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1.
Exp Eye Res ; 213: 108823, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34752817

RESUMO

Choroidal neovascularization (CNV), a feature of neovasular age-related macular degeneration (AMD), acts as a leading cause of vision loss in the elderly. Shikonin (SHI), a natural bioactive compound extracted from Chinese herb radix arnebiae, exerts anti-inflammatory and anti-angiogenic roles and also acts as a potential pyruvate kinase M2 (PKM2) inhibitor in macrophages. The major immune cells macrophages infiltrate the CNV lesions, where the production of pro-angiognic cytokines from macrophage facilitates the development of CNV. PKM2 contributes to the neovascular diseases. In this study, we found that SHI oral gavage alleviated the leakage, area and volume of mouse laser-induced CNV lesion and inhibited macrophage infiltration without ocular cytotoxicity. Moreover, SHI inhibited the secretion of pro-angiogenic cytokine, including basic fibroblast growth factor (FGF2), insulin-like growth factor-1 (IGF1), chemokine (C-C motif) ligand 2 (CCL2), placental growth factor and vascular endothelial growth factor (VEGF), from primary human macrophages by down-regulating PKM2/STAT3/CD163 pathway, indicating a novel potential therapy strategy for CNV.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Naftoquinonas/uso terapêutico , Piruvato Quinase/antagonistas & inibidores , Indutores da Angiogênese/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Western Blotting , Células Cultivadas , Neovascularização de Coroide/enzimologia , Cromatografia Líquida de Alta Pressão , Corantes/administração & dosagem , Citocinas/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Angiofluoresceinografia , Humanos , Marcação In Situ das Extremidades Cortadas , Verde de Indocianina/administração & dosagem , Macrófagos/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Piruvato Quinase/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo
2.
Biochim Biophys Acta Mol Basis Dis ; 1867(12): 166267, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34508829

RESUMO

Bromodomain and extraterminal (BET) proteins are promising therapeutic targets for hematological and solid tumors. However, BET inhibitor monotherapy did not show a significant therapeutic benefit for hepatocellular carcinoma (HCC) in preclinical trials. Here, we identified YAP/TAZ genes, as determinants for sensitivity to BET inhibitors. YAP/TAZ expression, especially TAZ, promote resistance to BET inhibitor. In addition, we analyzed that the mRNA level of PDE5 was positively correlated with YAP/TAZ based on TCGA database and demonstrated tadalafil, a PDE5 inhibitor, could block YAP/TAZ protein expression by activating Hippo pathway. Cotreatment with tadalafil and JQ-1 synergistically reduced YAP/TAZ protein expression, suppressed proliferation and induced G0-G1 arrest of cultured HCC cells. JQ-1 alone does not show significant benefits in a mouse model of HCC induced by c-Myc/N-Ras plasmids. In contrast, the combination, tadalafil and JQ-1, successfully suppressed tumor progression, enhanced antitumor immunity by improving the ratio of activated CD8 and extended the survival time of mice. Our data define the key role of YAP/TAZ in mediating resistance to BET inhibitor, described the PDE5/PKG/Hippo/YAP/TAZ axis and identified a common clinical drug that can be developed as an effective combined strategy to overcome BET inhibitor resistance in MYC/Ras-driven HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Proteínas do Tecido Nervoso/genética , Receptores de Superfície Celular/genética , Tadalafila/farmacologia , Proteínas de Sinalização YAP/genética , Animais , Azepinas/farmacologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Via de Sinalização Hippo/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Inibidores da Fosfodiesterase 5/farmacologia , Proteínas Proto-Oncogênicas c-myc/genética , Receptores de Superfície Celular/antagonistas & inibidores , Triazóis/farmacologia
3.
Neuroreport ; 32(12): 1041-1048, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34232130

RESUMO

Thiamine-dependent processes are critical in cerebral glucose metabolism, it is abnormity induces oxidative stress, inflammation and neurodegeneration. Nod-like receptor protein-3 (NLRP3) inflammasome-mediated inflammation is closely related to neurologic diseases and can be activated by oxidative stress. However, the impact of thiamine deficiency on NLRP3 inflammasome activation remains unknown. In this study, we found that NLRP3 inflammasomes were significantly activated in the microglia of thiamine deficiency mice model. In contrast, benfotiamine dampened inflammation NLRP3 mediated in BV2 cells stimulated with LPS and ATP through reducing mitochondrial reactive oxygen species levels and mitigating autophagy flux defect. These data identify an important role of thiamine metabolism in NLRP3 inflammasome activation, and correcting thiamine metabolism through benfotiamine provides a new therapeutic strategy for NLRP3 inflammasome related neurological, metabolic, and inflammatory diseases.


Assuntos
Microglia/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Deficiência de Tiamina/tratamento farmacológico , Deficiência de Tiamina/metabolismo , Tiamina/análogos & derivados , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Animais , Linhagem Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Tiamina/farmacologia , Tiamina/uso terapêutico , Resultado do Tratamento
4.
J Med Chem ; 63(9): 4957-4977, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32330040

RESUMO

In humans, bitter taste is mediated by 25 TAS2Rs. Many compounds, including certain active pharmaceutical ingredients, excipients, and nutraceuticals, impart their bitter taste (or in part) through TAS2R8 activation. However, effective TAS2R8 blockers that can either suppress or reduce the bitterness of these compounds have not been described. We are hereby reporting a series of novel 3-(pyrazol-4-yl) imidazolidine-2,4-diones as potent and selective TAS2R8 antagonists. In human sensory tests, S6821 and S7958, two of the most potent analogues from the series, demonstrated efficacy in blocking TAS2R8-mediated bitterness and were selected for development. Following data evaluation by expert panels of a number of national and multinational regulatory bodies, including the US, the EU, and Japan, S6821 and S7958 were approved as safe under conditions of intended use as bitter taste blockers.


Assuntos
Hidantoínas/farmacologia , Pirazóis/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Paladar/efeitos dos fármacos , Animais , Café/química , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Hidantoínas/síntese química , Hidantoínas/toxicidade , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/toxicidade , Ratos , Relação Estrutura-Atividade
5.
Clin Microbiol Infect ; 24 Suppl 2: S41-S52, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29426804

RESUMO

BACKGROUND: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biologic therapies. AIMS: To review, from an infectious diseases perspective, the safety profile of therapies targeting cell surface receptors and associated signaling pathways among cancer patients and to suggest preventive recommendations. SOURCES: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Vascular endothelial growth factor (VEGF)-targeted agents (bevacizumab and aflibercept) are associated with a meaningful increase in the risk of infection, likely due to drug-induced neutropaenia, although no clear benefit is expected from the universal use of anti-infective prophylaxis. VEGF tyrosine kinase inhibitors (i.e. sorafenib or sunitinib) do not seem to significantly affect host's susceptibility to infection, and universal anti-infective prophylaxis is not recommended either. Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) induce neutropaenia and secondary skin and soft tissue infection in cases of severe papulopustular rash. Systemic antibiotics (doxycycline or minocycline) should be administered to prevent the latter complication, whereas no recommendation can be established on the benefit from antiviral, antifungal or anti-Pneumocystis prophylaxis. A lower risk of infection is reported for anti-ErbB2/HER2 monoclonal antibodies (trastuzumab and pertuzumab) and ErbB receptor tyrosine kinase inhibitors (including dual-EGFR/ErbB2 inhibitors such as lapatinib or neratinib) compared to conventional chemotherapy, presumably as a result of the decreased occurrence of drug-induced neutropaenia. IMPLICATIONS: With the exception of VEGF-targeted agents, the overall risk of infection associated with the reviewed therapies seems to be low.


Assuntos
Terapia Biológica/efeitos adversos , Doenças Transmissíveis/terapia , Terapia de Alvo Molecular/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Terapia Biológica/métodos , Ensaios Clínicos como Assunto , Controle de Doenças Transmissíveis , Consenso , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Humanos , Hospedeiro Imunocomprometido , Terapia de Alvo Molecular/métodos , Receptores de Superfície Celular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos
6.
J Med Chem ; 60(13): 5638-5645, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28570808

RESUMO

The free fatty acid receptor 2 (FFA2/GPR43) is considered a potential target for treatment of metabolic and inflammatory diseases. Here we describe the development of the first fluorescent tracer for FFA2 intended as a tool for assessment of thermodynamic and kinetic binding parameters of unlabeled ligands. Starting with a known azetidine FFA2 antagonist, we used a carboxylic acid moiety known not to be critical for receptor interaction as attachment point for a nitrobenzoxadiazole (NBD) fluorophore. This led to the development of 4 (TUG-1609), a fluorescent tracer for FFA2 with favorable spectroscopic properties and high affinity, as determined by bioluminescence resonance energy transfer (BRET)-based saturation and kinetic binding experiments, as well as a high specific to nonspecific BRET binding signal. A BRET-based competition binding assay with 4 was also established and used to determine binding constants and kinetics of unlabeled ligands.


Assuntos
Corantes Fluorescentes/química , Oxidiazóis/química , Receptores de Superfície Celular/análise , Azetidinas/química , Azetidinas/metabolismo , Sítios de Ligação , Ligação Competitiva , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Corantes Fluorescentes/metabolismo , Humanos , Ligantes , Oxidiazóis/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Espectrometria de Fluorescência
7.
Inflammation ; 40(3): 745-751, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28303417

RESUMO

The acute lung injury (ALI) is a leading cause of morbidity and mortality in critically ill patients. Amygdalin is derived from the bitter apricot kernel, an efficacious Chinese herbal medicine. Although amygdalin is used by many cancer patients as an antitumor agent, there is no report about the effect of amygdalin on acute lung injury. Here we explored the protective effect of amygdalin on ALI using lipopolysaccharide (LPS)-induced murine model by detecting the lung wet/dry ratio, the myeloperoxidase (MPO) in lung tissues, inflammatory cells in the bronchoalveolar lavage fluid (BALF), inflammatory cytokines production, as well as NLRP3 and NF-κB signaling pathways. The results showed that amygdalin significantly reduced LPS-induced infiltration of inflammatory cells and the production of TNF-α, IL-1ß, and IL-6 in the BALF. The activity of MPO and lung wet/dry ratio were also attenuated by amygdalin. Furthermore, the western blotting analysis showed that amygdalin remarkably inhibited LPS-induced NF-κB and NLRP3 activation. These findings indicate that amygdalin has a protective effect on LPS-induced ALI in mice. The mechanism may be related to the inhibition of NF-κB and NLRP3 signaling pathways.


Assuntos
Amigdalina/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Amigdalina/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
J Vector Borne Dis ; 53(2): 179-84, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27353589

RESUMO

BACKGROUND & OBJECTIVES: It is well reported that exhaled CO 2 and skin odour from human being assist female mosquitoes to locate human host. Basically, the receptors for this activity are expressed in cpA neurons. In both Aedes aegypti and Anopheles gambiae, this CO 2-sensitive olfactory neuron detects myriad number of chemicals present in human skin. Therefore, manipulation of gustatory receptors housing these neurons may serve as important targets for behavioural intervention. The study was aimed towards virtual screening of small molecules in the analyzed conserved active site residues of gustatory receptor and molecular dynamics simulation study of optimum protein-ligand complex to identify a suitable lead molecule for distracting host-seeking behaviour of mosquitoes. METHODS: The conserved residue analysis of gustatory receptor (GR) of Ae. aegypti and An. gambiae was performed. The structure of GR protein from Ae. aegypti was modeled and validated, and then molecular docking was performed to screen 2903 small molecules against the predicted active residues of GR. Further, simulation studies were also carried out to prove protein-ligand stability. RESULTS: The glutamine 154 residue of GR was found to be highly conserved in Ae. aegypti and An. gambiae. Docking results indicated that the dodecanoic acid, 1,2,3-propanetriyl ester (dynasan 112) was interacting with this residue, as it showed better LibDock score than previously reported ethyl acetate used as mosquito repellant. Simulation studies indicated the structural instability of GR protein in docked form with dynasan 112 suggesting its involvement in structural changes. Based on the interaction energies and stability, this compound has been proposed to be used in mosquitoes' repellant. INTERPRETATION & CONCLUSION: A novel effective odorant acting as inhibitor of GR is proposed based on its stability, docking score, interactions and RMSD, considering ethyl pyruvate as a standard inhibitor. Host preference and host-seeking ability of mosquito vectors play key roles in disease transmission, a clear understanding of these aspects is essential for preventing the spread of the disease.


Assuntos
Aedes/química , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Praguicidas/química , Praguicidas/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/química , Animais , Anopheles/química , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Simulação de Acoplamento Molecular , Odorantes , Ligação Proteica
9.
Am J Chin Med ; 44(4): 771-84, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27222063

RESUMO

Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-[Formula: see text] converting enzyme (TACE). Pelargonidin is a well-known red pigment found in plants, and has been reported to have important biological activities that are potentially beneficial to human health. However, little is known about the effects of pelargonidin on EPCR shedding. We investigated this issue by monitoring the effects of pelargonidin on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-[Formula: see text]-, interleukin (IL)-1ß-, and cecal ligation and puncture (CLP)-mediated EPCR shedding and by investigating the underlying mechanism of pelargonidin action. Data demonstrate that pelargonidin induced potent inhibition of PMA-, TNF-[Formula: see text]-, IL-1ß-, and CLP-induced EPCR shedding by inhibiting the phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38, janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2. Pelargonidin also inhibited the expression and activity of PMA-induced TACE in endothelial cells. These results demonstrate the potential of pelargonidin as an anti-EPCR shedding reagent against PMA- and CLP-mediated EPCR shedding.


Assuntos
Proteína ADAM17/metabolismo , Antocianinas/farmacologia , Antígenos CD/metabolismo , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Receptores de Superfície Celular/metabolismo , Proteína ADAM17/antagonistas & inibidores , Proteína ADAM17/genética , Antígenos CD/genética , Regulação para Baixo/efeitos dos fármacos , Receptor de Proteína C Endotelial , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/genética , Humanos , Interleucina-1beta/metabolismo , Fosforilação/efeitos dos fármacos , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/genética , Acetato de Tetradecanoilforbol/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
10.
J Comput Aided Mol Des ; 29(6): 525-39, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25822046

RESUMO

Invasion of the red blood cell by Plasmodium falciparum parasites requires formation of an electron dense circumferential ring called the Moving Junction (MJ). The MJ is anchored by a high affinity complex of two parasite proteins: Apical Membrane Antigen 1 (PfAMA1) displayed on the surface of the parasite and Rhoptry Neck Protein 2 that is discharged from the parasite and imbedded in the membrane of the host cell. Structural studies of PfAMA1 revealed a conserved hydrophobic groove localized to the apical surface that coordinates RON2 and invasion inhibitory peptides. In the present work, we employed computational and biophysical methods to identify competitive P. falciparum AMA1-RON2 inhibitors with the goal of exploring the 'druggability' of this attractive antimalarial target. A virtual screen followed by molecular docking with the PfAMA1 crystal structure was performed using an eight million compound collection that included commercial molecules, the ChEMBL malaria library and approved drugs. The consensus approach resulted in the selection of inhibitor candidates. We also developed a fluorescence anisotropy assay using a modified inhibitory peptide to experimentally validate the ability of the selected compounds to inhibit the AMA1-RON2 interaction. Among those, we identified one compound that displayed significant inhibition. This study offers interesting clues to improve the throughput and reliability of screening for new drug leads.


Assuntos
Antígenos de Protozoários/metabolismo , Antimaláricos/química , Antimaláricos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas de Membrana/metabolismo , Proteínas de Protozoários/metabolismo , Receptores de Superfície Celular/metabolismo , Sequência de Aminoácidos , Antígenos de Protozoários/química , Biofísica , Desenho Assistido por Computador , Polarização de Fluorescência , Concentração Inibidora 50 , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/química , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Receptores de Superfície Celular/antagonistas & inibidores , Reprodutibilidade dos Testes , Bibliotecas de Moléculas Pequenas/química , Ressonância de Plasmônio de Superfície , Fluxo de Trabalho
11.
Circ Res ; 116(6): 1074-95, 2015 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-25767291

RESUMO

Hypertension is the most common modifiable risk factor for cardiovascular disease and death, and lowering blood pressure with antihypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. Despite a plethora of available treatment options, a substantial portion of the hypertensive population has uncontrolled blood pressure. The unmet need of controlling blood pressure in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. In this Compendium Review, we discuss new drugs and interventional treatments that are undergoing preclinical or clinical testing for hypertension treatment. New drug classes, eg, inhibitors of vasopeptidases, aldosterone synthase and soluble epoxide hydrolase, agonists of natriuretic peptide A and vasoactive intestinal peptide receptor 2, and a novel mineralocorticoid receptor antagonist are in phase II/III of development, while inhibitors of aminopeptidase A, dopamine ß-hydroxylase, and the intestinal Na(+)/H(+) exchanger 3, agonists of components of the angiotensin-converting enzyme 2/angiotensin(1-7)/Mas receptor axis and vaccines directed toward angiotensin II and its type 1 receptor are in phase I or preclinical development. The two main interventional approaches, transcatheter renal denervation and baroreflex activation therapy, are used in clinical practice for severe treatment resistant hypertension in some countries. Renal denervation is also being evaluated for treatment of various comorbidities, eg, chronic heart failure, cardiac arrhythmias and chronic renal failure. Novel interventional approaches in early development include carotid body ablation and arteriovenous fistula placement. Importantly, none of these novel drug or device treatments has been shown to prevent cardiovascular disease outcomes or death in hypertensive patients.


Assuntos
Anti-Hipertensivos/uso terapêutico , Drogas em Investigação/uso terapêutico , Hipertensão/terapia , Terapias em Estudo , Animais , Anti-Hipertensivos/farmacologia , Derivação Arteriovenosa Cirúrgica , Barorreflexo/fisiologia , Corpo Carotídeo/cirurgia , Ensaios Clínicos como Assunto , Comorbidade , Descompressão Cirúrgica , Desenho de Fármacos , Drogas em Investigação/farmacologia , Terapia por Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Ablação por Ultrassom Focalizado de Alta Intensidade , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/enzimologia , Hipertensão/patologia , Canais Iônicos/efeitos dos fármacos , Rim/inervação , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/fisiopatologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Modelos Animais , Terapia de Alvo Molecular , Estudos Multicêntricos como Assunto , Estresse Oxidativo/efeitos dos fármacos , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/prevenção & controle , Gravidez , Pressorreceptores/fisiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Superfície Celular/antagonistas & inibidores , Artéria Renal/cirurgia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Stents , Simpatectomia/métodos , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia
12.
Hypertension ; 65(2): 352-61, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25421983

RESUMO

We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/prevenção & controle , Fragmentos de Peptídeos/uso terapêutico , Receptores de Superfície Celular/antagonistas & inibidores , Renina/uso terapêutico , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , Angiotensina II/análise , Angiotensina II/fisiologia , Animais , Anti-Hipertensivos/administração & dosagem , Barorreflexo/efeitos dos fármacos , Ligação Competitiva , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Captopril/farmacologia , Linhagem Celular Tumoral , Acetato de Desoxicorticosterona/toxicidade , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/genética , Hipotálamo/química , Hipotálamo/efeitos dos fármacos , Infusões Intraventriculares , Transporte de Íons/efeitos dos fármacos , Losartan/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neuroblastoma , Fragmentos de Peptídeos/administração & dosagem , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Receptores de Superfície Celular/análise , Renina/administração & dosagem , Cloreto de Sódio/toxicidade , ATPases Vacuolares Próton-Translocadoras/análise , Receptor de Pró-Renina
13.
PLoS One ; 9(4): e94451, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24722342

RESUMO

Many (dietary) bitter compounds, e.g. flavonoids, activate bitter receptor hTAS2R39 in cell-based assays. Several flavonoids, amongst which some flavanones, are known not to activate this receptor. As certain flavanones are known to mask bitter taste sensorially, flavanones might act as bitter receptor antagonists. Fourteen flavanones were investigated for their potential to reduce activation of hTAS2R39 by epicatechin gallate (ECG), one of the main bitter compounds occurring in green tea. Three flavanones showed inhibitory behavior towards the activation of hTAS2R39 by ECG: 4'-fluoro-6-methoxyflavanone, 6,3'-dimethoxyflavanone, and 6-methoxyflavanone (in order of decreasing potency). The 6-methoxyflavanones also inhibited activation of hTAS2R14 (another bitter receptor activated by ECG), though to a lesser extent. Dose-response curves of ECG at various concentrations of the full antagonist 4'-fluoro-6-methoxyflavanone and wash-out experiments indicated reversible insurmountable antagonism. The same effect was observed for the structurally different agonist denatonium benzoate.


Assuntos
Catequina/análogos & derivados , Flavanonas/farmacologia , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Bioensaio , Cálcio/metabolismo , Sinalização do Cálcio , Catequina/antagonistas & inibidores , Catequina/química , Catequina/farmacologia , Flavanonas/química , Expressão Gênica , Células HEK293 , Humanos , Ligação Proteica , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Receptores de Superfície Celular/agonistas , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Relação Estrutura-Atividade , Paladar/fisiologia , Chá/química , Transgenes
14.
Future Med Chem ; 6(5): 515-27, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24649955

RESUMO

The productivity challenge facing the pharmaceutical industry is well documented. Strategies to improve productivity have mainly focused on enhancing efficiency, such as the application of Lean Six Sigma process improvement methods and the introduction of modeling and simulation in place of 'wet' experiments. While these strategies have their benefits, the real challenge is to improve effectiveness by reducing clinical failure rates. We advocate redesigning the screening cascade to identify and optimize novel compounds with improved efficacy against disease, not just with improved potency against the target. There should be greater use of disease-relevant phenotypic screens in conjunction with target-based assays to drive medicinal chemistry optimization. An opportunistic approach to polypharmacology is recommended. There should also be more emphasis on optimization of the molecular mechanism of action incorporating understanding of binding kinetics, consideration of covalent drug strategies and targeting allosteric modulators.


Assuntos
Descoberta de Drogas/métodos , Animais , Modelos Animais de Doenças , Desenho de Fármacos , Descoberta de Drogas/economia , Avaliação Pré-Clínica de Medicamentos , Indústria Farmacêutica , Enzimas/química , Enzimas/metabolismo , Humanos , Farmacocinética , Fenótipo , Polifarmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
15.
Chem Pharm Bull (Tokyo) ; 60(6): 747-51, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22689426

RESUMO

Several novel sulfides from acetone extracts of bulbs of garlic (Allium sativum L.), were identified and investigated. These were named garlicnins B(1) (1), C(1) (2), and D (3), and they were found to have the ability to control macrophage activation. Garlicnins B(1) (1) and C(1) (2) possess a new skeleton of cyclic sulfoxide and their structures of garlicnins B(1) (1) and C(1) (2) were characterized as 3,4-dimethyltetrahydrothiophene-S-oxide derivatives carrying the substitutions of a propenyl and a sulfenic acid, and an allyldithiine and a 1-propene-sulfenic acid (a), respectively. The mechanism of the proposed production of these compounds is discussed. Garlicnin D (3), dithiine-type, was estimated to be derived by addition of (a)+allyl thiosulfenic acid (b) derived from allicin. The identification of these novel sufoxides from onion and garlic accumulates a great deal of new chemistry to the Allium sulfide field, and future pharmacological investigations aid the development of natural, healthy foods and anti-cancer agents that could potentially prevent or combat disease.


Assuntos
Alho , Tiofenos/química , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Alho/química , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Tiofenos/farmacologia
16.
Expert Opin Investig Drugs ; 21(1): 67-81, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22149716

RESUMO

INTRODUCTION: Extensive studies have gone into understanding the differential role of the innate and adaptive arms of the immune system in the context of various diseases. Receptor-ligand interactions are responsible for mediating cross-talk between the innate and adaptive arms of the immune system, so as to effectively counter the pathogenic challenge. While TLRs remain the best studied innate immune receptor, many other receptor families are now coming to the fore for their role in various pathologies. Research has focused on the discovery of novel agonists and antagonists for these receptors as potential therapeutics. AREAS COVERED: In this review, we present an overview of the recent advances in the discovery of drugs targeting important receptors such as G-protein coupled receptors, TRAIL-R, IL-1ß receptor, PPARs, etc. All these receptors play a critical role in the modulation of the immune response. We focus on the recent paradigms applied for the generation of specific and effective therapeutics for these receptors and their status in clinical trials. EXPERT OPINION: Non-specific activation by antagonist/agonist is a difficult problem to dodge. This demands innovation in ligand designing with the use of strategies such as allosterism and dual-specific ligands. Rigorous preclinical and clinical studies are required in transforming a compound to a therapeutic.


Assuntos
Sistema Imunitário/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Receptores Imunológicos , Animais , Ensaios Clínicos como Assunto , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Sistema Imunitário/metabolismo , Receptores de Superfície Celular/agonistas , Receptores de Superfície Celular/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Imunológicos/agonistas , Receptores Imunológicos/antagonistas & inibidores
17.
Eur Heart J ; 32(22): 2739-47, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21951628

RESUMO

The conventional antihypertensive therapies including renin-angiotensin-aldosterone system antagonists (converting enzyme inhibitors, receptor blockers, renin inhibitors, and mineralocorticoid receptor blockers), diuretics, ß-blockers, and calcium channel blockers are variably successful in achieving the challenging target blood pressure values in hypertensive patients. Difficult to treat hypertension is still a commonly observed problem world-wide. A number of drugs are considered to be used as novel therapies for hypertension. Renalase supplementation, vasopeptidase inhibitors, endothelin antagonists, and especially aldosterone antagonists (aldosterone synthase inhibitors and novel selective mineralocorticoid receptor blockers) are considered an option in resistant hypertension. In addition, the aldosterone antagonists as well as (pro)renin receptor blockers or AT(2) receptor agonists might attenuate end-organ damage. This array of medications has now been complemented by a number of new approaches of non-pharmacological strategies including vaccination, genomic interference, controlled breathing, baroreflex activation, and probably most successfully renal denervation techniques. However, the progress on innovative therapies seems to be slow and the problem of resistant hypertension and proper blood pressure control appears to be still persisting. Therefore the regimens of currently available drugs are being fine-tuned, resulting in the establishment of several novel fixed-dose combinations including triple combinations with the aim to facilitate proper blood pressure control. It remains an exciting question which approach will confer the best blood pressure control and risk reduction in this tricky disease.


Assuntos
Anti-Hipertensivos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Hipertensão/terapia , Sistema Renina-Angiotensina/efeitos dos fármacos , Antagonistas Adrenérgicos beta/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Citocromo P-450 CYP11B2/antagonistas & inibidores , Combinação de Medicamentos , Antagonistas dos Receptores de Endotelina , Terapia Genética , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Monoaminoxidase/efeitos dos fármacos , Pressorreceptores/fisiologia , Inibidores de Proteases/uso terapêutico , Receptores de Superfície Celular/antagonistas & inibidores , Renina/antagonistas & inibidores , Terapia Respiratória/métodos , Simpatectomia/métodos , Vacinas , Yoga , Receptor de Pró-Renina
18.
Cancer Sci ; 102(1): 206-11, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21073634

RESUMO

Tumor-associated macrophages (TAM) of M2 phenotype promote tumor proliferation and are associated with a poor prognosis in patients with glioblastoma. We screened the natural compounds possessing an inhibitory effect on M2 polarization in human monocyte-derived macrophages. Among 130 purified natural compounds examined, corosolic acid significantly inhibited the expression of CD163, one of the phenotype markers of M2 macrophages, and also suppressed the secretion of IL-10, one of the anti-inflammatory cytokines preferentially produced by M2 macrophages, thus suggesting that corosolic acid suppresses M2 polarization of macrophages. Furthermore, corosolic acid inhibited the proliferation of glioblastoma cells, U373 and T98G, and the activation of signal transducer and activator of transcription-3 (STAT3) and nuclear factor-kappa B (NF-κB) in both human macrophages and glioblastoma cells. These results indicate that corosolic acid suppresses the M2 polarization of macrophages and tumor cell proliferation by inhibiting both STAT3 and NF-κB activation. Therefore, corosolic acid might be a potential new tool for tumor prevention and therapy.


Assuntos
Glioblastoma/tratamento farmacológico , Macrófagos/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Extratos Vegetais/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Triterpenos/farmacologia , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Linhagem Celular Tumoral , Polaridade Celular , Proliferação de Células/efeitos dos fármacos , Glioblastoma/patologia , Humanos , Macrófagos/fisiologia , NF-kappa B/fisiologia , Receptores de Superfície Celular/análise , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/efeitos dos fármacos
19.
Plant Cell Physiol ; 51(12): 2047-59, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21047814

RESUMO

We identified two phenylquinazoline compounds in a large-scale screening for cytokinin antagonists in yeast expressing the Arabidopsis cytokinin receptor cytokinin response 1/histidine kinase 4 (CRE1). After chemical modifications, we obtained compound S-4893, which non-competitively inhibited binding of the natural ligand 2-isopentenyladenine to CRE1. S-4893 antagonized cytokinin-induced activation of the Arabidopsis response regulator 5 promoter in Arabidopsis. Importantly, S-4893 had no detectable intrinsic cytokinin agonist activity in Arabidopsis or in the transformed yeast system. Cytokinin bioassay further demonstrated that S-4893 antagonized cytokinin-induced stimulation of callus formation and inhibition of root elongation. S-4893 also promoted seminal, crown and lateral root growth in rice, suggesting that S-4893 could potentially promote root growth in a variety of agronomically important plants. We believe S-4893 will be a useful tool in functional studies of cytokinin action in a wide range of plants and a lead compound for the development of useful root growth promoters in agriculture.


Assuntos
Proteínas de Arabidopsis/antagonistas & inibidores , Arabidopsis/crescimento & desenvolvimento , Oryza/crescimento & desenvolvimento , Raízes de Plantas/crescimento & desenvolvimento , Quinazolinas/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Arabidopsis/genética , Arabidopsis/fisiologia , Proteínas de Arabidopsis/biossíntese , Proteínas de Arabidopsis/genética , Citocininas/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Isopenteniladenosina/farmacologia , Oryza/genética , Oryza/fisiologia , Reguladores de Crescimento de Plantas/antagonistas & inibidores , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Plantas Geneticamente Modificadas/fisiologia , Ligação Proteica , Proteínas Quinases/biossíntese , Proteínas Quinases/genética , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/isolamento & purificação , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/genética , Plântula/crescimento & desenvolvimento , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/síntese química , Leveduras/genética , Leveduras/metabolismo
20.
Mol Cancer Ther ; 9(11): 3033-40, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20858723

RESUMO

Cellular uptake of cobalamin (Cbl) occurs by endocytosis of transcobalamin saturated with Cbl by the transcobalamin receptor (TCblR/CD320). The cell cycle-associated overexpression of this receptor in many cancer cells provides a suitable target for delivering chemotherapeutic drugs and cytotoxic molecules to these cells while minimizing the effect on the normal cell population. We have used monoclonal antibodies to the extracellular domain of TCblR to deliver saporin-conjugated secondary antibody to various cell lines propagating in culture. A molar ratio of 2.5:10 nmol/L of primary:secondary antibody concentration was identified as the lowest concentration needed to produce the optimum cytotoxic effect. The effect was more pronounced when cells were seeded at lower density, suggesting lack of cell division in a fraction of the cells at higher density as the likely explanation. Cells in suspension culture, such as K562 and U266 cells, were more severely affected than adherent cultures, such as SW48 and KB cells. This differential effect of the anti-TCblR-saporin antibody conjugate and the ability of an anti-TCblR antibody to target proliferating cells were further evident by the virtual lack of any effect on primary skin fibroblasts and minimal effect on bone marrow cells. These results indicate that preferential targeting of some cancer cells could be accomplished through the TCblR.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígenos CD/imunologia , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Proteínas Inativadoras de Ribossomos Tipo 1/administração & dosagem , Antígenos CD/genética , Antígenos CD/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/imunologia , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imunotoxinas/administração & dosagem , Células K562 , Neoplasias/genética , Neoplasias/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Saporinas , Transfecção
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