Biological evaluation of naproxen–dehydrodipeptide conjugates with self-hydrogelation capacity as dual LOX/COX inhibitors

The use of peptide–drug conjugates is emerging as a powerful strategy for targeted drug delivery. Previously, we have found that peptides conjugated to a non-steroidal anti-inflammatory drug (NSAID), more specifically naproxen–dehydrodipeptide conjugates, readily form nanostructured fibrilar supramolecular hydrogels. These hydrogels were revealed as efficacious nano-carriers for drug delivery applications. Moreover, the incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) rendered the hydrogels responsive to external magnetic fields, undergoing gel-to-solution phase transition upon remote magnetic excitation. Thus, magnetic dehydrodipeptide-based hydrogels may find interesting applications as responsive Magnetic Resonance Imaging (MRI) contrast agents and for magnetic hyperthermia-triggered drug-release applications. Supramolecular hydrogels where the hydrogelator molecule is endowed with intrinsic pharmacological properties can potentially fulfill a dual function in drug delivery systems as (passive) nanocariers for incorporated drugs and as active drugs themselves. In this present study, we investigated the pharmacological activities of a panel of naproxen–dehydrodipeptide conjugates, previously studied for their hydrogelation ability and as nanocarriers for drug-delivery applications. A focused library of dehydrodipeptides, containing N-terminal canonical amino acids (Phe, Tyr, Trp, Ala, Asp, Lys, Met) N-capped with naproxen and linked to a C-terminal dehydroaminoacid (ΔPhe, ΔAbu), were evaluated for their anti-inflammatory and anti-cancer activities, as well as for their cytotoxicity to non-cancer cells, using a variety of enzymatic and cellular assays. All compounds except one were able to significantly inhibit lipoxygenase (LOX) enzyme at a similar level to naproxen. One of the compounds 4 was able to inhibit the cyclooxygenase-2 (COX-2) to a greater extent than naproxen, without inhibiting cyclooxygenase-1 (COX-1), and therefore is a potential lead in the search for selective COX-2 inhibitors. This hydrogelator is a potential candidate for dual COX/LOX inhibition as an optimised strategy for treating inflammatory conditions.This work is funded by National Funds through FCT-Portuguese Foundation for Science and Technology under the Project cand CQ/UM UID/QUI/00686/2013 and UID/QUI/0686/2016. The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project No 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC).This work is funded by FEDER funds through the COMPETE 2020 Programme and National Funds through FCT-Portuguese Foundation for Science and Technology under the Project UID/CTM/50025/2013 and UIDB/50006/2020. We thank Vera Alexandra de Macedo Ribeiro for isolation of the 26S proteasome subunit. We acknowledge the precious advice of Tarsila Castro on the docking studies. For computing resources:”Search-ON2: Revitalization of HPC infrastructure of UMinho, (NORTE-07-0162-FEDER-000086), co-funded by the North Portugal Regional Operational Programme (ON.2-O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF)

A Wavelet Threshold Function for Treatment of Partial Discharge Measurements

Based on the wavelet transform filtering theory, the chapter will describe the elaboration of a wavelet threshold function intended for the denoising of the partial discharge phenomenon measurements. This new function, conveniently named Fleming threshold, is based on the logistic function, which is well known for its utility in several important areas. In the development is shown some variations in the application of the Fleming function, in an attempt to identify the decomposition levels where the thresholding process must be more stringent and those where it can be more lenient, which increases its effectiveness in the removal of noisy coefficients. The proposed function and its variants demonstrate excellent results compared to other wavelet thresholding methods already described in the literature, including the famous Hard and Soft functions

Selective impact of Tau loss on nociceptive primary afferents and pain sensation

Tau protein hyperphosphorylation and consequent malfunction are hallmarks of Alzheimer's disease pathology; importantly, pain perception is diminished in these patients. In physiological conditions, Tau contributes to cytoskeletal dynamics and in this way, influences a number of cellular mechanisms including axonal trafficking, myelination and synaptic plasticity, processes that are also implicated in pain perception. However, there is no in vivo evidence clarifying the role of Tau in nociception. Thus, we tested Tau-null (Tau-/-) and Tau+/+ mice for acute thermal pain (Hargreaves' test), acute and tonic inflammatory pain (formalin test) and mechanical allodynia (Von Frey test). We report that Tau-/- animals presented a decreased response to acute noxious stimuli when compared to Tau+/+ while their pain-related behavior is augmented under tonic painful stimuli. This increased reactivity to tonic pain was accompanied by enhanced formalin-evoked c-fos staining of second order nociceptive neurons at Tau-null dorsal horn. In addition, we analyzed the primary afferents conveying nociceptive signals, estimating sciatic nerve fiber density, myelination and nerve conduction. Ultrastructural analysis revealed a decreased C-fiber density in the sciatic nerve of Tau-null mice and a hypomyelination of myelinated fibers (Ad-fibers) - also confirmed by western blot analysis - followed by altered conduction properties of Tau-null sciatic nerves. To our knowledge, this is the first in vivo study that demonstrates that Tau depletion negatively affects the main systems conveying nociceptive information to the CNS, adding to our knowledge about Tau function(s) that might also be relevant for understanding peripheral neurological deficits in different Tauopathies.We would like to thank Drs Joao Relvas, Joana Paes de Faria Monteiro and Nuno Dias for their comments in this work. Many thanks to Dr Joao Relvas for the MBP antibody. The work was supported by grants "SFRH/BPD/80118/2011", "PTDC/SAU-NMC/113934/2009" funded by FCT - Portuguese Foundation for Science and Technology and project DoIT - Desenvolvimento e Operacionalizacao da Investigacao de Translacao (No. do projeto 13853), funded by Fund Europeu de Desenvolvimento Regional (FEDER) through the Programa Operacional Fatores de Competitividade (POFC). Author's contributions: experimental design - IS, HA, VP, AA, and NS; performed research - IS, HA, VP, AL, SL, SS, SP, AC, FPR, and RF; data analyses - IS, HA, AL, VP, SC, and FPR; and manuscript preparation - IS, HA, VP, and NS

The relationship between genetic risk variants with brain structure and function in bipolar disorder: A systematic review of genetic-neuroimaging studies

Genetic-neuroimaging paradigms could provide insights regarding the pathophysiology of bipolar disorder (BD). Nevertheless, findings have been inconsistent across studies. A systematic review of gene-imaging studies involving individuals with BD was conducted across electronic major databases from inception until January 9th, 2017. Forty-four studies met eligibility criteria (N=2122 BD participants). Twenty-six gene variants were investigated across candidate gene studies and 4 studies used a genome-wide association approach. Replicated evidence (i.e. in >2 studies) suggests that individuals with BD carrying the BDNF Val66Met risk allele could have reduced hippocampal volumes compared to non-carriers. This review underscores the potential of gene-neuroimaging paradigms to provide mechanistic insights for BD. However, this systematic review found a single replicated finding. Suggestions to improve the reproducibility of this emerging field are provided, including the adoption of a trans-diagnostic approac

Synthesis, anti-toxoplasma gondii and antimicrobial activities of 2-hydrazolyl-3-phenyl-5-(4-nitrobenzylidene)-4-thiazolidinone substituted derivatives

A novel series of 2-hydrazolyl-3-phenyl-5-(4-nitrobenzylidene)-4-thiazolidinone substituted (3a-p) has been synthesized. The intermediates 2-hydrazolyl-3-phenyl-4-thiazolidinone substituted (2a-p) were prepared by condensation of benzaldehyde 4-phenyl-3-thiosemicarbazone substituted (1a-p) with ethyl chloroacetate. Theses intermediates were submitted to reaction with ethyl 2-cyano-3-(4-nitrophenyl)-acetate to give the title compounds. The 4-thiazolidinones were screened for their anti-Toxoplasma gondii, and all derivatives promoted decrease of percentage of infection of Vero cells, with elimination of intracellular tachyzoites. The LD50 ranged around 0.5 mM for the intracellular parasites and were higher than 10 mM for Vero cells. According to results of antimicrobial activity, only two compounds showed significant inhibition against M. luteus, but demonstrated higher values of MIC and MBC when compared with standard drug.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Mucociliary clearance, airway inflammation and nasal symptoms in urban motorcyclists

OBJECTIVES: There is evidence that outdoor workers exposed to high levels of air pollution exhibit airway inflammation and increased airway symptoms. We hypothesized that these workers would experience increased airway symptoms and decreased nasal mucociliary clearance associated with their exposure to air pollution. METHODS: In total, 25 non-smoking commercial motorcyclists, aged 18-44 years, were included in this study. These drivers work 8-12 hours per day, 5 days per week, driving on urban streets. Nasal mucociliary clearance was measured by the saccharine transit test; airway acidification was measured by assessing the pH of exhaled breath condensate; and airway symptoms were measured by the Sino-nasal Outcome Test-20 questionnaire. To assess personal air pollution exposure, the subjects used a passive-diffusion nitrogen dioxide (NO2) concentration-monitoring system during the 14 days before each assessment. The associations between NO2 and the airway outcomes were analyzed using the Mann-Whitney test and the Chi-Square test. Clinicaltrials.gov: NCT01976039. RESULTS: Compared with clearance in healthy adult males, mucociliary clearance was decreased in 32% of the motorcyclists. Additionally, 64% of the motorcyclists had airway acidification and 92% experienced airway symptoms. The median personal NO2 exposure level was 75 mg/m3 for these subjects and a significant association was observed between NO2 and impaired mucociliary clearance (p = 0.036). CONCLUSION: Non-smoking commercial motorcyclists exhibit increased airway symptoms and airway acidification as well as decreased nasal mucociliary clearance, all of which are significantly associated with the amount of exposure to air pollution

Prioridades Axiológicas, Tempo de Serviço e Cidadania Organizacional

The objective of this research was to study the relationship between value priorities, tenure, and organizationalcitizenship. To our knowledge, personal value priorities have not been studied as antecedents of organizational behavior. Thesample was composed of 300 employees, men and women, with average age of 38.07 years. Two instruments were used: theSchwartz Value Inventory and the Organizational Citizenship Scale. Two groups of value priorities' subjects were considered:a high score group and a low score group. Three levels of organizational tenure were considered. The four second-order factorsof value priorities and the five organizational citizenship factors were considered for the analysis (Anova 2X3). Priorities ofself-transcendence, self-enhancement, collectivism and individualism values had a significant influence on several factors oforganizational citizenship. The impact of organizational tenure was limited to two factors: organizational climate and protectionof organizational patrimonyFoi objetivo desta pesquisa estudar a relação entre as prioridades axiológicas, o tempo de serviço e a cidadania organizacional. Os autores não têm conhecimento de que as prioridades axiológicas do indivíduo tenham sido estudadas comoantecedentes da cidadania organizacional. A amostra foi composta por 300 empregados, homens e mulheres, com idade média de 38,07 anos. Dois instrumentos de medida foram utilizados: o Inventário de Valores de Schwartz e a Escala de Cidadania Organizacional. Os sujeitos foram divididos em dois grupos de acordo com as suas prioridades axiológicas (escore alto e baixo). Os quatro fatores axiológicos de ordem superior e  os cinco fatores de cidadania organizacional foram considerados para a análise estatística (Anova 2X3). As prioridades ao nível dos valores de autotranscendência, autopromoção, individualismo e coletivismo tiveram influência significativa sobre vários fatores de cidadania organizacional. O impacto do tempo de serviço foi limitado a dois fatores: clima organizacional externo e proteção  ao patrimônio organizacional

A simple architecture with self-assembled monolayers to build immunosensors for detecting the pancreatic cancer biomarker CA19-9

Accepted ManuscriptThe challenge of the early diagnosis of pancreatic cancer in routine clinical practice requires low-cost means of detection, and this may be achieved with immunosensors based on electrical or electrochemical principles. In this paper, we report a potentially low-cost immunosensor built with interdigitated gold electrodes coated with a self-assembled monolayer and a layer of anti-CA19-9 antibodies, which is capable of detecting the pancreatic cancer biomarker CA19-9 using electrical impedance spectroscopy. Due to specific, irreversible adsorption of CA19-9 onto its corresponding antibody, according to data from polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS), the immunosensor is highly sensitive and selective. It could detect CA19-9 in commercial samples with a limit of detection of 0.68 U mL−1, in addition to distinguishing between blood serum samples from patients with different concentrations of CA19-9. Furthermore, by treating the capacitance data with information visualization methods, we were able to verify the selectivity and robustness of the immunosensor with regard to false positives, as the samples containing higher CA19-9 concentrations, including those from tumor cells, could be distinguished from those with possible interferents.CAPES, FAPESP (Grant 2013/14262-7 and 2012/15543-7), CNPq (150985/2017-7), nBioNet network and Barretos Cancer Hospital for financial supportinfo:eu-repo/semantics/publishedVersio