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1.
Biochem Pharmacol ; 180: 114191, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32777278

RESUMO

The protozoan parasite Leishmania braziliensis is a major causative agent of the neglected tropical diseases Cutaneous and Mucocutaneous Leishmaniases in the New World. There are no vaccines to prevent the infection and the treatment relies on few drugs that often display high toxicity and costs. Thus, chemotherapeutic alternatives are required. Histone Deacetylases (HDACs) are epigenetic enzymes involved in the control of chromatin structure. In this work, we tested an in-house library of 78 hydroxamic acid derivatives as putative inhibitors of L. braziliensis HDACs (HDACi). The compounds were evaluated in relation to the toxicity to the host cell macrophage and to the leishmanicidal effect against L. braziliensis during in vitro infection. Eight HDACi showed significant leishmanicidal effects and the top 5 compounds showed effective concentrations (EC50) in the range of 4.38 to 10.21 µM and selectivity indexes (SI) from of 6 to 21.7. Analyses by Transmission Electron Microscopy (TEM) indicated induction of apoptotic cell death of L. braziliensis amastigotes with a necrotic phenotype. An altered chromatin condensation pattern and cellular disorganization of intracellular amastigotes was also observed. A tight connection between the mitochondrion and nuclear protrusions, presumably of endoplasmic reticulum origin, was found in parasites but not in the host cell. In flow cytometry (FC) analyses, HDACi promoted parasite cell cycle arrest in the G2-M phase and no changes were found in macrophages. In addition, the direct effect of HDACi against the promastigotes showed apoptosis as the main mechanism of cell death. The FC results corroborate the TEM analyses indicating that the HDACi lead to changes in the cell cycle and induction of apoptosis of L. braziliensis. The production of nitric oxide by the infected macrophages was not altered after treatment with the top 5 compounds. Taken together, our results evidenced new HDACi as promising agents for the development of new treatments for American Tegumentary Leishmaniasis caused by L. braziliensis.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Leishmania braziliensis/efeitos dos fármacos , Leishmania braziliensis/enzimologia , Leishmaniose Cutânea/enzimologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Leishmania braziliensis/ultraestrutura , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/ultraestrutura , Camundongos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Células RAW 264.7
2.
Am J Med Sci ; 360(4): 329-337, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32631574

RESUMO

Methylene blue (MB) is considered to be the first synthetic medication ever used in humans. There are many indications for MB, including vasoplegic shock. Nitric oxide (NO), the central mediator of sepsis, promotes vasoplegia by enhancing the guanylate cyclase cyclic guanosine monophosphate second messenger system, the effect of which is attenuated by MB. Therefore, the use of MB represents a unique pharmacologic approach towards treating the underlying pathophysiology of vasoplegia in sepsis. There are numerous reports of the successful use of MB in refractory shock in the literature. This manuscript describes the historical aspects of the identification of NO as the endothelial derived relaxation factor and its role in the pathogenesis of vasoplegia in septic shock. An analysis of the existing evidence for the use of MB as an inhibitor of NO in vasodilatory shock is provided. The adverse effects associated with the use of MB and an approach to optimal dosing in septic shock are also addressed.


Assuntos
Azul de Metileno/uso terapêutico , Óxido Nítrico/antagonistas & inibidores , Choque Séptico/tratamento farmacológico , Vasoplegia/tratamento farmacológico , Humanos , Azul de Metileno/administração & dosagem , Azul de Metileno/efeitos adversos , Choque Séptico/complicações , Choque Séptico/metabolismo , Vasodilatação/efeitos dos fármacos , Vasoplegia/etiologia , Vasoplegia/metabolismo
3.
Nat Commun ; 11(1): 3688, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703948

RESUMO

Zeta inhibitory peptide (ZIP), a PKMζ inhibitor, is widely used to interfere with the maintenance of acquired memories. ZIP is able to erase memory even in the absence of PKMζ, via an unknown mechanism. We found that ZIP induces redistribution of the AMPARGluA1 in HEK293 cells and primary cortical neurons, and decreases AMPAR-mediated currents in the nucleus accumbens (NAc). These effects were mimicked by free arginine or by a modified ZIP in which all but the arginine residues were replaced by alanine. Redistribution was blocked by a peptidase-resistant version of ZIP and by treatment with the nitric oxide (NO)-synthase inhibitor L-NAME. ZIP increased GluA1-S831 phosphorylation and ZIP-induced redistribution was blocked by nitrosyl-mutant GluA1-C875S or serine-mutant GluA1-S831A. Introducing the cleavable arginine-alanine peptide into the NAc attenuated expression of cocaine-conditioned reward. Together, these results suggest that ZIP may act as an arginine donor, facilitating NO-dependent downregulation of AMPARs, thereby attenuating learning and memory.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Lipopeptídeos/farmacologia , Memória de Longo Prazo/efeitos dos fármacos , Óxido Nítrico/metabolismo , Receptores de AMPA/metabolismo , Animais , Cocaína/administração & dosagem , Regulação para Baixo , Endocitose/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Células HEK293 , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Modelos Animais , NG-Nitroarginina Metil Éster/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Óxido Nítrico/antagonistas & inibidores , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Fosforilação , Cultura Primária de Células , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Ratos , Receptores de AMPA/genética , Recompensa , Técnicas Estereotáxicas
4.
Pak J Pharm Sci ; 33(2): 615-619, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32276906

RESUMO

Benzimidazole and its derivatives found variety of biological activities, for the searching of its potent anti-inflammatory analogues, we synthesized four novel 4-(2-keto-1-benzimidazollinyl) piperidine derivatives (Q1 to Q4) by refluxing piperidine with substituted imidazole and subjected to in-vitro anti-inflammatory (ROS, NO) and antibacterial activities, structures were elucidated using spectroscopic techniques. Results revealed that compound Q1 showed most effective anti-inflammatory activity with IC 50 7.6±1.3 µg/ml compared with standard Ibuprofen having IC50 11.2±1.9µg/mL. Compound Q3 showed good activity for Nitrite accumulation by stimulating macrophages test similar to standard NG Methyl L-arginine acetate with IC50 value 24.2±0.8µg/mL. The antibacterial activity of these compounds were evaluated against selected Gram+ve E. faecalis, C. diphtheriae, S. aureus and Gram -ve organism E. coli, Enterobacter aerogenes and P. aeruginosa. Synthesized compounds showed low to moderate level of antibacterial activity Q1 showed the highest antibacterial activity against Enterococcus faecalis and Escherichia coli with zone of inhibition 18mm and Q3 showed highest activity against Corynebacterium diptheriae (ZOI:18mm). Structure-activity relationship (SAR) study revealed that among all the synthesized compounds unsubstituted naphthalene (Q1) and phenyl (Q3) ring containing derivatives were most potent.


Assuntos
Antibacterianos/síntese química , Anti-Inflamatórios/síntese química , Piperidinas/síntese química , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Testes de Sensibilidade Microbiana/métodos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Piperidinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 196: 112271, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32305784

RESUMO

A series of hybrids of MEK inhibitor and nitric oxide donor have been designed and synthesized. Compound 18h [4-(3-((3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-methyl-2-oxo-2H-chromen-7-yl)oxy) propoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide] was proven to be more potent than the clinical compound RO5126766 in MDA-MB-231 cells. Compound 18h can significantly reduce the levels of pMEK and pERK, induce cell apoptosis in MDA-MB-231 cells, and release NO in cells efficiently, suggesting that these hybrids, while displaying the properties of both MEK inhibitors and NO donors have a mechanism of action different from that of MEK inhibitors and NO donors. Thus, we are able to report a series of multitarget hybrids with better antitumor potency than a known MEK inhibitor and NO donor.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
J Fluoresc ; 30(3): 471-482, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32146651

RESUMO

Pyrimidine derivative Schiff base ligand (DPMC) stabilized metal nanoparticles of copper (DPMC-CuNPs) and nickel (DPMC-NiNPs) were synthesized by modified Brust-Schiffrin technique, which is a two-step phase transfer assisted synthesis. The prepared metal nanoparticles were confirmed by UV-Visible and Infrared spectroscopy. The size, surface morphology and the quality of the DPMC and its MNPs were analyzed by Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) methods respectively. Electrochemical behavior of the DPMC-CuNPs and DPMC-NiNPs was analyzed by cyclic voltammetry method. DNA binding studies of the synthesized compounds with CT-DNA were examined by four different techniques such as UV-Visible and emission spectroscopy, cyclic voltametry and viscometric measurments. Thermal denaturation and sono-chemical denaturation studies of DNA with the DPMC, DPMC-CuNPs and DPMC-NiNPs results also suggest the synthesized compounds have good DNA binding ability. Various antioxidant scavenging studies results shows that DPMC and its copper and nickel nanoparticles have significant antioxidant activity. Antimicrobial studies of the DPMC and its MNPs were studied by Agar-Agar well diffusion method. Anticancer studies of the DPMC and its MNPs show that the DPMC-CuNPs and DPMC-NiNPs have significant anticancer activity with least toxicity than the standard drug cis-platin. Graphical Abstract.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , DNA/química , Nanopartículas Metálicas/química , Pirimidinas/farmacologia , Células A549 , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Bactérias/efeitos dos fármacos , Compostos de Bifenilo/antagonistas & inibidores , Bovinos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cobre/química , Cobre/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Células Hep G2 , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Ligantes , Células MCF-7 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Níquel/química , Níquel/farmacologia , Óxido Nítrico/antagonistas & inibidores , Picratos/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/química , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Superóxidos/antagonistas & inibidores
7.
Nitric Oxide ; 98: 29-32, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32142901

RESUMO

MDMA abuse continues being a serious problem in our society. Environmental factors, such as stress, increase the vulnerability of individuals to develop drug abuse and we have observed that exposure to social defeat (SD) stress alters the sensitivity of mice to the rewarding effects of MDMA in the conditioned place preference (CPP) paradigm. In the present study, we evaluated the role of the nitric oxide (NO) pathway in the effects of SD on the rewarding properties of MDMA. Three groups of mice were treated with an inhibitor of NO synthesis, 7-nitroindazole (0, 7.25 and 12.5 mg/kg), before each exposure to SD and place conditioning with MDMA (1.25 mg/kg) on PND 54, 56, 58, and 60. One control group was not exposed to SD before place conditioning. In addition, we studied the effects of SD on the levels of nitrites in the striatum, hippocampus and frontal cortex. Our results showed that the low dose of 7-nitroindazole blocked the effects of SD on the rewarding properties of MDMA. Moreover, SD exposure increased the nitrites in the prefrontal cortex and hippocampus. These results demonstrated the role of NO signalling in the effects of SD stress in mice and suggested that the inhibition of NO synthesis may confer resilience to the effects of social stress on the rewarding properties of MDMA. The manipulation of the NO signalling pathway could be a useful target for the treatment of MDMA-dependent subjects who experienced high levels of stress.


Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Indazóis/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/antagonistas & inibidores , Óxido Nítrico/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Óxido Nítrico/análise , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico
8.
Nitric Oxide ; 98: 50-59, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32147582

RESUMO

BACKGROUND: Bacillus Calmette-Guerin (BCG) is the standard treatment for patients with high-risk non-muscle invasive bladder cancer (BC). Despite its success, about 30-50% of patients are refractory. It was reported that inducible nitric oxide synthase (iNOS) tumor expression is presented in 50% of human BC, associated with bad prognosis and BCG failure. OBJECTIVE: to evaluate in human bladder tumors the association between iNOS expression and the tumor microenvironment focusing on the immunosuppressive protein S100A9. Also, investigate in a preclinical murine MB49-BC model the tumor immunoresponse induced by BCG in combination with the nitric oxide production inhibitor l-NAME. RESULTS: In human bladder tumors, we detected a positive association between iNOS and S100A9 tumor expression, suggesting a relationship between both immunomodulatory proteins. We also found a positive correlation between iNOS tumor expression and the presence of S100A9+ tumor-infiltrating cells, suggesting an immunosuppressive tumor microenvironment induced by the nitric oxide production. Using the subcutaneous murine BC model, we show that similarly to the human pathology, MB49 tumors constitutively expressed iNOS and S100A9 protein. MB49 tumor-bearing mice presented an immunosuppressive systemic profile characterized by fewer cytotoxic cells (CD8+ and NK) and higher suppressor cells (Treg and myeloid-derived suppressor cells -MDSC-) compared to normal mice. BCG treatment reduced tumor growth, increasing local CD8+-infiltrating cells and induced a systemic increase in CD8+ and a reduction in Treg. BCG combined with l-NAME, significantly reduced tumor growth compared to BCG alone, diminishing iNOS and S100A9 tumor expression and increasing CD8+-infiltrating cells in tumor microenvironment. This local response was accompanied by the systemic increase in CD8+ and NK cells, and the reduction in Treg and MDSC, even more than BCG alone. Similar results were obtained using the orthotopic BC model, where an increase in specific cytotoxicity against MB49 tumor cells was detected. CONCLUSION: The present study provides preclinical information where NO inhibition in iNOS-expressing bladder tumors could contribute to improve BCG antitumor immune response. The association between iNOS and S100A9 in human BC supports the hypothesis that iNOS expression is a negative prognostic factor and a promising therapeutic target.


Assuntos
Adjuvantes Imunológicos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Vacina BCG/farmacologia , Óxido Nítrico/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adjuvantes Imunológicos/administração & dosagem , Animais , Antineoplásicos Imunológicos/administração & dosagem , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Calgranulina B/biossíntese , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , NG-Nitroarginina Metil Éster/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
9.
Chem Biodivers ; 17(5): e2000103, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32180346

RESUMO

Three dimeric cassane diterpenoids, caesalpanins A-C, were isolated from the seeds of Caesalpinia sappan L., as well as three known compounds. Their structures were determined via analysis of 1D-, 2D-NMR, and HR-ESI-MS data. Caesalpanins A and B were the second and third compounds that presented a nitrogen-containing cassane diterpenoid dimer linked through one ether bond between C-19 and C-20'. Caesalpanin B exhibited moderate cytotoxic activity against MCF-7 cell lines with IC50 value of 29.98 µm. Caesalpanins A and B had weak inhibitory effects against LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages at 50 µm with inhibitory rate of 36.01 % and 32.93 %, respectively.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Caesalpinia/química , Diterpenos/farmacologia , Sementes/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Células MCF-7 , Camundongos , Conformação Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
10.
Life Sci ; 248: 117471, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32112868

RESUMO

AIMS: This study aimed to explore the protective effects and possible mechanisms of baicalein on Aß25-35-induced toxicity. MAIN METHODS: Thioflavin-T (Th-T) dye was used to determine the effects of baicalein on Aß25-35 aggregation in vitro. PC12 cells were stimulated with Aß25-35, then the effects of baicalein on apoptosis, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP), mitochondrial respiratory complex I, reactive oxygen species (ROS) and nitric oxide (NO) levels were determined. Moreover, LC-MS metabolomics approach was used to detect metabolic changes induced by baicalein in Aß25-35-injured PC12 cells. KEY FINDINGS: The results showed that baicalein could inhibit the aggregation of Aß25-35 in vitro. Furthermore, pretreatment with baicalein significantly prevented Aß25-35-induced cell apoptosis, as manifested by increasing the levels of MMP, ATP and mitochondrial respiratory complex I, decreasing the contents of ROS and NO. LC-MS metabolomics revealed that baicalein can regulate 5 metabolites, mainly involving two metabolic pathways, arginine and proline metabolism, nicotinate and nicotinamide metabolism. SIGNIFICANCE: Our study revealed that baicalein has a protective effect on Aß25-35-induced neurotoxicity in PC12 cells, which may be related to inhibition of apoptosis and metabolic disorders.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Flavanonas/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Peptídeos beta-Amiloides/toxicidade , Animais , Arginina/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Niacina/metabolismo , Niacinamida/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Fragmentos de Peptídeos/toxicidade , Prolina/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
11.
Braz J Med Biol Res ; 53(3): e8853, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130289

RESUMO

Anaphylactic shock can be defined as an acute syndrome, and it is the most severe clinical manifestation of allergic diseases. Anaphylactoid reactions are similar to anaphylactic events but differ in the pathophysiological mechanism. Nitric oxide (NO) inhibitors during anaphylaxis suggest that NO might decrease the signs and symptoms of anaphylaxis but exacerbate associated vasodilation. Therefore, blocking the effects of NO on vascular smooth muscle by inhibiting the guanylate cyclase (GC) would be a reasonable strategy. This study aimed to investigate the effects of NO/cGMP pathway inhibitors methylene blue (MB), Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), and indigo carmine (IC) in shock induced by compound 48/80 (C48/80) in rats. The effect was assessed by invasive blood pressure measurement. Shock was initiated by C48/80 intravenous bolus injection 5 min before (prophylactic) or after (treatment) the administration of the inhibitors MB (3 mg/kg), L-NAME (1 mg/kg), and IC (3 mg/kg). Of the groups that received drugs as prophylaxis for shock, only the IC group did not present the final systolic blood pressure (SBP) better than the C48/80 group. Regarding shock treatment with the drugs tested, all groups had the final SBP similar to the C48/80group. Altogether, our results suggested that inhibition of GC and NO synthase in NO production pathway was not sufficient to revert hypotension or significantly improve survival.


Assuntos
Anafilaxia/tratamento farmacológico , GMP Cíclico/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Índigo Carmim/administração & dosagem , Masculino , Azul de Metileno/administração & dosagem , NG-Nitroarginina Metil Éster/administração & dosagem , Ratos , Ratos Wistar
12.
Eur J Med Chem ; 193: 112216, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32208222

RESUMO

Inflammation is a complex biological response to stimuli. Activated macrophages induced excessively release of pro-inflammatory cytokines and mediators such as endogenous radical nitric oxide (NO) play a significant role in the progression of multiple inflammatory diseases. Both natural and synthetic chalcones possess a wide range of bioactivities. In this work, thirty-nine chalcones and three related compounds, including several novel ones, based on bioactive kava chalcones were designed, synthesized and their inhibitory effects on NO production in RAW 264.7 cells were evaluated. The novel compound (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-(3-methoxy-4-(3-morpholinopropoxy)phenyl)prop-2-en-1-one (53) exhibited a better inhibitory activity (84.0%) on NO production at 10 µM (IC50 = 6.4 µM) with the lowest cytotoxicity (IC50 > 80 µM) among the tested compounds. Besides, western blot analysis indicated that compound 53 was a potent down-regulator of inducible nitric oxide synthase (iNOS) protein. Docking study revealed that compound 53 also can dock into the active site of iNOS. Furthermore, at the dose of 10 mg/kg/day, compound 53 could both significantly suppress the progression of inflammation on collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models. In addition, the structure-activity relationship (SAR) of the kava chalcones based analogs was also depicted.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite/tratamento farmacológico , Chalconas/farmacologia , Desenvolvimento de Medicamentos , Inflamação/tratamento farmacológico , Óxido Nítrico/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite/induzido quimicamente , Artrite/metabolismo , Células Cultivadas , Chalconas/síntese química , Chalconas/química , Doença Crônica , Colágeno , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Estrutura Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 193: 112217, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32182488

RESUMO

Because of the complex etiology in neuroinflammatory process, the design of multifunctional agents is a potent strategy to cure neuroinflammatory diseases including AD and PD. Herein, based on the combination principles, 23 of N-salicyloyl tryptamine derivatives as multifunctional agents were designed and their new application for anti-neuroinflammation was disclosed. In cyclooxygenase assay, two compounds 3 and 16 displayed extremely preferable COX-2 inhibition than N-salicyloyl tryptamine. In LPS-induced C6 and BV2 cell models, some compounds decreased the production of proinflammatory mediators NO, PGE2, TNF-α, iNOS, COX-2 and ROS, while increased the production of IL-10. Among them, compound 3 and 16 showed approximately six-fold better inhibition on nitric oxide production than N-salicyloyl tryptamine in C6. Besides, compounds 3, 13 and 16 attenuated the activation of BV2 and C6 cells. More importantly, in vivo, compounds 3 and 16 reduced GFAP and Iba-1 levels in the hippocampus, and displayed neuroprotection in Nissl staining. Besides, both compounds 3 and 16 had high safety (LD50 > 1000 mg/kg). Longer plasma half-life of compounds 3 and 16 than melatonin supported combination strategy. All these results demonstrated that N-salicyloyl tryptamine derivatives are potential anti-neuroinflammation agents for the treatment of neurodegenerative disorder.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Triptaminas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/química
14.
Mar Drugs ; 18(3)2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32111022

RESUMO

Chemical investigation on EtOAc extract of the deep-sea-derived fungus Trichobotrys effuse FS524 resulted in the isolation of six new highly substituted phenol derivatives trieffusols A-F (1-6), along with ten known relative analogues (7-16). Their structures with absolute configurations were extensively characterized on the basis of spectroscopic data analyses, single-crystal X-ray diffraction experiments, and electronic circular dichroism (ECD) calculations. Structurally, trieffusols A and B shared an unprecedented ploy-substituted 9-phenyl-hexahydroxanthone skeleton with an intriguing 6-6/6/6 tetracyclic fused ring system, which were often encountered as significant moieties in the pharmaceutical drugs but rarely discovered in natural products. In the screening towards their anti-inflammatory activities of 1-6, trieffusols C and D exhibited moderate inhibitory activities against nitric oxide (NO) production in LPS-induced RAW 264.7 macrophages with IC50 values ranging from 51.9 to 55.9 µM.


Assuntos
Anti-Inflamatórios/farmacologia , Fungos/química , Macrófagos/efeitos dos fármacos , Fenóis/farmacologia , Animais , Concentração Inibidora 50 , Camundongos , Óxido Nítrico/antagonistas & inibidores , Oceanos e Mares , Células RAW 264.7/efeitos dos fármacos
15.
J Enzyme Inhib Med Chem ; 35(1): 847-863, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32216479

RESUMO

Oxidative stress is one of the main causes of significant severe diseases. The discovery of new potent antioxidants with high efficiency and low toxicity is a great demand in the field of medicinal chemistry. Herein, we report the design, synthesis molecular modelling and biological evaluation of novel hybrids containing pyrazole, naphthalene and pyrazoline/isoxazoline moiety. Chalcones 2a-e were synthesized efficiently and were used as starting materials for synthesis of a variety of heterocycles. A novel series of pyrazoline 3a-e, phenylpyrazoline 4a-e, isoxazoline 5a-e and pyrazoline carbothioamide derivatives 6a-e were synthesized and screened for in vitro antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide radical scavenging assay as well as 15-lipoxygenase (15-LOX) inhibition activity. Compounds 3a, 4e, 5b, 5c, 6a, 6c, and 6e showed excellent radical scavenging activity in all three methods in comparison with ascorbic acid and 15-LOX inhibition potency using quercetin as standard then were subjected to in vivo study. Catalase (CAT) activity, glutathione (GSH) and malondialdehyde (MDA) levels were assayed in liver of treated rats. Compounds 5b, 5c, and 6e showed significant in vivo antioxidant potentials compared to control group at dose of 100 mg/kg B.W. Molecular docking of compound 6a endorsed its proper binding at the active site pocket of the human 15-LOX which explains its potent antioxidant activity in comparison with standard ascorbic acid.


Assuntos
Antioxidantes/farmacologia , Araquidonato 15-Lipoxigenase/metabolismo , Desenho de Fármacos , Inibidores de Lipoxigenase/farmacologia , Pirazóis/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Masculino , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Picratos/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Superóxidos/antagonistas & inibidores
16.
J Sep Sci ; 43(8): 1450-1457, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32031325

RESUMO

Buddleja officinalis Maxim., a deciduous, flowering shrub, is used as a traditional Chinese medicine; the bioactivity of B. officinalis is primarily due to flavonoids and phenylethanoid glycosides. In the study, acteoside and linarin were successfully isolated from B. officinalis by high-speed countercurrent chromatography with a two-phase solvent system composed of ethyl acetate: n-butanol: water (5:0.8:5, v/v/v). The purities of acteoside and linarin were determined to be 97.3 and 98.2%, respectively, using one-step high-speed countercurrent chromatography separation. The chemical structures of the two compounds were identified by electrospray ionization-mass spectrometry and nuclear magnetic resonance. After separation, the anti-inflammatory effects of the two compounds were evaluated using lipopolysaccharide-induced human umbilical vein endothelial cells. Acteoside and linarin inhibited the expression of nitric oxide, tumor necrosis factor α and interleukin 1ß, which demonstrated that acteoside and linarin possessed anti-inflammatory activity.


Assuntos
Anti-Inflamatórios/farmacologia , Flores/química , Glucosídeos/farmacologia , Glicosídeos/farmacologia , Loganiaceae/química , Óxido Nítrico/antagonistas & inibidores , Fenóis/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Células Cultivadas , Distribuição Contracorrente , Glucosídeos/química , Glucosídeos/isolamento & purificação , Glicosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Medicina Tradicional Chinesa , Estrutura Molecular , Óxido Nítrico/biossíntese , Fenóis/química , Fenóis/isolamento & purificação
17.
J Sep Sci ; 43(8): 1593-1602, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32032980

RESUMO

Glycyrrhiza uralensis Fisch., known as licorice, is one of the most famous traditional Chinese medicines. In this study, we perform a metabolome analysis using liquid chromatography-tandem mass spectrometry to assign bioactive components in different parts of licorice from different geographical origins in Gansu province of China. Sixteen potential biomarkers of taproots from different geographical origins were annotated, such as glycycoumarin, gancaonin Z, licoricone, and dihydroxy kanzonol H mainly exist in the sample of Jiuquan; neoliquiritin, 6'-acetylliquiritin, licochalcone B, isolicoflavonol, glycyrol, and methylated uralenin mainly exist in Glycyrrhiza uralensis from Lanzhou; gancaonin L, uralenin, and glycybridin I mainly exist in licorice from Wuwei for the first time.


Assuntos
Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Glycyrrhiza uralensis/metabolismo , Metabolômica , Óxido Nítrico/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Sobrevivência Celular/efeitos dos fármacos , China , Cromatografia Líquida , Glycyrrhiza uralensis/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Medicina Tradicional Chinesa , Camundongos , Óxido Nítrico/biossíntese , Células RAW 264.7 , Espectrometria de Massas em Tandem
18.
Acta Pharmacol Sin ; 41(4): 516-522, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32047262

RESUMO

Excessive nitric oxide (NO) causes extensive damage to the nervous system, and the adrenergic system is disordered in many neuropsychiatric diseases. However, the role of the adrenergic system in protection of the nervous system against sodium nitroprusside (SNP) injury remains unclear. In this study, we investigated the effect of ganoderic acid A (GA A) against SNP injury in neural cells and the role of adrenergic receptors in GA A neuroprotection. We found that SNP (0.125-2 mM) dose-dependently decreased the viability of both SH-SY5Y and PC12 cells and markedly increased NO contents. Pretreatment with GA A (10 µM) significantly attenuated SNP-induced cytotoxicity and NO increase in SH-SY5Y cells, but not in PC12 cells. Furthermore, pretreatment with GA A caused significantly higher adrenaline content in SH-SY5Y cells than in PC12 cells. In order to elucidate the mechanism of GA A-protecting SH-SY5Y cells, we added adrenaline, phentolamine, metoprolol, or ICI 118551 1 h before GA A was added to the culture medium. We found that addition of adrenaline (10 µM) significantly improved GA A protection in PC12 cells. The addition of ß1-adrenergic receptor antagonist metoprolol (10 µM) or ß2-adrenergic receptor antagonist ICI 118551 (0.1 µM) blocked the protective effect of GA A, whereas the addition of α-adrenergic receptor antagonist phentolamine (0.1 µM) did not affect GA A protection in SH-SY5Y cells. These results suggest that ß-adrenergic receptors play an important role in the protection of GA A in SH-SY5Y cells against SNP injuries, and excessive adrenaline system activation caused great damage to the nervous system.


Assuntos
Ácidos Heptanoicos/farmacologia , Lanosterol/análogos & derivados , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/antagonistas & inibidores , Receptores Adrenérgicos beta/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ácidos Heptanoicos/química , Humanos , Lanosterol/química , Lanosterol/farmacologia , Conformação Molecular , Fármacos Neuroprotetores/química , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
Drug Des Devel Ther ; 14: 697-713, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32109994

RESUMO

Background: Sanjie Zhentong capsule (SZC) offers excellent effect in treating adenomyosis (AM), which is a common and difficult gynecological disease in the clinic. However, the systematic analysis of its mechanism has not been carried out yet and further studies are needed to reveal the role of SZC. Methods: A systematic network pharmacology analysis was conducted by integrating construction of SZC compound database and AM target database, prediction of potential active compounds and targets by molecular docking combined with compound-target prediction graph (CTPG), protein-protein interaction (PPI) analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Then, the anti-inflammation experiments in vitro were performed by investigating SZC and the representative compounds regulating nitric oxide (NO), interleukin-6 (IL-6), and interleukin-10 (IL-10). Results: Our findings show that SZC mainly treated AM by stimulating 28 core targets through 30 key potential active compounds, and affecting 4 crucial pathways. The treatment was associated with inflammation reaction, hormone regulation, cell adhesion, proliferation, and angiogenesis. Additionally, SZC achieved the anti-inflammatory activity by the cooperation of the compounds through inhibiting NO and IL-6, both promoting and inhibiting IL-10. Conclusion: This study investigated the anti-inflammatory activity of SZC based on a systematic analysis of SZC remedying AM, which was revealed to be one of the essential mechanisms. These findings will provide valuable guidance for further research of the SZC treatment of AM, and help improve the comprehension of SZC pharmacological basis as well as AM pathogenesis.


Assuntos
Adenomiose/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Redes Neurais de Computação , Adenomiose/metabolismo , Animais , Cápsulas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Bases de Dados de Produtos Farmacêuticos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Medicina Tradicional Chinesa , Camundongos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7
20.
Org Lett ; 22(4): 1336-1339, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32037840

RESUMO

Aspermeroterpene A (1) with an unprecedented and highly congested 5/3/6/6/6/5 hexacyclic skeleton, together with two precursors aspermeroterpenes B (2) and C (3), were isolated from the marine-derived fungus Aspergillus terreus GZU-31-1. Their structures were elucidated by quantum chemical calculations, X-ray diffraction, and spectroscopic methods. The biogenetic pathway for 1-3 is proposed. Aspermeroterpenes A-C (1-3) showed significant inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 cells compared to positive control.


Assuntos
Aspergillus/química , Terpenos/farmacologia , Animais , Cristalografia por Raios X , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Terpenos/química , Terpenos/isolamento & purificação
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