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1.
Expert Opin Ther Pat ; 30(2): 137-145, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31865810

RESUMO

Introduction: The greater interest in TAAR1-mediated potential for the treatment of different pathologies, especially those related to CNS disorders, has given a considerable boost to the search for developing TAAR1-selective small molecules.Areas covered: During the last decade, the medicinal chemistry efforts have allowed the yield of various chemotypes to be properly dressed toward TAAR1 receptor. The more relevant chemical features and structure-activity relationship studies on the TAAR1 ligands will be discussed in order to guide future drug discovery investigations.Expert opinion: The discovery of TAAR receptors has allowed better investigation of the role played by TAs, not only as secondary neuromodulators, but also as neurotransmitters, even if it should still be completely clarified. This has drawn new ways for further insights around the TAAR1 involvement in numerous diseases. Despite this, the limited number of promising ligands targeting hTAAR1 orthologue makes the discovery of novel compounds still a challenging task. Relevant efforts have to be focused on safe ligands, devoid of any side-efficacy toward other highly related GPCR (monoaminergic systems). Moreover, species-specificity preferences experienced by numerous compounds so far investigated, based on rodent models and translated to the human environment, turn in a critical bottleneck in drug discovery.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Desenvolvimento de Medicamentos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Animais , Doenças do Sistema Nervoso Central/fisiopatologia , Descoberta de Drogas , Humanos , Ligantes , Patentes como Assunto , Receptores Acoplados a Proteínas-G/metabolismo , Relação Estrutura-Atividade
3.
Exp Eye Res ; 189: 107826, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31586450

RESUMO

PURPOSE: To investigate the potential protective effect of novel G protein coupled estrogen receptor (GPER1) against the neurotoxicity induced by NMDA in the mouse retina. METHODS: We induce retinal ganglion cells (RGCs) toxic injury through intravitreal injection of NMDA or acute ocular hypertension (AOH) induced by anterior chamber infusion with saline. Endogenous ligand 17-ß-estradiol (E2), GPER1 agonist (G-1), and E2 with GPER1 antagonist (G-15) or classic estrogen receptor α and ß (ERα and ERß) antagonist tamoxifen (TAM) were subcutaneous administered before NMDA to identify the possible involved receptors. Immunofluorescence staining was performed to explore the survival of RGCs and Müller cell gliosis. TUNEL staining was used to evaluate the RGC apoptosis. The involved molecular pathway was detected via antibody array expression profiling. RESULTS: Activation of estrogen receptor by E2 or G-1 could significantly rescue the RGCs injury in NMDA administration. The protective effect was carried exclusively by GPER1 activation. E2 application can still mimicked the protective function when estrogen receptor α and ß (ERα and ERß) blocked by tamoxifen (TAM), while the effects was blocked by GPER1 antagonist G-15. Moreover, the TUNEL positive RGCs and GFAP expression level were both attenuated in G-1 application and the effects could be reversed by G-15. In addition, application of the PI3K/Akt antagonist LY294002 counteracted the effect of G-1. And a number of apoptosis regulatory factors decreased dramatically in the G-1 group, including Bad, Caspase 3, Caspase 7, Smad2, P-53 and TAK1. Also, similar protective effect of G-1 was spotted in acute ocular hypertension (AOH) model. CONCLUSION: Estrogen played a protective role via a novel estrogen receptor, GPER1, instead of classical receptors ERα or ERß. Activation of GPER1 attenuated RGCs apoptosis and Müller cells gliosis, indicating GPER1 as a potential treatment target in RGCs degeneration diseases.


Assuntos
Regulação da Expressão Gênica , RNA/genética , Receptores Estrogênicos/genética , Receptores Acoplados a Proteínas-G/genética , Degeneração Retiniana/genética , Células Ganglionares da Retina/metabolismo , Tamoxifeno/farmacologia , Animais , Apoptose , Western Blotting , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , N-Metilaspartato/toxicidade , RNA/metabolismo , Receptores Estrogênicos/biossíntese , Receptores Estrogênicos/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/biossíntese , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia
4.
Med Sci Monit ; 25: 7407-7417, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31609302

RESUMO

BACKGROUND The initiation of atherosclerosis (AS) is attributed to the dysfunction of endothelial cells (ECs) via the inhibition of g protein-coupled estrogen receptor (GPER). In the current study, we assessed the potential of Ginsenoside Rb1 (Rb1) to attenuate the dysfunction of ECs via GPER-mediated PI3K/Akt pathway. MATERIAL AND METHODS AS was induced in rabbits and then the AS rabbits were treated with Rb1. Thereafter, the ECs were isolated from AS and healthy rabbits, and treated with Rb1. The effect of Rb1 on blood lipid levels in AS rabbits and on apoptosis, inflammatory response, and GPER/PI3K/Akt axis activity in ECs was detected. Furthermore, the activities of GPER and PI3K were modulated to verify the key role of the axis in the anti-AS effect of Rb1. RESULTS The levels of total cholesterol, low-density lipoprotein (LDL), and triglyceride in AS rabbits were suppressed by Rb1 while the high-density lipoprotein (HDL) level was increased. In in vitro assays, Rb1 administration inhibited apoptosis process and the production of pro-inflammation cytokines in AS ECs. The expression levels of GPER, p-PI3K, and p-Akt were upregulated by Rb1, associated with the increased level of Bcl-2 and reduced level of Bax. When the activity of GPER was inhibited by GP-15 in AS ECs, the treatment effect of Rb1 was blocked. However, the activation of PI3K could restore the protective effect of Rb1 after the inhibition of GPER. CONCLUSIONS The anti-AS potential of Rb1 was exerted by restoring the regular function of ECs via the activation of GPER-mediated PI3K/Akt signaling.


Assuntos
Aterosclerose/fisiopatologia , Células Endoteliais/efeitos dos fármacos , Ginsenosídeos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , China , Dieta Hiperlipídica , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Quinase 3 de Receptor Acoplado a Proteína G , Ginsenosídeos/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositóis , Proteínas Proto-Oncogênicas c-akt/metabolismo , Coelhos , Receptores Estrogênicos/efeitos dos fármacos , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Endocr Regul ; 53(3): 154-164, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517630

RESUMO

OBJECTIVES: Aldosterone rapidly enhances protein kinase C (PKC) alpha and beta1 proteins in the rat kidney. The G protein-coupled receptor 30 (GPR30)-mediated PKC pathway is involved in the inhibition of the potassium channel in HEK-239 cells. GPR30 mediates rapid actions of aldosterone in vitro. There are no reports available regarding the aldosterone action on other PKC isoforms and GPR30 proteins in vivo. The aim of the present study was to examine rapid actions of aldosterone on protein levels of phosphorylated PKC (p-PKC) delta, p-PKC epsilon, and GPR30 simultaneously in the rat kidney. METHODS: Male Wistar rats were intraperitoneally injected with normal saline solution or aldosterone (150 µg/kg body weight). After 30 minutes, abundance and immunoreactivity of p-PKC delta, p-PKC epsilon, and GPR30 were determined by Western blot analysis and immunohisto-chemistry, respectively. RESULTS: Aldosterone administration significantly increased the renal protein abundance of p-PKC delta by 80% (p<0.01) and decreased p-PKC epsilon protein by 50% (p<0.05). Aldosterone injection enhanced protein immunoreactivity of p-PKC delta but suppressed p-PKC epsilon protein intensity in both kidney cortex and medulla. Protein abundance of GPR30 was elevated by aldosterone treatment (p<0.05), whereas the immunoreactivity was obviously changed in the kidney cortex and inner medulla. Aldosterone translocated p-PKC delta and GPR30 proteins to the brush border membrane of proximal convoluted tubules. CONCLUSIONS: This is the first in vivo study simultaneously demonstrating that aldosterone administration rapidly elevates protein abundance of p-PKC delta and GPR30, while p-PKC epsilon protein is suppressed in rat kidney. The stimulation of p-PKC delta protein levels by aldosterone may be involved in the activation of GPR30.


Assuntos
Aldosterona/farmacologia , Rim/efeitos dos fármacos , Proteína Quinase C-delta/metabolismo , Proteína Quinase C-épsilon/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Aldosterona/sangue , Aldosterona/urina , Animais , Rim/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Proteína Quinase C-delta/efeitos dos fármacos , Proteína Quinase C-épsilon/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Fatores de Tempo
6.
Med Hypotheses ; 131: 109301, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443771

RESUMO

Caffeine is a well-established ergogenic aid, with its performance-enhancing effects replicated across a variety of exercise types. Caffeine exerts its performance-benefits through many mechanisms, including acting as an adenosine receptor antagonist, and serving to reduce sensations of fatigue and pain. One potential mechanism that is currently underexplored is whether caffeine's bitter taste mediates some of its ergogenic effects, which is discussed in this article. Previous research has demonstrated that bitter tastants have the ability to enhance performance, and this effect is mediated by bitter taste receptors in the mouth and gastrointestinal tract. Additionally, the ability to detect bitter tastes is subject to individual variation, raising the potential that the demonstrated inter-individual response to a standardised caffeine dose is potentially driven by differences in taste response. Finally, it appears that some of caffeine's performance-enhancing effects are driven by expectancy. As bitter taste may serve as a signal that caffeine has been ingested, it is possible that some of the expectancy effects of caffeine ingestion are driven by its bitter taste. These aspects all have potentially important implications for future research, as well as for how athletes and coaches utilise caffeine around competition, both of which are explored in depth here.


Assuntos
Cafeína/farmacologia , Modelos Biológicos , Substâncias para Melhoria do Desempenho/farmacologia , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Paladar , Antecipação Psicológica , Desempenho Atlético , Variação Biológica Individual , Cafeína/administração & dosagem , Cafeína/química , Carboidratos/administração & dosagem , Carboidratos/farmacologia , Sinais (Psicologia) , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiologia , Humanos , Modelos Psicológicos , Antissépticos Bucais , Substâncias para Melhoria do Desempenho/química , Receptores Acoplados a Proteínas-G/fisiologia , Percepção Gustatória/genética
7.
Nutrients ; 11(9)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466230

RESUMO

Taste receptors, first identified on the tongue, are best known for their role in guiding our dietary preferences. The expression of taste receptors for umami, sweet, and bitter have been demonstrated in tissues outside of the oral cavity, including in the airway, brain, gastrointestinal tract, and reproductive organs. The extra-oral taste receptor chemosensory pathways and the endogenous taste receptor ligands are generally unknown, but there is increasing data suggesting that taste receptors are involved in regulating some aspects of innate immunity, and may potentially control the composition of the nasal microbiome in healthy individuals or patients with upper respiratory diseases like chronic rhinosinusitis (CRS). For this reason, taste receptors may serve as potential therapeutic targets, providing alternatives to conventional antibiotics. This review focuses on the physiology of sweet (T1R) and bitter (T2R) taste receptors in the airway and their activation by secreted bacterial products. There is particular focus on T2R38 in sinonasal ciliated cells, as well as the sweet and bitter receptors found on specialized sinonasal solitary chemosensory cells. Additionally, this review explores the impact of genetic variations in these receptors on the differential susceptibility of patients to upper airway infections, such as CRS.


Assuntos
Imunidade Inata , Imunidade nas Mucosas , Receptores Acoplados a Proteínas-G/metabolismo , Mucosa Respiratória/metabolismo , Sistema Respiratório/metabolismo , Infecções Respiratórias/metabolismo , Paladar , Animais , Antibacterianos/uso terapêutico , Bactérias/imunologia , Bactérias/metabolismo , Cílios/imunologia , Cílios/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade nas Mucosas/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/microbiologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Transdução de Sinais , Paladar/efeitos dos fármacos
8.
J Pediatr Surg ; 54(11): 2392-2397, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31036368

RESUMO

BACKGROUND: A single dose of IV fish oil (FO) before hepatic ischemia reperfusion injury (HIRI) increases hepatocyte proliferation and reduces necrosis in wild type (WT) mice. It has been suggested that the GPR120 receptor on Kupffer cells mediates FO's ability to reduce HIRI. The purpose of this study was to determine whether GPR120 is required for FO to reduce HIRI. METHODS: Sixty-four (n = 8/group) adult male WT (C57BL/6) and GPR120 knockout (KO) mice received IV FO (1 g/kg) or saline 1 h prior to HIRI or sham operation. Mice were euthanized 24 h postoperatively for analysis of hepatic histology, NFκB activity, and serum alanine transaminase (ALT) levels. RESULTS: FO pretreated livers had less necrosis after HIRI than saline pretreated livers in both WT (mean ±â€¯SEM 25.9 ±â€¯7.3% less, P = 0.007) and KO (36.6 ±â€¯7.3% less, P < 0.0001) mice. There was no significant difference in percent necrosis between WT-FO and KO-FO groups. Sham groups demonstrated minimal necrosis (0-1.9%). Mean [95% CI] ALT after HIRI was significantly higher (P = 0.04) in WT-Saline mice (1604 U/L [751-3427]) compared to WT-FO (321 U/L [150-686]) but was not significantly higher in KO-Saline mice compared to KO-FO. There were no differences in ALT between WT-FO and KO-FO mice who underwent HIRI or between groups who underwent sham surgery. There were no differences in NFκB or IKKß activation among groups as measured by Western blot analysis. CONCLUSIONS: IV FO pretreatment was able to reduce HIRI in GPR120 KO mice, suggesting the hepatoprotective effects of FO are not mediated by GPR120 alone.


Assuntos
Ácidos Graxos Ômega-3/farmacologia , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Alanina Transaminase/sangue , Animais , Proliferação de Células , Hepatócitos/citologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subunidade p50 de NF-kappa B/metabolismo , Necrose/patologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos
9.
Cardiovasc Toxicol ; 19(3): 198-209, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30955163

RESUMO

Air pollution is the leading environmental risk factor for disease and premature death in the world. This is mainly due to exposure to urban air particle matter (PM), in particular, fine and ultrafine combustion-derived particles (CDP) from traffic-related air pollution. PM and CDP, including particles from diesel exhaust (DEP), and cigarette smoke have been linked to various cardiovascular diseases (CVDs) including atherosclerosis, but the underlying cellular mechanisms remain unclear. Moreover, CDP typically consist of carbon cores with a complex mixture of organic chemicals such as polycyclic aromatic hydrocarbons (PAHs) adhered. The relative contribution of the carbon core and adhered soluble components to cardiovascular effects of CDP is still a matter of discussion. In the present review, we summarize evidence showing that CDP affects intracellular calcium regulation, and argue that CDP-induced impairment of normal calcium control may be a critical cellular event through which CDP exposure contributes to development or exacerbation of cardiovascular disease. Furthermore, we highlight in vitro research suggesting that adhered organic chemicals such as PAHs may be key drivers of these responses. CDP, extractable organic material from CDP (CDP-EOM), and PAHs may increase intracellular calcium levels by interacting with calcium channels like transient receptor potential (TRP) channels, and receptors such as G protein-coupled receptors (GPCR; e.g., beta-adrenergic receptors [ßAR] and protease-activated receptor 2 [PAR-2]) and the aryl hydrocarbon receptor (AhR). Clarifying a possible role of calcium signaling and mechanisms involved may increase our understanding of how air pollution contributes to CVD.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Endotélio Vascular/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Material Particulado/efeitos adversos , Poluição Relacionada com o Tráfego/efeitos adversos , Doenças Vasculares/induzido quimicamente , Emissões de Veículos/toxicidade , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Homeostase , Humanos , Prognóstico , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo , Medição de Risco , Canais de Receptores Transientes de Potencial/efeitos dos fármacos , Canais de Receptores Transientes de Potencial/metabolismo , Doenças Vasculares/metabolismo , Doenças Vasculares/fisiopatologia
10.
Methods Mol Biol ; 1947: 361-376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30969428

RESUMO

Engineered G protein-coupled receptors (DREADDs, designer receptors exclusively activated by designer drugs) are convenient tools for specific activation of GPCR signaling in many cell types. DREADDs have been utilized as research tools to study numerous cellular and physiologic processes, including regulation of neuronal activity, behavior, and metabolism. Mice with random insertion transgenes and adeno-associated viruses have been widely used to express DREADDs in individual cell types. We recently created and characterized ROSA26-GsDREADD knock-in mice to allow Cre recombinase-dependent expression of a Gαs-coupled DREADD (GsD) fused to GFP in distinct cell populations in vivo. These animals also harbor a CREB-activated luciferase reporter gene for analysis of CREB activity by in vivo imaging, ex vivo imaging, or biochemical reporter assays. In this chapter, we provide detailed methods for breeding GsD animals, inducing GsD expression, stimulating GsD activity, and measuring basal and stimulated CREB reporter bioluminescence in tissues in vivo, ex vivo, and in vitro. These animals are available from our laboratory for non-profit research.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Genes Reporter , Processamento de Imagem Assistida por Computador/métodos , Medições Luminescentes/métodos , Moduladores de Transporte de Membrana/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , Integrases/metabolismo , Camundongos , Especificidade de Órgãos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais
11.
J Sci Food Agric ; 99(11): 4952-4962, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30953347

RESUMO

BACKGROUND: Long-term artificial sweetener consumption has been reported to induce glucose intolerance, and the intestinal microbiota seems as an important target. While the impacts of artificial sweeteners on energy balance remain controversial, this work aimed to evaluate the protective effects in mice of a low digestible carbohydrate (LDC) diet on plasma glucose, plasma fasting insulin, sweet taste receptors, glucose transporters, and absorption of carbohydrates, together with consumption of acesulfame potassium (AK) or saccharin (SAC). RESULTS: Artificial sweetener was administered to mice for 12 weeks to induce glucose metabolism disorders; mice were treated with an LDC diet for the final 6 weeks. The experimental groups were treated with an LDC diet that had the same energy as the normal-diet group. Prolonged administration of artificial sweeteners led to metabolic dysfunction, characterized by significantly increased plasma glucose, insulin resistance, sweet taste receptors, glucose transporters, and absorption of carbohydrates. Treatment with an LDC diet positively modulated these altered parameters, suggesting overall beneficial effects of an LDC diet on detrimental changes associated with artificial sweeteners. CONCLUSIONS: Reducing digestible carbohydrates in the diet can significantly reduce the absorption of carbohydrates and improve glucose metabolism disorders caused by dietary factors. These effects may be due to the fact that reducing the amount of digestible carbohydrates in the feed can reduce the number of intestinal sweet receptors induced by exposure to artificial sweeteners. © 2019 Society of Chemical Industry.


Assuntos
Dieta com Restrição de Carboidratos , Carboidratos da Dieta/farmacocinética , Duodeno/metabolismo , Transtornos do Metabolismo de Glucose/induzido quimicamente , Edulcorantes/efeitos adversos , Animais , Glicemia/análise , Carboidratos da Dieta/administração & dosagem , Digestão , Duodeno/química , Microbioma Gastrointestinal/efeitos dos fármacos , Intolerância à Glucose/induzido quimicamente , Transtornos do Metabolismo de Glucose/metabolismo , Insulina/sangue , Resistência à Insulina , Absorção Intestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Receptores Acoplados a Proteínas-G/análise , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Paladar/efeitos dos fármacos , Ganho de Peso
12.
Nutrients ; 11(3)2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884834

RESUMO

Individuals widely use non-nutritive sweeteners (NNS) in attempts to lower their overall daily caloric intake, lose weight, and sustain a healthy diet. There are insufficient scientific data that support the safety of consuming NNS. However, recent studies have suggested that NNS consumption can induce gut microbiota dysbiosis and promote glucose intolerance in healthy individuals that may result in the development of type 2 diabetes mellitus (T2DM). This sequence of events may result in changes in the gut microbiota composition through microRNA (miRNA)-mediated changes. The mechanism(s) by which miRNAs alter gene expression of different bacterial species provides a link between the consumption of NNS and the development of metabolic changes. Another potential mechanism that connects NNS to metabolic changes is the molecular crosstalk between the insulin receptor (IR) and G protein-coupled receptors (GPCRs). Here, we aim to highlight the role of NNS in obesity and discuss IR-GPCR crosstalk and miRNA-mediated changes, in the manipulation of the gut microbiota composition and T2DM pathogenesis.


Assuntos
Diabetes Mellitus Tipo 2/induzido quimicamente , Disbiose/induzido quimicamente , Síndrome Metabólica/induzido quimicamente , MicroRNAs/efeitos dos fármacos , Adoçantes não Calóricos/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Obesidade/metabolismo , Receptor de Insulina/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos
13.
Trends Pharmacol Sci ; 40(4): 278-293, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30871735

RESUMO

The family of adhesion G protein-coupled receptors (aGPCRs) consists of 33 members in humans. Although the majority are orphan receptors with unknown functions, many reports have demonstrated critical functions for some members of this family in organogenesis, neurodevelopment, myelination, angiogenesis, and cancer progression. Importantly, mutations in several aGPCRs have been linked to human diseases. The crystal structure of a shared protein domain, the GPCR Autoproteolysis INducing (GAIN) domain, has enabled the discovery of a common signaling mechanism - a tethered agonist - for this class of receptors. A series of recent reports has shed new light on their biological functions and disease relevance. This review focuses on these recent advances in our understanding of aGPCR biology in the nervous system and the untapped potential of aGPCRs as novel therapeutic targets for neurological disease.


Assuntos
Terapia de Alvo Molecular , Doenças do Sistema Nervoso/tratamento farmacológico , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Desenvolvimento de Medicamentos/métodos , Humanos , Mutação , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/fisiopatologia , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais
14.
Proc Natl Acad Sci U S A ; 116(14): 7123-7128, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30872479

RESUMO

The long-chain fatty acid receptor FFAR1/GPR40 binds agonists in both an interhelical site between the extracellular segments of transmembrane helix (TM)-III and TM-IV and a lipid-exposed groove between the intracellular segments of these helices. Molecular dynamics simulations of FFAR1 with agonist removed demonstrated a major rearrangement of the polar and charged anchor point residues for the carboxylic acid moiety of the agonist in the interhelical site, which was associated with closure of a neighboring, solvent-exposed pocket between the extracellular poles of TM-I, TM-II, and TM-VII. A synthetic compound designed to bind in this pocket, and thereby prevent its closure, was identified through structure-based virtual screening and shown to function both as an agonist and as an allosteric modulator of receptor activation. This discovery of an allosteric agonist for a previously unexploited, dynamic pocket in FFAR1 demonstrates both the power of including molecular dynamics in the drug discovery process and that this specific, clinically proven, but difficult, antidiabetes target can be addressed by chemotypes different from existing ligands.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Simulação de Dinâmica Molecular , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Sítio Alostérico , Benzofuranos/antagonistas & inibidores , Sítios de Ligação , Cristalografia por Raios X , Humanos , Ligantes , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Conformação Proteica , Receptores Acoplados a Proteínas-G/genética , Sulfonas/antagonistas & inibidores
15.
Expert Opin Ther Pat ; 29(2): 85-95, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30640576

RESUMO

INTRODUCTION: The GPR17 receptor, phylogenetically related to both purinergic P2Y and CysLT receptors, is mainly expressed in the CNS and, in general, in organs that can typically undergo ischemic damage. This receptor is involved in various pathologies including stroke, brain and spinal cord trauma, multiple sclerosis and in all diseases characterized by neuronal and myelin dysfunction. Therefore, there is a strong needed to identify molecules capable of binding specifically to GPR17 receptors. AREAS COVERED: The review provides a summary of patents, published between 2009 and 2018, on chemicals and biologics and their clinical use. In this work, information is reported about the representative structures and biological activity of recently developed GPR17 receptor ligands. EXPERT OPINION: The GPR17 receptor is an enigmatic receptor and an interesting therapeutic target in a variety of brain disorders and demyelinating diseases such as multiple sclerosis, stroke, schizophrenia, and depression. The modulation of this receptor could also be potentially useful in obesity treatment. Unfortunately, so far, there are no compounds under investigation in clinical trials but many researchers and companies are investing in the discovery of future potential GPR17 receptor drugs.


Assuntos
Descoberta de Drogas/métodos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Animais , Encefalopatias/tratamento farmacológico , Encefalopatias/fisiopatologia , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/fisiopatologia , Humanos , Ligantes , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Patentes como Assunto , Receptores Acoplados a Proteínas-G/metabolismo
16.
Food Res Int ; 115: 504-510, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30599971

RESUMO

Unlike all other caffeinated plants, guayusa (Ilex guayusa Loes.) and maté (Ilex paraguariensis A. St. Hill) contain high amounts of pentacyclic triterpenoid acids and alcohols. A phytochemical investigation on these plants revealed a similar triterpenoid profile and a content of ursolic acid (0.7-1%) and amyrin esters (up to 0.5%), quite unusual for dietary plants. The major constituent of the amyrin complex from both plants is α-amyrin palmitate (2a), accompanied by lower amounts of its corresponding palmitoleate (2b) and by the corresponding constitutional isomers from the ß-series (3a and 3b, respectively). Ursolic acid (1) was identified as the responsible for the activity of maté and guayusa extracts in the activation of TGR5, a nuclear receptor of relevance for the prevention and management of diabetes and metabolic syndrome because of its involvement in the regulation of energy expenditure and insulin sensitivity.


Assuntos
Cafeína/análise , Ilex guayusa/química , Ilex paraguariensis/química , Extratos Vegetais/análise , Triterpenos/análise , Diabetes Mellitus/prevenção & controle , Resistência à Insulina , Síndrome Metabólica/prevenção & controle , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Fatores de Transcrição/efeitos dos fármacos , Triterpenos/química , Triterpenos/farmacologia
17.
ACS Chem Neurosci ; 10(1): 552-562, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30343564

RESUMO

The mammalian olfactory receptors (ORs) constitute a large subfamily of the Class A G-protein coupled receptors (GPCRs). The molecular details of how these receptors convert odorant chemical information into neural signal are unknown, but are predicted by analogy to other GPCRs to involve stabilization of the activated form of the OR by the odorant. An alternative hypothesis maintains that the vibrational modes of an odorant's bonds constitute the main determinant for OR activation, and that odorants containing deuterium in place of hydrogen should activate different sets of OR family members. Experiments using heterologously expressed ORs have failed to show different responses for deuterated odorants, but experiments in the sensory neuron environment have been lacking. We tested the response to deuterated and nondeuterated versions of p-cymene, 1-octanol, 1-undecanol, and octanal in dissociated mouse olfactory receptor neurons (ORNs) by calcium imaging. In all, we tested 23 812 cells, including a subset expressing recombinant mouse olfactory receptor 2 ( Olfr2/OR-I7 ), and found that nearly all of the 1610 odorant-responding neurons were unable to distinguish the D- and H-odorants. These results support the conclusion that if mammals can perceive deuterated odorants differently, the difference arises from the receptor-independent steps of olfaction. Nevertheless, 0.81% of the responding ORNs responded differently to D- and H-odorants, and those in the octanal experiments responded selectively to H-octanal at concentrations from 3 to 100 µM. The few ORs responding differently to H and D may be hypersensitive to one of the several H/D physicochemical differences, such as the difference in H/D hydrophobicity.


Assuntos
Cálcio/metabolismo , Deutério/farmacologia , Neurônios Receptores Olfatórios/efeitos dos fármacos , Receptores Odorantes/metabolismo , Aldeídos/farmacologia , Animais , Camundongos , Odorantes , Neurônios Receptores Olfatórios/fisiologia , Receptores Acoplados a Proteínas-G/efeitos dos fármacos
18.
ACS Chem Neurosci ; 10(1): 716-727, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30346710

RESUMO

G protein-coupled receptor 55 (GPR55) is highly expressed in brain and peripheral nervous system. Originally deorphanized as a cannabinoid receptor, recently GPR55 has been described as a lysophospholipid-responsive receptor, specifically toward lysophosphatidylinositol and lysophosphatidyl-ß-d-glucoside (LysoPtdGlc). To characterize lysolipid-GPR55 interaction, synthetic access to LysoPtdGlc and selected analogues was established utilizing a phosphorus(III)-based chemical approach. The biological activity of each synthetic lipid was assessed using a GPR55-dependent chemotropism assay in primary sensory neurons. Combined with molecular dynamics simulations the potential ligand entry port and binding pocket specifics are discussed. These results highlight the preference for gluco- over inositol- and galacto-configured headgroups.


Assuntos
Canabinoides/metabolismo , Glucose/metabolismo , Inositol/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Galinhas , Humanos , Lisofosfolipídeos/farmacologia , Simulação de Dinâmica Molecular , Receptores de Canabinoides/metabolismo , Receptores Acoplados a Proteínas-G/efeitos dos fármacos
19.
Graefes Arch Clin Exp Ophthalmol ; 257(1): 71-81, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30353220

RESUMO

BACKGROUND: One of the most prevalent microvascular complications for patients with diabetes is diabetic retinopathy (DR) associated with increased retinal endothelial blood vessel formation. Treatments to reduce vascularisation in the retinal endothelium are linked to improved sight in patients with DR. Recently, we have demonstrated the novel protective role of the artificial sweetener, sucralose, and the sweet taste receptor, T1R3, in the pulmonary endothelium to reduce vascular leak. In the present study, we examined the role of sucralose and sweet taste receptors on vasculogenic processes (proliferation, migration, adhesion and tube formation) in a cell model of the retinal endothelium. METHODS: We exposed human retinal microvascular endothelial cells (RMVEC) to VEGF as an in vitro model of DR in the presence and absence of T1R3 agonist sucralose. RESULTS: In RMVEC, we observed increased VEGF-induced cell proliferation, migration, adhesion and tube formation, which was significantly attenuated by exposure to the artificial sweetener sucralose. Following siRNA knockdown of the sweet taste receptor, T1R3, but not T1R2, the protective effect of sucralose on VEGF-induced RMVEC vasculogenic processes was blocked. We further demonstrate that sucralose attenuates VEGF-induced Akt phosphorylation to protect the retinal microvasculature. CONCLUSION: These studies are the first to demonstrate a protective effect of an artificial sweetener, through the sweet taste receptor T1R3, on VEGF-induced vasculogenesis in a retinal microvascular endothelial cell line.


Assuntos
Retinopatia Diabética/complicações , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , Receptores Acoplados a Proteínas-G/genética , Neovascularização Retiniana/genética , Vasos Retinianos/patologia , Sacarose/análogos & derivados , Western Blotting , Linhagem Celular , Movimento Celular , Proliferação de Células , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Endotélio Vascular/patologia , Ensaio de Imunoadsorção Enzimática , Humanos , Microvasos/metabolismo , Microvasos/patologia , RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas-G/biossíntese , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Neovascularização Retiniana/etiologia , Neovascularização Retiniana/patologia , Vasos Retinianos/metabolismo , Sacarose/farmacologia
20.
J Neurochem ; 148(1): 29-45, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295919

RESUMO

Methamphetamine (Meth) is a potent and commonly abused psychostimulant. Meth alters neuron and astrocyte activity; yet the underlying mechanism(s) is not fully understood. Here we assessed the impact of acute Meth on human fetal astrocytes (HFAs) using whole-cell patch-clamping. We found that HFAs displayed a large voltage-gated K+ efflux (IKv ) through Kv /Kv -like channels during membrane depolarization, and a smaller K+ influx (Ikir ) via inward-rectifying Kir /Kir -like channels during membrane hyperpolarization. Meth at a 'recreational' (20 µM) or toxic/fatal (100 µM) concentration depolarized resting membrane potential (RMP) and suppressed IKv/Kv-like . These changes were associated with a decreased time constant (Ƭ), and mimicked by blocking the two-pore domain K+ (K2P )/K2P -like and Kv /Kv -like channels, respectively. Meth also diminished IKir/Kir-like , but only at toxic/fatal levels. Given that Meth is a potent agonist for the trace amine-associated receptor type-1 (TAAR1), and TAAR1-coupled cAMP/cAMP-activated protein kinase (PKA) cascade, we further evaluated whether the Meth impact on K+ efflux was mediated by this pathway. We found that antagonizing TAAR1 with N-(3-Ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide (EPPTB) reversed Meth-induced suppression of IKv/Kv-like ; and inhibiting PKA activity by H89 abolished Meth effects on suppressing IKv/Kv-like . Antagonizing TAAR1 might also attenuate Meth-induced RMP depolarization. Voltage-gated Ca2+ currents were not detected in HFAs. These novel findings demonstrate that Meth suppresses IKv/Kv-like by facilitating the TAAR1/Gs /cAMP/PKA cascade and altering the kinetics of Kv /Kv -like channel gating, but reduces K2P /K2P -like channel activity through other pathway(s), in HFAs. Given that Meth-induced decrease in astrocytic K+ efflux through K2P /K2P -like and Kv /Kv -like channels reduces extracellular K+ levels, such reduction could consequently contribute to a decreased excitability of surrounding neurons. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.


Assuntos
Astrócitos/efeitos dos fármacos , Metanfetamina/toxicidade , Canais de Potássio/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Astrócitos/metabolismo , Células Cultivadas , Estimulantes do Sistema Nervoso Central/toxicidade , Feto , Humanos , Potenciais da Membrana/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos
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