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1.
Arterioscler Thromb Vasc Biol ; 40(8): 1891-1904, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32493172

RESUMO

OBJECTIVE: Platelets are critical to the formation of a hemostatic plug and the pathogenesis of atherothrombosis. Preclinical animal models, especially the mouse, provide an important platform to assess the efficacy and safety of antiplatelet drugs. However, these studies are limited by inherent differences between human and mouse platelets and the species-selectivity of many drugs. To circumvent these limitations, we developed a new protocol for the adoptive transfer of human platelets into thrombocytopenic nonobese diabetic/severe combined immune deficiency mice, that is, a model where all endogenous platelets are replaced by human platelets in mice accepting xenogeneic tissues. Approach and Results: To demonstrate the power of this new model, we visualized and quantified hemostatic plug formation and stability by intravital spinning disk confocal microscopy following laser ablation injury to the saphenous vein. Integrin αIIbß3-dependent hemostatic platelet plug formation was achieved within ≈30 seconds after laser ablation injury in humanized platelet mice. Pretreatment of mice with standard dual antiplatelet therapy (Aspirin+Ticagrelor) or PAR1 inhibitor, L-003959712 (an analog of vorapaxar), mildly prolonged the bleeding time and significantly reduced platelet adhesion to the site of injury. Consistent with findings from clinical trials, inhibition of PAR1 in combination with dual antiplatelet therapy markedly prolonged bleeding time in humanized platelet mice. CONCLUSIONS: We propose that this novel mouse model will provide a robust platform to test and predict the safety and efficacy of experimental antiplatelet drugs and to characterize the hemostatic function of synthetic, stored and patient platelets.


Assuntos
Plaquetas/fisiologia , Hemostasia/efeitos dos fármacos , Transferência Adotiva , Animais , Benzofuranos/farmacologia , Carbamatos/farmacologia , Terapia Antiplaquetária Dupla/efeitos adversos , Humanos , Masculino , Camundongos , Modelos Animais , Receptor PAR-1/antagonistas & inibidores
2.
F1000Res ; 9: 129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194944

RESUMO

We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL pro) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart.  With the 3CL pro molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache.  The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.


Assuntos
Benzimidazóis/farmacologia , Betacoronavirus/efeitos dos fármacos , Carbamatos/farmacologia , Infecções por Coronavirus , Cisteína Endopeptidases/química , Fluorenos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Pandemias , Pneumonia Viral , Proteínas não Estruturais Virais/química , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Humanos , Pneumonia Viral/tratamento farmacológico
3.
Gen Physiol Biophys ; 39(2): 169-177, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32329444

RESUMO

The present study aimed to investigate the effects of histone deacetylase 6 (HDAC6) inhibitor Cay10603 (Cay) on high glucose (HG)-stimulated human retinal pigment epithelium (RPE) cells and its underlying mechanisms. ARPE-19 cells were cultured under normal glucose (NG) or high glucose (HG) conditions. The results revealed that HDAC6 was upregulated in HG-stimulated ARPE-19 cells. Cay treatment caused a decrease in intracellular reactive oxygen species (ROS). The levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were reduced accompanied by increase in the activities of superoxide dismutase (SOD) and catalase (CAT) after treatment with Cay. Besides, Cay decreased the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6 and monocyte chemoattractant protein-1 (MCP-1) in supernatant. Meanwhile, the apoptotic rate in Cay-treated ARPE-19 cells notably reduced, coupled with an upregulation in Bcl-2 expression and a downregulation in cleaved caspase-3 and cleaved caspase-9 expression. Cay decreased the expression of phospho (p)-NF-κB p65, p-IκB-α, NLRP3, cleaved caspase-1 and ASC while increased the expression of NF-κB p65 (cytoplasm). Taken together, these findings demonstrated that Cay suppressed HG-induced oxidative stress, inflammation and apoptosis via regulating NF-κB and NLRP3 inflammasome pathway in HG-induced ARPE-19 cells, suggesting that Cay might be a therapeutic agent for the treatment of diabetic retinopathy.


Assuntos
Apoptose , Carbamatos/farmacologia , Células Epiteliais/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Oxazóis/farmacologia , Estresse Oxidativo , Células Epiteliais/citologia , Glucose , Humanos , Inflamação , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Retina/citologia
4.
J Pharmacol Exp Ther ; 373(3): 353-360, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32241809

RESUMO

Fatty acid amide hydrolase (FAAH) is a key enzyme in the endocannabinoid system. N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide ([11C]DFMC) was developed as an irreversible-type positron emission tomography (PET) tracer for FAAH. Here, we attempted to noninvasively estimate rate constant k3 (rate of transfer to the specifically-bound compartment) as a direct index for FAAH in the rat brain. First, the two-tissue compartment model analysis including three parameters [K1-k3, two-tissue compartment model for the irreversible-type radiotracer (2TCMi)] in PET study with [11C]DFMC was conducted, which provided 0.21 ± 0.04 ml·cm-3·min-1 of the net uptake value (Ki), an indirect index for FAAH, in the FAAH-richest region (the cingulate cortex). Subsequently, to noninvasively estimate Ki value, the reference model analysis (Patlak graphical analysis reference model) was tried using a time-activity curve of the spinal cord. In that result, the noninvasive Ki value (KREF) was concisely estimated with high correlation (r > 0.95) to Ki values based on 2TCMi. Using estimated KREF value, we tried to obtain calculated-k3 based on previously defined equations. The calculated k3 was successfully estimated with high correlation (r = 0.95) to direct k3 in 2TCMi. Finally, the dose relationship study using calculated k3 demonstrated that in vivo ED50 value of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate, a major inhibitor of FAAH, was 66.4 µg/kg in rat brain. In conclusion, we proposed the calculated k3 as an alternative index corresponding to regional FAAH concentrations and suggested that PET with [11C]DFMC enables occupancy study for new pharmaceuticals targeting FAAH. SIGNIFICANCE STATEMENT: In the present study, we proposed calculated k3 as an alternative index corresponding with fatty acid amide hydrolase concentration. By using calculated k3, in vivo ED50 of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate was successfully estimated to be 66.4 µg/kg for rats. Thus, we demonstrated the pharmacological utility of positron emission tomography with N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide.


Assuntos
Amidoidrolases/metabolismo , Encéfalo/metabolismo , Carbamatos/farmacologia , Radioisótopos de Carbono/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Roedores/metabolismo , Animais , Endocanabinoides/metabolismo , Masculino , Compostos Radiofarmacêuticos/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/fisiologia
5.
Mol Cell Biol ; 40(13)2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32284347

RESUMO

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has well-established roles in DNA double-strand break repair, and recently, nonrepair functions have also been reported. To better understand its cellular functions, we deleted DNA-PKcs from HeLa and A549 cells using CRISPR/Cas9. The resulting cells were radiation sensitive, had reduced expression of ataxia-telangiectasia mutated (ATM), and exhibited multiple mitotic defects. Mechanistically, nocodazole-induced upregulation of cyclin B1, anillin, and securin was decreased in DNA-PKcs-deficient cells, as were phosphorylation of Aurora A on threonine 288, phosphorylation of Polo-like kinase 1 (PLK1) on threonine 210, and phosphorylation of targeting protein for Xenopus Klp2 (TPX2) on serine 121. Moreover, reduced nocodazole-induced expression of anillin, securin, and cyclin B1 and phosphorylation of PLK1, Aurora A, and TPX2 were rescued by inhibition of the anaphase-promoting complex/cyclosome (APC/C) by proTAME, which prevents binding of the APC/C-activating proteins Cdc20 and Cdh1 to the APC/C. Altogether, our studies suggest that loss of DNA-PKcs prevents inactivation of the APC/C in nocodazole-treated cells.


Assuntos
Ciclossomo-Complexo Promotor de Anáfase/antagonistas & inibidores , Antineoplásicos/farmacologia , Proteínas Contráteis/genética , Proteína Quinase Ativada por DNA/genética , Inibidores Enzimáticos/farmacologia , Nocodazol/farmacologia , Células A549 , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Animais , Aurora Quinase A/metabolismo , Sistemas CRISPR-Cas , Carbamatos/farmacologia , Proteínas de Ciclo Celular/metabolismo , Proteínas Contráteis/metabolismo , Proteína Quinase Ativada por DNA/metabolismo , Diaminas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Células HeLa , Humanos , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Regulação para Cima/efeitos dos fármacos , Xenopus
6.
Expert Opin Pharmacother ; 21(9): 997-1004, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32237914

RESUMO

INTRODUCTION: In chronic obstructive pulmonary disease (COPD), inhaled long-acting antimuscarinic agents (LAMA) are effective maintenance therapies used across all severity stages of the disease. Most of them are administered via dry powder inhalers, but these devices require a potent inspiratory flow which cannot be effectively achieved by patients with advanced disease. In such patients, inhaled therapy via nebulization might be an option. AREAS COVERED: Revefenacin is a LAMA that was specifically formulated for once daily nebulization and which was authorized by the FDA as a maintenance therapy for COPD. In phase II and III clinical studies discussed in this review, revefenacin demonstrated its rapid onset of action and sustained effect on lung function on both a short- and long-term basis. EXPERT OPINION: Nebulized revefenacin with once daily use does not require any particular effort of administration and hence can be used by patients with severe airways obstruction or by those having milder cognitive deficits. Further studies are needed, however, to better document the long-term cardiovascular safety and its ability to reduce the exacerbation rate.


Assuntos
Benzamidas/uso terapêutico , Carbamatos/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Benzamidas/farmacocinética , Benzamidas/farmacologia , Carbamatos/farmacocinética , Carbamatos/farmacologia , Humanos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia
7.
Am J Med Sci ; 359(4): 212-217, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32200914

RESUMO

BACKGROUND: Acarbose and repaglinide are two safe and effective antidiabetic agents that are especially in wide use in Asian and Middle Eastern countries. These two prandial agents share some outstanding qualities that their newer counterparts do not. While globally available in generic versions, both are oral and cheap. There is a paucity of data regarding their comparative efficacy. Herein, a head-to-head comparison of the efficacy of the two in treatment of postprandial hyperglycemia of newly-diagnosed type 2 diabetes was investigated. MATERIALS AND METHODS: One hundred and sixty-four newly-diagnosed type 2 diabetes patients with fasting plasma glucose levels of <7.2 mmol/L (130 mg/dL) but 2-hour postprandial glucose (2hPPG) levels of >10 mmol/L (180 mg/dL) were consecutively alternated between acarbose- and repaglinide-treatment for 6 months. RESULTS: Per protocol analysis, 67% of acarbose-treated patients versus 85% of repaglinide-treated patients achieved 2hPPG levels of <10 mmol/L (180 mg/dL) (P = 0.05). Treatment adherence rates were 52.4% and 72%, respectively (P < 0.02). Thirteen of the repaglinide-treated and 2 of acarbose-treated patients reported at least one episode of hypoglycemia (P < 0.03). Fasting plasma glucose, 2hPPG, glycated hemoglobin and basal insulin requirement decreased more significantly with repaglinde than acarbose (P, <0.05, <0.04, <0.04 and <0.03, respectively). Weight increased with repaglinide and decreased with acarbose (P = 0.03). There were no significant changes in LDL levels with either treatment (P = 0.58), but triglycerides decreased more significantly with acarbose treatment (P = 0.03) CONCLUSIONS: Significantly higher rates of treatment-adherence and at-target glycemic levels were seen with repaglinide treatment. Weight decreased with acarbose and increased with repaglinide treatment. Hypoglycemic episodes were much less frequent with acarbose treatment.


Assuntos
Acarbose/farmacologia , Carbamatos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/metabolismo , Hipoglicemiantes/farmacologia , Piperidinas/farmacologia , Adulto , Idoso , Glicemia/análise , Feminino , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade
8.
Nat Chem Biol ; 16(5): 546-555, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32152539

RESUMO

The anaphase-promoting complex/cyclosome (APC/C) is a ubiquitin ligase that initiates anaphase and mitotic exit. APC/C is activated by Cdc20 and inhibited by the mitotic checkpoint complex (MCC), which delays mitotic exit when the spindle assembly checkpoint (SAC) is activated. We previously identified apcin as a small molecule ligand of Cdc20 that inhibits APC/CCdc20 and prolongs mitosis. Here we find that apcin paradoxically shortens mitosis when SAC activity is high. These opposing effects of apcin arise from targeting of a common binding site in Cdc20 required for both substrate ubiquitination and MCC-dependent APC/C inhibition. Furthermore, we found that apcin cooperates with p31comet to relieve MCC-dependent inhibition of APC/C. Apcin therefore causes either net APC/C inhibition, prolonging mitosis when SAC activity is low, or net APC/C activation, shortening mitosis when SAC activity is high, demonstrating that a small molecule can produce opposing biological effects depending on regulatory context.


Assuntos
Ciclossomo-Complexo Promotor de Anáfase/antagonistas & inibidores , Carbamatos/farmacologia , Proteínas Cdc20/antagonistas & inibidores , Diaminas/farmacologia , Mitose/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Sítios de Ligação , Proteínas de Ciclo Celular/metabolismo , Ciclina B1/metabolismo , Células HCT116 , Células HeLa , Humanos , Nocodazol/farmacologia , Proteínas Nucleares/metabolismo , Fuso Acromático/efeitos dos fármacos , Fuso Acromático/metabolismo , Telomerase/genética , Telomerase/metabolismo , Imagem com Lapso de Tempo , Ubiquitinação
9.
Future Oncol ; 16(6): 161-173, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32027186

RESUMO

Approximately 10-15% of colorectal cancers (CRCs) harbor an activating BRAF mutation, leading to tumor growth promotion by activation of the mitogen-activated protein kinases pathway. BRAFV600E mutations are prognostic for treatment failure after first-line systemic therapy in the metastatic setting. In contrast to the efficacy of combined BRAF and MEK inhibition in melanoma, BRAFV600E mutant CRC is intrinsically unresponsive due to upregulation of HER/EGFR. However, combining the EGFR inhibitor cetuximab, the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib improves overall survival. This review discusses the current treatment field for patients with BRAFV600E mutant metastatic CRC and summarizes the pharmacology, efficacy and safety of the novel doublet and triplet therapies consisting of encorafenib and cetuximab with or without binimetinib.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Terapia de Alvo Molecular , Mutação , Metástase Neoplásica , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Resultado do Tratamento
10.
PLoS One ; 15(1): e0227556, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929586

RESUMO

Oxathiapiprolin is a fungicide effective against downy mildews of cucumber (Pseudoperonospora cubensis) and basil (Peronospora belbahrii) and late blight of tomato (Phytophthora infestans). To avoid fungicide resistance, it is recommended to apply oxathiapiprolin as a mixture with a partner fungicide that have a different mode of action. Here it is shown that a single application of oxathiapiprolin, benthiavalicarb, or their mixture (3+7, w/w) to the root of nursery plants grown in multi-cell trays provided prolonged systemic protection against late blight and downy mildews in growth chambers and in field tests. Soil application of 1mg active ingredient per plant provided durable protection of up to four weeks in tomato against late blight, cucumber against downy mildew and basil against downy mildew. Not only did the mixture of oxathiapiprolin and benthiavalicarb provide excellent systemic control of these diseases but also mutual protection against resistance towards both oxathiapiprolin and benthiavalicarb.


Assuntos
Carbamatos/farmacologia , Fungicidas Industriais/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Peronospora/efeitos dos fármacos , Doenças das Plantas/prevenção & controle , Pirazóis/farmacologia , Cucumis sativus/efeitos dos fármacos , Cucumis sativus/crescimento & desenvolvimento , Cucumis sativus/parasitologia , Lycopersicon esculentum/efeitos dos fármacos , Lycopersicon esculentum/crescimento & desenvolvimento , Lycopersicon esculentum/parasitologia , Peronospora/patogenicidade , Doenças das Plantas/parasitologia , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/parasitologia
11.
J Pharmacol Exp Ther ; 373(1): 72-80, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31969383

RESUMO

Spinal cord injury (SCI) usually leads to acute neuronal death and delayed secondary degeneration, resulting in sensory dysfunction, paralysis, and chronic pain. Excessive excitation is one of the critical factors leading to secondary neural damage initiated by various insults. KCNQ/Kv7 channels are highly expressed in spinal neurons and axons and play an important role in controlling their excitability. Enhancing KCNQ channel activity by using its specific opener retigabine could thus be a plausible treatment strategy to reduce the pathology after SCI. We produced contusive SCI at T10 in adult male rats, which then received 10 consecutive days' treatment with retigabine or vehicle starting 3 hours or 3 days after contusion. Two different concentrations and two different delivery methods were applied. Delivery of retigabine via Alzet osmotic pumps, but not intraperitoneal injections 3 hours after contusion, promoted recovery of locomotor function. Remarkably, retigabine delivery in both methods significantly attenuated the development of mechanical stimuli-induced hyperreflexia and spontaneous pain; however, no significant difference in the thermal threshold was observed. Although retigabine delivered 3 days after contusion significantly attenuated the development of mechanical hypersensitivity and spontaneous pain, the locomotor function is not improved by the delayed treatments. Finally, we found that early application of retigabine attenuates the inflammatory activity in the spinal cord and increases the survival of white matter after SCI. Our results suggest that decreasing neuronal excitability by targeting KCNQ/Kv7 channels at acute stage aids the recovery of locomotor function and attenuates the development of neuropathic pain after SCI. SIGNIFICANCE STATEMENT: Several pharmacological interventions have been proposed for spinal cord injury (SCI) treatment, but none have been shown to be both effective and safe in clinical trials. Necrotic neuronal death and chronic pain are often the cost of pathological neural excitation after SCI. We show that early, brief application of retigabine could aid locomotor and sensory neurobehavioral recovery after SCI, supporting the use of this drug in the clinic to promote motor and sensory function in patients with SCI.


Assuntos
Canais de Potássio KCNQ/agonistas , Canais de Potássio KCNQ/metabolismo , Locomoção/fisiologia , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/metabolismo , Animais , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Moduladores de Transporte de Membrana/farmacologia , Moduladores de Transporte de Membrana/uso terapêutico , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Vértebras Torácicas/lesões
12.
Eur J Med Chem ; 187: 111913, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31837501

RESUMO

In order to produce an effective and multi-targeted clinical drug that could prevent progressive neurodegeneration, a series of diosgenin carbamate derivatives were designed, synthesized and tested for their anti-inflammatory, antioxidant and anti-Aß activities. The results demonstrated that compound M15 was the most promising derivative against inflammatory (NO inhibition 22.7 ± 2.2%,10 µM) and cellular damage induced by H2O2 (SH-SY5Y cell protection = 75.3 ± 3.4%, 10 µM) or Aß (astrocytes protection = 70.2 ± 6.5%, 10 µM). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, Aß42 and pro-inflammatory proteins. Western blot demonstrated that M15 decreased IL-1ß, IL-6 and TNF-α level, which may contribute to its anti-inflammatory effects. In addition, M15 maintained mitochondrial function as well as cell viability through reducing H2O2-induced ROS production. The results indicated that oral administration of M15 attenuated memory deficits and played a neuroprotective effect on subcutaneous (s.c.) D-gal aging mice. In summary, M15 could be considered as a potential multifunctional neuroprotective agent due to the effects of anti-inflammatory, antioxidant and anti-Aß activities.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Carbamatos/farmacologia , Diosgenina/farmacologia , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Carbamatos/síntese química , Carbamatos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diosgenina/síntese química , Diosgenina/química , Relação Dose-Resposta a Droga , Galactose/administração & dosagem , Galactose/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade
13.
Expert Opin Pharmacother ; 21(2): 155-161, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31790307

RESUMO

Introduction: In the treatment of advanced BRAF-mutant melanoma, selective regulation of the MAPK pathway with BRAF and MEK inhibition has emerged as one of the mainstays of therapy.Areas covered: The authors present the current data on encorafenib as a compound, its pharmacokinetic and pharmacodynamics properties. This review includes current data on encorafenib therapy as a single agent as well as in combination with the MEK-inhibitor binimetinib and other systemic therapies.Expert opinion: BRAF inhibition with encorafenib exhibits substantial antitumor activity with less paradoxical MAPK pathway activation leading to treatment resistance. Combination therapy with MEK inhibitors improves response rate, progression-free survival, and overall survival in patients with BRAF-mutant metastatic melanoma compared to prior treatment regimens. Serious adverse events, including the development of cutaneous malignancies, are reported at lower rates with combination therapy, while less severe events such as pyrexia can be more common. Existing data is lacking for a recommendation of triplet therapy, although results from multiple ongoing trials are highly anticipated.


Assuntos
Carbamatos/administração & dosagem , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzimidazóis/administração & dosagem , Carbamatos/farmacologia , Humanos , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/farmacologia
14.
Cells ; 9(1)2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31861249

RESUMO

The transcription factor FOXO3 is associated with poor outcome in high-stage neuroblastoma (NB), as it facilitates chemoprotection and tumor angiogenesis. In other tumor entities, FOXO3 stimulates metastasis formation, one of the biggest challenges in the treatment of aggressive NB. However, the impact of FOXO3 on the metastatic potential of neuronal tumor cells remains largely unknown. In the present study, we uncover the small leucine-rich proteoglycan family member lumican (LUM) as a FOXO3-regulated gene that stimulates cellular migration in NB. By a drug-library screen we identified the small molecular weight compound repaglinide (RPG) as a putative FOXO3 inhibitor. Here, we verify that RPG binds to the FOXO3-DNA-binding-domain (DBD) and thereby silences the transcriptional activity of FOXO3. Consistent with the concept that the FOXO3/LUM axis enhances the migratory capacity of aggressive NB cells, we demonstrate that stable knockdown of LUM abrogates the FOXO3-mediated increase in cellular migration. Importantly, FOXO3 inhibition by RPG represses the binding of FOXO3 to the LUM promoter, inhibits FOXO3-mediated LUM RNA and protein expression, and efficiently abrogates FOXO3-triggered cellular "wound healing" as well as spheroid-based 3D-migration. Thus, silencing the FOXO3/LUM axis by the FDA-approved compound RPG represents a promising strategy for novel therapeutic interventions in NB and other FOXO3-dependent tumors.


Assuntos
Carbamatos/farmacologia , Regulação para Baixo , Proteína Forkhead Box O3/metabolismo , Lumicana/genética , Neuroblastoma/genética , Piperidinas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proteína Forkhead Box O3/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Lumicana/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica/efeitos dos fármacos
15.
Int J Mol Sci ; 20(21)2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31671776

RESUMO

A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. In fact, some of the newly prepared molecules revealed comparable or even better inhibitory activities compared to the marketed drugs (rivastigmine or galanthamine) and commercially applied pesticide Diuron®, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (2) and benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (3) were characterized by fairly high selective indexes. Specifically, compound 2 was prescribed with the lowest IC50 value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules 3 and benzyl-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (4) are in line with rivastigmine activity. Moreover, a structure-activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity-activity landscape index for BChE inhibitory response values. The 'indirect' ligand-based and 'direct' protein-mediated in silico approaches were applied to specify electronic/steric/lipophilic factors that are potentially valid for quantitative (Q)SAR modeling of the carbamate analogues. The stochastic model validation was used to generate an 'average' 3D-QSAR pharmacophore pattern. Finally, the target-oriented molecular docking was employed to (re)arrange the spatial distribution of the ligand property space for BChE and photosystem II (PSII).


Assuntos
Carbamatos/química , Carbamatos/farmacologia , Inibidores da Colinesterase/química , Silício/química , Sítios de Ligação , Butirilcolinesterase , Sobrevivência Celular/efeitos dos fármacos , Cloroplastos , Inibidores da Colinesterase/farmacologia , Transporte de Elétrons/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Simulação de Acoplamento Molecular , Complexo de Proteína do Fotossistema II , Spinacia oleracea , Relação Estrutura-Atividade , Células THP-1/efeitos dos fármacos
16.
Int J Mol Sci ; 20(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775247

RESUMO

Gene expression and tumor growth can be regulated by methylation levels of lysine residues on histones, which are controlled by histone lysine demethylases (KDMs). Series of benzo[b]tellurophene and benzo[b]selenophene compounds were designed and synthesized and they were evaluated for histone H3 lysine 9 demethylase (KDM4) inhibitory activity. Among the carbamates, alcohol and aromatic derivatives, tert-butyl benzo[b]tellurophen-2-ylmethylcarbamate (compound 1c) revealed KDM4 specific inhibitory activity in cervical cancer HeLa cells, whereas the corresponding selenium or oxygen substitute compounds did not display any inhibitory activity toward KDM4. Compound 1c also induced cell death in cervical and colon cancer but not in normal cells. Thus, compound 1c, a novel inhibitor of KDM4, constitutes a potential therapeutic and research tool against cancer.


Assuntos
Carbamatos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Histonas/química , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Lisina/química , Carbamatos/química , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Inibidores Enzimáticos/química , Células HeLa , Humanos , Células Tumorais Cultivadas
17.
Genes (Basel) ; 10(10)2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614683

RESUMO

Growing resistance is reported to carbamate insecticides in malaria vectors in Cameroon. However, the contribution of acetylcholinesterase (Ace-1) to this resistance remains uncharacterised. Here, we established that the G119S mutation is driving resistance to carbamates in Anopheles gambiae populations from Cameroon. Insecticide bioassay on field-collected mosquitoes from Bankeng, a locality in southern Cameroon, showed high resistance to the carbamates bendiocarb (64.8% ± 3.5% mortality) and propoxur (55.71% ± 2.9%) but a full susceptibility to the organophosphate fenitrothion. The TaqMan genotyping of the G119S mutation in field-collected adults revealed the presence of this resistance allele (39%). A significant correlation was observed between the Ace-1R and carbamate resistance at allelic ((bendiocarb; odds ratio (OR) = 75.9; p < 0.0001) and (propoxur; OR = 1514; p < 0.0001)) and genotypic (homozygote resistant vs. homozygote susceptible (bendiocarb; OR = 120.8; p < 0.0001) and (propoxur; OR = 3277; p < 0.0001)) levels. Furthermore, the presence of the mutation was confirmed by sequencing an Ace-1 portion flanking codon 119. The cloning of this fragment revealed a likely duplication of Ace-1 in Cameroon as mosquitoes exhibited at least three distinct haplotypes. Phylogenetic analyses showed that the predominant Ace-1R allele is identical to that from West Africa suggesting a recent introduction of this allele in Central Africa from the West. The spread of this Ace-1R represents a serious challenge to future implementation of indoor residual spraying (IRS)-based interventions using carbamates or organophosphates in Cameroon.


Assuntos
Acetilcolinesterase/genética , Anopheles/genética , Resistência a Inseticidas/genética , Acetilcolinesterase/metabolismo , Animais , Anopheles/efeitos dos fármacos , Anopheles/patogenicidade , Camarões , Carbamatos/metabolismo , Carbamatos/farmacologia , Vetores de Doenças , Fenitrotion , Resistência a Inseticidas/efeitos dos fármacos , Inseticidas/farmacologia , Malária/transmissão , Controle de Mosquitos , Mosquitos Vetores , Mutação/efeitos dos fármacos , Fenilcarbamatos , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Propoxur
18.
Transpl Infect Dis ; 21(6): e13165, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31487082

RESUMO

Direct-acting antivirals (DAAs) demonstrated high efficacy and safety even in the post-liver transplant (LT) setting and in HIV-infected patients, but data are very limited in the early post-LT period with the most recently available DAA. Two HIV/HCV-coinfected LT recipients (both grafts from HIV/HCV-negative donors) experienced early HCV recurrence with severe hepatitis and were treated with sofosbuvir/velpatasvir for 12 weeks. Unfortunately, both patients failed: one (genotype 4d) showed virological breakthrough at week 3 with resistance-associated substitutions (RASs) for both NS5A and NS5B, while the other (genotype 1a) experienced virological relapse without RAS. Both progressed to fibrosing cholestatic hepatitis and were successfully retreated with glecaprevir/pibrentasvir for 16 weeks achieving sustained virological response. The higher prevalence of RAS in experienced genotype 4 patients and the long time to viral suppression observed in subjects with fibrosing cholestatic hepatitis should be taken into account, considering longer treatment duration to increase the chances of achieving sustained virological response.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Carbamatos/farmacologia , Infecções por HIV/complicações , Hepacivirus/isolamento & purificação , Hepatite C Crônica/terapia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Transplante de Fígado/efeitos adversos , Pirrolidinas/farmacologia , Quinoxalinas/farmacologia , Sofosbuvir/farmacologia , Sulfonamidas/farmacologia , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/virologia , Combinação de Medicamentos , Farmacorresistência Viral/genética , Infecções por HIV/imunologia , Infecções por HIV/terapia , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite C Crônica/complicações , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/cirurgia , Cirrose Hepática/virologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/genética , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , RNA Viral/genética , RNA Viral/isolamento & purificação , Recidiva , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada , Falha de Tratamento , Carga Viral/efeitos dos fármacos , Proteínas não Estruturais Virais/genética
19.
Int J Mol Sci ; 20(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487785

RESUMO

Kv7.2-Kv7.5 channels mediate the M-current (IKM), a K+-selective current regulating neuronal excitability and representing an attractive target for pharmacological therapy against hyperexcitability diseases such as pain. Kv7 channels interact functionally with transient receptor potential vanilloid 1 (TRPV1) channels activated by endogenous and/or exogenous pain-inducing substances, such as bradykinin (BK) or capsaicin (CAP), respectively; however, whether Kv7 channels of specific molecular composition provide a dominant contribution in BK- or CAP-evoked responses is yet unknown. To this aim, Kv7 transcripts expression and function were assessed in F11 immortalized sensorial neurons, a cellular model widely used to assess nociceptive molecular mechanisms. In these cells, the effects of the pan-Kv7 activator retigabine were investigated, as well as the effects of ICA-27243 and (S)-1, two Kv7 activators acting preferentially on Kv7.2/Kv7.3 and Kv7.4/Kv7.5 channels, respectively, on BK- and CAP-induced changes in intracellular Ca2+ concentrations ([Ca2+]i). The results obtained revealed the expression of transcripts of all Kv7 genes, leading to an IKM-like current. Moreover, all tested Kv7 openers inhibited BK- and CAP-induced responses by a similar extent (~60%); at least for BK-induced Ca2+ responses, the potency of retigabine (IC50~1 µM) was higher than that of ICA-27243 (IC50~5 µM) and (S)-1 (IC50~7 µM). Altogether, these results suggest that IKM activation effectively counteracts the cellular processes triggered by TRPV1-mediated pain-inducing stimuli, and highlight a possible critical contribution of Kv7.4 subunits.


Assuntos
Sinalização do Cálcio , Capsaicina/farmacologia , Canais de Potássio KCNQ/metabolismo , Células Receptoras Sensoriais/metabolismo , Fármacos do Sistema Sensorial/farmacologia , Canais de Cátion TRPV/metabolismo , Animais , Bradicinina/farmacologia , Cálcio/metabolismo , Carbamatos/farmacologia , Linhagem Celular , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Moduladores de Transporte de Membrana/farmacologia , Fenilenodiaminas/farmacologia , Ratos , Células Receptoras Sensoriais/efeitos dos fármacos
20.
Infez Med ; 27(3): 239-250, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31545767

RESUMO

After a long period of interferon-and ribavirin-based therapy (IFN/RBV), a very fast evolution in the development of directly acting antivirals (DAAs) has now established a totally new paradigm for the treatment chronic HCV infection. An efficacy rate within the 95-100% interval, safer and more tolerable drugs, much shorter treatment duration and a quicker establishment of the sustained virological response (SVR) are among the most relevant properties of new DAAs as compared to former IFN/RBV therapies. The last wave of DAAs is also characterized by a lesser tendency to generate or being victim of drug-drug interactions. Nevertheless, since the circumstances in which patients are also recipients of other medications are rather frequent, individualization of treatment is advised in order to minimize the risk of drug-drug interactions of clinical relevance. Three two-drug regimens are available in Italy for the treatment of chronic HCV infection: sofosbuvir/velpatasvir (SOF/VEL), glecaprevir/pibrentasvir (GLE/PIB) and grazoprevir/elbasvir (GZP/RLB). Based on the officially released summary of product characteristics (SmPC) of these three co-formulated dual regimens, we performed a comparative analysis concerning the drug-drug interactions possibly affecting the DAA regimens. According to specific individual conditions, including co-morbidities, the choice of the most appropriate regimen must carefully take into account, among the different variables, the metabolic profile of both DAAs and concurrent medications. The differences among the three regimens offer the possibility to avoid the occurrence of clinically relevant drug-drug interactions in most circumstance.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Benzofuranos/farmacologia , Carbamatos/farmacologia , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Imidazóis/farmacologia , Pirrolidinas/farmacologia , Quinoxalinas/farmacologia , Sofosbuvir/farmacologia , Sulfonamidas/farmacologia , Antivirais/metabolismo , Antivirais/uso terapêutico , Benzimidazóis/metabolismo , Benzofuranos/metabolismo , Carbamatos/metabolismo , Combinação de Medicamentos , Interações Medicamentosas , Hepatite C Crônica/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Imidazóis/metabolismo , Interferon-alfa/uso terapêutico , Itália , Polimedicação , Pirrolidinas/metabolismo , Quinoxalinas/metabolismo , Sofosbuvir/metabolismo , Sulfonamidas/metabolismo
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