Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.536
Filtrar
1.
Life Sci Alliance ; 5(1)2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34764206

RESUMO

Understanding pathways that might impact coronavirus disease 2019 (COVID-19) manifestations and disease outcomes is necessary for better disease management and for therapeutic development. Here, we analyzed alterations in sphingolipid (SL) levels upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection induced elevation of SL levels in both cells and sera of infected mice. A significant increase in glycosphingolipid levels was induced early post SARS-CoV-2 infection, which was essential for viral replication. This elevation could be reversed by treatment with glucosylceramide synthase inhibitors. Levels of sphinganine, sphingosine, GA1, and GM3 were significantly increased in both cells and the murine model upon SARS-CoV-2 infection. The potential involvement of SLs in COVID-19 pathology is discussed.


Assuntos
COVID-19/metabolismo , Modelos Animais de Doenças , Esfingolipídeos/metabolismo , Replicação Viral/fisiologia , Animais , COVID-19/prevenção & controle , COVID-19/virologia , Chlorocebus aethiops , Cromatografia Líquida/métodos , Dioxanos/farmacologia , Gangliosídeos/sangue , Gangliosídeos/metabolismo , Glucosiltransferases/antagonistas & inibidores , Glucosiltransferases/metabolismo , Humanos , Espectrometria de Massas/métodos , Camundongos Transgênicos , Pirrolidinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Esfingolipídeos/sangue , Esfingosina/análogos & derivados , Esfingosina/sangue , Esfingosina/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
2.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638879

RESUMO

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers in humans. At early stages CRC is treated by surgery and at advanced stages combined with chemotherapy. We examined here the potential effect of glucosylceramide synthase (GCS)-inhibition on CRC biology. GCS is the rate-limiting enzyme in the glycosphingolipid (GSL)-biosynthesis pathway and overexpressed in many human tumors. We suppressed GSL-biosynthesis using the GCS inhibitor Genz-123346 (Genz), NB-DNJ (Miglustat) or by genetic targeting of the GCS-encoding gene UDP-glucose-ceramide-glucosyltransferase- (UGCG). GCS-inhibition or GSL-depletion led to a marked arrest of the cell cycle in Lovo cells. UGCG silencing strongly also inhibited tumor spheroid growth in Lovo cells and moderately in HCT116 cells. MS/MS analysis demonstrated markedly elevated levels of sphingomyelin (SM) and phosphatidylcholine (PC) that occurred in a Genz-concentration dependent manner. Ultrastructural analysis of Genz-treated cells indicated multi-lamellar lipid storage in vesicular compartments. In mice, Genz lowered the incidence of experimentally induced colorectal tumors and in particular the growth of colorectal adenomas. These results highlight the potential for GCS-based inhibition in the treatment of CRC.


Assuntos
Ciclo Celular/efeitos dos fármacos , Neoplasias do Colo , Dioxanos/farmacologia , Glicoesfingolipídeos , Pirrolidinas/farmacologia , Esferoides Celulares , Animais , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Glucosiltransferases/antagonistas & inibidores , Glucosiltransferases/metabolismo , Glicoesfingolipídeos/biossíntese , Glicoesfingolipídeos/genética , Células HCT116 , Humanos , Camundongos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
3.
Int J Biol Macromol ; 181: 540-551, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33766592

RESUMO

Biomaterial research has improved the delivery and efficacy of drugs over a wide range of pharmaceutical applications. The objective of this study was to synthesize benzodioxane coupled piperazine decorated chitosan silver nanoparticle (Bcp*C@AgNPs) against methicillin-resistant Staphylococcus aureus (MRSA) and to assess the nanoparticle as an effective candidate for antibacterial and anti-biofilm care. Antibacterial activity of the compound was examined and minimum inhibitory concentration (MIC) was observed at (10.21 ± 0.03 ZOI) a concentration of 200 µg/mL. The Bcp*C@AgNPs interferes with surface adherence of MRSA, suggesting an anti-biofilm distinctive property that is verified for the first time by confocal laser microscopic studies. By ADMET studies the absorption, distribution, metabolism, excretion and toxicity of the compound was examined. The interaction solidity and the stability of the compound when surrounded by water molecules were analyzed by docking and dynamic simulation analysis. The myoblast cell line (L6) was considered for toxicity study and was observed that the compound exhibited less toxic effect. This current research highlights the biocidal efficiency of Bcp*C@AgNPs with their bactericidal and anti-biofilm properties over potential interesting clinical trial targets in future.


Assuntos
Biofilmes/efeitos dos fármacos , Quitosana/síntese química , Dioxanos/farmacologia , Nanopartículas Metálicas/química , Staphylococcus aureus Resistente à Meticilina/fisiologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Piperazina/farmacologia , Prata/farmacologia , Animais , Anti-Infecciosos/farmacologia , Linhagem Celular , Quitosana/química , Fluorescência , Ligantes , Nanopartículas Metálicas/ultraestrutura , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana , Piperazina/química , Plâncton/efeitos dos fármacos , Ratos , Testes de Toxicidade
4.
J Biol Chem ; 296: 100470, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33639165

RESUMO

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health. Vaccines are ideal solutions to prevent infection, but treatments are also needed for those who have contracted the virus to limit negative outcomes, when vaccines are not applicable. Viruses must cross host cell membranes during their life cycle, creating a dependency on processes involving membrane dynamics. Thus, in this study, we examined whether the synthetic machinery for glycosphingolipids, biologically active components of cell membranes, can serve as a therapeutic target to combat SARS-CoV-2. We examined the antiviral effect of two specific inhibitors of glucosylceramide synthase (GCS): (i) Genz-123346, an analogue of the United States Food and Drug Administration-approved drug Cerdelga and (ii) GENZ-667161, an analogue of venglustat, which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit replication of SARS-CoV-2. Moreover, these inhibitors also disrupt replication of influenza virus A/PR/8/34 (H1N1). Our data imply that synthesis of glycosphingolipids is necessary to support viral life cycles and suggest that GCS inhibitors should be further explored as antiviral therapies.


Assuntos
Antivirais/farmacologia , Carbamatos/farmacologia , Dioxanos/farmacologia , Glucosiltransferases/antagonistas & inibidores , Glicoesfingolipídeos/antagonistas & inibidores , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Pirrolidinas/farmacologia , Quinuclidinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/síntese química , COVID-19/tratamento farmacológico , COVID-19/enzimologia , COVID-19/virologia , Carbamatos/síntese química , Membrana Celular/efeitos dos fármacos , Membrana Celular/enzimologia , Membrana Celular/virologia , Chlorocebus aethiops , Ensaios Clínicos Fase III como Assunto , Dioxanos/síntese química , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica , Glucosiltransferases/genética , Glucosiltransferases/metabolismo , Glicoesfingolipídeos/biossíntese , Interações Hospedeiro-Patógeno/genética , Humanos , Vírus da Influenza A Subtipo H1N1/crescimento & desenvolvimento , Vírus da Influenza A Subtipo H1N1/metabolismo , Influenza Humana/tratamento farmacológico , Influenza Humana/enzimologia , Influenza Humana/virologia , Células Madin Darby de Rim Canino , Pirrolidinas/síntese química , Quinuclidinas/síntese química , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/metabolismo , Transdução de Sinais , Células Vero , Replicação Viral/efeitos dos fármacos
5.
Mol Pharmacol ; 99(3): 175-183, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33384285

RESUMO

Acyl-CoA:cholesterol acyltransferase (ACAT) mediates cellular cholesterol esterification. In atherosclerotic plaque macrophages, ACAT promotes cholesteryl ester accumulation, resulting in foam cell formation and atherosclerosis progression. Its complete inactivation in mice, however, showed toxic effects because of an excess of free cholesterol (FC) in macrophages, which can cause endoplasmic reticulum stress, cholesterol crystal formation, and inflammasome activation. Our previous studies showed that long-term partial ACAT inhibition, achieved by dietary supplementation with Fujirebio F1394, delays atherosclerosis progression in apoprotein E-deficient (Apoe -/-) mice by reducing plaque foam cell formation without inflammatory or toxic effects. Here, we determined whether short-term partial inhibition of ACAT, in combination with an enhanced systemic FC acceptor capacity, has synergistic benefits. Thus, we crossbred Apoe -/- with human apoprotein A1-transgenic (APOA1 tg/tg) mice, which have elevated cholesterol-effluxing high-density lipoprotein particles, and subjected Apoe -/- and APOA1 tg/tg/Apoe -/- mice to an atherogenic diet to develop advanced plaques. Then mice were either euthanized (baseline) or fed purified standard diet with or without F1394 for 4 more weeks. Plaques of APOA1 tg/tg/Apoe -/- mice fed F1394 showed a 60% reduction of macrophages accompanied by multiple other benefits, such as reduced inflammation and favorable changes in extracellular composition, in comparison with Apoe -/- baseline mice. In addition, there was no accumulation of cholesterol crystals or signs of toxicity. Overall, these results show that short-term partial ACAT inhibition, coupled to increased cholesterol efflux capacity, favorably remodels atherosclerosis lesions, supporting the potential of these combined therapies in the treatment of advanced atherosclerosis. SIGNIFICANCE STATEMENT: Short-term pharmacological inhibition of acyl-CoA:cholesterol acyltransferase-mediated cholesterol esterification, in combination with increased free cholesterol efflux acceptors, has positive effects in mice by 1) reducing the inflammatory state of the plaque macrophages and 2) favoring compositional changes associated with plaque stabilization. These effects occur without toxicity, showing the potential of these combined therapies in the treatment of advanced atherosclerosis.


Assuntos
Acetil-CoA C-Acetiltransferase/antagonistas & inibidores , Apolipoproteína A-I/genética , Apolipoproteínas E/genética , Aterosclerose/terapia , Cicloexanos/administração & dosagem , Dioxanos/administração & dosagem , Animais , Aterosclerose/genética , Cruzamento , Cicloexanos/farmacologia , Suplementos Nutricionais , Dioxanos/farmacologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Marcadores Genéticos/efeitos dos fármacos , Humanos , Lipoproteínas HDL/sangue , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Resultado do Tratamento
6.
Bull Exp Biol Med ; 170(1): 88-92, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33231798

RESUMO

We compared in vitro degradation and physical properties of polypropylene and a biodegradable polymer synthesized by electrospinning and consisting of 65% polycaprolactone and 35% polytrimethylene carbonate as a possible alternative material for use in surgery for pelvic floor muscle failure. Samples of the studied polymers were implanted to 10 male Wistar rats into the interfascial space on the back (polypropylene on the right side and biodegradable polymer on the left side). The synthesized biopolymer was characterized by elongation and tear resistance, similar to those of polypropylene. During the period from the third to the sixth month after implantation, the area of fibrosis around individual polypropylene and biopolymer fibers increased by 16.7 and 107.9%, respectively, while remaining reduced compared to polypropylene. The total fibrosis area in 6 months after implantation of polypropylene and biopolymer samples significantly increased by 18% (p=0.0097) and 48% (p=0.05), respectively, i.e. fibrosing processes were more intense in case of biopolymer. Induction of more pronounced fibrosis can be an advantage of the synthesized biopolymer when choosing the material for fabrication of implants and their use for correction of incompetence of the ligamentous and muscular apparatus.


Assuntos
Implantes Absorvíveis , Materiais Biocompatíveis/metabolismo , Dioxanos/metabolismo , Poliésteres/metabolismo , Polímeros/metabolismo , Polipropilenos/metabolismo , Telas Cirúrgicas , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/farmacologia , Dioxanos/síntese química , Dioxanos/farmacologia , Fáscia/efeitos dos fármacos , Fáscia/ultraestrutura , Fibrose , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Teste de Materiais , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/cirurgia , Músculo Esquelético/ultraestrutura , Poliésteres/síntese química , Poliésteres/farmacologia , Polímeros/síntese química , Polímeros/farmacologia , Polipropilenos/síntese química , Polipropilenos/farmacologia , Ratos , Ratos Wistar
7.
J Med Chem ; 63(21): 13140-13158, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33091297

RESUMO

Leishmaniases are neglected diseases that can be treated with a limited drug arsenal; the development of new molecules is therefore a priority. Recent evidence indicates that endoperoxides, including artemisinin and its derivatives, possess antileishmanial activity. Here, 1,2-dioxanes were synthesized with their corresponding tetrahydropyrans lacking the peroxide bridge, to ascertain if this group is a key pharmacophoric requirement for the antileishmanial bioactivity. Newly synthesized compounds were examined in vitro, and their mechanism of action was preliminarily investigated. Three endoperoxides and their corresponding tetrahydropyrans effectively inhibited the growth of Leishmania donovani promastigotes and amastigotes, and iron did not play a significant role in their activation. Further, reactive oxygen species were produced in both endoperoxide- and tetrahydropyran-treated promastigotes. In conclusion, the peroxide group proved not to be crucial for the antileishmanial bioactivity of endoperoxides, under the tested conditions. Our findings reveal the potential of both 1,2-dioxanes and tetrahydropyrans as lead compounds for novel therapies against Leishmania.


Assuntos
Antiprotozoários/farmacologia , Dioxanos/química , Leishmania donovani/efeitos dos fármacos , Piranos/química , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cristalografia por Raios X , Dioxanos/síntese química , Dioxanos/farmacologia , Desenho de Fármacos , Humanos , Quelantes de Ferro/farmacologia , Leishmania donovani/fisiologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Conformação Molecular , Piranos/síntese química , Piranos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Células Vero
8.
J Enzyme Inhib Med Chem ; 35(1): 1513-1523, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32705910

RESUMO

The inhibition of monoamine oxidase B (MAO-B) could be an effective approach for the treatment of various neurological disorders. In this study, a series of 1, 4-benzodioxan-substituted chalcone derivatives were designed, synthesised and evaluated for their inhibitory activity against human MAO-B (hMAO-B). The majority of these compounds showed inhibitory activity and high selectivity. The most potent compound, (E)-1-(3-bromo-4-fluorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)prop-2-en-1-one (22), exhibited an IC50 of 0.026 µM with a selectivity index greater than 1538. Kinetics and reversibility studies confirmed that the representative active compounds acted as competitive and reversible inhibitors of hMAO-B. The enzyme-inhibitor interactions were investigated by molecular docking studies and the rationale was provided. As these potent hMAO-B inhibitors exhibited low neurotoxicity and possessed promising drug-like properties, we believe that these active compounds could be further investigated as potential drug candidates for future in vivo studies.


Assuntos
Chalconas/farmacologia , Dioxanos/farmacologia , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Chalconas/síntese química , Chalconas/química , Dioxanos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 193: 112218, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32208223

RESUMO

Cathepsin X is a cysteine carboxypeptidase that is involved in various physiological and pathological processes. In particular, highly elevated expression and activity of cathepsin X has been observed in cancers and neurodegenerative diseases. Previously, we identified compound Z9 (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((4-isopropyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one) as a potent and specific reversible cathepsin X inhibitor. Here, we have explored the effects of chemical variations to Z9 of either benzodioxine or triazol moieties, and the importance of the central ketomethylenethio linker. The ketomethylenethio linker was crucial for cathepsin X inhibition, whereas changes of the triazole heterocycle did not alter the inhibitory potencies to a greater extent. Replacement of benzodioxine moiety with substituted benzenes reduced cathepsin X inhibition. Overall, several synthesized compounds showed similar or improved inhibitory potencies against cathepsin X compared to Z9, with IC50 values of 7.1 µM-13.6 µM. Additionally, 25 inhibited prostate cancer cell migration by 21%, which is under the control of cathepsin X.


Assuntos
Antineoplásicos/farmacologia , Carboxipeptidases/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Dioxanos/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carboxipeptidases/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Dioxanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Células PC-3 , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Triazóis/química , Células Tumorais Cultivadas
10.
Cells ; 9(2)2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085378

RESUMO

The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While α1- and ß-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about α2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of α2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the α2-AR blocker mesedin to deactivate hepatic stellate cells (HSCs) and to increase the permeability of human liver sinusoidal endothelial cells (hLSECs). The mRNA of α2a-, α2b-, and α2c-AR subtypes was uniformly upregulated in carbon tetrachloride-treated mice vs the controls, while in bile duct-ligated mice, only α2b-AR increased in response to liver injury. In murine HSCs, mesedin led to a decrease in α-smooth muscle actin, transforming growth factor-ß and α2a-AR expression, which was indicated by RT-qPCR, immunocytochemistry, and Western blot analyses. In a hLSEC line, an increased expression of endothelial nitric oxide synthase was detected along with downregulated transforming growth factor-ß. In conclusion, we suggest that the α2-AR blockade alleviates the activation of HSCs and may increase the permeability of liver sinusoids during liver injury.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Dioxanos/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Receptores Adrenérgicos alfa 2/genética , Tiazóis/uso terapêutico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Dioxanos/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Cirrose Hepática/fisiopatologia , Camundongos , Tiazóis/farmacologia
11.
Pharmacol Rep ; 72(2): 427-434, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32002826

RESUMO

BACKGROUND: In our previous work, spiroxatrine was taken as reference compound to develop selective NOP ligands. Therefore, several triazaspirodecanone derivatives were synthesized. Here, we verify their selectivity towards other 5-HT1 receptor subtypes and with respect to α2-AR (Adrenergic Receptors). METHODS: Binding affinities were determined on cells expressing human cloned receptors for 5-HT1A/B/D and α2A/B/C subtypes. The Ki values were determined for those with at least 50% radioligand inhibition. RESULTS: All our derivatives show a moderate affinity for α2 subtypes, spanning from 5 to 7.5 pKi values. Moreover, they show affinity values in a µM-nM range at the 5-HT1A receptor, while they are practically inactive at 5-HT1B and 5-HT1D subtypes. Compound 11, the best of the series, has a 5-HT1A pKi value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT1A favorable selectivity ratio of 52, 8 and 29, respectively over α2A, α2B and α2C adrenoceptor subtypes. CONCLUSIONS: In this SAR study, a 5-HT1A selective ligand has been identified in which a tetralone moiety replaced the 1,4-benzodioxane of spiroxatrine and the methylene linker to the triazaspirodecanone portion was maintained in position 2.


Assuntos
Dioxanos/farmacologia , Descoberta de Drogas , Receptor 5-HT1A de Serotonina/metabolismo , Compostos de Espiro/farmacologia , Animais , Ligação Competitiva , Células CHO , Cricetulus , Dioxanos/química , Dioxanos/metabolismo , Humanos , Ligantes , Estrutura Molecular , Ligação Proteica , Ensaio Radioligante , Receptor 5-HT1A de Serotonina/genética , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Relação Estrutura-Atividade
12.
Noise Health ; 22(106): 63-69, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33402606

RESUMO

Background: Noise is one of the environmental factors, which is considered as a powerful stressor for the organism. Generally, the acoustic stress affects the behavior and physiological state of humans and animals. Aims: The goal of this study is to investigate the relationship between chronic noise exposure and the effects of adrenergic alpha-2 receptor antagonists, beditin and mesedin, on the anxiety and oxidation of plasma proteins and fibrinogen in rats. Methods: The experiments were carried out on non-linear albino male rats, divided into four groups (six animals in each): 1. Healthy controls 2. Exposed to noise of a level 91 dB(A), eight hours daily, during 7, 30 and 60 days; 3. Injected with 2 mg/kg of beditin (2-(2-amino-4-thiazolyl)-1,4-benzodioxane hydrochloride)); 4. Injected with 10 mg/kg mesedin (2-(2-methyl-amino-thiozolyl)-1,4-benzodioxane hydrochloride). For evaluating the cognitive impairment, the Any-maze test was applied. The level of carbonylation of proteins was assessed by reaction with 2,4-dinitrophenylhydrazine, spectrophotometrically. Results: Chronic noise decreased locomotor activity and increased anxiety and oxidation of plasma protein and fibrinogen. Intensity of these changes were dependent on the duration of noise exposure. Conclusion: The Alpha 2 adrenoblockers alleviate oxidative modification of plasma proteins and reduce the cognitive impairment caused by chronic exposure to noise.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Ansiedade/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Ruído/efeitos adversos , Oxirredução/efeitos dos fármacos , Animais , Ansiedade/etiologia , Proteínas Sanguíneas/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Dioxanos/farmacologia , Exposição Ambiental/efeitos adversos , Locomoção , Masculino , Aprendizagem em Labirinto , Ratos , Espectrofotometria , Estresse Fisiológico/efeitos dos fármacos , Tiazóis/farmacologia
13.
Macromol Biosci ; 20(2): e1900344, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31854121

RESUMO

Intestinal resection and anastomosis are performed in over a million people with various bowel diseases annually. Excessive fibrosis and anastomotic site leakage are the main complications of anastomosis surgery, despite great improvements in operative technique and equipment in recent years. In this study, cRGD modified poly(p-dioxanone-co-l-Phe) (PDPA) membranes are designed and applied in intestinal anastomosis to simultaneously solve the two aforementioned complications. cRGD is modified onto PDPA membranes through both physical absorption and π-π accumulation between d-Phe of cRGD and l-Phe of PDPA. Although cRGD modification enhanced the biocompatibility of PDPA membranes, cRGD modified PDPA membrane suppresses fibroblast proliferation both in vitro and in vivo as a result of degradation and subsequent release of fibroblast suppressive l-Phe from PDPA. Meanwhile, platelets are entrapped by cRGD modified PDPA membranes through the specific binding of cRGD and platelet GPIIbIIIa . cRGD modified PDPA membranes are applied in rat intestinal anastomosis, and both adhesion and stenosis are successfully prevented at anastomotic sites. At the same time, bursting pressure, which represents healing intensity at anastomotic sites, is promoted. The gathering and activation of platelets on PDPA membranes induce secretion of autologous PDGF and VEGF to facilitate angiogenesis and subsequent healing of anastomotic sites.


Assuntos
Anastomose Cirúrgica , Plaquetas/metabolismo , Dioxanos , Intestinos/cirurgia , Membranas Artificiais , Polímeros , Aderências Teciduais/prevenção & controle , Animais , Plaquetas/patologia , Linhagem Celular , Dioxanos/química , Dioxanos/farmacologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Intestinos/patologia , Camundongos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Polímeros/química , Polímeros/farmacologia , Ratos , Ratos Sprague-Dawley , Aderências Teciduais/metabolismo , Aderências Teciduais/patologia
14.
J Neurosci Res ; 98(1): 201-211, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30895638

RESUMO

Approaches that facilitate the recovery from coma would have enormous impacts on patient outcomes and medical economics. Orexin-producing neurons release orexins (also known as hypocretins) energy-dependently to maintain arousal. Hyperbaric oxygen (HBO) could increase ATP levels by preserving mitochondrial function. We investigated, for the first time, the arousal effects of HBO and orexins mechanisms in a rat model of unconsciousness induced by ketamine or ethanol. A total of 120 Sprague-Dawley male rats were used in this study. Unconsciousness was induced either by intraperitoneal injection of ketamine or ethanol. The HBO treatment (100% O2 at 3 ATA) was administered immediately after unconsciousness induction for 1 hr. SB334867, orexin-1 receptor (OX1R) inhibitor, or JNJ10397049, orexin-2 receptor (OX2R) inhibitor was administered 30 min intraperitoneally before unconsciousness induction. Loss of righting reflex test (LORR) and Garcia test were used to evaluate the unconsciousness duration and neurological deficits after recovering from unconsciousness, respectively. Enzyme-linked immunosorbent assay was used to measure brain tissue ATP and orexin A levels. Ketamine or ethanol injection resulted in LORR immediately and neurological deficits 6 hr after unconsciousness induction. HBO treatment significantly reduced the LORR duration, improved Garcia scores and unregulated ATP and orexin A levels in the brain tissue. Administration of OX1R inhibitor or OX2 R inhibitor abolished arousal and neurological benefits of HBO. In conclusion, HBO exerted arousal-promoting effects on unconscious rats induced by ketamine or ethanol. The underlying mechanism was via, at least in part, ATP/orexin A upregulation. HBO may be a practical clinical approach to accelerate unconsciousness recovery in patients.


Assuntos
Antagonistas dos Receptores de Orexina/farmacologia , Orexinas/metabolismo , Inconsciência/metabolismo , Regulação para Cima , Animais , Nível de Alerta/efeitos dos fármacos , Benzoxazóis/farmacologia , Dioxanos/farmacologia , Etanol , Oxigenação Hiperbárica , Ketamina , Masculino , Naftiridinas/farmacologia , Compostos de Fenilureia/farmacologia , Ratos , Ratos Sprague-Dawley , Reflexo de Endireitamento/efeitos dos fármacos , Inconsciência/induzido quimicamente , Ureia/análogos & derivados , Ureia/farmacologia
15.
Nat Commun ; 10(1): 5232, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745079

RESUMO

Recently, the targeting of ERK with ATP-competitive inhibitors has emerged as a potential clinical strategy to overcome acquired resistance to BRAF and MEK inhibitor combination therapies. In this study, we investigate an alternative strategy of targeting the D-recruitment site (DRS) of ERK. The DRS is a conserved region that lies distal to the active site and mediates ERK-protein interactions. We demonstrate that the small molecule BI-78D3 binds to the DRS of ERK2 and forms a covalent adduct with a conserved cysteine residue (C159) within the pocket and disrupts signaling in vivo. BI-78D3 does not covalently modify p38MAPK, JNK or ERK5. BI-78D3 promotes apoptosis in BRAF inhibitor-naive and resistant melanoma cells containing a BRAF V600E mutation. These studies provide the basis for designing modulators of protein-protein interactions involving ERK, with the potential to impact ERK signaling dynamics and to induce cell cycle arrest and apoptosis in ERK-dependent cancers.


Assuntos
Dioxanos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/tratamento farmacológico , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Tiazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Sítios de Ligação/genética , Linhagem Celular Tumoral , Cisteína/genética , Cisteína/metabolismo , Dioxanos/metabolismo , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/genética , Melanoma/genética , Melanoma/metabolismo , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/metabolismo
16.
Drug Des Devel Ther ; 13: 2393-2404, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409973

RESUMO

Purpose: To evaluate the antihepatotoxic activity of dihydropyrimidinone derivative linked with 1,4-benzodioxane. Methods: A series of novel dihydropyrimidinone derivatives linked with 1,4-benzodioxane moiety were synthesized in good yield. Modern spectroscopic techniques and elemental analysis were used for the identification of the synthesized compounds. The hepatoprotective properties of compound 2, 4-(4-nitrophenyl)-5-(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)-3,4-dihydropyrimidin-2(1H)-one, was evaluated in a carbon tetrachloride (CCl4)-induced hepatotoxicity rat model. Results: Administration of compound 2 prior to CCl4 exposure produced a dose-dependent decrease in the levels of elevated biochemical parameters compared with the standard drug silymarin. CCl4 induced oxidative stress, increased lipid profile, and decreased high-density lipoprotein (HDL) levels. Compound 2 (20 mg/kg) significantly reduced the lipid profile and significantly improved HDL levels in a dose-dependent manner. CCl4 treatment increased malondialdehyde (MDA) level and decreased nonprotein thiol (NP-SH) and total protein (TP) in liver tissues. Pretreatment of rats with compound 2 (20 mg/kg) decreased MDA level and increased NP-SH and TP in liver tissues. Histopathological examination of liver tissues also confirmed the hepatoprotective activity of compound 2. Conclusion: These results demonstrate the antihepatotoxic activity of compound 2 in CCl4-induced hepatotoxicity model.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Dioxanos/farmacologia , Substâncias Protetoras/farmacologia , Pirimidinonas/farmacologia , Animais , Tetracloreto de Carbono , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dioxanos/administração & dosagem , Dioxanos/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/química , Pirimidinonas/administração & dosagem , Pirimidinonas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade
17.
Kidney Int ; 96(2): 327-341, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31101366

RESUMO

To elucidate the physiologic function of renal globotriaosylceramide (Gb3/CD77), which up-to-date has been associated exclusively with Shiga toxin binding, we have analyzed renal function in Gb3-deficient mice. Gb3 synthase KO (Gb3S-/-) mice displayed an increased renal albumin and low molecular weight protein excretion compared to WT. Gb3 localized at the brush border and within vesicular structures in WT proximal tubules and has now been shown to be closely associated with the receptor complex megalin/cubilin and with albumin uptake. In two clinically relevant mouse models of acute kidney injury caused by myoglobin as seen in rhabdomyolysis and the aminoglycoside gentamicin, Gb3S-/- mice showed a preserved renal function and morphology, compared to WT. Pharmacologic inhibition of glucosylceramide-based glycosphingolipids, including Gb3, in WT mice corroborated the results of genetically Gb3-deficient mice. In conclusion, our data significantly advance the current knowledge on the physiologic and pathophysiologic role of Gb3 in proximal tubules, showing an involvement in the reabsorption of filtered albumin, myoglobin and the aminoglycoside gentamicin.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Albuminas/metabolismo , Dioxanos/farmacologia , Galactosiltransferases/antagonistas & inibidores , Pirrolidinas/farmacologia , Reabsorção Renal/efeitos dos fármacos , Triexosilceramidas/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Dioxanos/uso terapêutico , Modelos Animais de Doenças , Galactosiltransferases/genética , Galactosiltransferases/metabolismo , Gentamicinas/metabolismo , Gentamicinas/toxicidade , Humanos , Microscopia Intravital , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Túbulos Renais Proximais/ultraestrutura , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Microscopia de Fluorescência por Excitação Multifotônica , Microvilosidades/efeitos dos fármacos , Microvilosidades/metabolismo , Mioglobina/metabolismo , Mioglobina/toxicidade , Pirrolidinas/uso terapêutico , Receptores de Superfície Celular/metabolismo , Eliminação Renal/efeitos dos fármacos
18.
J Mol Cell Cardiol ; 131: 82-90, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31015037

RESUMO

Diabetes is associated with cardiac inflammation and impaired endothelium-dependent coronary vasodilation, but molecular mechanisms involved in this dysfunction remain unclear. We examined contributions of inflammatory molecules lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), stress-activated kinases (c-Jun N-terminal kinase [JNK] and p38), arginase, and reactive oxygen species to coronary arteriolar dysfunction in a porcine model of type 1 diabetes. Coronary arterioles were isolated from streptozocin-induced diabetic pigs and control pigs for vasoreactivity and molecular/biochemical studies. Endothelium-dependent nitric oxide (NO)-mediated vasodilation to serotonin was diminished after 2 weeks of diabetes, without altering endothelium-independent vasodilation to sodium nitroprusside. Superoxide scavenger TEMPOL, NO precursor L-arginine, arginase inhibitor nor-NOHA, anti-LOX-1 antibody or JNK inhibitors SP600125 and BI-78D3 improved dilation of diabetic vessels to serotonin. However, hydrogen peroxide scavenger catalase, anti-IgG antibody or p38 kinase inhibitor SB203580 had no effect. Combined inhibition of arginase and superoxide levels did not further improve vasodilation. Arginase-I mRNA expression, LOX-1 and JNK protein expression, and superoxide levels were elevated in diabetic arterioles. In conclusion, sequential activation of LOX-1, JNK, and L-arginine consuming enzyme arginase-I in diabetes elicits superoxide-dependent oxidative stress and impairs endothelial NO-mediated dilation in coronary arterioles. Therapeutic targeting of these adverse vascular molecules may improve coronary arteriolar function during diabetes.


Assuntos
Arginase/metabolismo , Arteríolas/metabolismo , Vasos Coronários/metabolismo , Diabetes Mellitus Experimental/complicações , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Receptores Depuradores Classe E/metabolismo , Animais , Antracenos/farmacologia , Arginase/genética , Arteríolas/patologia , Vasos Coronários/patologia , Óxidos N-Cíclicos/farmacologia , Diabetes Mellitus Experimental/metabolismo , Dioxanos/farmacologia , Imidazóis/farmacologia , Técnicas In Vitro , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Masculino , Óxido Nítrico/farmacologia , Piridinas/farmacologia , Receptores Depuradores Classe E/genética , Serotonina/farmacologia , Marcadores de Spin , Suínos , Tiazóis/farmacologia , Vasodilatação/efeitos dos fármacos
19.
Eur J Med Chem ; 168: 461-473, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30844609

RESUMO

A series of derivatives obtained by moving the aromatic moiety on the 1,4-dioxane ring of compounds 1-3 from position 6 to position 2 or 3 was prepared and evaluated for the affinity for 5-HT1A receptor (5-HT1AR) and α1-adrenoceptor (α1-AR) subtypes. Moreover, the flexible 2-ethanolamine linker of the most interesting compounds was replaced by the more conformationally constrained piperazine ring. In vitro functional studies performed on derivatives showing the highest affinities for 5-HT1AR highlighted that the shifting of the diphenyl moiety of derivatives 2 and 13 from position 6 to position 3 of the 1,4-dioxane nucleus, affording 11 and 16, respectively, modulated the 5-HT1AR functional profile from agonism to antagonism. Docking simulations, performed on the human 5-HT1AR, further rationalized the biological results, delving into the features which modulate the shift between agonist and antagonist activity. Interestingly, compound 11, endowed with mixed 5-HT1AR/α1d-AR antagonist profile, showed antiproliferative and cytotoxic effects on both PC-3 and DU-145 prostate cancer cell lines higher than those of the α1d-AR antagonist 2 and the 5-HT1AR antagonist 16. The experiments performed in the presence of the endogenous agonists norepinephrine and serotonin confirmed the involvement of both receptor systems in the antitumor activity of 11.


Assuntos
Antineoplásicos/farmacologia , Dioxanos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptor 5-HT1A de Serotonina/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dioxanos/síntese química , Dioxanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 170: 126-140, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878827

RESUMO

The treatment of human leishmaniasis is currently based on few compounds that are highly toxic, expensive and have a high rate of treatment failure. A number of recent studies on new drugs focuses on natural or semi-synthetic compounds. Among them, the endoperoxide artemisinin, extracted from Artemisia annua, and some of its derivatives have shown leishmanicidal activity. In the present work, a series of structurally simple, fully synthetic 1,2-dioxanes were evaluated for in vitro antileishmanial activity against promastigotes of Leishmania donovani; the cytotoxicity for mammalian cells was also assessed. The six most promising compounds in terms of activity and selectivity were further investigated for their antileishmanial activity on the promastigote forms of L. tropica, L. major and L. infantum and against L. donovani amastigotes. The good performance in terms of potency and selectivity makes these six hits promising candidates for a preliminary lead optimization as antileishmanial agents.


Assuntos
Dioxanos/química , Dioxanos/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Animais , Chlorocebus aethiops , Dioxanos/síntese química , Desenho de Fármacos , Humanos , Testes de Sensibilidade Parasitária , Células Vero
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...