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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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 Drogas , 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
7.
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
8.
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
9.
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
10.
Mol Pharmacol ; 96(1): 56-72, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31036559

RESUMO

The effects of phosphodiesterase (PDE) 4 inhibitors on gene expression changes in BEAS-2B human airway epithelial cells are reported and discussed in relation to the mechanism(s) of action of roflumilast in chronic obstructive pulmonary disease (COPD). Microarray-based gene expression profiling failed to identify mRNA transcripts that were differentially regulated by the PDE4 inhibitor 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) after 1, 2, 6, or 18 hours of exposure. However, real-time polymerase chain reaction analysis revealed that GSK 256066 was a weak stimulus, and the negative microarray results reflected low statistical power due to small sample sizes. Furthermore, GSK 256066, roflumilast, and its biologically active metabolite roflumilast N-oxide generally potentiated gene expression changes produced by the long-acting ß 2-adrenoceptor agonists (LABAs) salmeterol, indacaterol, and formoterol. Many of these genes encode proteins with antiviral, anti-inflammatory, and antibacterial activities that could contribute to the clinical efficacy of roflumilast in COPD. RNA-sequencing experiments established that the sensitivity of genes to salmeterol varied by ∼7.5-fold. Consequently, the degree to which a PDE4 inhibitor potentiated the effect of a given concentration of LABA was gene-dependent. Operational model fitting of concentration-response curve data from cells subjected to fractional, ß 2-adrenoceptor inactivation determined that PDE4 inhibition increased the potency and doubled the efficacy of LABAs. Thus, adding roflumilast to standard triple therapy, as COPD guidelines recommend, may have clinical relevance, especially in target tissues where LABAs behave as partial agonists. Collectively, these results suggest that the genomic impact of roflumilast, including its ability to augment LABA-induced gene expression changes, may contribute to its therapeutic activity in COPD.


Assuntos
Perfilação da Expressão Gênica/métodos , Indanos/farmacologia , Pulmão/citologia , Inibidores da Fosfodiesterase 4/farmacologia , Quinolonas/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Aminopiridinas/farmacologia , Aminoquinolinas/farmacologia , Benzamidas/farmacologia , Linhagem Celular , Ciclopropanos/farmacologia , Sinergismo Farmacológico , Células Epiteliais/química , Células Epiteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/química , Pulmão/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos , Xinafoato de Salmeterol/farmacologia , Sulfonas/farmacologia
11.
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
12.
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
13.
Expert Opin Pharmacother ; 20(9): 1065-1073, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30990759

RESUMO

INTRODUCTION: Non-24-h sleep-wake rhythm disorder (non-24) is observed in approximately half of totally blind individuals, a condition caused by their circadian pacemaker in the suprachiasmatic nucleus not being entrained to 24 h due to a lack of light perceptions. These subjects have a progressively delayed circadian cycle each day, non-24 periodically inducing nighttime insomnia and daytime sleepiness. Tasimelteon is a dual melatonin receptor agonist with high affinity for the melatonin 2 receptor, and it entrains endogenous melatonin rhythms and sleep-wake cycles in individuals with non-24. Areas covered: Herein, the authors review the treatment of non-24 with tasimelteon. The authors further compare tasimelteon with other melatonin receptor agonists. Expert opinion: The treatment strategies for non-24 aim to resynchronize the free-running rhythm with the 24 h light-dark cycle. Tasimelteon entrains circadian rhythms and improves the sleep-wake functions of individuals with non-24. Furthermore, the RESET study demonstrated that 20% of patients that discontinued tasimelteon maintained circadian entrainment whereas 90% of those who continued it maintained circadian entrainment. Long-term administration of tasimelteon is safe and well tolerated, and it is the only pharmacological therapy approved by the US Food and Drug Administration and the European Medicines Agency for non-24.


Assuntos
Benzofuranos/uso terapêutico , Ciclopropanos/uso terapêutico , Receptores de Melatonina/uso terapêutico , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Adolescente , Adulto , Benzofuranos/farmacologia , Ciclopropanos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Int J Mol Sci ; 20(5)2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30823420

RESUMO

The concept of "Sweet Immunity" postulates that sugar metabolism and signaling influence plant immune networks. In this study, we tested the potential of commercially available inulin-type fructans to limit disease symptoms caused by Botrytis cinerea in lettuce. Spraying mature lettuce leaves, with inulin-type fructans derived from burdock or chicory was as effective in reducing grey mold disease symptoms caused by Botrytis cinerea as spraying with oligogalacturonides (OGs). OGs are well-known defense elicitors in several plant species. Spraying with inulin and OGs induced accumulation of hydrogen peroxide and levels further increased upon pathogen infection. Inulin and OGs were no longer able to limit Botrytis infection when plants were treated with the ethylene signaling inhibitor 1-methylcyclopropene (1-MCP), indicating that a functional ethylene signaling pathway is needed for the enhanced defense response. Soluble sugars accumulated in leaves primed with OGs, while 1-MCP treatment had an overall negative effect on the sucrose pool. Accumulation of γ-aminobutyric acid (GABA), a stress-associated non-proteinogenic amino acid and possible signaling compound, was observed in inulin-treated samples after infection and negatively affected by the 1-MCP treatment. We have demonstrated for the first time that commercially available inulin-type fructans and OGs can improve the defensive capacity of lettuce, an economically important species. We discuss our results in the context of a possible recognition of fructans as Damage or Microbe Associated Molecular Patterns.


Assuntos
Botrytis/patogenicidade , Inulina/farmacologia , Alface/imunologia , Imunidade Vegetal , Ciclopropanos/farmacologia , Etilenos/metabolismo , Peróxido de Hidrogênio/metabolismo , Alface/efeitos dos fármacos , Alface/microbiologia , Ácido gama-Aminobutírico/metabolismo
15.
J Diabetes Res ; 2019: 1897174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911550

RESUMO

Aims: The purpose of the present research is to investigate the effects of the VHL protein antagonist, VH298, on functional activities of fibroblasts and vascular endothelial cells and the effects on the wound healing process in a streptozotocin-induced hyperglycaemic rat model. Methods: HIF-1α and hydroxy-HIF-1α protein levels in VH298-treated rat fibroblasts (rFb) were measured by immunoblotting, rFb proliferation was detected by the CCK-8 assay, and mRNA levels of related genes were measured by quantitative RT-PCR. In vitro wound healing was simulated by the scratch test; angiogenesis was measured by the human umbilical vein endothelial cell (hUVEC) tube formation assay. VH298 or PBS was locally injected into wounds in rat models with streptozotocin- (STZ-) induced hyperglycaemia, the wound tissues were harvested, and haematoxylin-eosin (HE) and Masson trichrome staining and immunohistochemical processes were conducted. Results: HIF-1α and hydroxy-HIF-1α levels increased in VH298-treated rFb, in a time- and dose-dependent manner. Thirty micromolar VH298 could significantly increase cell proliferation, angiogenesis, and gene expression of type I collagen-α1 (Col1-α1), vascular endothelial growth factor A (VEGF-A), and insulin-like growth factor 1 (IGF-1). The VH298-treated wound had a better healing pattern, activation of HIF-1 signalling, and vascularization. Conclusions: Taken together, VH298 activated the HIF-1 signalling pathway by stabilizing both HIF-1α and hydroxy-HIF-1α. VH298 enhanced rFb functions, promoted hUVEC angiogenesis, and accelerated wound healing in the rat model mimicking diabetes mellitus.


Assuntos
Ciclopropanos/farmacologia , Diabetes Mellitus Experimental/metabolismo , Inibidores Enzimáticos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pirrolidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , Ratos , Cicatrização/fisiologia
16.
PLoS Negl Trop Dis ; 13(3): e0007188, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30856177

RESUMO

This work describes the use of entomological studies combined with in silico models (computer simulations derived from numerical models) to assess the efficacy of a novel device for controlled release of spatial repellents. Controlled Release Devices (CRDs) were tested with different concentrations of metofluthrin and tested against An. quadrimaculatus mosquitoes using arm-in cage, semi-field, and outdoor studies. Arm-in-cage trials showed an approximate mean values for mosquito knockdown of 40% and mosquito bite reduction of 80% for the optimal metofluthrin formulation for a 15-minute trial. Semi-field outdoor studies showed a mean mortality of a 50% for 24 hour trial and 75% for a 48 hour trial for optimal concentrations. Outdoors studies showed an approximate mean mortality rate of 50% for a 24 hour trial for optimal concentrations. Numerical simulations based on Computational Fluid Dynamics (CFD) were performed in order to obtain spatial concentration profiles for 24 hour and 48 hour periods. Experimental results were correlated with simulation results in order to obtain a functional model that linked mosquito mortality with the estimated spatial concentration for a given period of time. Such correlation provides a powerful insight in predicting the effectiveness of the CRDs as a vector-control tool. While CRDs represent an alternative to current spatial repellent delivery methods, such as coils, candles, electric repellents, and passive emanators based on impregnated strips, the presented method can be applied to any spatial vector control treatment by correlating entomological endpoints, i.e. mortality, with in-silico simulations to predict overall efficacy. The presented work therefore presents a new methodology for improving design, development and deployment of vector-control tools to reduce transmission of vector-borne diseases, including malaria and dengue.


Assuntos
Anopheles/efeitos dos fármacos , Anopheles/crescimento & desenvolvimento , Inseticidas/administração & dosagem , Controle de Mosquitos/instrumentação , Controle de Mosquitos/métodos , Animais , Bioensaio , Simulação por Computador , Ciclopropanos/administração & dosagem , Ciclopropanos/farmacologia , Entomologia , Feminino , Fluorbenzenos/administração & dosagem , Fluorbenzenos/farmacologia , Inseticidas/farmacologia , Análise Espaço-Temporal , Análise de Sobrevida
17.
Life Sci ; 222: 245-254, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30858122

RESUMO

BACKGROUND: Phosphodiestrase (PDE) enzymes are suggested to play a leading role in fibrogenesis of liver where studies showed the possible implication of PDE 1 & 4 in liver injury proposing them as possible targets for treating liver fibrosis. AIM: The present study was designed to investigate, for the first time, the possible therapeutic effects of selective inhibitors of PDE-1 (vinpocetine) and PDE-4 (roflumilast) in liver fibrosis induced by diethylnitrosamine (DEN) in rats. MAIN METHODS: Rats were given DEN (100 mg/kg, i.p.) once weekly for 6 weeks to induce liver fibrosis. Vinpocetine (10 mg/kg/day) or roflumilast (0.5 mg/kg/day) was then orally administered for 2 weeks. KEY FINDINGS: Vinpocetine significantly suppressed the contents of hydroxyproline, transforming growth factor-beta 1 (TGF-ß1), nuclear factor-kappa B (NF-κB) whereas roflumilast normalized them. Moreover, tumor necrosis factor-alpha (TNF-α) content and protein expressions of toll-like receptor 4 (TLR4) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly decreased whereas cAMP response element binding (CREB) protein expression was significantly elevated by both treatments. Additionally, vinpocetine and roflumilast up-regulated the gene expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) receptor where roflumilast showed better results. PDE1 and 4 activities were inhibited by vinpocetine and roflumilast, respectively. The superior results offered by roflumilast could be related to the higher cAMP level obtained relative to vinpocetine. SIGNIFICANCE: Our study manifested the up-regulation of PDE enzymes (1 & 4) in liver fibrosis and addressed the therapeutic role of vinpocetine and roflumilast as PDEIs through a cAMP-mediated TLR4 inflammatory and fibrogenic signaling pathways.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Cirrose Hepática/metabolismo , Inibidores da Fosfodiesterase 4/uso terapêutico , Receptor 4 Toll-Like/metabolismo , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Masculino , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Alcaloides de Vinca/farmacologia , Alcaloides de Vinca/uso terapêutico
18.
Food Chem ; 283: 588-595, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30722915

RESUMO

Pitaya fruit is susceptible to fungal attack and shrivelling during storage. This study investigated the individual and combined effect of 1-methylcyclopropene (1-MCP) and carvacrol (CVR) on red pitaya. Fruits were treated with 1 µL L-1 1-MCP, 20 µL L-1 CVR or their combination (1-MCP + CVR), and then storage at 7 °C for 30 days. 1-MCP + CVR was more effective in suppressing decay and maintaining quality during storage than individual treatment of 1-MCP or CVR. In addition, 1-MCP + CVR treatment led to decreased levels of O2-, H2O2, and lipid peroxidation, concomitant with increased activities of superoxide dismutase, catalase, and ascorbate peroxidase, and elevated total phenolic content, as compared to the individual application. Moreover, transmission electron microscopy observation showed that the combined treatment protected cell ultrastructure from oxidative damage. This study suggests 1-MCP combined with CVR may be a useful method for the preservation of pitaya fruit.


Assuntos
Ciclopropanos/farmacologia , Conservação de Alimentos/métodos , Monoterpenos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Cactaceae/química , Cactaceae/metabolismo , Sinergismo Farmacológico , Frutas/química , Frutas/metabolismo , Peróxido de Hidrogênio/metabolismo , Malondialdeído/metabolismo , Oxirredutases/metabolismo , Fenóis/análise , Espectrofotometria , Regulação para Cima/efeitos dos fármacos
19.
Hum Exp Toxicol ; 38(5): 588-597, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30744402

RESUMO

OBJECTIVE: In the present study, the protective effect of Roflumilast (ROF, a selective phosphodiesterase (PDE-4) inhibitor) was investigated against cadmium (Cd)-induced nephrotoxicity in rats. METHODS: A total of 24 rats were selected and randomly divided into four groups ( n = 6). Group 1 served as the control; groups 2-4 administered with CdCl2 (3 mg/kg, i.p.) for 7 days; groups 3 and 4 were co-administered with ROF in doses of 0.5 and 1.5 mg/kg, orally for 7 consecutive days. Nephrotoxicity was evaluated by measuring urine volume, urea and creatinine levels in urine and serum. Oxidative stress was confirmed by measuring malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) levels in kidney tissue followed by histopathological studies. RESULTS: CdCl2 administration results in a significant ( p < 0.01) decrease in urine volume, urea, and creatinine levels in urine, as well as GSH, SOD, and CAT levels in renal tissue. In addition, Cd also produced significantly increased ( p < 0.01) urea and creatinine levels in serum and TBARS levels in renal tissues. Rats treated with ROF significantly ( p < 0.01) restore the altered levels of kidney injury markers, nonenzymatic antioxidant, as well as depleted enzymes in dose-dependent manner. An increased expression of NF-κB p65 and decreased expression of GST and NQO1 in the Cd only treated group were significantly reversed by high dose of ROF (1.5 mg/kg). Histopathological changes were also ameliorated by ROF administration in Cd-treated groups. CONCLUSION: In conclusion, ROF treatment showed protective effect against renal damage and increased oxidative stress induced by Cd administration.


Assuntos
Aminopiridinas/uso terapêutico , Benzamidas/uso terapêutico , Cloreto de Cádmio/toxicidade , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/uso terapêutico , Aminopiridinas/farmacologia , Animais , Benzamidas/farmacologia , Catalase/metabolismo , Creatinina/sangue , Creatinina/urina , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Glutationa/metabolismo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , NAD(P)H Desidrogenase (Quinona)/metabolismo , NF-kappa B/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Ratos Wistar , Superóxido Dismutase/metabolismo , Ureia/sangue , Ureia/urina
20.
Neurobiol Aging ; 77: 37-43, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30776650

RESUMO

There is ample evidence that phosphodiesterase 4 (PDE4) inhibition can improve memory performance in animal studies. In the present study, we examined the acute effects of the PDE4 inhibitor roflumilast on memory performance in healthy individuals (60-80 years of age). We tested the effects of acute roflumilast administration (100, 250, 1000 µg) in a double-blind, placebo-controlled, 4-way crossover design. Participants were first screened for their verbal word memory performance to ensure normal memory performance (within 0.5 standard deviation from norm score; n = 20) Drug effects on memory performance were tested in a verbal memory test and a spatial memory test. Reported side effects of drug treatment were registered. Roflumilast (100 µg) improved the delayed recall performance of the participants (Cohen's d, 0.69). No effects were observed in the spatial memory task. Roflumilast was well tolerated at this low dose. Although no clear adverse side effects were reported at the low dose, mild adverse events (including headache, dizziness, insomnia, and diarrhea) were reported after the 1000 µg dose. The present study provides first evidence that the PDE4 inhibitor roflumilast improves verbal memory performance in old participants. The current data encourage further development of PDE4 inhibitors for improving memory.


Assuntos
Aminopiridinas/administração & dosagem , Aminopiridinas/farmacologia , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Envelhecimento Saudável/psicologia , Memória/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/administração & dosagem , Inibidores da Fosfodiesterase 4/farmacologia , Comportamento Verbal/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/efeitos adversos , Benzamidas/efeitos adversos , Cognição/efeitos dos fármacos , Estudos Cross-Over , AMP Cíclico/fisiologia , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Ciclopropanos/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Rememoração Mental/efeitos dos fármacos , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 4/efeitos adversos , Estimulação Química
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