobial susceptibility was determined by broth microdilution. Isolates were submitted to whole genome sequencing using Illumina platform and genetic similarity was determined by PFGE, MLST, and cgMLST. Genome analysis was used to identify intrinsic and acquired resistance determinants, including mutations in the AdeRSABC efflux system and in outer membrane proteins (OMPs). All isolates were identified as A. baumannii and grouped into 4 pulsotypes by PFGE, which belonged to clonal complexes (CC) 15 Pas /103 Ox ( n = 4) and 79 Pas /113 Ox ( n = 14), corresponding to IC4 and IC5, respectively. High MIC values to carbapenems, broad-spectrum cephalosporins, amikacin, and ciprofloxacin were observed in all isolates, while MICs of ampicillin/sulbactam, gentamicin, and tigecycline varied among the isolates. Minocycline was the most active antimicrobial agent tested. Moreover, 12 isolates (66.7%) were considered resistant to polymyxins. Besides intrinsic OXA-51 and ADC variants, all isolates harbored an acquired carbapenem-hydrolyzing class D β-lactamase (CHDL) encoding gene, either bla OXA– 23 or bla OXA– 72 . A diversity of aminoglycoside modifying enzymes and resistance determinants to other antimicrobial classes were found, as well as mutations in gyrA and parC . Non-synonymous mutations have also been identified in the AdeRSABC efflux system and in most OMPs, but they were considered natural polymorphisms. Moreover, resistance to polymyxins among isolates belonging to IC5 were associated to non-synonymous mutations in pmrB , but no known polymyxin resistance mechanism was identified in isolates belonging to IC4. In conclusion, A. baumannii clinical isolates belonging to South America’s major clones present a myriad of antimicrobial resistance determinants. Special attention should be paid to natural polymorphisms observed in each clonal lineage, especially regarding non-synonymous mutations in constitutive genes associated with distinct resistance phenotypes.

Purpose This study aims to identify the countries’ innovation factors that are determinant for them to achieve higher levels of development. In addition, the research identified which of these factors should be prioritized so the countries can move up in the rank of the most competitive. Design/methodology/approach The study used the indicators of innovation and the stage of development of 137 countries proposed by the Global Competitiveness Report published by the World Economic Forum and techniques of multivariate data analysis. Findings The results indicated that all the factors tested are determinant to lead the countries throughout their stages of development. The research highlights that the factors “Quality of scientific research institutions” and “Patent Cooperation Treaty (PCT) patent applications” should be equally prioritized for the countries’ development. Practical implications The results suggested that the factors Capacity for Innovation, Quality of Scientific Research Institutions, Company Spending on Research and Development (R&amp;D), University–Industry Collaboration in R&amp;D, Government Procurement of Advanced Technology Products, Availability of Scientists and Engineers and PCT Patent Applications are decisive for positioning countries in terms of their stage of development and should be part of their public policy and enterprises’ strategic planning. Originality/value The findings show that countries should prioritize the factors Quality of Scientific Research Institutions and PCT Patent Applications, as these factors, when acting together, predict the evolution to higher stages of development.

Alzheimer's disease (AD) is a late-onset, progressive degenerative disorder that affects mainly the judgment, emotional stability, and memory domains. AD is the outcome of a complex interaction among several factors which are not fully understood yet; nevertheless, it is clear that oxidative stress and inflammatory pathways are among these factors. 65 elderly subjects (42 cognitively intact and 23 with probable Alzheimer's disease) were selected for this study. We evaluated erythrocyte activities of superoxide dismutase, catalase, and glutathione peroxidase as well as plasma levels of total glutathione, α-tocopherol, β-carotene, lycopene, and coenzyme Q10. These antioxidant parameters were confronted with plasmatic levels of protein and lipid oxidation products. Additionally, we measured basal expression of monocyte HLA-DR and CD-11b, as well as monocyte production of cytokines IL1-α, IL-6, and TNF-α. AD patients presented lower plasmatic levels of α-tocopherol when compared to control ones and also higher basal monocyte HLA-DR expression associated with higher IL-1α production when stimulated by LPS. These findings support the inflammatory theory of AD and point out that this disease is associated with a higher basal activation of circulating monocytes that may be a result of α-tocopherol stock depletion.

The rates of recurrent venous thromboembolism (RVTE) vary widely, and its causes still need to be elucidated. Statistical multivariate methods can be used to determine disease predictors and improve current methods for risk calculation. The objective of this study was to apply principal component analysis to a set of data containing clinical records of patients with previous venous thromboembolism and extract the main factors that predict recurrent thrombosis. Records of 39 factors including blood and lipid parameters, hereditary thrombophilia, antiphospholipid syndrome, clinical data regarding previous thrombosis and treatment, and Doppler ultrasound results were collected from 235 patients. The results showed that 13 principal components were associated with RVTE and that 18 of 39 factors are the important for the analysis. These factors include red blood cell, white blood cell, hematocrit, red cell distribution width, glucose, lipids, natural anticoagulant, creatinine, age, as well as first deep vein thrombosis data (distal/proximal, d-dimer, and time of anticoagulation). The results demonstrated that simple clinical parameters easy to be collected can be used to predict rates of recurrence and to develop new clinical decision support systems to predict the rates of RVTE.

OBJECTIVES: Carbapenem-resistant Pseudomonas aeruginosa (CR-PSA) imposes great limitations on empirical therapeutic choices, which are further complicated by metallo-β-lactamase production. This study evaluated in vitro antimicrobial synergy of ceftolozane/tazobactam in combination with aztreonam and fosfomycin against MDR PSA. METHODS: MICs were determined by broth microdilution and gradient strips. The effect of ceftolozane/tazobactam+aztreonam and ceftolozane/tazobactam+fosfomycin combinations were tested against 27 MDR PSA isolates carrying blaSPM-1 (n = 13), blaIMP (n = 4), blaVIM (n = 3), blaGES-1 (n = 2) and blaCTX-M-like (n = 2), and 3 isolates with no acquired β-lactamase production detected by gradient diffusion strip crossing (GDSC). Six genetically unrelated SPM-1-producing isolates were also evaluated by time-kill analysis (TKA). RESULTS: All CR-PSA isolates harbouring blaSPM-1, blaGES-1 and blaIMP-1 were categorized as resistant to ceftolozane/tazobactam, meropenem and fosfomycin, with 70% being susceptible to aztreonam. Synergism for ceftolozane/tazobactam+fosfomycin and ceftolozane/tazobactam+aztreonam combinations was observed for 88.9% (24/27) and 18.5% (5/27) of the isolates by GDSC, respectively. A 3- to 9-fold reduction in ceftolozane/tazobactam MICs was observed, depending on the combination. Ceftolozane/tazobactam+fosfomycin was synergistic by TKA against one of six SPM-1-producing isolates, with additional non-synergistic bacterial density reduction for another isolate. Aztreonam peak concentrations alone demonstrated a ≥3 log10 cfu/mL reduction against all six isolates, but all strains were within the susceptible range for the drug. No antagonism was observed. CONCLUSIONS: In the context of increasing CR-PSA and the genetic diversity of resistance mechanisms, new combinations and stewardship strategies may need to be explored in the face of increasingly difficult to treat pathogens.

The parameter plane investigation for a family of two-dimensional, nonlinear, and area contracting map is made. Several dynamical features in the system such as tangent, period-doubling, pitchfork, and cusp bifurcations were found and discussed together with cascades of period-adding, period-doubling, and the Feigeinbaum scenario. The presence of spring and saddle-area structures allow us to conclude that cubic homoclinic tangencies are present in the system. A set of complex sets such as streets with the same periodicity and the period-adding of spring-areas are observed in the parameter space of the mapping.

Crataegus oxyacantha, a plant of the Rosaceae family also known "English hawthorn, haw, maybush, or whitethorn," has long been used for medicinal purposes such as digestive disorders, hyperlipidemia, dyspnea, inducing diuresis, and preventing kidney stones. However, the predominant use of this plant has been to treat cardiovascular disorders. Due to a lack of studies on the genotoxicity of C. oxyacantha, this investigation was undertaken to determine whether its fruit extract exerts cytotoxic, genotoxic, or clastogenic/aneugenic effects in leukocytes and HepG2 (liver hepatocellular carcinoma) cultured human cells, or mutagenic effects in TA100 and TA98 strains of Salmonella typhimurium bacterium. Genotoxicity analysis showed that the extract produced no marked genotoxic effects at concentrations of 2.5 or 5 µg/ml in either cell type; however, at concentrations of 10 µg/ml or higher significant DNA damage was detected. The micronucleus test also demonstrated that concentrations of 10 µg/ml or higher produced clastogenic/aneugenic responses. In the Ames test, the extract induced mutagenic effects in TA98 strain of S. typhimurium with metabolic activation at all tested concentrations (2.5 to 500 µg/ml). Data indicate that, under certain experimental conditions, the fruit extract of C. oxyacantha exerts genotoxic and clastogenic/aneugenic effects in cultured human cells, and with metabolism mutagenicity occurs in bacteria cells.

OBJECTIVES: In order to assess if ambient air pollution in urban areas could be related to alterations in male/female ratio this study objectives to evaluate changes in ambient particulate matter (PM10) concentrations after implementation of pollution control programmes in São Paulo city and the secondary sex ratio (SRR). DESIGN AND METHODS: A time series study was conducted. São Paulo's districts were stratified according to the PM10 concentrations levels and were used as a marker of overall air pollution. The male ratio was chosen to represent the secondary sex ratio (SSR=total male birth/total births). The SSR data from each area was analysed according to the time variation and PM10 concentration areas using descriptive statistics. The strength association between annual average of PM10 concentration and SSR was performed through exponential regression, and it was adopted as a statistical significance level of p<0.05. RESULTS: The exponential regression showed a negative and significant association between PM10 and SSR. SSR varied from 51.4% to 50.7% in São Paulo in the analysed period (2000-2007). Considering the PM10 average concentration in São Paulo city of 44.72 μg/m(3) in the study period, the SSR decline reached almost 4.37%, equivalent to 30 934 less male births. CONCLUSIONS: Ambient levels of PM10 are negatively associated with changes in the SSR. Therefore, we can speculate that higher levels of particulate pollution could be related to increased rates of female births.

Abstract We analyzed the variability of downward solar irradiance reaching the surface at São Paulo city, Brazil, and estimated the climatological aerosol and cloud radiative effects. Eleven years of irradiance were analyzed, from 2005 to 2015. To distinguish the aerosol from the cloud effect, the radiative transfer code LibRadtran was used to calculate downward solar irradiance. Two runs were performed, one considering only ozone and water vapor daily variability, with AOD set to zero and the second allowing the three variables to change, according to mean climatological values. The difference of the 24 h mean irradiance calculated with and without aerosol resulted in the shortwave aerosol direct radiative effect, while the difference between the measured and calculated, including the aerosol, represented the cloud effect. Results showed that, climatologically, clouds can be 4 times more effective than aerosols. The cloud shortwave radiative effect presented a maximum reduction of about −170 W m −2 in January and a minimum in July, of −37 W m −2 . The aerosol direct radiative effect was maximum in spring, when the transport of smoke from the Amazon and central parts of South America is frequent toward São Paulo. Around mid‐September, the 24 h radiative effect due to aerosol only was estimated to be −50 W m −2 . Throughout the rest of the year, the mean aerosol effect was around −20 W m −2 and was attributed to local urban sources. The effect of the cloud fraction on the cloud modification factor, defined as the ratio of all‐sky irradiation to cloudless sky irradiation, showed dependence on the cloud height. Low clouds presented the highest impact while the presence of high clouds only almost did not affect solar transmittance, even in overcast conditions.

Essential oils of ripe fruits from Schinus terebinthifolius (Anacardiaceae), obtained using a pilot extractor and a Clevenger apparatus were chemically characterized. Due the high amount of (-)- α-pinene in both oils, this monoterpene was tested against the protozoan parasite Trypanosoma cruzi, showing a moderate potential (IC50 63.56 µg/mL) when compared to benznidazole (IC50 43.14 µg/mL). Otherwise, (-)- α-pinene oxide did not showed anti-trypanosomal activity (IC50 > 400 µg/mL) while (-)-pinane showed an IC50 of 56.50 µg/mL. The obtained results indicated that the epoxydation of α-pinene results to the loss of the anti-parasitic activity while its hydrogenation product, contributed slightly to the increased activity.

Histamine is a chemical transmitter found practically in whole organism and exerts its effects through the interaction with H1 to H4 histaminergic receptors. Specifically, H4 receptors are found mainly in immune cells and blood-forming tissues, thus are involved in inflammatory and immune processes, as well as some actions in central nervous system. Therefore, H4 receptor ligands can have applications in the treatment of chronic inflammatory and immune diseases and may be novel therapeutic option in these conditions. Several H4 receptor ligands have been described from early 2000's until nowadays, being imidazole, indolecarboxamide, 2-aminopyrimidine, quinazoline, and quinoxaline scaffolds the most explored and discussed in this review. Moreover, several studies of molecular modeling using homology models of H4 receptor and QSAR data of the ligands are summarized. The increasing and promising therapeutic applications are leading these compounds to clinical trials, which probably will be part of the next generation of blockbuster drugs.

OBJECTIVE: The diagnosis of multiple sclerosis (MS) has changed over the last decade, but remains a composite of clinical assessment and magnetic resonance imaging to prove dissemination of lesions in time and space. The intrathecal synthesis of immunoglobulin may be a nonspecific marker and there are no plasma biomarkers that are useful in the diagnosis of MS, presenting additional challenges to their early detection. METHODS: We performed a preliminary untargeted qualitative lipidomics mass spectrometry analysis, comparing cerebrospinal fluid (CSF) and plasma samples from patients with MS, other inflammatory neurological diseases and idiopathic intracranial hypertension. RESULTS: Lipid identification revealed that fatty acids and sphingolipids were the most abundant classes of lipids in the CSF and that glycerolipids and fatty acids were the main class of lipids in the plasma of patients with MS. The area under the curve was 0.995 (0.912-1) and 0.78 (0.583-0.917), respectively. The permutation test indicated that this ion combination was useful for distinguishing MS from other inflammatory diseases (p < 0.001 and 0.055, respectively). CONCLUSION: This study concluded that the CSF and plasma from patients with MS bear a unique lipid signature that can be useful as a diagnostic biomarker.