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1.
PLoS Comput Biol ; 16(9): e1008190, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32976489

RESUMO

Spatial repellents (SRs) reduce human-mosquito contact by preventing mosquito entrance into human-occupied spaces and interfering with host-seeking and blood-feeding. A new model to synthesize experimental data on the effects of transfluthrin on Aedes aegypti explores how SR effects interact to impact the epidemiology of diseases vectored by these mosquitoes. Our results indicate that the greatest impact on force of infection is expected to derive from the chemical's lethal effect but delayed biting and the negative effect this may have on the mosquito population could elicit substantial impact in the absence of lethality. The relative contributions of these effects depend on coverage, chemical dose, and housing density. We also demonstrate that, through an increase in the number of potentially infectious mosquito bites, increased partial blood-feeding and reduced exiting may elicit adverse impacts, which could offset gains achieved by other effects. Our analysis demonstrates how small-scale experimental data can be leveraged to derive expectations of epidemiological impact of SRs deployed at larger scales.


Assuntos
Aedes/microbiologia , Repelentes de Insetos , Controle de Mosquitos/métodos , Mosquitos Vetores , Aedes/virologia , Animais , Ciclopropanos/farmacologia , Fluorbenzenos/farmacologia
2.
PLoS One ; 15(8): e0237353, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785255

RESUMO

Airborne spatial repellency (SR) is characterized and distinguished from other chemical actions including contact locomotor excitation and toxicity. The use of volatile spatial repellents is a potential new intervention class for combatting mosquito-borne pathogen transmission; therefore, continuing investigations on the actions of these chemicals that modify mosquito host-seeking behavior (i.e., bite prevention) is needed. The objective of this study is to characterize the key behavioral avoidance actions of transfluthrin (TFT) to advance spatial repellent development into practical products. Behavioral avoidance responses were observed for adult laboratory strains of Aedes aegypti, Anopheles minimus and An. dirus, and two field populations of An. harrisoni and Ae. aegypti, respectively. Established TFT sublethal (LC50 and LC75), lethal concentrations (LC99) and discriminating concentrations (DCs) were selected corresponding to each mosquito test species. Spatial repellency and contact excitation ('irritancy') responses on adult mosquitoes to TFT were assessed using an excito-repellency assay system. At LC50, TFT exhibited strong avoidance with An. minimus (60.1% escape) and An. dirus (80% escape) laboratory strains, showing between 12 and 16x greater escape response than Ae. aegypti (5% escape). Repellency responses for field collected Ae. aegypti and An. harrisoni were 54.9 and 47.1% escape, respectively. After adjusting the initial contact escape response (a measure of combined irritancy and repellency) to estimate only escape due to contact, the LC50 and LC99 showed moderate escape irritancy with laboratory Ae. aegypti (41.4% escape) and no contact activity against the field population. Adjustment showed only weak contact activity (16.1% escape) in laboratory An. minimus at LC50. Spatial repellency is the predominant mode of action of TFT among colonized and field mosquitoes used in this study. Established baseline (susceptible) dose-response curves assist in optimizing SR products for mosquito control and pathogen transmission prevention.


Assuntos
Comportamento Animal/efeitos dos fármacos , Ciclopropanos/farmacologia , Fluorbenzenos/farmacologia , Repelentes de Insetos/farmacologia , Mosquitos Vetores/efeitos dos fármacos , Compostos Orgânicos Voláteis/farmacologia , Aedes/efeitos dos fármacos , Aedes/fisiologia , Animais , Anopheles/efeitos dos fármacos , Anopheles/fisiologia , Aprendizagem da Esquiva , Relação Dose-Resposta a Droga , Feminino , Controle de Mosquitos/métodos , Mosquitos Vetores/fisiologia , Doenças Transmitidas por Vetores/prevenção & controle
3.
Food Chem ; 330: 127256, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32540529

RESUMO

The objective of the present study was to investigate the effectiveness of different 1-MCP treatment patterns on alleviating chilling injury (CI) of postharvest nectarine stored at 0 ± 1 °C. Nectarine fruits were subjected to the following treatments: Single-High dose 1-MCP treatment (S-H): 1 µL L-1 application before storage; Multi-low dose 1-MCP treatment: (M-L) Five 0.25 µL L-1 applications after 0, 5, 10, 15, and 20 d of storage; Multi-high dose 1-MCP treatment (M-H): Five 1 µL L-1 applications after 0, 5, 10, 15 and 20 d of storage. The results showed that although all 1-MCP treatments alleviated CI, M-H 1-MCP treatment is the most effective pattern in alleviating CI of nectarine fruit in S-H, M-L, and M-H 1-MCP treatments. Moreover, this study indicated that the reduction of CI in nectarine by 1-MCP application was related to its regulations of ROS and energy metabolism.


Assuntos
Ciclopropanos/farmacologia , Prunus/efeitos dos fármacos , Temperatura Baixa , Metabolismo Energético , Armazenamento de Alimentos/métodos , Frutas/efeitos dos fármacos , Frutas/metabolismo , Néctar de Plantas , Prunus/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
Exp Parasitol ; 208: 107793, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31711973

RESUMO

Praziquantel (PZQ) is the sole drug used to treat schistosomiasis, and the probability of developing resistance is growing the longer it is relied upon, justifying the search for alternatives. Phosphodiesterases (PDEs), particularly the PDE4 family, have attracted considerable attention as drug targets, including in Schistosoma mansoni, and especially SmPDE4A. This study investigates the potential antischistosomal activity of human PDE4 and potent SmPDE4A inhibitor roflumilast, either alone or combined with PZQ. In vitro, roflumilast resulted in a significant, concentration-dependent reduction in egg production but not of worm viability. In vitro exposure to roflumilast in combination with a low concentration of PZQ was less effective than PZQ alone, pointing to antagonism. S. mansoni-infected mice treated with roflumilast showed significant reductions in worm burden (27%) as well as hepatic and intestinal egg burdens (~28%) two weeks post treatment. Scanning EM of worms isolated from roflumilast-treated and untreated mice did not reveal noticeable changes to their tegument. S. mansoni-infected mice treated with a fixed dosage of roflumilast and a variable dosage of PZQ resulted in a higher reduction in worm burden, reduced hepatic egg counts, absence of immature eggs and a marked increase in dead eggs, compared to PZQ alone. However, the combination resulted in increased animal mortality, probably attributable to pharmacodynamic interactions between the two drugs. Although this study marks the first report of in vivo antischistosomal potential by a PDE inhibitor, an important proof of concept, we conclude that the antischistosomal effects of roflumilast are insufficient to warrant further development.


Assuntos
Aminopiridinas/farmacologia , Anti-Helmínticos/farmacologia , Benzamidas/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/efeitos dos fármacos , Ciclopropanos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Concentração Inibidora 50 , Masculino , Camundongos , Microscopia Eletrônica de Varredura , Oviposição/efeitos dos fármacos , Praziquantel/farmacologia , Schistosoma mansoni/enzimologia , Schistosoma mansoni/fisiologia , Schistosoma mansoni/ultraestrutura
5.
Gut ; 69(2): 365-379, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31076403

RESUMO

OBJECTIVE: Hepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy. DESIGN: Functional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet and verified by clinical specimens. Mechanistic studies were conducted in human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically trialled BET bromodomain inhibitor i-BET762 was determined. RESULTS: Accumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumour eradication and prolonged survival in the fibrotic-HCC mouse model. CONCLUSION: Our results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.


Assuntos
Carcinoma Hepatocelular/terapia , Imunoterapia/métodos , Neoplasias Hepáticas/terapia , Animais , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/imunologia , Reprogramação Celular/imunologia , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Células Estreladas do Fígado/imunologia , Humanos , Tolerância Imunológica , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/terapia , Masculino , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Células Supressoras Mieloides/imunologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas , Microambiente Tumoral , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
6.
Am J Physiol Lung Cell Mol Physiol ; 318(1): L59-L64, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31664853

RESUMO

Cigarette smoke (CS), a highly complex mixture containing more than 4,000 compounds, causes aberrant cell responses leading to tissue damage around the airways and alveoli, which underlies various lung diseases. Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cyclic nucleotides. PDE inhibition induces bronchodilation, reduces the activation and recruitment of inflammatory cells, and the release of various cytokines. Currently, the selective PDE4 inhibitor roflumilast is an approved add-on treatment for patients with severe chronic obstructive pulmonary disease with chronic bronchitis and a history of frequent exacerbations. Additional selective PDE inhibitors are being tested in preclinical and clinical studies. However, the effect of chronic CS exposure on the expression of PDEs is unknown. Using mRNA isolated from nasal and bronchial brushes and lung tissues of never smokers and current smokers, we compared the gene expression of 25 PDE coding genes. Additionally, the expression and distribution of PDE3A and PDE4D in human lung tissues was examined. This study reveals that chronic CS exposure modulates the expression of various PDE members. Thus, CS exposure may change the levels of intracellular cyclic nucleotides and thereby impact the efficiency of PDE-targeted therapies.


Assuntos
Pulmão/efeitos dos fármacos , Diester Fosfórico Hidrolases/metabolismo , Fumaça/efeitos adversos , Produtos do Tabaco/efeitos adversos , Adulto , Aminopiridinas/farmacologia , Benzamidas/farmacologia , Ciclopropanos/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 4/farmacologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , RNA Mensageiro/metabolismo , Fumar/efeitos adversos
7.
Prostate ; 80(4): 319-328, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31868960

RESUMO

BACKGROUND: Castration-resistant prostate cancer can develop resistance to enzalutamide because of androgen receptor (AR) point mutations, AR overexpression, constitutively active AR splice variants, and/or elevated intratumoral androgen synthesis. The point mutation ARF876L was reported to be stimulated, instead of inhibited, by enzalutamide, thus contributing to enzalutamide resistance. We have recently developed JJ-450 as a novel AR antagonist with the potential to treat enzalutamide-resistant castration-resistant prostate cancer (CRPC). METHODS: We employed several assays to determine the impact of JJ-450 and enzalutamide on prostate cancer cell lines expressing green fluorescent protein (GFP)-ARF876L . These assays include a prostate-specific antigen enhancer/promoter-based luciferase assay to determine AR transcriptional activity, a quantitative real-time polymerase chain reaction assay, and Western blot analysis to detect expression of AR-target genes at the messenger RNA and protein level, fluorescence microscopy to show AR subcellular localization, and a 5-bromo-2'-deoxyuridine assay to measure prostate cancer cell proliferation. RESULTS: As expected, enzalutamide inhibited wild-type (WT) AR but not ARF876L transcriptional activity in the luciferase assay. In contrast, JJ-450 inhibited both WT-AR and ARF876L transcriptional activity to a similar extent. Also, enzalutamide retarded androgen-induced nuclear import of GFP-AR, but not GFP-ARF876L , whereas JJ-450 retarded nuclear import of both GFP-AR and GFP-ARF876L . To further evaluate JJ-450 inhibition of ARF876L , we stably transfected C4-2 cells separately with GFP-AR or GFP-ARF876L . Enzalutamide inhibited endogenous AR-target gene expression in C4-2-GFP-ARWT , but not in the C4-2-GFP-ARF876L subline, whereas JJ-450 inhibited AR-target gene expression in both C4-2 sublines. More importantly, enzalutamide inhibited proliferation of C4-2-GFP-ARWT , but not of the C4-2-GFP-ARF876L subline, whereas JJ-450 inhibited proliferation of both C4-2 sublines. CONCLUSION: JJ-450 inhibits enzalutamide-resistant ARF876L mutant nuclear translocation and function. Our findings suggest that JJ-450 and its analogs should be further developed to provide a potential new approach for the treatment of enzalutamide-resistant CRPC.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Feniltioidantoína/análogos & derivados , Piperazinas/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Derivados de Benzeno/farmacologia , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Ciclopropanos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Células PC-3 , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transcrição Genética/efeitos dos fármacos
8.
J Sci Food Agric ; 100(5): 2082-2089, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31875963

RESUMO

BACKGROUND: Lodging can negatively affect yield and quality of barley grain. Synthetic plant growth regulators (PGRs) reduce lodging by producing shorter, thicker, and stronger stems. However, the impact of applying PGRs on malting performance of barley is not known. The objective of this work was to assess the effect of application of three PGRs (ethephon, chlormequat chloride, and trinexapac-ethyl) in combination with different seeding rates on the malting quality of barley grown in several locations and years in western Canada. RESULTS: The kernel weight in PGR-treated barley was reduced by 1.7% to 6.5% compared with the nontreated grain. Application of PGRs had no effect on the concentration of proteins and germination energy. Seeding rates significantly affected kernel weight, protein content, and germination index (GI), but no interactions between PGRs and seeding rates were observed. The smaller kernels of ethephon- and trinexapac-treated barley showed good hydration and grain modification during malting, as indicated by high levels of starch-converting enzymes, high Kolbach indices, and low levels of wort ß-glucans. Overall, the fine extract of malt from PGR-treated barley was slightly lower than that of the control malt; however, the extract reduction was statistically significant only for chlormequat- and trinexapac-treated barley. CONCLUSIONS: The application of PGRs had significant effects on kernel plumpness and kernel weight, but the effects of PGR application on the malting quality were generally small and insignificant. The decision of PGRs application on malting barley needs to be considered in combination with potential benefits of PGRs in mitigating lodging and their effects on the agronomic performance of barley. © Her Majesty the Queen in Right of Canada 2019.


Assuntos
Grão Comestível/química , Qualidade dos Alimentos , Hordeum/química , Reguladores de Crescimento de Planta/farmacologia , Canadá , Clormequat/análise , Clormequat/farmacologia , Ciclopropanos/análise , Ciclopropanos/farmacologia , Germinação , Compostos Organofosforados/análise , Compostos Organofosforados/farmacologia , Reguladores de Crescimento de Planta/análise , Quinonas/análise , Quinonas/farmacologia , beta-Glucanas/análise
9.
Food Chem ; 308: 125707, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31669943

RESUMO

The ripening of the apple (Malus × domestica Borkh.) fruit is regulated by the phytohormone ethylene, where degreening is an important physiological metabolism caused by chlorophyll (Chl) degradation. However, to date, research on how ethylene affects the Chl degradation pathway of apple peel during ripening remains scarce. In this study, the effects of ethylene on the expression of Chl catabolic genes (CCGs) of apple peel during ripening were studied by treating harvested commercial mature apples with 0.5 µL L-1 1-methylcyclopropene (1-MCP). The results showed that 1-MCP treatment led to a delayed climacteric peak of respiration and ethylene production, exhibiting higher Chl content and hue angle (H˚) compared to untreated fruit during ripening. Lower quantities of pheophorbide a oxygenase (PAO), pheophytinase (PPH) and red Chl catabolite reductase (RCCR) were also observed in peel tissues under 1-MCP treatment during ripening. Further study with quantitative real-time polymerase chain reaction (qPCR) revealed that the expression of CCGs, except for MdNYE1a, increased atdifferentdegrees upon ripening. Meanwhile, the apples treated with 1-MCP presented a downregulated expression of MdRCCR2, MdNYC1, MdNYC3 and MdNOL2 and a fluctuating expression of MdNYE1a, MdPPH1, MdPAO6, MdPAO8 and MdHCAR compared with the controls during ripening. Our results indicated the regulatory role of ethylene in the Chl degradation pathway of apple peel during ripening.


Assuntos
Clorofila/metabolismo , Ciclopropanos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Malus/metabolismo , Reguladores de Crescimento de Planta/farmacologia , Etilenos/metabolismo , Armazenamento de Alimentos , Frutas/efeitos dos fármacos , Frutas/metabolismo , Malus/efeitos dos fármacos , Proteínas de Plantas/metabolismo
10.
PLoS One ; 14(12): e0226564, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31860681

RESUMO

Here we describe a collaboration between industry, the National Health Service (NHS) and academia that sought to demonstrate how early understanding of both pharmacology and genomics can improve strategies for the development of precision medicines. Diseased tissue ethically acquired from patients suffering from chronic obstructive pulmonary disease (COPD), was used to investigate inter-patient variability in drug efficacy using ex vivo organocultures of fresh lung tissue as the test system. The reduction in inflammatory cytokines in the presence of various test drugs was used as the measure of drug efficacy and the individual patient responses were then matched against genotype and microRNA profiles in an attempt to identify unique predictors of drug responsiveness. Our findings suggest that genetic variation in CYP2E1 and SMAD3 genes may partly explain the observed variation in drug response.


Assuntos
Genômica/métodos , Pulmão/crescimento & desenvolvimento , Técnicas de Cultura de Órgãos/métodos , Variantes Farmacogenômicos , Doença Pulmonar Obstrutiva Crônica/genética , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Fluticasona/farmacologia , Fluticasona/uso terapêutico , Fumarato de Formoterol/farmacologia , Fumarato de Formoterol/uso terapêutico , Humanos , Pulmão/química , Pulmão/efeitos dos fármacos , MicroRNAs/genética , Modelos Biológicos , Medicina de Precisão , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Medicina Estatal , Sequenciamento Completo do Exoma
11.
Endocrinology ; 160(12): 2959-2968, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31613319

RESUMO

Longitudinal observation of pancreatic ß-cell mass (BCM) remains challenging because noninvasive techniques for determining BCM in vivo have not been established. Such observations would be useful for the monitoring of type 2 diabetes mellitus, a progressive disease involving loss of pancreatic BCM and function. An indium 111 (111In)-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) targeting the glucagon-like peptide-1 receptor has been developed recently as a promising probe for quantifying the BCM noninvasively. In the present study, we used the 111In-exendin-4 single-photon emission CT/CT (SPECT/CT) technique to investigate the efficacy of DS-8500a, a novel G protein-coupled receptor-119 agonist currently under investigation for type 2 diabetes mellitus treatment in prediabetic db/db mice under dietary restriction. During the 8-week study, the treatment of mice with DS-8500a delayed and attenuated the progression of glucose intolerance compared with mice under dietary restriction alone. 111In-exendin-4 SPECT/CT of db/db mice revealed continuously decreasing radioactive isotope (RI) intensity in the pancreas during the 8-week intervention. DS-8500a attenuated this decrease and preserved pancreatic RI accumulation compared with dietary restriction alone at the end of the observation period. This result was corroborated not only by ex vivo pancreatic analysis using the [Lys12(111In-BnDTPA-Ahx)]exendin-4 probe but also by conventional histological BCM analysis. These results indicate that DS-8500a attenuates the progression of BCM loss beyond that of dietary restriction alone in prediabetic db/db mice. These results have shown that 111In-exendin-4 SPECT/CT will be useful for noninvasive longitudinal investigation of BCM in vivo.


Assuntos
Benzamidas/farmacologia , Ciclopropanos/farmacologia , Diabetes Mellitus Experimental/diagnóstico por imagem , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Oxidiazóis/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Benzamidas/uso terapêutico , Ciclopropanos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Exenatida , Hipoglicemiantes/uso terapêutico , Radioisótopos de Índio , Estudos Longitudinais , Masculino , Camundongos Endogâmicos C57BL , Oxidiazóis/uso terapêutico , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
12.
J Vet Med Sci ; 81(10): 1509-1514, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31484844

RESUMO

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) acts to inhibit protein translation through phosphorylating a specific substrate, eEF2. We previously found that the increased eEF2K expression in mesenteric artery mediates hypertension development in spontaneously hypertensive rats. More recently, we have revealed that a selective eEF2K inhibitor, A484954 induced vasorelaxation via opening inward rectifier K+ channel and activating ß2-adrenergic receptor in smooth muscle of rat isolated mesenteric artery, which contributes to prevent noradrenaline-induced acute increase in blood pressure (BP). In this study, we further explored acute effects of A484954 on BP in rats, especially focusing the action on ß-adrenergic receptor. We also examined whether A484954 affects contraction and heart rate (HR) of isolated heart. BP and HR were measured by a carotid cannulation method in rats. Isometric contraction and HR in rat isolated atria were also measured pharmacologically. A484954 potentiated adrenaline-induced decrease in diastolic BP (DBP) but not increase in systolic BP (SBP). A484954 potentiated isoproterenol-induced decrease in DBP but not SBP. Contrastingly, A484954 prevented a non-ß-adrenergic receptor agonist, angiotensin II-induced increase in both SBP and DBP. In isolated left atria, A484954 caused contraction, which was prevented by a ß-adrenergic receptor antagonist, propranolol. In isolated right atria, A484954 increased HR. In conclusion, we for the first time demonstrated that A484954 potentiates ß-adrenergic receptor agonist-induced decrease in DBP possibly through vasorelaxation mediated via activating ß2-adrenergic receptor. It was also demonstrated that A484954 causes contraction of rat isolated heart via activating ß1-adrenergic receptor.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ciclopropanos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Vasodilatação/efeitos dos fármacos , Antagonistas Adrenérgicos beta/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Determinação da Pressão Arterial , Frequência Cardíaca/efeitos dos fármacos , Masculino , Contração Miocárdica/efeitos dos fármacos , Propranolol/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/metabolismo
13.
J Plant Physiol ; 242: 153033, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31472448

RESUMO

A small family of ARGOS genes encodes transmembrane proteins that act as negative regulators of ethylene signaling. Recent studies show that ARGOS genes are involved in the regulation of plant growth under the influence of stress factors. However, the role of ARGOS genes in this process is poorly known. Thereby, our goal was to determine the expression profile of these genes in Arabidopsis thaliana and Nicotiana tabacum in response to phytohormone treatment and stress factors. We discovered that expression of the AtARGOS and AtARGOS-LIKE genes of A. thaliana is regulated by ethylene and depends on environmental conditions. The highest expression level of the NtARGOS-LIKE1 gene of tobacco (NtARL1) was observed in blooming flowers and young organs. It was induced by auxins, ethylene, ABA, methyl jasmonate as well as hypothermia, drought, salinity and heat stresses. To evaluate the impact of ARGOS genes on plant growth under stress, we created transgenic tobacco plants with constitutive expression of the AtARGOS-LIKE gene of A. thaliana (AtARL), controlled by a strong Dahlia mosaic virus promoter. Overexpression of the AtARL gene contributed to an increase in the volume and quantity of mesophyll cells in the leaves of tobacco under normal conditions, and also to an improvement in root growth under salinity, cold and cadmium treatment. The AtARL transgene produced a positive effect on shoot growth when exposed to drought and high salinity, and a negative effect under cold stress. Accordingly, genes of the ARGOS family can be recommended as targets for genetic engineering and genome editing in order to enhance productivity and stress tolerance of economically important plants.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Proteínas de Membrana/genética , Plantas Geneticamente Modificadas/genética , Tabaco/crescimento & desenvolvimento , Acetatos/farmacologia , Adaptação Fisiológica/genética , Proteínas de Arabidopsis/metabolismo , Cádmio/toxicidade , Resposta ao Choque Frio , Ciclopentanos/farmacologia , Ciclopropanos/farmacologia , Secas , Etilenos/farmacologia , Flores/genética , Flores/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Oxilipinas/farmacologia , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Domínios Proteicos/genética , Cloreto de Sódio/farmacologia , Estresse Fisiológico , Tabaco/genética
14.
Eur J Med Chem ; 182: 111626, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31445232

RESUMO

A new series of fluorinated 5-HT2C agonists were designed and synthesized on the basis of our previous work on 2-phenylcyclopropylmethylamines as a potential approach for the treatment of central nervous system disorders. Key fluorinated cyclopropane moieties were constructed through transition metal catalyzed [2 + 1]-cycloaddition of aromatic vinyl fluorides, and the absolute stereochemistry of the representative compound (-)-21a was established. Functional activity measuring calcium flux at 5-HT2 receptors reveals high potency for compounds (+)-21a-d. In particular, (+)-21b had no detectable 5-HT2B agonism and displayed reasonable selectivity against 5-HT2A. Molecular docking studies were further performed to explain the compounds' possible binding poses to the 5-HT2C receptor.


Assuntos
Ciclopropanos/farmacologia , Desenho de Fármacos , Metilaminas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Ciclopropanos/síntese química , Ciclopropanos/química , Relação Dose-Resposta a Droga , Halogenação , Humanos , Metilaminas/síntese química , Metilaminas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptor 5-HT2B de Serotonina/metabolismo , Relação Estrutura-Atividade
15.
BMC Plant Biol ; 19(1): 309, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299898

RESUMO

BACKGROUND: Ethylene promotes fruit ripening whereas 1-methylcyclopropene (1-MCP), a non-toxic antagonist of ethylene, delays fruit ripening via the inhibition of ethylene receptor. However, unsuitable 1-MCP treatment can cause fruit ripening disorders. RESULTS: In this study, we show that short-term 1-MCP treatment (400 nL•L- 1, 2 h) significantly delays papaya fruit ripening with normal ripening characteristics. However, long-term 1-MCP treatment (400 nL•L- 1, 16 h) causes a "rubbery" texture of fruit. The comparative transcriptome analysis showed that a total of 5529 genes were differently expressed during fruit ripening compared to freshly harvested fruits. Comprehensive functional enrichment analysis showed that the metabolic pathways of carbon metabolism, plant hormone signal transduction, biosynthesis of amino acids, and starch and sucrose metabolism are involved in fruit ripening. 1-MCP treatment significantly affected fruit transcript levels. A total of 3595 and 5998 differently expressed genes (DEGs) were identified between short-term 1-MCP, long-term 1-MCP treatment and the control, respectively. DEGs are mostly enriched in the similar pathway involved in fruit ripening. A large number of DEGs were also identified between long-term and short-term 1-MCP treatment, with most of the DEGs being enriched in carbon metabolism, starch and sucrose metabolism, plant hormone signal transduction, and biosynthesis of amino acids. The 1-MCP treatments accelerated the lignin accumulation and delayed cellulose degradation during fruit ripening. Considering the rubbery phenotype, we inferred that the cell wall metabolism and hormone signal pathways are closely related to papaya fruit ripening disorder. The RNA-Seq output was confirmed using RT-qPCR by 28 selected genes that were involved in cell wall metabolism and hormone signal pathways. CONCLUSIONS: These results showed that long-term 1-MCP treatment severely inhibited ethylene signaling and the cell wall metabolism pathways, which may result in the failure of cell wall degradation and fruit softening. Our results reveal multiple ripening-associated events during papaya fruit ripening and provide a foundation for understanding the molecular mechanisms underlying 1-MCP treatment on fruit ripening and the regulatory networks.


Assuntos
Carica/genética , Ciclopropanos/farmacologia , Etilenos/antagonistas & inibidores , Reguladores de Crescimento de Planta/antagonistas & inibidores , Proteínas de Plantas/metabolismo , Transcriptoma , Carica/crescimento & desenvolvimento , Frutas/genética , Frutas/crescimento & desenvolvimento , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética
16.
J Eur Acad Dermatol Venereol ; 33(11): 2101-2105, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31265155

RESUMO

BACKGROUND: Keratinocyte cancers (KC) are common and pose a significant financial burden globally. Ultraviolet radiation is a significant factor in their development, through mutagenesis promotion but also through local and systemic immunosuppression. Although systemic immunosuppression is well understood, cutaneous immunity has been more difficult to evaluate. OBJECTIVES: This study used a contact sensitizer, diphencyprone (DPCP), which elicits a contact hypersensitivity reaction in skin, to compare the degree of reactivity to DPCP in patients with a high KC burden versus those with a low KC burden. METHODS: A prospective study was performed in immunocompetent patients aged 70 ± 5 years of age, comparing patients with a high KC burden (>10 previous KC) with those with a low KC burden (<2 previous KC). All patients were sensitized with 2% DPCP and then patch tested two weeks later with eight different concentrations of DPCP with the threshold concentration and total degree of reaction recorded. RESULTS: Nine patients were recruited, 5 in the 'high cancer' group and 4 in the 'low cancer' group. All patients were Fitzpatrick skin type 1 or 2. All patients developed a reaction to DPCP. Patients in the low cancer group developed a reaction at a significantly lower threshold DPCP concentration than the high cancer group (P = 0.039). The cumulative intensity of reaction was higher in the low cancer group (P = 0.087). CONCLUSION: Patients with a high KC burden required a higher threshold concentration of DPCP to elicit a hypersensitivity reaction, supporting the concept of a lower skin immunity in these patients. DPCP reactivity threshold could be a useful tool in the evaluation of skin immunity and propensity to develop keratinocyte cancers.


Assuntos
Ciclopropanos/imunologia , Ciclopropanos/farmacologia , Dermatite de Contato/imunologia , Queratinócitos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Idoso , Dermatite de Contato/etiologia , Feminino , Humanos , Testes Imunológicos , Masculino , Estudos Prospectivos
17.
PLoS One ; 14(6): e0218656, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220169

RESUMO

Sugarcane ripening in Louisiana is necessary to ensure adequate sucrose levels in early-season harvested sugarcane. The response of nine sugarcane cultivar's yield components to glyphosate and trinexapac-ethyl ripeners was determined in field trials. Glyphosate (210 g ae ha-1) and trinexapac-ethyl (200 g ai ha-1) treatments failed to increase sucrose yields more than non-ripened sugarcane. Sugarcane ripened with glyphosate or trinexapac-ethyl increased theoretical recoverable sucrose (TRS) 4 to 12% more than non-ripened sugarcane in seven out of nine cultivars, but greater TRS values were counterpoised by lower sugarcane stalk weight. An unintentional consequence of reduced late-season vegetative growth may benefit growers by allowing them to harvest more sugarcane hectares to meet their daily load quota and exposes fewer hectares to a freeze event. The cultivars HoCP 00-950, Ho 09-804, and HoCP 09-840 were not responsive to glyphosate or trinexapac-ethyl ripeners and should not be treated. A delayed harvest from 28 to 49 days after treatment (DAT) coincided with greater TRS values and 17% more sucrose yield.


Assuntos
Ciclopropanos/farmacologia , Glicina/análogos & derivados , Quinonas/farmacologia , Saccharum/efeitos dos fármacos , Saccharum/crescimento & desenvolvimento , Saccharum/metabolismo , Sacarose/metabolismo , Agricultura , Produção Agrícola , Glicina/farmacologia , Louisiana , Estações do Ano , Fatores de Tempo
18.
J Pharmacol Exp Ther ; 370(2): 172-181, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31182471

RESUMO

The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca2+ signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1-/- ) mice. Treatment with SCO-267 activated Gq signaling in both high- and low-FFAR1-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1-/- mice, indicating a GPR40-dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.


Assuntos
Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Ciclopropanos/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Obesidade/complicações , Piperidinas/farmacologia , Propionatos/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Células CHO , Cricetulus , Ciclopropanos/uso terapêutico , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Cães , Ingestão de Alimentos/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Secreção de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Piperidinas/uso terapêutico , Propionatos/uso terapêutico , Ratos
19.
J Plant Physiol ; 238: 63-71, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31146183

RESUMO

This study aimed to investigate the firmness retention by ethylene treatment in olive fruit, as observed earlier. Ethylene concentrations up to 1000 µL L-1 were applied to dark green 'Konservolia' olives harvested shortly before the green maturation and exposed to 20 °C for up to 9 d. Surprisingly, the results indicated a tendency to fruit firmness increases in concentration-dependent manner in a non-climacteric fruit. The highest concentration increased the firmness within 12 h by approximately 1.35-fold, but transiently for approximately up to 5 d; all ethylene inhibitors tested, either of synthesis (ethoxyvinyl glycine or AVG), or perception (1 -methyl-cyclopropene or 1-MCP, and silver nitrate) prevented the firmness increase. Texture was evaluated by firmness and changes in lignin, cellulose (CL), total pectins (TPC), water soluble pectins (WSP) and total non-cellulosic sugars (total sugars) concentrations, and in pectin esterification degree (DE) in the alcohol insoluble residue (AIR) of 'Konservolia' fruit pericarp during 1.5-d, 5-d and 10-d treatments with 1000 µL L-1 ethylene at 20 °C. Pectins in AIR were also extracted sequentially with cyclohexane-trans-1,2-diaminetetra-acetate (CDTA), Na2CO3, 1 M and 4 M KOH. The results showed that on day 1.5, the increased firmness was consistent with increased CL (crystalline formation, as observed by microscopy), total sugars and DE levels, but reduced WSP, whereas softening reversed the changes and lowered TPC and CDTA-soluble pectins in all fruit on day 10. However, on day 5 ethylene-treated olives exhibited a transitional phase during softening, characterized by retention of high TPC concentration and energy demand, as indicated by elevated respiration rates. The inhibitor 1-MCP, applied before ethylene, did inhibit the responses to ethylene treatment. Ethylene firming effect and the respective cell wall changes in olives are demonstrated for first time. The experiments could be used for research on perception and transcription responses to ethylene in olive, a non-climacteric fruit. In practice, high ethylene concentrations could also be beneficial for firmness increase and/or short storage of dark green olives.


Assuntos
Parede Celular/metabolismo , Ciclopropanos/farmacologia , Etilenos/metabolismo , Frutas/metabolismo , Olea/metabolismo , Parede Celular/efeitos dos fármacos , Celulose/metabolismo , Produção Agrícola/métodos , Relação Dose-Resposta a Droga , Etilenos/antagonistas & inibidores , Etilenos/farmacologia , Qualidade dos Alimentos , Frutas/efeitos dos fármacos , Frutas/crescimento & desenvolvimento , Lignina/metabolismo , Olea/efeitos dos fármacos , Olea/crescimento & desenvolvimento , Pectinas/metabolismo
20.
Planta ; 250(1): 381-390, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31062160

RESUMO

MAIN CONCLUSION: Ethylene receptor is crucial for PCD and aerenchyma formation in Typha angustifolia leaves. Not only does it receive and deliver the ethylene signal, but it probably can determine the cell fate during aerenchyma morphogenesis, which is due to the receptor expression quantity. Aquatic plant oxygen delivery relies on aerenchyma, which is formed by a programmed cell death (PCD) procedure. However, cells in the outer edge of the aerenchyma (palisade cells and septum cells) remain intact, and the mechanism is unclear. Here, we offer a hypothesis: cells that have a higher content of ethylene receptors do not undergo PCD. In this study, we investigated the leaf aerenchyma of the aquatic plant Typha angustifolia. Ethephon and pyrazinamide (PZA, an inhibitor of ACC oxidase) were used to confirm that ethylene is an essential hormone for PCD of leaf aerenchyma cells in T. angustifolia. That the ethylene receptor was an indispensable factor in this PCD was confirmed by 1-MCP (an inhibitor of the ethylene receptor) treatment. Although PCD can be avoided by blocking the ethylene receptor, excessive ethylene receptors also protect cells from PCD. TaETR1, TaETR2 and TaEIN4 in the T. angustifolia leaf were detected by immunofluorescence (IF) using polyclonal antibodies. The result showed that the content of ethylene receptors in PCD-unsusceptible cells was 4-14 times higher than that one in PCD-susceptible cells, suggesting that PCD-susceptible cells undergo the PCD programme, while PCD-unsusceptible cells do not due to the content difference in the ethylene receptor in different cells. A higher level of ethylene receptor content makes the cells insensitive to ethylene, thereby avoiding cell death and degradation.


Assuntos
Reguladores de Crescimento de Planta/farmacologia , Proteínas de Plantas/metabolismo , Receptores de Superfície Celular/metabolismo , Typhaceae/fisiologia , Aminoácido Oxirredutases/antagonistas & inibidores , Apoptose/genética , Diferenciação Celular/genética , Ciclopropanos/farmacologia , Etilenos/metabolismo , Compostos Organofosforados/farmacologia , Reguladores de Crescimento de Planta/metabolismo , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/enzimologia , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/fisiologia , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/genética , Pirazinamida/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/genética , Typhaceae/efeitos dos fármacos , Typhaceae/enzimologia , Typhaceae/crescimento & desenvolvimento
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