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1.
J Pharmacol Exp Ther ; 376(1): 1-11, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33087396

RESUMO

The endocannabinoid, anandamide (AEA), stimulates cannabinoid receptors (CBRs) and is enriched in the kidney, especially the renal medulla. AEA infused into the renal outer medulla of mice stimulates urine flow rate and salt excretion. Here we show that these effects are blocked by the CBR type 1 (CB1) inverse agonist, rimonabant. Immunohistochemical analysis demonstrated the presence of CB1 in thick ascending limb (TAL) tubules. Western immunoblotting demonstrated the presence of CB1 (52 kDa) in the cortex and outer medulla of mouse kidney. The effect of direct [CP55940 (CP) or AEA] or indirect [fatty acyl amide hydrolase (FAAH) inhibitor, PF3845 (PF)] cannabinoidimetics on Na+ transport in isolated mouse TAL tubules was studied using the Na+-sensitive dye, SBFI-AM. Switching from 0 Na+ solution to control Ringer's solution (CR) rapidly increased TAL cell [Na+]i Addition of CP to CR produced a further elevation, similar in magnitude to that of ouabain, a Na+-K+-ATPase inhibitor. This [Na+]i-elevating effect of CP was time-dependent, required the presence of Na+ in the bathing solution, and was insensitive to Na+-K+-2Cl- cotransporter inhibition. Addition of PF to CR elevated [Na+]i in FAAH wild-type but not FAAH knockout (KO) TALs, whereas the additions of CP and AEA to PF-treated FAAH KO TALs increased [Na+]i An interaction between cannabinoidimetics and ouabain (Ou) was observed. Ou produced less increase in [Na+]i after cannabinoidimetic treatment, whereas cannabinoidimetics had less effect after Ou treatment. It is concluded that cannabinoidimetics, including CP and AEA, inhibit Na+ transport in TALs by inhibiting Na+ exit via Na+-K+-ATPase. SIGNIFICANCE STATEMENT: Cannabinoids including endocannabinoids induce renal urine and salt excretion and are proposed to play a physiological role in the regulation of blood pressure. Our data suggest that the mechanism of the cannabinoids involves inhibition of the sodium pump, Na+-K+-ATPase, in thick ascending limb cells and, likely, other proximal and distal tubular segments of the kidney nephron.


Assuntos
Antagonistas de Receptores de Canabinoides/farmacologia , Cicloexanóis/farmacologia , Diurese , Alça do Néfron/metabolismo , Natriurese , Rimonabanto/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/genética , Animais , Ácidos Araquidônicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Endocanabinoides/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ouabaína/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Piridinas/farmacologia , Sódio/metabolismo , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores
2.
Leuk Res ; 95: 106389, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32540572

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is a highly heterogeneous malignant hematological disorder arising from T-cell progenitors. This study was aimed to evaluate the cytotoxic effect of CP55940 on human peripheral blood lymphocytes (PBL) and on T-ALL cells (Jurkat). PBL and Jurkat cells were treated with CP55940 (0-20 µM), and morphological changes in the cell nucleus/ DNA, mitochondrial membrane potential (ΔΨm), and intracellular reactive oxygen species levels were determined by fluorescence microscopy and flow cytometry. Cellular apoptosis markers were also evaluated by western blotting, pharmacological inhibition and immunofluorescence. CP55940 induced apoptotic cell death in Jurkat cells, but not in PBL, in a dose-response manner with increasing fragmentation of DNA, arrest of cell cycle and damage of ΔΨm. CP55940 increased dichlorofluorescein fluorescence (DCF) intensity, increased DJ-1 Cys106- sulfonate, a marker of intracellular stress, induced the up-regulation of p53 and phosphorylation of transcription factor c-JUN. It increased the expression of BAX and PUMA, up-regulated mitochondrial proteins PINK1 and Parkin, and activated CASPASE-3. Antioxidant NAC, pifithrin-α, and SP600125 blocked CP55940 deleterious effect on Jurkat cells. However, the potent and highly specific cannabinoid CB1 and CB2 receptor inverse agonist SR141716 and SR144528 were unable to blunt CP55940-induced apoptosis in Jurkat cells. Conclusively CP55940 provokes cell death in Jurkat through CBR-independent mechanism. Interestingly, CP55940 was also cytotoxic to ex vivo T-ALL cells from chemotherapy-resistant pediatric patients. In conclusion, CP55940 selectively induces apoptosis in Jurkat cells through a H2O2-mediated signaling pathway. Our findings support the use of cannabinoids as a potential treatment for T-ALL cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cicloexanóis/farmacologia , Peróxido de Hidrogênio/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Humanos , Células Jurkat , Estresse Oxidativo/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
3.
Behav Pharmacol ; 31(2&3): 233-248, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32101988

RESUMO

The opioid epidemic underscores the need for safer and more effective treatments for pain. Combining opioid receptor agonists with drugs that relieve pain through nonopioid mechanisms could be a useful strategy for reducing the dose of opioid needed to treat pain, thereby reducing risks associated with opioids alone. Opioid/cannabinoid mixtures might be useful in this context; individually, opioids and cannabinoids have modest effects on cognition, and it is important to determine whether those effects occur with mixtures. Delay discounting and delayed matching-to-sample tasks were used to examine effects of the mu-opioid receptor agonist morphine (0.32-5.6 mg/kg), the cannabinoid CB1/CB2 receptor agonist CP55940 (0.0032-0.1 mg/kg), and morphine/CP55940 mixtures on impulsivity (n = 3) and memory (n = 4) in rhesus monkeys. Alone, each drug decreased rate of responding without modifying choice in the delay-discounting task, and morphine/CP55940 mixtures reduced choice of one pellet in a delay dependent manner, with monkeys instead choosing delayed delivery of the larger number of pellets. With the exception of one dose in one monkey, accuracy in the delayed matching-to-sample task was not altered by either drug alone. Morphine/CP55940 mixtures decreased accuracy in two monkeys, but the doses in the mixture were equal to or greater than doses that decreased accuracy or response rate with either drug alone. Rate-decreasing effects of morphine/CP55940 mixtures were additive. These data support the notion that opioid/cannabinoid mixtures that might be effective for treating pain do not have greater, and might have less, adverse effects compared with larger doses of each drug alone.


Assuntos
Analgésicos Opioides/farmacologia , Canabinoides/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Memória/efeitos dos fármacos , Analgésicos Opioides/metabolismo , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Canabinoides/metabolismo , Cognição/efeitos dos fármacos , Cicloexanóis/farmacologia , Desvalorização pelo Atraso/efeitos dos fármacos , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Feminino , Macaca mulatta , Masculino , Morfina/farmacologia , Receptores Opioides mu/agonistas
4.
Sci Rep ; 10(1): 656, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959858

RESUMO

Giant clams have evolved to maximize sunlight utilization by their photosymbiotic partners, while affording them protection from harmful ultraviolet (UV) light. The presence of UV absorbing substances in the mantle is thought to be critical for light protection; however, the exact localization of such compounds remains unknown. Here, we applied a combination of UV liquid chromatography (LC), LC-mass spectrometry (MS), MS imaging, and UV micrography to localize UV absorbing substances in the giant clam Tridacna crocea. LC-MS analysis revealed that the animal contained three classes of mycosporines: progenitor, primary, and secondary mycosporines. MS imaging revealed that primary and secondary mycosporines were localized in the outermost layer of the mantle; whereas progenitor mycosporines were distributed throughout the mantle tissue. These findings were consistent with the results of UV micrography, which revealed that the surface layer of the mantle absorbed UV light at 320 ± 10 nm. This is the first report indicating that progenitor and primary mycosporines are metabolized to secondary mycosporines by the giant clam and that they are differentially localized in the surface layer of the mantle to protect the animal from UV light.


Assuntos
Bivalves/metabolismo , Cromatografia Líquida/métodos , Cicloexanóis/metabolismo , Espectrometria de Massas/métodos , Protetores Solares/metabolismo , Animais , Protetores Solares/análise , Raios Ultravioleta
5.
J Pharmacol Exp Ther ; 373(1): 44-50, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31941717

RESUMO

Marijuana and other cannabinoid compounds are widely used by cocaine users. Preclinical animal studies suggest that these compounds can increase the reinforcing effects of cocaine under some schedules of cocaine self-administration and reinstatement, but not in all cases. To date, no studies have used a food-cocaine concurrent choice procedure, which allows for assessment of drug effects on response allocation, not just changes in cocaine self-administration. The goal of the present study was to examine the effects of compounds differing in their efficacy at the cannabinoid receptor (CBR) on cocaine self-administration using a food-drug choice procedure in monkeys. Four adult male rhesus monkeys were trained to self-administer cocaine in the context of an alternative food (1.0-g banana-flavored pellets) reinforcer, such that complete cocaine dose-response curves (0, 0.003-0.1 mg/kg per injection) were determined each session. Monkeys were tested acutely with the CBR full agonist CP 55,940 (0.001-0.01 mg/kg); the CBR partial agonist Δ9-tetrahydrocannabinol (THC; 0.03-0.3 mg/kg), which is also the primary active ingredient in marijuana and the CBR antagonist rimonabant (0.3-3.0 mg/kg). Cocaine choice increased in a dose-dependent manner. Acute treatment with CP 55,940 decreased cocaine choice, whereas THC and rimonabant enhanced the reinforcing effects of cocaine. Chronic (7-day) treatment with CP 55,940 resulted in tolerance to the decreases in cocaine choice. These findings with Δ9-THC provide support for a potential mechanism for co-abuse of marijuana and cocaine. Additional research with chronic treatment with full CBR agonists on attenuating the reinforcing strength of cocaine is warranted. SIGNIFICANCE STATEMENT: Co-abuse of tetrahydrocannabinol and cocaine is a significant public health problem. The use of animal models allows for the determination of how cannabinoid receptor stimulation or blockade influences the reinforcing strength of cocaine.


Assuntos
Canabinoides/administração & dosagem , Comportamento de Escolha/efeitos dos fármacos , Cocaína/administração & dosagem , Cicloexanóis/administração & dosagem , Preferências Alimentares/efeitos dos fármacos , Preferências Alimentares/psicologia , Animais , Comportamento de Escolha/fisiologia , Inibidores da Captação de Dopamina/administração & dosagem , Preferências Alimentares/fisiologia , Macaca mulatta , Masculino , Autoadministração
6.
J Pharm Pharmacol ; 72(1): 84-91, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31722122

RESUMO

OBJECTIVES: To determine if diminished orthosteric agonist binding due to mutations in extracellular loops 1 or 2 of the cannabinoid receptor 1 (CB1 ) can be overcome by an allosteric modulator and restore agonist binding. METHODS: Binding assays were performed using a range of concentrations of orthosteric compound, in the presence or absence of a set concentration of the allosteric modulator PSNCBAM-1 to determine the EC50 in its absence or presence. KEY FINDINGS: Single mutations in extracellular loop 1 or 2 of CB1 showed weak or no binding of agonist CP55940 to the receptor. Interestingly, upon addition of the allosteric modulator PSNCBAM-1, this binding was restored typically to wild-type CB1 levels. In a few cases, the allosteric modulator ORG27569 was compared with PSNCBAM-1 for CP55940 binding and it also restored binding. Further, wild-type levels of inverse agonist bound the CB1 mutants in the absence of modulator, suggesting the mutants were originally folded like the wild type. CONCLUSIONS: Based on our findings, we provide evidence of a therapeutic application for allosteric modulators in situations where a mutation in the receptor may hinder its function. By utilizing allosteric modulators, restoration of orthosteric binding may be possible.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Cicloexanóis/farmacologia , Indóis/farmacologia , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Rimonabanto/farmacologia , Sítios de Ligação , Agonistas de Receptores de Canabinoides/metabolismo , Cicloexanóis/metabolismo , Células HEK293 , Humanos , Indóis/metabolismo , Ligantes , Mutação , Compostos de Fenilureia/metabolismo , Piperidinas/metabolismo , Ligação Proteica , Conformação Proteica , Piridinas/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto/metabolismo , Relação Estrutura-Atividade
7.
Molecules ; 24(24)2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31817626

RESUMO

The unpleasant stale note is a negative factor hindering the consumption of instant ripened Pu-erh tea products. This study focused on investigating volatile chemicals in instant ripened Pu-erh tea that could mask the stale note via sensory evaluation, gas chromatography-mass spectrometry (GC-MS), and gas chromatography-olfactometry (GC-O) analyses. GC-MS and GC-O analyses showed that linalool, linalool oxides, trans-ß-ionone, benzeneacetaldehyde, and methoxybenzenes were the major aroma contributors to the simultaneous distillation and extraction (SDE) extract of instant ripened Pu-erh tea. Sensory evaluation showed that the SDE extract had a strong stale note, which was due to methoxybenzenes. By investigating suppressive interaction among flavour components, the stale note from methoxybenzenes was shown to have reciprocal masking interactions with sweet, floral, and green notes. Moreover, the validation experiment showed that the addition of 40 µg/mL of trans-ß-ionone in the instant ripened Pu-erh tea completely masked the stale note and improved the overall aromatic acceptance. These results elucidate the volatile chemicals that could mask the stale note of instant ripened Pu-erh tea products, which might help to develop high quality products made from instant ripened Pu-erh tea.


Assuntos
Extratos Vegetais/química , Chá/química , Monoterpenos Acíclicos/química , Anisóis/química , Cicloexanóis/química , Cromatografia Gasosa-Espectrometria de Massas , Compostos de Tritil/química
8.
Sci Prog ; 102(4): 287-303, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31818205

RESUMO

Mycosporine-like amino acids have long been known as a natural form of photoprotection for fungi and cyanobacteria. This review will highlight the key time-resolved experimental and theoretical techniques unravelling their photochemistry and photophysics, and directly link this to their use in commercial skin-care products, namely as sunscreen filters. Three case studies have been selected, each having aided advancement in this burgeoning field of research. We discuss these studies in the context of photoprotection and conclude by evaluating the necessary future steps towards translating the photochemistry and photophysics insight of these nature derived sunscreen filters to commercial application.


Assuntos
Cianobactérias/metabolismo , Cicloexanóis/metabolismo , Fungos/metabolismo , Luz , Cianobactérias/química , Cicloexanóis/química , Fungos/química , Protetores Solares/química , Protetores Solares/metabolismo , Protetores Solares/farmacologia
10.
ACS Synth Biol ; 8(11): 2464-2471, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31689088

RESUMO

Sunscreen-containing skincare products protect the skin from damage caused by sun exposure. However, many of them contain oxybenzone and/or octinoxate, which have been reported to be toxic to juvenile coral and to cause coral bleaching. Thus, there is a growing need for new sunscreen compounds that are less harmful to the environment. Here, we report an engineered biosynthetic pathway employing genes from a vertebrate and two Gram-(+) bacteria that forms novel sunscreen compounds with hybrid structures of gadusol and mycosporine-like amino acids, both of which are found in marine environments. These compounds, named gadusporines, have unique UV absorbance at 340 nm, expanding the range of mycosporine- and gadusol-based sunscreen products. The synthesis of gadusporines in Streptomyces coelicolor establishes a platform for the design and production of novel sunscreens.


Assuntos
Engenharia Metabólica/métodos , Rhodococcus/genética , Streptomyces coelicolor/metabolismo , Streptomyces/genética , Protetores Solares/síntese química , Peixe-Zebra/genética , Aminoácidos/química , Animais , Antozoários/efeitos dos fármacos , Benzofenonas/efeitos adversos , Benzofenonas/farmacologia , Cinamatos/efeitos adversos , Cinamatos/farmacologia , Cicloexanóis/química , Plasmídeos/genética , Creme para a Pele/química , Raios Ultravioleta
11.
Sci Rep ; 9(1): 16940, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729460

RESUMO

Bacterial periplasmic-binding proteins have been acclaimed as general biosensing platform, but their range of natural ligands is too limited for optimal development of chemical compound detection. Computational redesign of the ligand-binding pocket of periplasmic-binding proteins may yield variants with new properties, but, despite earlier claims, genuine changes of specificity to non-natural ligands have so far not been achieved. In order to better understand the reasons of such limited success, we revisited here the Escherichia coli RbsB ribose-binding protein, aiming to achieve perceptible transition from ribose to structurally related chemical ligands 1,3-cyclohexanediol and cyclohexanol. Combinations of mutations were computationally predicted for nine residues in the RbsB binding pocket, then synthesized and tested in an E. coli reporter chassis. Two million variants were screened in a microcolony-in-bead fluorescence-assisted sorting procedure, which yielded six mutants no longer responsive to ribose but with 1.2-1.5 times induction in presence of 1 mM 1,3-cyclohexanediol, one of which responded to cyclohexanol as well. Isothermal microcalorimetry confirmed 1,3-cyclohexanediol binding, although only two mutant proteins were sufficiently stable upon purification. Circular dichroism spectroscopy indicated discernable structural differences between these two mutant proteins and wild-type RbsB. This and further quantification of periplasmic-space abundance suggested most mutants to be prone to misfolding and/or with defects in translocation compared to wild-type. Our results thus affirm that computational design and library screening can yield RbsB mutants with recognition of non-natural but structurally similar ligands. The inherent arisal of protein instability or misfolding concomitant with designed altered ligand-binding pockets should be overcome by new experimental strategies or by improved future protein design algorithms.


Assuntos
Sítios de Ligação , Cicloexanóis/química , Desenho de Fármacos , Proteínas de Escherichia coli/química , Escherichia coli/metabolismo , Modelos Moleculares , Proteínas Periplásmicas de Ligação/química , Aminoácidos , Avaliação Pré-Clínica de Medicamentos , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/genética , Biblioteca Gênica , Ligantes , Mutação , Proteínas Periplásmicas de Ligação/antagonistas & inibidores , Proteínas Periplásmicas de Ligação/genética , Relação Estrutura-Atividade
12.
Pharmacol Res Perspect ; 7(6): e00542, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768260

RESUMO

The G-protein-coupled receptor GPR132, also known as G2A, is activated by 9-hydroxyoctadecadienoic acid (9-HODE) and other oxidized fatty acids. Other suggested GPR132 agonists including lysophosphatidylcholine (LPC) have not been readily reproduced. Here, we identify N-acylamides in particular N-acylglycines, as lipid activators of GPR132 with comparable activity to 9-HODE. The order-of-potency is N-palmitoylglycine > 9-HODE ≈ N-linoleoylglycine > linoleamide > N-oleoylglycine ≈ N-stereoylglycine > N-arachidonoylglycine > N-docosehexanoylglycine. Physiological concentrations of N-acylglycines in tissue are sufficient to activate GPR132. N-linoleoylglycine and 9-HODE also activate rat and mouse GPR132, despite limited sequence conservation to human. We describe pharmacological tools for GPR132, identified through drug screening. SKF-95667 is a novel GPR132 agonist. SB-583831 and SB-583355 are peptidomimetic molecules containing core amino acids (glycine and phenylalanine, respectively), and structurally related to previously described ligands. A telmisartan analog, GSK1820795A, antagonizes the actions of N-acylamides at GPR132. The synthetic cannabinoid CP-55 940 also activates GPR132. Molecular docking to a homology model suggested a site for lipid binding, predicting the acyl side-chain to extend into the membrane bilayer between TM4 and TM5 of GPR132. Small-molecule ligands are envisaged to occupy a "classical" site encapsulated in the 7TM bundle. Structure-directed mutagenesis indicates a critical role for arginine at position 203 in transmembrane domain 5 to mediate GPR132 activation by N-acylamides. Our data suggest distinct modes of binding for small-molecule and lipid agonists to the GPR132 receptor. Antagonists, such as those described here, will be vital to understand the physiological role of this long-studied target.


Assuntos
Proteínas de Ciclo Celular/agonistas , Glicina/análogos & derivados , Ácidos Palmíticos/farmacologia , Peptidomiméticos/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Células CHO , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Cricetulus , Cicloexanóis/farmacologia , Antagonismo de Drogas , Ácidos Graxos Insaturados/farmacologia , Glicina/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Homologia Estrutural de Proteína , Telmisartan/análogos & derivados , Telmisartan/farmacologia
13.
J Photochem Photobiol B ; 201: 111684, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31733505

RESUMO

Since the beginning of life on Earth, cyanobacteria have been exposed to natural ultraviolet-A radiation (UV-A, 315-400 nm) and ultraviolet-B radiation (UV-B, 280-315 nm), affecting their cells' biomolecules. These photoautotrophic organisms have needed to evolve to survive and thus, have developed different mechanisms against ultraviolet radiation. These mechanisms include UVR avoidance, DNA repair, and cell protection by producing photoprotective compounds like Scytonemin, carotenoids, and Mycosporine-like amino acids (MAAs). Lyngbya marine species are commercially important due to their secondary metabolites that show a range of biological activities including antibacterial, insecticidal, anticancer, antifungal, and enzyme inhibitor. The main topic in this review covers the Lyngbya sp., a cyanobacteria genus that presents photoprotection provided by the UV-absorbing/screening compounds such as MAAs and Scytonemin. These compounds have considerable potentialities to be used in the cosmeceutical, pharmaceutical, biotechnological and biomedical sectors and other related manufacturing industries with an additional value of environment friendly in nature. Scytonemin has UV protectant, anti-inflammatory, anti-proliferative, and antioxidant activity. MAAs act as sunscreens, provide additional protection as antioxidants, can be used as UV protectors, activators of cell proliferation, skin-care products, and even as photo-stabilizing additives in paints, plastics, and varnishes. The five MAAs identified so far in Lyngbya sp. are Asterina-330, M-312, Palythine, Porphyra-334, and Shinorine are capable of dissipating absorbed radiation as harmless heat without producing reactive oxygen species.


Assuntos
Aminoácidos/química , Cianobactérias/metabolismo , Cicloexanóis/química , Indóis/química , Fenóis/química , Protetores Solares/química , Raios Ultravioleta , Aminoácidos/isolamento & purificação , Antioxidantes/química , Cicloexanóis/isolamento & purificação , Indóis/isolamento & purificação , Fenóis/isolamento & purificação , Protetores Solares/metabolismo
14.
Eur J Pharmacol ; 865: 172806, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31738934

RESUMO

Δ9-THC suppresses cisplatin-induced vomiting through activation of cannabinoid CB1 receptors. Cisplatin-evoked emesis is predominantly due to release of serotonin and substance P (SP) in the gut and the brainstem which subsequently stimulate their corresponding 5-HT3-and neurokinin NK1-receptors to induce vomiting. Δ9-THC can inhibit vomiting caused either by the serotonin precursor 5-HTP, or the 5-HT3 receptor selective agonist, 2-methyserotonin. In the current study, we explored whether Δ9-THC and related CB1/CB2 receptor agonists (WIN55,212-2 and CP55,940) inhibit vomiting evoked by SP (50 mg/kg, i.p.) or the NK1 receptor selective agonist GR73632 (5 mg/kg, i.p.). Behavioral methods were employed to determine the antiemetic efficacy of cannabinoids in least shrews. Our results showed that administration of varying doses of Δ9-THC (i.p. or s.c.), WIN55,212-2 (i.p.), or CP55,940 (i.p.) caused significant suppression of SP-evoked vomiting in a dose-dependent manner. When tested against GR73632, Δ9-THC also dose-dependently reduced the evoked emesis. The antiemetic effect of Δ9-THC against SP-induced vomiting was prevented by low non-emetic doses of the CB1 receptor inverse-agonist/antagonist SR141716A (<10 mg/kg). We also found that the NK1 receptor antagonist netupitant can significantly suppress vomiting caused by a large emetic dose of SR141716A (20 mg/kg). In sum, Δ9-THC and related cannabinoids suppress vomiting evoked by the nonselective (SP) and selective (GR73632) neurokinin NK1 receptor agonists via stimulation of cannabinoid CB1 receptors.


Assuntos
Benzoxazinas/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Canabinoides/uso terapêutico , Cicloexanóis/uso terapêutico , Dronabinol/uso terapêutico , Morfolinas/uso terapêutico , Naftalenos/uso terapêutico , Receptores da Neurocinina-1/fisiologia , Vômito/tratamento farmacológico , Animais , Feminino , Masculino , Fragmentos de Peptídeos/farmacologia , Musaranhos , Substância P/análogos & derivados , Substância P/farmacologia , Vômito/induzido quimicamente
15.
Nat Chem Biol ; 15(12): 1199-1205, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31659318

RESUMO

The CB1 receptor mediates the central nervous system response to cannabinoids, and is a drug target for pain, anxiety and seizures. CB1 also responds to allosteric modulators, which influence cannabinoid binding and efficacy. To understand the mechanism of these compounds, we solved the crystal structure of CB1 with the negative allosteric modulator (NAM) ORG27569 and the agonist CP55940. The structure reveals that the NAM binds to an extrahelical site within the inner leaflet of the membrane, which overlaps with a conserved site of cholesterol interaction in many G protein-coupled receptors (GPCRs). The ternary structure with ORG27569 and CP55940 captures an intermediate state of the receptor, in which aromatic residues at the base of the agonist-binding pocket adopt an inactive conformation despite the large contraction of the orthosteric pocket. The structure illustrates a potential strategy for drug modulation of CB1 and other class A GPCRs.


Assuntos
Receptor CB1 de Canabinoide/metabolismo , Regulação Alostérica , Cristalização , Cicloexanóis/farmacologia , Humanos , Ligação Proteica , Receptor CB1 de Canabinoide/agonistas
16.
Drug Des Devel Ther ; 13: 3343-3355, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571835

RESUMO

Objective: To investigate the effects of Chinese herb Danzhi Xiaoyao pills on the pharmacokinetics of venlafaxine and its metabolites O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) in beagles by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Methods: Six beagles (half male, half female) were chosen to test, being fasted before the experiment but having free access to drinking water 1 day before being fed drugs. After oral administration of venlafaxine hydrochloride tablets (10.28 mg/kg), the blood samples were collected in succession at different points in time. After 1-week washout period, Danzhi Xiaoyao pills (0.6g/kg) were given through oral administration to the six beagles every morning until the 7th day, venlafaxine hydrochloride tablets (10.28 mg/kg) were given after feeding Danzhi Xiaoyao pills (0.6g/kg) half an hour and blood samples were collected continuously at different points. All samples were analyzed by UPLC-MS/MS, and the main pharmacokinetic parameters of venlafaxine, ODV and NDV were computed by DAS 2.0. Results: The Cmax of the venlafaxine group (control group) and the combination group (experimental group) were (2267.26±252.89) ng/mL and (1542.64±190.73) ng/mL, respectively. The AUC(0-∞) of the two groups were (13,934.79±3609.23) ng·h/mL and (8001.91±2167.58) ng·h/mL, respectively. The ODV Cmax of the two groups were (2253.80±215.81) ng/mL and (2721.37±118.20) ng/mL, and AUC(0-∞) were (13,974.99±2784.04) ng·h/mL and (17,539.44±1894.29) ng·h/mL, respectively. The NDV Cmax of the two groups were (50.98±5.76) ng/mL and (58.74±12.33) ng/mL, and AUC(0-∞) were (179.26±34.94) ng·h/mL and (220.68±51.41) ng·h/mL, respectively. After administration of Danzhi Xiaoyao pills, the Cmax and AUC(0-∞) of venlafaxine decreased significantly, indicating that the plasma exposure of venlafaxine decreased. The increase of Cmax and AUC(0-∞) of ODV and NDV indicated a rise in plasma exposure. Conclusion: Danzhi Xiaoyao pills can accelerate the metabolism of venlafaxine in beagles. In clinical, when venlafaxine was co-administrated with Danzhi Xiaoyao pills, dose adjustment of venlafaxine should be taken into account.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Cloridrato de Venlafaxina/farmacocinética , Animais , Área Sob a Curva , Cromatografia Líquida , Cicloexanóis/sangue , Cicloexanóis/farmacocinética , Succinato de Desvenlafaxina/sangue , Cães , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Masculino , Comprimidos , Espectrometria de Massas em Tandem
17.
Acta Trop ; 200: 105163, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31494122

RESUMO

Linalool oxide (LO) and hexanoic acid (HA) represent plant- and human-derived odorants, respectively, previously found as attractants for the dengue vector Aedes aegypti. Here, we investigated if a blend of both compounds can improve captures of this mosquito species in field trials in two dengue endemic sites, Kilifi and Busia Counties in Kenya. Ae. aegypti captures were significantly higher in Kilifi than Busia (χ21,142 = 170.63, P < 0.0001) and varied by treatments (χ25,137 = 151.19, P = 0.002). We found that CO2-baited BG Sentinel traps combined with a blend of both odorants decreased Ae. aegypti captures about 2- to 4-fold compared to captures with the individual compounds (LO or HA) used as positive controls. This was the case for all blends of LO and HA, irrespective of the doses tested. Our findings indicate that combining plant- and human-derived odors may elicit a masking effect in trapping Ae. aegypti. These results partly corroborate previous findings for malaria mosquitoes which showed that combining lures from both host sources either decreases or increases trap catches depending on the dose. Further investigations in the usefulness of combining plant and animal odorants in mosquito trapping are therefore necessary.


Assuntos
Monoterpenos Acíclicos/farmacologia , Aedes/efeitos dos fármacos , Caproatos/farmacologia , Cicloexanóis/farmacologia , Dengue/transmissão , Controle de Mosquitos/métodos , Mosquitos Vetores/efeitos dos fármacos , Odorantes , Plantas/química , Compostos de Tritil/farmacologia , Animais , Vetores de Doenças , Feminino , Humanos , Quênia
18.
Nutrients ; 11(8)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394768

RESUMO

To investigate the effect of a hot water extract of C. longa L. (WEC) containing anti-inflammatory agents, bisacurone, and turmeronol on chronic inflammation, a randomized double-blind placebo-controlled study was conducted in middle-aged and elderly subjects aged 50-69 years with overweight or prehypertension/mild hypertension. The subjects consumed 900 mg WEC tablets, containing 400 µg bisacurone, 80 µg turmeronol A and 20 µg turmeronol B (WEC group: n = 45), or placebo tablets without WEC (placebo group: n = 45) daily for 12 weeks. Serum inflammatory and metabolic markers were measured. The subjects also completed the MOS 36-item short-form health survey (SF-36) and the Profile of Mood States scale (POMS). In the WEC group, the serum levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and soluble vascular cell adhesion molecule-1 decreased significantly. Compared with the placebo group, the WEC group had significantly lower serum levels of glucose, hemoglobin A1c, and triglycerides, as well as higher serum levels of high-density lipoprotein cholesterol. The WEC group also showed significant improvement of SF-36 scores (for general health, vitality, mental health, and mental summary component) and POMS scores for positive mood states (vigor-activity and friendliness). In conclusion, WEC may ameliorate chronic low-grade inflammation, thus contributing to the improvement of associated metabolic disorders and general health.


Assuntos
Biomarcadores/sangue , Curcuma/química , Hipertensão/sangue , Inflamação/sangue , Sobrepeso/sangue , Extratos Vegetais/farmacologia , Idoso , Cicloexanóis/administração & dosagem , Método Duplo-Cego , Humanos , Saúde Mental , Pessoa de Meia-Idade , Placebos , Pré-Hipertensão/sangue , Sesquiterpenos/administração & dosagem , Água
19.
J Agric Food Chem ; 67(34): 9468-9476, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31379158

RESUMO

The aroma quality of citrus fruit is determined by volatiles that are present at extremely low levels in the citrus fruit juice sacs; it can be greatly improved by increasing volatiles. In this study, we showed that the contents of cis- and trans-linalool oxides were significantly increased in the juice sacs of three pummelos artificially pollinated with the Citrus mangshanensis (MS) pollen. A novel cytochrome P450 78A7 gene (CitLO1) was significantly upregulated in the juice sacs of Huanong Red pummelo pollinated with MS pollen in comparison to that with open pollination. Compared to wild-type tobacco Bright-Yellow2 cells, transgenic cells overexpressing CitLO1 promoted a 3- to 4-fold more conversion of (-)-linalool to cis- and trans-linalool oxides. Overall, our results suggest that MS pollen has a xenia effect on pummelo fruit aroma quality, and CitLO1 is a linalool oxide synthase gene that played an important role in the xenia effect.


Assuntos
Citrus/metabolismo , Cicloexanóis/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Frutas/metabolismo , Monoterpenos/metabolismo , Proteínas de Plantas/genética , Compostos de Tritil/metabolismo , Monoterpenos Acíclicos , Citrus/química , Citrus/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Frutas/química , Frutas/genética , Humanos , Odorantes/análise , Proteínas de Plantas/metabolismo , Pólen/genética , Pólen/metabolismo , Paladar , Compostos Orgânicos Voláteis/química , Compostos Orgânicos Voláteis/metabolismo
20.
Food Microbiol ; 84: 103240, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31421790

RESUMO

This study evaluated whether the pre-exposure (24, 48 and 72 h) to sublethal conditions caused by acetic acid (AA), lactic acid (LA), sodium chloride (NaCl) or potassium chloride (KCl) could induce increased cross-tolerance to the essential oils from Origanum vulgare L. (OVEO) and Rosmarinus officinalis L. (ROEO) in different Listeria monocytogenes strains. Damage to membrane integrity, membrane potential, enzymatic activity and efflux activity in L. monocytogenes cells pre-exposed (24 h) to AA or NaCl and further treated with OVEO or ROEO (8 and 24 h) were investigated using flow cytometry (FC). Results of minimum inhibitory concentration (MIC) modulation test showed that pre-exposure to sublethal conditions caused by organic acids or salts increased cross-tolerance only to ROEO, since MIC of ROEO increased up to 4.8-fold against pre-exposed cells. Otherwise, MIC of OVEO against these pre-exposed cells was up to ten-fold lower than that observed against not pre-exposed cells, indicating no increase in cross-tolerance. Bacterial survival assays showed that ROEO only decreased the counts over time of cells not pre-exposed to organic acids or salts, while OVEO decreased similarly or more the counts of pre-exposed cells compared to not pre-exposed cells. Results of FC analysis showed that all measured functions in L. monocytogenes cells pre-exposed to AA or NaCl and treated with OVEO or ROEO were affected, although with different intensities. These data indicate that exposure to sublethal conditions imposed by organic acids or salts could result in a phenotype of increased cross-tolerance to ROEO but not to OVEO in L. monocytogenes.


Assuntos
Listeria monocytogenes/efeitos dos fármacos , Óleos Voláteis/farmacologia , Origanum/química , Rosmarinus/química , Sais/farmacologia , Ácido Acético/farmacologia , Cicloexanóis/farmacologia , Microbiologia de Alimentos , Conservantes de Alimentos/farmacologia , Listeria monocytogenes/fisiologia , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Cloreto de Sódio/farmacologia , Estresse Fisiológico
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