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1.
Eur J Med Chem ; 187: 111924, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31855792

RESUMO

Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis. The resultant ferrocenyl 1,3-benzoxazine compounds displayed high potency and selectivity against the investigated diseases, with IC50 values in the low and sub-micromolar range against both chloroquine-sensitive (3D7) and resistant (Dd2) strains of the Plasmodium falciparum parasite. On the other hand, antitrypanosomal (Trypanosoma brucei brucei) potencies were observed between 0.15 and 38.6 µM. The majority of the compounds were not active against breast cancer cells (HCC70), however, for the toxic compounds, IC50 values ranged from 11.0 to 30.5 µM. Preliminary structure-activity relationships revealed the basic oxazine sub-ring and lipophilic benzene substituents to be conducive for biological efficacy of the ferrocenyl 1,3-benzoxazines reported in the study. DNA interaction studies performed on the most promising compound 4c suggested that DNA damage may be one possible mode of action of this class of compounds.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Benzoxazinas/farmacologia , Reposicionamento de Medicamentos , Plasmodium falciparum/efeitos dos fármacos , Polímeros/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzoxazinas/síntese química , Benzoxazinas/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Polímeros/síntese química , Polímeros/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
2.
Life Sci ; 232: 116670, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31330139

RESUMO

AIM: Migraine is a neurological debilitating disorder. Previous studies have shown that cannabinoid receptor agonists have analgesic effects in various models of pain. In this study, therefore, we investigated anti-nociceptive effects of WIN 55,212-2, and the role of either CB1 or CB2 receptors in nitroglycerine (NTG)-induced animal model of migraine. METHODS: The present study was conducted on both male and female rats receiving NTG (10 mg/kg, i.p.) to induce acute (single dose of NTG) and chronic (repetitive doses of NTG) models of migraine. Additionally, three groups received WIN 55,212-2 (0.33, 1, 3 mg/kg, i.p.) 45 min before behavioral tests. Additionally, AM251 and AM630 (CB1 and CB2 receptor antagonist, respectively, 1 mg/kg, i.p.) were used to evaluate the possible involvement of CB1 and CB2 receptors during the protective effects of WIN 55,212-2. KEY FINDINGS: We found that NTG (10 mg/kg, i.p.) in both acute and chronic models increased sensitivity to pain. In acute model, we found that WIN 55,212-2 (almost high doses) decreases the level of pain mainly through CB1 receptor due to CB1 antagonist abrogates its protective effects, however, in formalin test CB2 receptors also had crucial roles in both phases at 3 mg/kg of WIN 55,212-2. In chronic model, WIN 55,212-2 (0.33, 1 and 3 mg/kg) significantly attenuated NTG-induced hyperalgesia through both CB1 and CB2 receptors. SIGNIFICANCE: Our data supported the argument that activation of CB1 and CB2 receptors by WIN 55,212-2 may be considered a new medication for migraine, however in lack of each receptor leads to different responses from deletion to the reduction of analgesic effects.


Assuntos
Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/prevenção & controle , Morfolinas/farmacologia , Naftalenos/farmacologia , Nitroglicerina/toxicidade , Animais , Benzoxazinas/administração & dosagem , Agonistas de Receptores de Canabinoides/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Masculino , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Ratos
3.
J Agric Food Chem ; 67(33): 9254-9264, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31356740

RESUMO

In continuation of our search for potent protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) inhibitors, we designed and synthesized a series of novel herbicidal cycloalka[d]quinazoline-2,4-dione-benzoxazinones. The bioassay results of these synthesized compounds indicated that most of the compounds exhibited very strong Nicotiana tabacum PPO (NtPPO) inhibition activity. More than half of the 37 synthesized compounds displayed over 80% control of all three tested broadleaf weeds at 37.5-150 g ai/ha by postemergent application, and a majority of them showed no phytotoxicity toward at least one kind of crop at 150 g ai/ha. Promisingly, 17i (Ki = 6.7 nM) was 6 and 4 times more potent than flumioxazin (Ki = 46 nM) and trifludimoxazin (Ki = 31 nM), respectively. Moreover, 17i displayed excellent, broad-spectrum herbicidal activity, even at levels as low as 37.5 g ai/ha, and it was determined to be safe for wheat at 150 g ai/ha in postemergent application, indicating the great potential for 17i development as a herbicide for weed control in wheat fields.


Assuntos
Benzoxazinas/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Herbicidas/química , Herbicidas/farmacologia , Proteínas de Plantas/antagonistas & inibidores , Protoporfirinogênio Oxidase/antagonistas & inibidores , Quinazolinas/química , Benzoxazinas/farmacologia , Desenho de Drogas , Cinética , Proteínas de Plantas/química , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/enzimologia , Protoporfirinogênio Oxidase/química , Relação Quantitativa Estrutura-Atividade , Quinazolinas/farmacologia , Tabaco/efeitos dos fármacos , Tabaco/enzimologia , Controle de Plantas Daninhas
4.
Eur J Med Chem ; 178: 667-686, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31228810

RESUMO

PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI3K/mTOR inhibitor with an IC50 of 0.63 nM against PI3Kα. In a wide panel of protein kinases assays, no off-target interactions of 8d-1 were identified. 8d-1 was orally available, and displayed favorable pharmacokinetic parameters in mice (oral bioavailability of 24.1%). In addition, 8d-1 demonstrated significant efficiency in Hela/A549 tumor xenograft models (TGI of 87.7% at dose of 50 mg/kg in Hela model) without causing significant weight loss and toxicity during 30 days treatment. Based on the bioassays, compound 8d-1 could be used as an anti-cancer drug candidate.


Assuntos
Antineoplásicos/farmacologia , Benzoxazinas/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Benzoxazinas/administração & dosagem , Benzoxazinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo
5.
Front Neural Circuits ; 13: 37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31164809

RESUMO

The sole output of the retina to the brain is a signal that results from the integration of excitatory and inhibitory synaptic inputs at the level of retinal ganglion cells (RGCs). Endogenous cannabinoids (eCBs) are found throughout the central nervous system where they modulate synaptic excitability. Cannabinoid receptors and their ligands have been localized to most retinal neurons in mammals, yet their impact on retinal processing is not well known. Here, we set out to investigate the role of the cannabinoid system in retinal signaling using electrophysiological recordings from ON-sustained (ON-S) RGCs that displayed morphological and physiological signatures of ON alpha RGCs in dark adapted mouse retina. We studied the effect of the cannabinoid agonist WIN55212-2 and the inverse agonist AM251 on the spatial tuning of ON-S RGCs. WIN55212-2 significantly reduced their spontaneous spiking activity and responses to optimal spot size as well as altered their spatial tuning by reducing light driven excitatory and inhibitory inputs to RGCs. AM251 produced the opposite effect, increasing spontaneous spiking activity and peak response as well as increasing inhibitory and excitatory inputs. In addition, AM251 sharpened the spatial tuning of ON-S RGCs by increasing the inhibitory effect of the surround. These results demonstrate the presence of a functional cannabinergic system in the retina as well as sensitivity of ON-RGCs to cannabinoids. These results reveal a neuromodulatory system that can regulate the sensitivity and excitability of retinal synapses in a dynamic, activity dependent manner and that endocannabinoids may play a significant role in retinal processing.


Assuntos
Canabinoides/metabolismo , Potenciais Evocados Visuais/fisiologia , Células Ganglionares da Retina/metabolismo , Transmissão Sináptica/fisiologia , Animais , Benzoxazinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Potenciais Evocados Visuais/efeitos dos fármacos , Luz , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
6.
Drugs ; 79(9): 997-1008, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31119643

RESUMO

Tiotropium/olodaterol (Stiolto® Respimat®; Spiolto® Respimat®) is an inhaled fixed-dose combination of the long-acting muscarinic antagonist tiotropium bromide (hereafter referred to as tiotropium) and the long-acting ß2-adrenergic agonist olodaterol. It is available in several countries, including the USA, Japan, China and those of the EU, where it is indicated for the long-term maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). The efficacy of tiotropium/olodaterol 5/5 µg/day in patients with COPD was evaluated in phase III or IV trials of 6-52 weeks' duration. Tiotropium/olodaterol improved lung function to a greater extent than each of its individual components or placebo in 12- and 52-week trials. In 6-week trials, tiotropium/olodaterol provided greater lung function benefits over 24 h than the individual components, placebo or twice-daily fluticasone propionate/salmeterol. Tiotropium/olodaterol also demonstrated beneficial effects on health-related quality of life (HR-QoL), dyspnoea, inspiratory capacity, exercise endurance and the need for rescue medication. In an 8-week open-label trial, umeclidinium/vilanterol was superior to tiotropium/olodaterol for the primary endpoint of trough forced expiratory volume in 1 s. The tolerability profile of tiotropium/olodaterol was generally similar to that of the individual components. In conclusion, tiotropium/olodaterol provides a useful option for the maintenance treatment of COPD, with the convenience of once-daily administration via a single inhaler.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Benzoxazinas/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/uso terapêutico , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Benzoxazinas/farmacologia , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Fase IV como Assunto , Combinação de Medicamentos , Humanos , Antagonistas Muscarínicos/farmacologia , Qualidade de Vida , Brometo de Tiotrópio/farmacologia , Resultado do Tratamento
7.
J Acquir Immune Defic Syndr ; 81(2): 163-165, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31095006

RESUMO

BACKGROUND: Progestin contraception has been linked to higher risk of female to male sexual HIV transmission. SETTING: A clinical trial among HIV-infected women in Lilongwe, Malawi, randomized to initiation of depomedroxyprogesterone acetate injectable or levonorgestrel implant, and followed for up to 33 months, with the outcome of HIV shedding in the genital tract. METHODS: We compared the frequency and magnitude of HIV genital shedding before and after initiation of contraception and between study arms among women receiving antiretroviral therapy (ART). Genital HIV RNA was measured in TearFlo Strips using the Abbott RealTime HIV-1 assay. RESULTS: Among 68 HIV-infected Malawian women on ART, randomization to depot medroxyprogesterone acetate compared with the levonorgestrel implant was not associated with genital shedding and neither progestin contraceptive was associated with increased HIV genital shedding, for up to 33 months after contraceptive initiation. Having detectable plasma HIV [adjusted risk ratio (RR) 10.5; 95% confidence interval (CI): 3.18 to 34.7] and detectable genital shedding before contraceptive initiation (adjusted RR 3.53; 95% CI: 1.31 to 9.47) were associated with a higher risk of detectable genital shedding after contraceptive initiation. Higher plasma efavirenz concentrations were associated with a lower risk of detectable genital shedding (adjusted RR 0.85; 95% CI: 0.73 to 0.99, per increase of 1000 ng/mL). CONCLUSION: Among HIV-infected women receiving ART, our results provide evidence that progestin contraception does not impact women's risk of transmission of HIV to partners. Our finding that detectable genital shedding before contraceptive initiation independently predicts shedding suggests that there may be other individual-level biological or behavioral factors that increase the risk for shedding.


Assuntos
Antirretrovirais/uso terapêutico , Anticoncepção , Infecções por HIV/tratamento farmacológico , Progestinas , Eliminação de Partículas Virais/efeitos dos fármacos , Adulto , Antirretrovirais/farmacologia , Benzoxazinas/sangue , Benzoxazinas/farmacologia , Colo do Útero/virologia , Anticoncepcionais Femininos/farmacologia , Implantes de Medicamento , Feminino , Seguimentos , Genitália Feminina , Infecções por HIV/transmissão , Infecções por HIV/virologia , Humanos , Levanogestrel/farmacologia , Levanogestrel/uso terapêutico , Malaui , Acetato de Medroxiprogesterona/farmacologia , Acetato de Medroxiprogesterona/uso terapêutico , Resultado do Tratamento
8.
Expert Opin Drug Metab Toxicol ; 15(5): 407-415, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30991855

RESUMO

INTRODUCTION: About 40% of patients with epilepsy are associated with drug-resistant seizures, therefore there has been a continuous search for novel treatment approaches. In experimental studies, natural and synthetic cannabimimetic compounds alone or combined with antiepileptic drugs (AEDs) have been extensively studied and cannabidiol, a naturally occurring compound, has been involved in a number of clinical trials. Areas covered: The authors have performed a literature search (PubMed database up to December 2018) for studies evaluating interactions between AEDs and cannabinoid receptor ligands in experimental models of seizures. Clinical data relate to the add-on treatment with cannabidiol. Expert opinion: WIN55,212-2 mesylate (WIN, a non-selective agonist of CB1 and CB2 receptors) significantly potentiated the anticonvulsant activity of various  AEDs in mice. Profound neurotoxic effects accompanied combinations of WIN with conventional AEDs. Among conventional and newer AEDs, ACEA (a selective CB1 receptor agonist) enhanced the protective action of phenobarbital and levetiracetam without accompanying adverse effects or pharmacokinetic interactions. Cannabidiol proved effective in clinical trials, reducing seizure frequency and the most frequently observed adverse effects were diarrhea, somnolence, and poor appetite. The retention rate was within 14-24% (12-14 weeks - 1 year) but it reached the level of 35% after 2 years.


Assuntos
Anticonvulsivantes/administração & dosagem , Canabinoides/administração & dosagem , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacologia , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Benzoxazinas/farmacologia , Canabinoides/efeitos adversos , Canabinoides/farmacologia , Modelos Animais de Doenças , Interações de Medicamentos , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Humanos , Camundongos , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Morfolinas/farmacologia , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Naftalenos/farmacologia
9.
Ther Adv Respir Dis ; 13: 1753466619843426, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002020

RESUMO

Long-acting bronchodilators are the cornerstone of pharmacologic treatment of chronic obstructive pulmonary disease (COPD). Spiolto® or Stiolto® is a fixed-dose combination (FDC) containing two long-acting bronchodilators, the long-acting muscarinic receptor antagonist tiotropium (TIO) and the long-acting ß2-adrenoceptor agonist olodaterol (OLO), formulated in the Respimat® Soft Mist™ inhaler. A total of 13 large, multicentre studies of up to 52 weeks' duration have documented its efficacy in more than 15,000 patients with COPD. TIO/OLO 5/5 µg FDC significantly increases pulmonary function compared with placebo and its respective constituent mono-components TIO 5 µg and OLO 5 µg. TIO/OLO 5/5 µg also results in statistically and clinically significant improvements in patient-reported outcomes, such as dyspnoea, use of rescue medication, and health status. Addition of OLO 5 µg to TIO 5 µg reduces the rate of moderate-to-severe exacerbations by approximately 10%. Compared with placebo and TIO 5 µg, TIO/OLO 5/5 µg significantly improves exercise capacity (e.g. endurance time) and physical activity, the latter increase being reached by a unique combination behavioural modification intervention, dual bronchodilatation and exercise training. Overall, the likelihood for patients to experience a clinically significant benefit is higher with TIO/OLO 5/5 µg than with its constituent mono-components, which usually yield smaller improvements which do not always reach statistical significance, compared with baseline or placebo. This supports the early introduction of TIO/OLO 5/5 µg in the management of patients with symptomatic COPD.


Assuntos
Benzoxazinas/administração & dosagem , Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/administração & dosagem , Benzoxazinas/farmacologia , Broncodilatadores/farmacologia , Preparações de Ação Retardada , Combinação de Medicamentos , Humanos , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Índice de Gravidade de Doença , Brometo de Tiotrópio/farmacologia
10.
J Pharmacol Sci ; 139(4): 275-279, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30928089

RESUMO

OBJECTIVE: This study aims to investigate the prevalence and types of drug resistance mutations among patients failing first-line antiretroviral therapy (ART). METHODS: Plasma samples from 112 patients with human immunodeficiency virus-1 (HIV-1) were collected for virus RNA extract and gene amplification. The mutations related to drug resistance were detected and the incidence was statistically analyzed, and the drug resistance rate against common drugs was also evaluated. RESULTS: 103 cases were successfully amplified, and the main drug resistance mutations in the reverse transcriptase (RT) region were M184V (50.49%), K103N (28.16%), Y181C (25.24%), and K65R (27.18%), while no drug main resistance mutation was found in the protease (PR) region. The incidence of drug resistance mutations was significantly different among patients with different ages, routes of infection, duration of treatment, initial ART regimens and viral load. The drug resistance rate to the common drugs was assessed, including Efavirenz (EFV, 71.84%), Nevirapine (NVP, 74.76%), Lamivudine (3TC, 66.02%), Zidovudine (AZT, 4.85%), Stavudine (D4T, 16.51%), and Tenofovir (TDF, 21.36%). CONCLUSION: The drug resistance mutations to NRTIs and NNRTIs are complex and highly prevalent, which was the leading cause of first-line ART failure. This study provides significant theoretical support for developing the second-line and third-line therapeutic schemes.


Assuntos
Terapia Antirretroviral de Alta Atividade , Antivirais/farmacologia , Benzoxazinas/farmacologia , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Mutação , Nevirapina/farmacologia , Adulto , Feminino , Humanos , Incidência , Lamivudina/farmacologia , Masculino , Pessoa de Meia-Idade , Estavudina/farmacologia , Tenofovir/farmacologia , Falha de Tratamento , Carga Viral , Zidovudina/farmacologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-30980840

RESUMO

S 47445 is a positive allosteric modulator of glutamate AMPA-type receptors that possesses procognitive, neurotrophic and enhancing synaptic plasticity properties. Its chronic administration promotes antidepressant- and anxiolytic-like effects in different rodent models of depression. We have evaluated the behavioral effects of S 47445 in the bilateral olfactory bulbectomy mice model (OB) and the adaptive changes in those proteins associated to brain neuroplasticity (BDNF and mTOR pathway). Following OB surgery, adult C57BL/6J male mice were chronically administered S 47445 (1, 3 and 10 mg/kg/day; i.p.) and fluoxetine (18 mg/kg/day; i.p.), and then behaviorally tested in the open field test. Afterwards, the expression levels of BDNF, mTOR, phospho-mTOR, 4EBP1 and phospho-4EBP1 were evaluated in hippocampus and prefrontal cortex. Both drugs reduced the OB-induced locomotor activity, a predictive outcome of antidepressant efficacy, with a similar temporal pattern of action. S 47445, but not fluoxetine, showed an anxiolytic effect as reflected by an increased central activity. Chronic administration of S 47445 reversed OB-induced changes in BDNF and phopho-mTOR expression in hippocampus but not in prefrontal cortex. The chronic administration of S 47445 induced antidepressant- and anxiolytic-like effects at low-medium doses (1 and 3 mg/kg/day, i.p.) associated with the reversal of OB-induced changes in hippocampal BDNF and mTOR signaling pathways.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Benzoxazinas/farmacologia , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Bulbo Olfatório/cirurgia , Triazinas/farmacologia , Animais , Antidepressivos de Segunda Geração/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fluoxetina/farmacologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Bulbo Olfatório/fisiologia , Receptores de AMPA/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
12.
Mol Immunol ; 109: 140-148, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30951933

RESUMO

Bladder cancer (BC) is a malignant tumor of urinary epithelium. Gemcitabine is an introduced treatment for BC and also has immunomodulatory function, but the immunoregulation mechanism is not clear. In this study, we found that gemcitabine-treated BC cell recruited more monocyte-myeloid-derived suppressed cells (M-MDSCs), which played a significant role in immune suppression and contributed to cancer progression. We found that this phenomenon was induced by Chemokine (C-C motif) ligand 2 (CCL2), an M-MDSCs recruitment related monomeric polypeptide. Gemcitabine treatment promotes the generation of CCL2 and CCL2 could attach to C-C chemokine receptor type 2 (CCR2) to recruit M-MDSCs. We used RS 504393, a selective CCR2 antagonist, to inhibit the recruitment of M-MDSCs. RS 504393 improved the prognosis by blocking chemotaxis of M-MDSCs, and this finding sheds lights on how to prevent and alleviate the side effects occurred on the gemcitabine-treated BC patients.


Assuntos
Benzoxazinas/uso terapêutico , Desoxicitidina/análogos & derivados , Células Supressoras Mieloides/patologia , Compostos de Espiro/uso terapêutico , Microambiente Tumoral/imunologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia , Animais , Benzoxazinas/química , Benzoxazinas/farmacologia , Linhagem Celular Tumoral , Quimiocina CCL2/biossíntese , Desoxicitidina/química , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/patologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Análise de Sobrevida , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Microambiente Tumoral/efeitos dos fármacos , Neoplasias da Bexiga Urinária/patologia
13.
Cell Mol Neurobiol ; 39(5): 605-617, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30850915

RESUMO

Severe and poorly treated pain often accompanies breast cancer. Thus, novel mechanisms involved in breast cancer-induced pain should be investigated. Then, it is necessary to characterize animal models that are reliable with the symptoms and progression of the disease as observed in humans. Explaining cancer-induced nociception in a murine model of breast carcinoma was the aim of this study. 4T1 (104) lineage cells were inoculated in the right fourth mammary fat pad of female BALB/c mice; after this, mechanical and cold allodynia, or mouse grimace scale (MGS) were observed for 30 days. To determine the presence of bone metastasis, we performed the metastatic clonogenic test and measure calcium serum levels. At 20 days after tumor induction, the antinociceptive effect of analgesics used to relieve pain in cancer patients (acetaminophen, naproxen, codeine or morphine) or a cannabinoid agonist (WIN 55,212-2) was tested. Mice inoculated with 4T1 cells developed mechanical and cold allodynia and increased MGS. Bone metastasis was confirmed using the clonogenic assay, and hypercalcemia was observed 20 days after cells inoculation. All analgesic drugs reduced the mechanical and cold allodynia, while the MGS was decreased only by the administration of naproxen, codeine, or morphine. Also, WIN 55,212-2 improved all nociceptive measures. This pain model could be a reliable form to observe the mechanisms of breast cancer-induced pain or to observe the efficacy of novel analgesic compounds.


Assuntos
Neoplasias Mamárias Animais/patologia , Nociceptividade , Acetaminofen/farmacologia , Acetaminofen/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Benzoxazinas/farmacologia , Benzoxazinas/uso terapêutico , Neoplasias Ósseas/sangue , Neoplasias Ósseas/secundário , Cálcio/sangue , Canabinoides/agonistas , Linhagem Celular Tumoral , Codeína/farmacologia , Codeína/uso terapêutico , Modelos Animais de Doenças , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Locomoção , Neoplasias Mamárias Animais/sangue , Neoplasias Mamárias Animais/complicações , Neoplasias Mamárias Animais/fisiopatologia , Camundongos Endogâmicos BALB C , Morfina/farmacologia , Morfina/uso terapêutico , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Naproxeno/farmacologia , Naproxeno/uso terapêutico , Medição da Dor
14.
Pulm Pharmacol Ther ; 56: 39-50, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30876907

RESUMO

Combining a long-acting ß2-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the LAMA tiotropium bromide, and the LABA olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/olodaterol combination induced a significant synergistic relaxant response (P < 0.05 vs. expected additive effect) in medium bronchi and small airways pre-contracted by carbachol, by enhancing relaxation +22.13 ± 4.42% and +26.31 ± 12.39%, respectively. The combination of tiotropium bromide and olodaterol also reduced the airway smooth muscle contractility elicited by transmural stimulation by 73.60 ± 3.10%. The extent of synergy was strong to very strong, and was supported by the release of neuronal acetylcholine, cyclic adenosine monophosphate levels, and activation of iberiotoxin-sensitive KCa++ channels. Conversely, the interaction between tiotropium bromide and olodaterl was independent of the activity at M2 muscarinic receptors. These results indicate that tiotropium bromide/olodaterol combination leads to a potent and durable synergistic relaxation of human medium bronchi and small airways. Further pharmacological studies are needed to confirm these results in clinical settings.


Assuntos
Benzoxazinas/farmacologia , Brônquios/efeitos dos fármacos , Broncodilatadores/farmacologia , Músculo Liso/efeitos dos fármacos , Brometo de Tiotrópio/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Idoso , Benzoxazinas/administração & dosagem , Brônquios/metabolismo , Broncodilatadores/administração & dosagem , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Músculo Liso/metabolismo , Brometo de Tiotrópio/administração & dosagem
15.
Mol Neurobiol ; 56(9): 6472-6486, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30838518

RESUMO

Development of progenitors in the embryonic retina is modulated by signaling molecules, and cannabinoid receptors are highly expressed in the early developing retina. Here, we investigated whether the CB1/CB2 receptor agonist WIN 5212-2 (WIN) modulated the proliferation, viability, and calcium responses in chick embryo retinal progenitors in culture. A decline in [3H]-thymidine incorporation was observed when cultures were incubated with 0.5-1.0 µM WIN, an effect that was mimicked by URB602 and URB597, inhibitors of the monoacylglycerol lipase and fatty acid amide hydrolase, respectively. A reduction in the number of proliferating cell nuclear antigen-positive nuclei was also noticed in WIN-treated cultures, suggesting that activation of cannabinoid receptors decreases the proliferation of cultured retinal progenitors. WIN (0.5-5.0 µM), but not capsaicin, decreased retinal cell viability, an effect that was blocked by CB1 and CB2 receptor antagonists and by the P2X7 receptor antagonist A438079, implicating this nucleotide receptor in the cannabinoid-mediated cell death. Treatment with WIN also induced an increase in mitochondrial superoxide and P2X7 receptor-mediated uptake of sulforhodamine B in the cultured cells. While a high proportion of cultured cells responded to glutamate, GABA, and 50 mM KCl with intracellular calcium shifts, very few cells responded to the activation of P2X7 receptors by ATP. Noteworthy, while decreasing the number of cells responding to glutamate, GABA, and KCl, treatment of the cultures with WIN induced a significant increase in the number of cells responding to 1 mM ATP, suggesting that activation of cannabinoid receptors primes P2X7 receptor calcium signaling in retinal progenitors in culture.


Assuntos
Apoptose/efeitos dos fármacos , Canabinoides/farmacologia , Neuroglia/citologia , Receptores Purinérgicos P2X7/metabolismo , Retina/citologia , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/metabolismo , Animais , Benzoxazinas/farmacologia , Cálcio/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Corantes Fluorescentes/metabolismo , Morfolinas/farmacologia , Naftalenos/farmacologia , Nestina/metabolismo , Fenótipo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Células-Tronco/efeitos dos fármacos
16.
Biochemistry ; 58(16): 2176-2187, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30900874

RESUMO

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are considered noncompetitive inhibitors that structurally alter reverse transcriptase (RT) and dramatically decrease catalysis. In this report, biochemical analysis with various divalent cations was used to demonstrate that NNRTIs and divalent cation-dNTP complexes are mutually exclusive, inhibiting each other's binding to RT/primer/template (RT-P/T) complexes. The binding of catalytically competent divalent cation-dNTP complexes to RT-P/T was measured with Mg2+, Mn2+, Zn2+, Co2+, and Ni2+ using Ca2+, a noncatalytic cation, for displacement. Binding strength order was Mn2+ ≈ Zn2+ ≫ Co2+ > Mg2+ ≈ Ni2+. Consistent with but not exclusive to mutually exclusive binding, primer extension assays showed that stronger divalent cation-dNTP complexes were more resistant to NNRTIs (efavirenz (EFV), rilpivirine (RPV), and nevirapine (NVP)). Filtration assays demonstrated that divalent cation-dNTP complexes inhibited the binding of 14C-labeled EFV to RT-P/T with stronger binding complexes formed with Mn2+ inhibiting more potently than those with Mg2+. Conversely, filter binding assays demonstrated that EFV inhibited 3H-labeled dNTP binding to RT-P/T complexes with displacement of Mn2+-dNTP complexes requiring much greater concentrations of EFV than the more weakly bound Mg2+-dNTP complexes. EFV bound relatively weakly to the NNRTI resistant K103N RT; but, binding was modestly enhanced in the presence of P/T, and EFV was easily displaced by divalent cation-dNTP complexes. This suggests that K103N overcomes EFV inhibition mostly by binding more weakly to the drug and is in contrast to other reports that indicate K103N has little to no effect on drug or dNTP binding. Overall, this biochemical analysis supports recent biophysical analyses of NNRTI-RT interactions that indicate mutually exclusive binding.


Assuntos
Benzoxazinas/metabolismo , Cátions Bivalentes/metabolismo , Transcriptase Reversa do HIV/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Rilpivirina/metabolismo , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , Sequência de Bases , Benzoxazinas/farmacologia , Ligação Competitiva , Cátions Bivalentes/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Nucleotídeos/genética , Nucleotídeos/metabolismo , Ligação Proteica , Inibidores da Transcriptase Reversa/farmacologia , Rilpivirina/farmacologia
17.
Neurobiol Dis ; 125: 135-145, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30716469

RESUMO

Endocannabinoids (eCBs) and serotonin (5-HT) play a neuromodulatory role in the central nervous system. Both eCBs and 5-HT regulate neuronal excitability and their pharmacological potentiation has been shown to control seizures in pre-clinical and human studies. Compelling evidence indicates that eCB and 5-HT systems interact to modulate several physiological and pathological brain functions, such as food intake, pain, drug addiction, depression, and anxiety. Nevertheless, there is no evidence of an eCB/5-HT interaction in experimental and human epilepsies, including status epilepticus (SE). Here, we performed video-EEG recording in behaving rats treated with the pro-convulsant agent pilocarpine (PILO), in order to study the effect of the activation of CB1/5-HT2 receptors and their interaction on SE. Synthetic cannabinoid agonist WIN55,212-2 (WIN) decreased behavioral seizure severity of PILO-induced SE at 2 mg/kg (but not at 1 and 5 mg/kg, i.p.), while 5-HT2B/2C receptor agonist RO60-0175 (RO; 1, 3, 10 mg/kg, i.p.) was devoid of any effect. RO 3 mg/kg was instead capable of potentiating the effect of WIN 2 mg/kg on the Racine scale score. Surprisingly, neither WIN 2 mg/kg nor RO 3 mg/kg had any effect on the incidence and the intensity of EEG seizures when administered alone. However, WIN+RO co-administration reduced the incidence and the severity of EEG SE and increased the latency to SE onset after PILO injection. WIN+RO effects were blocked by the selective CB1R antagonist AM251 and the 5-HT2BR antagonist RS127445, but not by the 5-HT2CR antagonist SB242084 or the 5-HT2AR antagonist MDL11,939. These data revealed a synergistic interaction between CB1R/5-HT2BR in the expression of PILO-induced SE.


Assuntos
Receptor CB1 de Canabinoide/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Estado Epiléptico/metabolismo , Animais , Benzoxazinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Masculino , Morfolinas/farmacologia , Agonistas Muscarínicos/toxicidade , Naftalenos/farmacologia , Pilocarpina/toxicidade , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor 5-HT2B de Serotonina/efeitos dos fármacos , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Estado Epiléptico/induzido quimicamente
18.
J Colloid Interface Sci ; 542: 198-206, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30739009

RESUMO

Multiple viruses can cause infection and death of millions annually. Of these, flaviviruses are found to be highly prevalent in recent years with no distinctive antiviral therapies. Therefore, there is a desperate need for broad-spectrum antiviral drugs that can be active against a large number of existing and emerging viruses. Herein, we prepared a kind of benzoxazine monomer derived carbon dots (BZM-CDs) and demonstrated their infection-blocking ability against life-threatening flaviviruses (Japanese encephalitis, Zika, and dengue viruses) and non-enveloped viruses (porcine parvovirus and adenovirus-associated virus). It was found that BZM-CDs could directly bind to the surface of the virion, and eventually the first step of virus-cell interaction was impeded. The developed nanoparticles are active against both flaviviruses and non-enveloped viruses in vitro. Thus, the application of BZM-CDs may constitute an intriguing broad-spectrum approach to rein in viral infections.


Assuntos
Antivirais/farmacologia , Benzoxazinas/farmacologia , Carbono/química , Nanopartículas/química , Pontos Quânticos , Animais , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Flavivirus/efeitos dos fármacos , Células HEK293 , Humanos , Tamanho da Partícula , Propriedades de Superfície , Células Vero , Vírion/efeitos dos fármacos
19.
Neurosci Lett ; 701: 100-105, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-30776493

RESUMO

P2X4 receptor (P2X4R), a subtype of P2 purinergic receptors, is an ATP-gated receptor through which activity of spinal microglia instigates pain hypersensitivity in various pain conditions. Accumulating evidence indicates that monocyte chemoattractant protein-1 (MCP-1) plays an important role in chronic pain facilitation, and it could stimulate microglia activation and involve in regulating P2X4R expression. However, the mechanism of MCP-1 in regulating the expression of P2X4R in microglia is poorly understood, and whether MCP-1 can aggravate pain via up-regulating spinal P2X4R expression in Cancer-induced Bone Pain (CIBP) remains unclear. In this study, we observed that Iba-1 and P2X4R expression is increased in microglia treated with MCP-1, and blockade with a selective CCR2 antagonist RS-504393 suppressed microglia activation and reduced P2X4R expression in cultured microglia. In response to MCP-1, the expression level of p-Akt was also increased and RS-504393 inhibited the increase. Besides, PI3K inhibitor LY 294002 could attenuate MCP-1-induced P2X4R expression in cultured microglia. MCP-1 was found to be associated with P2X4R expression and mechanical allodynia induced by CIBP in vivo since the expression of MCP-1 was increased in CIBP and RS-504393 alleviated the P2X4R expression and mechanical allodynia in CIBP. Moreover, RS-504393 also reduced the increase of p-Akt induced by CIBP. Inhibition of PI3K/Akt pathway may partly reduce MCP-1/CCR2-induced expression of P2X4R and mechanical allodynia in CIBP rats.


Assuntos
Dor do Câncer/metabolismo , Quimiocina CCL2/farmacologia , Microglia/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Animais , Benzoxazinas/farmacologia , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral , Quimiocina CCL2/metabolismo , Cromonas/farmacologia , Feminino , Hiperalgesia/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Proteínas dos Microfilamentos/metabolismo , Microglia/metabolismo , Morfolinas/farmacologia , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Transdução de Sinais , Compostos de Espiro/farmacologia
20.
Toxicol In Vitro ; 57: 233-243, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30776504

RESUMO

Despite the standard approaches to treat the highly aggressive and invasive glioblastoma (GBM), it remains incurable. In this sense, cannabinoids highlight as a promising tool, because this tumor overexpresses CB1 and/or CB2 receptors and being, therefore, can be susceptible to cannabinoids treatment. Thus, this work investigated the action of the cannabinoid agonist WIN55-212-2 on GBM cell lines and non-malignant cell lines, in vitro and in vivo. WIN was selectively cytotoxic to GBM cells. These presented blebbing and nuclear alterations in addition to cell shrinkage and chromatin condensation. WIN also significantly inhibited the migration of GAMG and U251 cells. Finally, the data also showed that the antitumor effects of WIN are exerted, at least to some extent, by the expression of p53 and increased cathepsin D in addition to the decreased expression of HSP70.This data can indicate caspase-independent cell death mechanism. In addition, WIN decreased tumoral perimeter as well as caused a reduction the blood vessels in this area, without causing lysis, hemorrhage or blood clotting. So, the findings herein presented reinforce the usefulness of cannabinoids as a candidate for further evaluation in treatment in glioblastoma treatment.


Assuntos
Benzoxazinas/farmacologia , Glioblastoma/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Morfolinas/farmacologia , Naftalenos/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspases , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Galinhas , Membrana Corioalantoide/efeitos dos fármacos , Membrana Corioalantoide/fisiologia , Humanos
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