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Vaccinia-related kinase 1 (VRK1) and the δ and ε isoforms of casein kinase 1 (CK1) are linked to various disease-relevant pathways. However, the lack of tool compounds for these kinases has significantly hampered our understanding of their cellular functions and therapeutic potential. Here, we describe the structure-based development of potent inhibitors of VRK1, a kinase highly expressed in various tumor types and crucial for cell proliferation and genome integrity. Kinome-wide profiling revealed that our compounds also inhibit CK1δ and CK1ε. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion. Complementary studies with existing CK1δ and CK1ε inhibitors suggest that these kinases may play overlapping roles in cell proliferation and genome instability. Together, our findings highlight the potential of VRK1 inhibition in treating p53-deficient tumors and possibly enhancing the efficacy of existing cancer therapies that target DNA stability or cell division.
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Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Pteridinas , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Pteridinas/farmacologia , Pteridinas/química , Pteridinas/síntese química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Caseína Quinase Idelta/antagonistas & inibidores , Caseína Quinase Idelta/metabolismo , Caseína Quinase 1 épsilon/antagonistas & inibidores , Caseína Quinase 1 épsilon/metabolismo , Linhagem Celular TumoralRESUMO
Most scientific studies on microplastic (MP) pollution report their results as number of particles (e.g., particles/m2, particles/m3, particles/kg dw). An important limitation of this expression is to consider all MP particles as environmentally equivalent, regardless of their size, volume, mass, or specific surface area. Using a theoretical approach, we advocate that including such morphological attributes reveals significant differences in results of supposedly equivalent samples that consider only the number of particles. Our goal is to present how particle size and shape produce different results for hypothetical samples with the same number of particles. Therefore, from these examples we expect to stimulate the debate and contribute to improve accuracy and comparability of studies on MP pollution.
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The extensive use of pesticides in agriculture has significantly impacted the environment and human health, as these pollutants are inadequately disposed of into water bodies. In addition, pesticides can cause adverse effects on humans and aquatic animals due to their incomplete removal from the aqueous medium by conventional wastewater treatments. Therefore, processes such as heterogeneous photocatalysis and adsorption by nanocomposites have received special attention in the scientific community due to their unique properties and ability to degrade and remove several organic pollutants, including pesticides. This report reviews the use of nanocomposites in pesticide adsorption and photocatalytic degradation from aqueous solutions. A bibliographic search was performed using the ScienceDirect, American Chemical Society (ACS), and Royal Society of Chemistry (RSC) indexes, using Boolean logic and the following descriptors: "pesticide degradation" AND "photocatalysis" AND "nanocomposites"; "nanocomposites" AND "pesticides" AND "adsorption". The search was limited to research article documents in the last ten years (from January 2012 to June 2022). The results made it possible to verify that the most dangerous pesticides are not the most commonly degraded/removed from wastewater. At the same time, the potential of the supported nanocatalysts and nanoadsorbents in the decontamination of wastewater-containing pesticides is confirmed once they present reduced bandgap energy, which occurs over a wide range of wavelengths. Moreover, due to the great affinity of the supported nanocatalysts with pesticides, better charge separation, high removal, and degradation values are reported for these organic compounds. Thus, the class of the nanocomposites investigated in this work, magnetic or not, can be characterized as suitable nanomaterials with potential and unique properties useful in heterogeneous photocatalysts and the adsorption of pesticides.
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Nanocompostos , Praguicidas , Poluentes Químicos da Água , Animais , Humanos , Nanocompostos/química , Praguicidas/química , Águas Residuárias , Água/química , Poluentes Químicos da Água/químicaRESUMO
Aim: Previous studies showed that granulocyte-colony stimulating factor (G-CSF) improved heart function in a mice model of Chronic Chagas Cardiomyopathy (CCC). Herein, we report the interim results of the safety and efficacy of G-CSF therapy vs. placebo in adults with Chagas cardiomyopathy. Methods: Patients with CCC, New York Heart Association (NYHA) functional class II to IV and left ventricular ejection fraction (LVEF) 50% or below were included. A randomization list using blocks of 2 and 4 and an allocation rate of 1:1 was generated by R software which was stratified by functional class. Double blinding was done to both arms and assessors were masked to allocations. All patients received standard heart failure treatment for 2 months before 1:1 randomization to either the G-CSF (10 mcg/kg/day subcutaneously) or placebo group (1 mL of 0.9% saline subcutaneously). The primary endpoint was either maintenance or improvement of NYHA class from baseline to 6-12 months after treatment, and intention-to-treat analysis was used. Results: We screened 535 patients with CCC in Salvador, Brazil, of whom 37 were randomized. Overall, baseline characteristics were well-balanced between groups. Most patients had NYHA class II heart failure (86.4%); low mean LVEF was 32 ± 7% in the G-CSF group and 33 ± 10% in the placebo group. Frequency of primary endpoint was 78% (95% CI 0.60-0.97) vs. 66% (95% CI 0.40-0.86), p = 0.47, at 6 months and 68% (95% CI 0.43-0.87) vs. 72% (95% CI 0.46-0.90), p = 0.80, at 12 months in placebo and G-CSF groups, respectively. G-CSF treatment was safe, without any related serious adverse events. There was no difference in mortality between both arms, with five deaths (18.5%) in treatment vs. four (12.5%) in the placebo arm. Exploratory analysis demonstrated that the maximum rate of oxygen consumption during exercise (VO2 max) showed an improving trend in the G-CSF group. Conclusion: G-CSF therapy was safe and well-tolerated in 12 months of follow-up. Although prevention of symptom progression could not be demonstrated in the present study, our results support further investigation of G-CSF therapy in Chagas cardiomyopathy patients. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT02154269].
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The discovery of potent and selective inhibitors for understudied kinases can provide relevant pharmacological tools to illuminate their biological functions. DYRK1A and DYRK1B are protein kinases linked to chronic human diseases. Current DYRK1A/DYRK1B inhibitors also antagonize the function of related protein kinases, such as CDC2-like kinases (CLK1, CLK2, CLK4) and DYRK2. Here, we reveal narrow spectrum dual inhibitors of DYRK1A and DYRK1B based on a benzothiophene scaffold. Compound optimization exploited structural differences in the ATP-binding sites of the DYRK1 kinases and resulted in the discovery of 3n, a potent and cell-permeable DYRK1A/DYRK1B inhibitor. This compound has a different scaffold and a narrower off-target profile compared to current DYRK1A/DYRK1B inhibitors. We expect the benzothiophene derivatives described here to aid establishing DYRK1A/DYRK1B cellular functions and their role in human pathologies.
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Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases , Proteínas Tirosina Quinases/metabolismo , TiofenosRESUMO
The bioaccessibility and subsequent uptake by Caco-2 human intestinal cells of chlorophyll pigments from Scenedesmus obliquus were determined for the first time. In order to evaluate the impact of different types of the matrix on bioaccessibility of chlorophyll from microalgae, three different products were evaluated: isolated chlorophyll extract (ICE); wet ultrasonicated biomass (WUB); and whole dried biomass (WDB). The samples were submitted to in vitro digestion model according to the INFOGEST protocol, and Caco-2 cells determined the intestinal uptake. Chlorophyll pigments were determined by HPLC-PDA-MS/MS. A total of ten chlorophyll pigments (8,318.48 µg g-1) were separated in S. obliquus biomass, with chlorophyll a (3,507.76 µg g-1) and pheophytin a' (1,598.09 µg g-1) the major ones. After in vitro digestion, all tested products showed bioaccessible chlorophylls. However, the total bioaccessibility results were as follows: ICE (33.45%), WUB (2.65%), WDB (0.33%). Five compounds were bioaccessible in ICE, three in WUB, and one in WDB. The hydroxypheophytin a showed the highest bioaccessibility (212%) in ICE, while pheophytin a' in WUB (11%) and WDB (2%). As a result, bioavailability estimates of ICE using the Caco-2 cell showed hydroxypheophytin a (102.53%), followed by pheophytin a' (64.69%) as the chlorophyll pigments most abundant in intestinal cells. In summary, from a nutritional perspective, these three types of the matrix (WDB, WUB, and ICE) influence the promotion of chlorophyll bioaccessibility. In this way, the data suggest that chlorophylls bioaccessibility from ICE is greater than that in WDB and WUB. Therefore, ICE should be considered a product that provides bioavailable chlorophyll and could be the best choice, such as ingredients in the development of functional foods chlorophyll-based.
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Clorofila , Microalgas , Células CACO-2 , Clorofila A , Humanos , Absorção Intestinal , Espectrometria de Massas em TandemRESUMO
Tall trees are key drivers of ecosystem processes in tropical forest, but the controls on the distribution of the very tallest trees remain poorly understood. The recent discovery of grove of giant trees over 80 meters tall in the Amazon forest requires a reevaluation of current thinking. We used high-resolution airborne laser surveys to measure canopy height across 282,750 ha of old-growth and second-growth forests randomly sampling the entire Brazilian Amazon. We investigated how resources and disturbances shape the maximum height distribution across the Brazilian Amazon through the relations between the occurrence of giant trees and environmental factors. Common drivers of height development are fundamentally different from those influencing the occurrence of giant trees. We found that changes in wind and light availability drive giant tree distribution as much as precipitation and temperature, together shaping the forest structure of the Brazilian Amazon. The location of giant trees should be carefully considered by policymakers when identifying important hot spots for the conservation of biodiversity in the Amazon.
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Ecossistema , Árvores , Biodiversidade , Brasil , Florestas , Clima TropicalRESUMO
(1) Background: Although the advances in diagnostic and treatment strategies, lung cancer remains the leading cause of cancer-related deaths, worldwide, with survival rates as low as 16% in developed countries. Low survival rates are mainly due to late diagnosis and the lack of effective treatment. Therefore, the identification of novel, clinically useful biomarkers is still needed for patients with advanced disease stage and poor survival. Micro(mi)RNAs are non-coding RNAs and potent regulators of gene expression with a possible role as diagnostic, prognostic and predictive biomarkers in cancer. (2) Methods: We applied global miRNA expression profiling analysis using TaqMan® arrays in paired tumor and normal lung tissues (n = 38) from treatment-naïve patients with lung adenocarcinoma (AD; n = 23) and lung squamous cell carcinoma (SCC; n = 15). miRNA target genes were validated using The Cancer Genome Atlas (TCGA) lung AD (n = 561) and lung SCC (n = 523) RNA-Seq datasets. (3) Results: We identified 33 significantly deregulated miRNAs (fold change, FC ≥ 2.0 and p < 0.05) in tumors relative to normal lung tissues, regardless of tumor histology. Enrichment analysis confirmed that genes targeted by the 33 miRNAs are aberrantly expressed in lung AD and SCC, and modulate known pathways in lung cancer. Additionally, high expression of miR-25-3p was significantly associated (p < 0.05) with poor patient survival, when considering both tumor histologies. (4) Conclusions: miR-25-3p may be a potential prognostic biomarker in non-small cell lung cancer. Genes targeted by miRNAs regulate EGFR and TGFß signaling, among other known pathways relevant to lung tumorigenesis.
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Bryconops cyrtogaster, a poorly known species endemic from the Oyapock River at the border between French Guyana and Brazil, is redescribed herein based on examination of available type material, as well as newly collected material. Additionally, a new rheophilic species from the rio Jari rapids, lower Amazon basin, Brazil, is described. The two species belong to the subgenus Creatochanes and are unique among the congeneres for possessing a posteriorly positioned humeral blotch at the level of the sixth and seventh lateral line scales. They differ from each other by meristic and morphometric characters. The list of endemic species in the rio Jari basin is revised.
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Caraciformes/classificação , Escamas de Animais/anatomia & histologia , Animais , Brasil , Caraciformes/anatomia & histologia , Rios , Especificidade da EspécieRESUMO
Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (26) displayed an IC50 value of 150 nM and was fairly selective in a panel of 48 human kinases (selectivity score S(50%) of 0.04). Differences in compound binding mode and substituent preferences between the two VRKs were identified by the structure-activity relationship combined with the crystallographic analysis of key compounds. We expect our results to serve as a starting point for the design of more specific and potent inhibitors against each of the two VRKs.
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A recent study based on genomic data by Roxo et al. (2019) provided a phylogeny of the Loricariidae, the largest catfish family and second largest Neotropical fish family with approximately 1,000 species. The study represents a valuable and innovative contribution for understanding higher-level relationships within the family. The phylogenetic tree inferred by Roxo et al. (2019) thoroughly corroborates the monophyly and relationships of most currently accepted subfamilies of Loricariidae, based on a fair taxon sampling (nearly 14% of the species in the family) representing most genera of each but one of the subfamilies, the Lithogeninae, the sister-group of the remaining members of the family (Pereira & Reis, 2017; Reis et al., 2017). In addition to a hypothesis of relationships, Roxo et al. (2019) also proposed a series of lower-level taxonomic changes, which are deemed premature considering that the taxonomic sampling of the study targeted higher-level clades, and go against one of the pillars of biological classification: nomenclatural stability (e.g., Heterick & Majer, 2018; Beninger & Backeljau, 2019). Here we (1) discuss implications of inadequate taxonomic sampling as a basis for changes in classification of species; (2) explain why the taxonomic sampling design of Roxo et al. (2019) is inadequate for the proposed nomenclatural changes; and (3) advocate that changes to classifications must be grounded on phylogenies with dense sampling of taxa at the relevant level.
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Peixes-Gato , Animais , FilogeniaRESUMO
A new species, Poecilia (Pamphorichthys) akroa, is described from the Rio Tocantins drainage, Brazil. The new species differs from the remaining species of the genus by the possession of 10 or 11 pectoral-fin rays, entire preopercular ramus and posterior portion of the supraorbital ramus of the cephalic sensory system enclosed in canals, a faint longitudinal band along the body, a single gonapophysis, a homogeneous reticulate color pattern on sides of body, urogenital region of females heavily pigmented, distalmost segments of the anterior branch (4a) of the fourth gonopodial ray fused into an elongated segment turned anteriorly, subdistal segments of anterior branch (5a) of fifth gonopodial ray simple, without anterior (ventral) projections, dorsal fin with pigmentation at its distal portion and with a basal black blotch, and chromatophores more concentrated on the posterior margin of the mid-ventral scale series of the caudal peduncle and ventrolateral margin of the adjacent scales forming a series of rhombi posterior to anal fin.
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Ciprinodontiformes , Poecilia , Animais , Brasil , Cor , Feminino , PigmentaçãoRESUMO
An innovative use of thermal infrared enthalpimetry (TIE) is proposed for the determination of alcoholic content of red and white wines. Notwithstanding the presence of ethanol in beverages, absolute ethanol was added directly to wines, and the temperature rise caused by the heat of dilution was monitored using an infrared camera. Analytical signals were obtained in only 10â¯s for four samples simultaneously, and a calibration curve was constructed with hydroalcoholic reference solutions. A linear calibration curve was obtained from 3.0 to 18.0% (v/v) ethanol (R2â¯=â¯0.9987). The results showed agreement ranging from 98.2 to 104.0% with 942.06 and 969.12 methods of AOAC. Organic compounds (e.g., sugar) did not interfere in the determinations. The proposed method provided fast results, with a throughput of 480 samples per hour and negligible energy consumption (0.001â¯kWh). In addition, the consumption of reagents was reduced when compared with conventional method fulfilling green analytical chemistry requirements.
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Etanol/análise , Fotografação , Espectrofotometria Infravermelho , Vinho/análise , Calibragem , Etanol/normas , Química Verde , Processamento de Imagem Assistida por Computador , Espectrofotometria Infravermelho/normas , Vinho/normasRESUMO
Creagrutus yudja is described from the Rio Xingu basin, Brazil. It is distinguished from its congeners by the lack of infraorbital 6, the shallower body (13.7-19.2% of SL), the presence of 34-36 perforated lateral line scales, and the presence of 4-6 post-anal scales. The inclusion of the new species on the available, morphology-based phylogenetic study of Creagrutus placed C. yudja as the sister-species of C. nigrotaeniatus, but the clade including those species is not recovered as sister to the pair C. cracentis + C. maxillaris, suggesting independent modifications of the dentition pattern typical of Creagrutus to a condition similar to the plesiomorphic characid condition within the genus.
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Characidae , Animais , Brasil , Caraciformes , Filogenia , RiosRESUMO
Chrysin is a natural flavonoid which is found in bee propolis, honey and various plants, and neuroprotective effect of chrysin in mice was previously demonstrated by our group. Neuroinflammation, neurotrophic factors and neuronal recovery factors associated with the neuroprotective effect of this flavonoid require further investigations. Thus, now we investigated the possible involvement of inflammatory cytokines, neurotrophic factors and neuronal recovery in the effect of chrysin in 6-hydroxidopamine (6-OHDA), a well-established model of Parkinson's disease, in striatum of mice. The 6-OHDA microinjection induced behavioral alterations on the rotarod test and apomorphine-induced circling behavior in mice. 6-OHDA administration elevated levels of tumour necrosis factor-α, interferon-gamma, interleukin-1ß, interleukin-2, interleukin-6 and nuclear factor-kappa B and decreased the interleukin-10 levels, total reactive antioxidant potential and total antioxidant reactivity in striatum, as well as, modified the calcium-binding protein B (S100B), brain-derived neurotrophic factor, nerve growth factor and glial cell line-derived neurotrophic factor levels. The intrastriatal injection of 6-OHDA also induced an decrease of dopamine, 3,4-dihydroxyphenylacetic acid, homovanylic acid levels and tyrosine hydroxylase content. Oral treatment with chrysin (10 mg/kg, 28 days), culminated with the prevention of these alterations occasioned by 6-OHDA. These results corroborated with the neuroprotective effect of chrysin in the treatment of Parkinson's disease and, indicated the mechanism involved throught the inflammatory cytokines, neurotrophic factors and recovery of dopaminergic neurons in striatum.
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Flavonoides/farmacologia , Inflamação/prevenção & controle , Fatores de Crescimento Neural/metabolismo , Oxidopamina/efeitos adversos , Doença de Parkinson Secundária/prevenção & controle , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Biomarcadores , Dopamina/metabolismo , Regulação da Expressão Gênica/fisiologia , Ácido Homovanílico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/genética , Distribuição AleatóriaRESUMO
A new species of penguin tetra, Thayeria tapajonica, is described from the rio Tapajós basin. It is most similar to T. boehlkei by presenting a straight midlateral stripe running anteriorly to immediately posterior to the head, while in T. ifati and T. obliqua the midlateral stripe is restricted to the caudal peduncle, merging with an anterodorsal oblique stripe. The new species is restricted to the rio Tapajós basin downriver of the confluence of the rio Juruena and rio Teles Pires, and lower rio Teles Pires, where its distribution overlaps with T. boehlkei.
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Characidae , Animais , Brasil , Caraciformes , RiosRESUMO
Regional lymph nodes are affected frequently by melanoma metastasis. Its microenvironment may be associated with tumor progression. We investigated sentinel nodes with and without tumor and negative nodes surrounding positive nodes, looking for patterns related to tumor immune interaction and lymphovascular progression. We quantified programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1, vascular endothelial growth factor (VEGF)-A/VEGF-C expressions in lymph nodes of 103 patients who underwent sentinel lymph node biopsy. Two groups were studied: negative sentinel lymph nodes and positive ones. Negative lymph nodes of sequential lymphadenectomy from positive cases were also studied. Markers were assessed by immunohistochemistry. Results were related to clinical/histological outcomes. VEGF-A/VEGF-C analysis showed higher positivity in metastatic nodes and higher positivity in the surrounding negative nodes from positive cases in comparison with nonmetastatic patients. Programmed cell death-ligand 1, studied only in metastasis, presented high positivity, not associated with prognosis. PD-1 expressions were similar in the groups with a 1% cutoff and higher in the metastasis with a 5% cutoff. Higher VEGF-A expression was related to higher pathological stages. PD-1 expression in the lymph node was associated with higher survival. Other clinical and histopatological variables were not associated with marker expression patterns. VEGF-A and VEGF-C expressions in lymph nodes were associated with the presence of lymph node metastasis. PD-1 expression in the lymph node was related to higher survival rates and this should be explored in the context of adjuvant immunotherapy.
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Antígeno B7-H1/biossíntese , Linfonodos/metabolismo , Melanoma/metabolismo , Receptor de Morte Celular Programada 1/biossíntese , Neoplasias Cutâneas/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator C de Crescimento do Endotélio Vascular/biossíntese , Adulto , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/patologia , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem , Melanoma Maligno CutâneoRESUMO
The identification of chlorophyll molecules with peroxyl radical scavenger capacity in microalgae Phormidium autumnale was determined. The ultrasound-assisted extraction was utilized for obtaining the chlorophyll compounds from biomass. A total of eleven molecules were separated in microalgae chlorophyll extract, with pheophytin a' (371µg·g-1) and chlorophyll a (159.3µg·g-1) as the major ones. The chlorophyll extract was shown to be a potent scavenger of peroxyl radical, being almost 200 times more potent than α-tocopherol. These facts suggest the microalgae Phormidium autumnale as potential source of bioactive tetrapyrrole compounds.
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Asphodelaceae/metabolismo , Clorofila/farmacologia , Manipulação de Alimentos/métodos , Sequestradores de Radicais Livres/farmacologia , Microalgas/metabolismo , Peróxidos/química , Ultrassom , Clorofila/isolamento & purificação , Clorofila A/isolamento & purificação , Clorofila A/farmacologia , Cromatografia Líquida de Alta Pressão , Sequestradores de Radicais Livres/isolamento & purificação , Microalgas/crescimento & desenvolvimento , Feofitinas/isolamento & purificação , Feofitinas/farmacologia , Espectrometria de Massas em Tandem , Asphodelaceae/crescimento & desenvolvimento , alfa-Tocoferol/farmacologiaRESUMO
The aim of the present study was to investigate the effects of SCH58261, a selective adenosine A2A receptor antagonist, on striatal toxicity induced by 3-nitropropionic acid (3-NP) in rats. The experimental protocol consisted of 10 administrations (once a day) of SCH58261 (0.01 or 0.05 mg/kg/day, intraperitoneal, i.p.). From 7th to 10th day, 3-NP (20 mg/kg/day, i.p.) was injected 1 h after SCH58261 administration. Twenty-four hours after the last 3-NP injection, the body weight gain, locomotor activity (open-field test), motor coordination (rotarod test), striatal succinate dehydrogenase (SDH) activity and parameters linked to striatal oxidative status were evaluated in rats. The marked body weight loss resulting from 3-NP injections in rats was partially protected by SCH 58261 at both doses. SCH 58261 at the highest dose was effective against impairments on motor coordination and locomotor activity induced by 3-NP. SCH 58261 was unable to restore the inhibition of SDH activity caused by 3-NP. In addition, the increase in striatal reactive species (RS) levels, depletion of reduced glutathione (GSH) content and stimulation of glutathione reductase (GR) activity provoked by 3-NP injections were alleviated by both doses of SCH 58261. The highest dose of SCH 58261 was also effective in attenuating the increase of protein carbonyl levels as well as the inhibition of glutathione peroxidase (GPx) activity in rats exposed to 3-NP. Our results revealed that reduction of oxidative stress in rat striatum by adenosine A2A receptor antagonism contributes for alleviating 3-NP-induced toxicity.
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Antagonistas do Receptor A2 de Adenosina/farmacologia , Corpo Estriado/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nitrocompostos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Propionatos/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Animais , Corpo Estriado/metabolismo , Glutationa/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Teste de Desempenho do Rota-RodRESUMO
The human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes and linked to a variety of tumors. However, understanding the cellular role of VRKs and establishing their potential use as targets for therapeutic intervention has been limited by the lack of tool compounds that can specifically modulate the activity of these kinases in cells. Here we identified BI-D1870, a dihydropteridine inhibitor of RSK kinases, as a promising starting point for the development of chemical probes targeting the active VRKs. We solved co-crystal structures of both VRK1 and VRK2 bound to BI-D1870 and of VRK1 bound to two broad-spectrum inhibitors. These structures revealed that both VRKs can adopt a P-loop folded conformation, which is stabilized by different mechanisms on each protein. Based on these structures, we suggest modifications to the dihydropteridine scaffold that can be explored to produce potent and specific inhibitors towards VRK1 and VRK2.