RESUMO
Malaria is the leading parasitic disease worldwide, with P. vivax being a major challenge for its control. Several studies have indicated metabolomics as a promising tool for combating the disease. The study evaluated plasma metabolomic profiles of patients with recurrent and non-recurrent P. vivax malaria in the Brazilian Amazon. Metabolites extracted from the plasma of P. vivax-infected patients were subjected to LC-MS analysis. Untargeted metabolomics was applied to investigate the metabolic profile of the plasma in the two groups. Overall, 51 recurrent and 59 non-recurrent patients were included in the study. Longitudinal metabolomic analysis revealed 52 and 37 significant metabolite features from the recurrent and non-recurrent participants, respectively. Recurrence was associated with disturbances in eicosanoid metabolism. Comparison between groups suggest alterations in vitamin B6 (pyridoxine) metabolism, tyrosine metabolism, 3-oxo-10-octadecatrienoate ß-oxidation, and alkaloid biosynthesis II. Integrative network analysis revealed enrichment of other metabolic pathways for the recurrent phenotype, including the butanoate metabolism, aspartate and asparagine metabolism, and N-glycan biosynthesis. The metabolites and metabolic pathways predicted in our study suggest potential biomarkers of recurrence and provide insights into targets for antimalarial development against P. vivax.
Assuntos
Antimaláricos , Malária Vivax , Malária , Humanos , Malária Vivax/parasitologia , Metabolômica , Malária/parasitologia , Metaboloma , Antimaláricos/uso terapêuticoRESUMO
IMPORTANCE: The SARS-CoV-2 virus infection in humans induces significant inflammatory and systemic reactions and complications of which corticosteroids like methylprednisolone have been recommended as treatment. Our understanding of the metabolic and metabolomic pathway dysregulations while using intravenous corticosteroids in COVID-19 is limited. This study will help enlighten the metabolic and metabolomic pathway dysregulations underlying high daily doses of intravenous methylprednisolone in COVID-19 patients compared to those receiving placebo. The information on key metabolites and pathways identified in this study together with the crosstalk with the inflammation and biochemistry components may be used, in the future, to leverage the use of methylprednisolone in any future pandemics from the coronavirus family.
Assuntos
COVID-19 , Humanos , Metilprednisolona/efeitos adversos , SARS-CoV-2 , Administração Intravenosa , Corticosteroides/efeitos adversosRESUMO
In the scope of a research program with the goal of developing treatments for inflammatory diseases, the pharmacological evaluation of LQFM291, designed by molecular hybridization from butylated hydroxytoluene and paracetamol, was described. The antioxidant profile of LQFM291 was evaluated by electrochemical measurement. Also, acute or repeated treatments with equimolar doses to paracetamol were used to evaluate the antinociceptive and/or anti-inflammatory activities of LQFM291 in animal models. The toxicologic potential of LQFM291 was also evaluated and compared to paracetamol through biochemical and histopathological analysis after the repeated treatment schedule. As a result of the acute treatment, paracetamol showed a similar antinociceptive effect in formalin test compared to LQFM291. Whereas, after the repeated treatment, when carrageenan-induced hyperalgesia and edema tests were performed, paracetamol showed a delayed antinociceptive and anti-inflammatory effect compared to LQFM291. Furthermore, as other advantages the LQFM291 showed a high redox capacity, a gastroprotective activity and a safety pharmacological profile without any liver or kidney damage. These effects can be related to the prevention of oxidative stress by reduction of protein and lipid peroxidation in gastric tissue, maintenance of glutathione levels in hepatic homogenate, and a systemic reduction of pro-inflammatory cytokine levels, which may characterize the LQFM291 as a more viable and effective alternative to relief pain and inflammatory signs in patients with chronic disorders.
Assuntos
Acetaminofen , Anti-Inflamatórios , Animais , Humanos , Acetaminofen/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Dor/tratamento farmacológico , Carragenina , Extratos Vegetais/farmacologia , Analgésicos/efeitos adversos , Edema/induzido quimicamente , Edema/tratamento farmacológicoRESUMO
Trimetozine is used to be indicated for the treatment of mental illnesses, particularly anxiety. The present study provides data on the pharmacological profile of trimetozine derivative morpholine (3,5-di-tert-butyl-4-hydroxyphenyl) methanone (LQFM289) which was designed from molecular hybridization of trimetozine lead compound and 2,6-di-tert-butyl-hydroxytoluene to develop new anxiolytic drugs. Here, we conduct molecular dynamics simulations, docking studies, receptor binding assays, and in silico ADMET profiling of LQFM289 before its behavioral and biochemical assessment in mice within the dose range of 5-20 mg/kg. The docking of LQFM289 showed strong interactions with the benzodiazepine binding sites and matched well with receptor binding data. With the ADMET profile of this trimetozine derivative that predicts a high intestinal absorption and permeability to blood-brain barrier without being inhibited by the permeability glycoprotein, the oral administration of LQFM289 10 mg/kg consistently induced anxiolytic-like behavior of the mice exposed to the open field and light-dark box apparatus without eliciting motor incoordination in the wire, rotarod, and chimney tests. A decrease in the wire and rotarod´s fall latency coupled with an increase in the chimney test´s climbing time and a decrease in the number of crossings in the open field apparatus at the dose of 20 mg/kg of this trimetozine derivative suggest sedative or motor coordination impairment at this highest dose. The attenuation of the anxiolytic-like effects of LQFM289 (10 mg/kg) by flumazenil pretreatment implicates the participation of benzodiazepine binding sites. The lowering of corticosterone and tumor necrosis factor alpha (cytokine) in LQFM289-treated mice at a single oral (acute) dose of 10 mg/kg suggests that the anxiolytic-like effect of this compound also involves the recruitment of non-benzodiazepine binding sites/GABAergic molecular machinery.
Assuntos
Ansiolíticos , Camundongos , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Benzodiazepinas/farmacologia , Hipnóticos e Sedativos/farmacologia , Ansiedade/tratamento farmacológico , Morfolinas/farmacologia , Comportamento AnimalRESUMO
Advances have been made in the search for new multi-target modulators to control pain and inflammation. Therefore, compound 3,5-di-tert-butyl-4-hydroxyphenyl)(4-methylpiperazin-1-yl)methanone (LQFM202) was synthesised and evaluated. First, in vitro assays were performed for COX-1, COX-2, and 5-LOX enzymes. Subsequently, adult female Swiss albino mice treated orally with LQFM202 at doses of 25-200 mg/kg were subjected to acetic acid-induced writhing, formalin-induced pain, carrageenan-induced hyperalgesia, carrageenan- or zymosan-induced paw oedema, or pleurisy. LQFM202 inhibited COX-1, COX-2, and LOX-5 (IC50 = 3499 µM, 1565 µM, and 1343 µM, respectively). In acute animal models, LQFM202 (50, 100, or 200 mg/kg) decreased the amount of abdominal writhing (29%, 52% and 48%, respectively). Pain in the second phase of the formalin test was reduced by 46% with intermediate dose. LQFM202 (100 mg/kg) reduced the difference in nociceptive threshold in all 4 h evaluated (46%, 37%, 30%, and 26%, respectively). LQFM202 (50 mg/kg) decreased the carrageenan-oedema from the second hour (27%, 31% and 25%, respectively); however, LQFM202 (100 mg/kg) decreased the carrageenan-oedema in all hours evaluated (35%, 42%, 48% and 50%, respectively). When using zymosan, LQFM202 (50 mg/kg) decreased the oedema in all hours evaluated (33%, 32%, 31% and 20%, respectively). In the carrageenan-pleurisy test, LQFM202 (50 mg/kg) reduced significantly the number of polymorphonuclear cells (34%), the myeloperoxidase activity (53%), TNF-α levels (47%), and IL-1ß levels (58.8%). When using zymosan, LQFM202 (50 mg/kg) reduced the number of polymorphonuclear and mononuclear cells (54% and 79%, respectively); and the myeloperoxidase activity (46%). These results suggest antinociceptive and anti-inflammatory effects of LQFM202.
Assuntos
Analgésicos , Pleurisia , Animais , Camundongos , Feminino , Analgésicos/farmacologia , Carragenina/farmacologia , Ciclo-Oxigenase 2 , Peroxidase , Zimosan , Anti-Inflamatórios/farmacologia , Dor/tratamento farmacológico , Inflamação/tratamento farmacológico , Pleurisia/tratamento farmacológico , Piperazinas , Edema/tratamento farmacológico , Extratos Vegetais/farmacologiaRESUMO
Monolithic polymers are described as continuous and highly porous materials. They have been gaining popularity as an effective extracting phase for some sample preparation methods, due to their variety of functionalities, such as wide pH range tolerance, good permeability, and its ability to allow changes into their surface. Polypyrrole represents an interesting alternative for the modification in extraction phases due to its well related ability to perform multiple interactions, such as acid-base, π - π, ion exchange, interactions with hydrophobic affinities or polar functional groups. Among the different sample preparation techniques, solid-phase extraction (SPE) is one of the most popular and used; a miniaturized version of SPE is the disposable pipette extraction (DPX). DPX is a recent miniaturized extraction technique that usually employing silica-based sorbents inside a pipette tip (5 or 1 mL). The present study proposes the development of a monolithic extraction phase composed by styrene divinylbenzene (1:1) modified with polypyrrole for SPE and DPX techniques. The efficiency of the material was evaluated in face of the extraction of different samples and analytes, triazine herbicides in water and dexamethasone in synthetic synovial liquid by conventional and miniaturized solid-phase extraction techniques. The extractions performed by SPE and DPX presented absolute recovery values ranging from 74.8 to 105.0%, inter-day precision ranging from 0.6 to 14.0%, and limit of quantification of 0.5 and 5.0 ng.mL-1, respectively. The DPX miniaturized method exhibited results equivalent to the methods reported in the literature for extraction of dexamethasone in synovial fluid samples. Moreover, this technique proved to be quicker and cheaper than SPE, and produced fewer residual volumes, supporting the preference for green chemistry. Monolithic polymers modified with polypyrrole presented to be a feasible alternative extraction phase for miniaturized sample preparation techniques.
Assuntos
Métodos Analíticos de Preparação de Amostras , Miniaturização/métodos , Polímeros/isolamento & purificação , Pirróis/isolamento & purificação , Adsorção , Interações Hidrofóbicas e Hidrofílicas , Nitrogênio/química , Polimerização , Extração em Fase Sólida , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Água/química , Poluentes Químicos da Água/análiseRESUMO
The aim of this study was to evaluate the shear bond strength of resin composite repairs with and without aging of the surface to be repaired, using different adhesive systems and resin composites. Ninety specimens were prepared: 10 for the Control Group (GC - without repair); 40 for Group I (GI - repairs after 7 days) and 40 for Group II (GII - repairs after 180 days). Groups I and II were divided into 4 subgroups of 10 specimens each, according to the adhesive system and composite resin used: A) Adper Scotch Bond Multipurpose + Filtek Z350 XT; B) Adper Single Bond Plus + Filtek Z350 XT; C) Adper Scotch Bond Multipurpose + Esthet-X; D) Adper Single Bond Plus + Esthet-X. The specimens were tested for shear strength in a universal testing machine. The results were analyzed by two-factor one-way ANOVA and Fisher's post hoc tests (alpha=0.05). The control group had better performance than the other groups. There was no significant difference when comparing different adhesive systems and composite resins. Repairs performed at 7 days were better than those performed at 180 days. The composite repairs decreased the mechanical strength of the restoration. Aging of the resin substrate may decrease repair bond strength over time, regardless of the type of adhesive systems and resin composites used.
Avaliar a resistência de união ao cisalhamento de reparos de resina composta com e sem envelhecimento da superfície a ser reparada, utilizando diferentes sistemas adesivos. Noventa corpos de prova foram confeccionados sendo: 10 para o Grupo Controle (GC - sem reparo); 40 para o Grupo I (GI - reparos após 7 dias) e 40 para o Grupo II (GII reparos após 180 dias). Para os reparos, os grupos GI e GII foram subdivididos em 4 subgrupos com 10 corpos de prova, variando o sistema adesivo e a resina composta: A) Adper Scotch Bond Multipurpose+ Filtek Z350XT; B)Adper Single Bond Plus+ Filtek Z350XT; C)Adper Scotch Bond Multipurpose+ Esthet-X; D) Adper Single Bond Plus+ Esthet-X. Os corpos de prova foram submetidos a uma força de cisalhamento em uma máquina de ensaio universal (EMIC). Os resultados foram analisados pelo teste estatístico Anova dois fatores, seguido pelo teste de Fisher´s. Observou-se melhor comportamento do grupo controle sobre os demais grupos, além disso, os reparos realizados aos 7 dias foram superiores aos dos realizados em 180 dias. Não houve diferença significativaquando se comparou diferentes sistemas adesivos e resinas compostas. Os reparos de resina composta diminuem a resistência mecânica da restauração.O envelheci mento do substrato de resina pode diminuir a resistência ao reparo ao longo do tempo, independentemente do tipo de sistemas adesivos e resinas compostas utilizados.
Assuntos
Resinas Compostas , Cimentos Dentários , Reparação de Restauração Dentária , Restauração Dentária Permanente , Colagem Dentária , Teste de Materiais , Fatores de TempoRESUMO
This study evaluated the probability of survival (reliability) of platform-switched fixed dental prostheses (FDPs) cemented on different implant-abutment connection designs. Eighty-four-three-unit FDPs (molar pontic) were cemented on abutments connected to two implants of external or internal hexagon connection. Four groups (n = 21 each) were established: external hexagon connection and regular platform (ERC); external hexagon connection and switched platform (ESC); internal hexagon and regular platform (IRC); and internal hexagon and switched platform (ISC). Prostheses were subjected to step-stress accelerated life testing in water. Weibull curves and probability of survival for a mission of 100,000 cycles at 400 N (two-sided 90% CI) were calculated. The beta values of 0.22, 0.48, 0.50, and 1.25 for groups ERC, ESC, IRC, and ISC, respectively, indicated a limited role of fatigue in damage accumulation, except for group ISC. Survival decreased for both platform-switched groups (ESC: 74%, and ISC: 59%) compared with the regular matching platform counterparts (ERC: 95%, and IRC: 98%). Characteristic strength was higher only for ERC compared with ESC, but not different between internal connections. Failures chiefly involved the abutment screw. Platform switching decreased the probability of survival of FDPs on both external and internal connections. The absence in loss of characteristic strength observed in internal hexagon connections favor their use compared with platform-switched external hexagon connections.
Assuntos
Coroas , Projeto do Implante Dentário-Pivô , Falha de Restauração Dentária , Dente Suporte , Implantes Dentários , Planejamento de Prótese Dentária , Análise do Estresse Dentário , Reprodutibilidade dos TestesRESUMO
The aim of this study was to evaluate the shear bond strengthof resin composite repairs with and without aging of thesurface to be repaired, using different adhesive systems andresin composites. Ninety specimens were prepared: 10 for theControl Group (GC - without repair); 40 for Group I (GI -repairs after 7 days) and 40 for Group II (GII - repairs after180 days). Groups I and II were divided into 4 subgroups of10 specimens each, according to the adhesive system andcomposite resin used: A) Adper Scotch Bond Multipurpose +Filtek Z350 XT; B) Adper Single Bond Plus + Filtek Z350 XT;C) Adper Scotch Bond Multipurpose + Esthet-X; D) AdperSingle Bond Plus + Esthet-X. The specimens were tested forshear strength in a universal testing machine. The resultswere analyzed by two-factor one-way ANOVA and Fisherspost hoc tests (alpha=0.05). The control group had betterperformance than the other groups. There was no significantdifference when comparing different adhesive systems andcomposite resins. Repairs performed at 7 days were betterthan those performed at 180 days. The composite repairsdecreased the mechanical strength of the restoration. Agingof the resin substrate may decrease repair bond strength overtime, regardless of the type of adhesive systems and resin composites used.
Avaliar a resistência de união ao cisalhamento de reparos deresina composta com e sem envelhecimento da superfície a serreparada, utilizando diferentes sistemas adesivos. Noventacorpos de prova foram confeccionados sendo: 10 para o GrupoControle (GC - sem reparo); 40 para o Grupo I (GI - reparosapós 7 dias) e 40 para o Grupo II (GII reparos após 180 dias).Para os reparos, os grupos GI e GII foram subdivididos em 4subgrupos com 10 corpos de prova, variando o sistema adesivoe a resina composta: A) Adper Scotch Bond Multipurpose+Filtek Z350XT; B)Adper Single Bond Plus+ Filtek Z350XT;C)Adper Scotch Bond Multipurpose+ Esthet-X; D) AdperSingle Bond Plus+ Esthet-X. Os corpos de prova foramsubmetidos a uma força de cisalhamento em uma máquina deensaio universal (EMIC). Os resultados foram analisados peloteste estatístico Anova dois fatores, seguido pelo teste deFisher ́s. Observou-se melhor comportamento do grupocontrole sobre os demais grupos, além disso, os reparosrealizados aos 7 dias foram superiores aos dos realizados em180 dias. Não houve diferença significativaquando secomparou diferentes sistemas adesivos e resinas compostas.Os reparos de resina composta diminuem a resistênciamecânica da restauração.O envelheci mento do substrato deresina pode diminuir a resistência ao reparo ao longo dotempo, independentemente do tipo de sistemas adesivos eresinas compostas utilizados.
Assuntos
Colagem Dentária/métodos , Reparação de Restauração Dentária/métodos , Resinas Compostas/uso terapêutico , Desgaste de Restauração Dentária/efeitos adversos , Teste de Materiais , Resinas Compostas/classificação , Resistência ao CisalhamentoRESUMO
The objective of this study was to evaluate the use of a two-step total etch and rinse adhesive, the correlation between the hyybrid layer thickness (HL) and bond strength (BS), and between resin tag length (RT) and bond strength in the same teeth, and also to evaluate the fracture patterns of the tested specimens. Ten human molars were used for the restorative procedure and then sectioned in two halves (mesio-distally). The materials used were Adper Single Bond 2, 3M ESPE, Ultra etch gel, Ultradent and Filtek Z250, 3M ESPE. One half were utilized to measure the HL thickness and RT length through light microscopy analysis (400x), and the other half was subject to a microtensile test to measure the BS. The fractured surfaces were analyzed by scanning electron microscopy and fracture patterns classified. The Pearson correlation test was applied (p = 0.05). The results of the analyses of each specimen then were correlated: mean HL thickness = 4.39 (0.48) microm, mean length of RT = 9.94 (1.69) microm, mean BS = 23.98 (10.24) MPa. A statistically significant correlation between HL thickness and bond strength was found (r = 0.93). The two step etch and rinse adhesive system, showed a strong correlation between HL thickness and bond strength. The most common fractures were adhesive, followed by cohesive in resin.
Assuntos
Colagem Dentária , Cimentos Dentários , Análise do Estresse Dentário , Adesivos Dentinários , Dentina , Resinas Sintéticas , Resistência à Tração , Humanos , Técnicas In Vitro , Teste de Materiais , Dente Molar , Propriedades de SuperfícieRESUMO
In this study, we investigated agents that increased intracellular calcium levels and their correlation with apoptotic cell death induction. We used rat astrocytes to investigate the increase in cytosolic Ca2+ (Ca(c)2+) and apoptosis induction by drugs that mobilize Ca2+ from different sources. We observed that thapsigargin (Thap), caffeine (Caff) and FCCP which caused similar increases in Ca(c)2+ levels (30-40%), also induced similar apoptotic rates (30-35%). On the other hand, antimycin (Anti), staurosporine (STS) and ethanol (Eth) promoted higher increases in Ca(c)2+ (55-65 %) and higher apoptotic rates (55-85%). Eth induced cell death in a concentration- and time-dependent manner. After treatment with Eth plus Caff for 6, 12 and 24 h, these effects were strongly potentiated. Results suggest that there might be a correlation between Ca(c)2+ increase and the rate of apoptosis. It is possible that Eth induces cell death by activation of more than one pathway and Ca2+ might be one of the elements involved. The present work indicates that Ca2+ can potentiate death by ethanol in rat astrocytes.