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1.
J Enzyme Inhib Med Chem ; 34(1): 1321-1346, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31328585

RESUMO

For over half a century, the carbazole skeleton has been the key structural motif of many biologically active compounds including natural and synthetic products. Carbazoles have taken an important part in all the existing anti-cancer drugs because of their discovery from a large variety of organisms, including bacteria, fungi, plants, and animals. In this article, we specifically explored the literature from 2012 to 2018 on the anti-tumour activities reported to carbazole derivatives and we have critically collected the most significant data. The most described carbazole anti-tumour agents were classified according to their structure, starting from the tricyclic-carbazole motif to fused tetra-, penta-, hexa- and heptacyclic carbazoles. To date, three derivatives are available on the market and approved in cancer therapy.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias/patologia
2.
Anticancer Res ; 39(7): 3579-3584, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262882

RESUMO

BACKGROUND/AIM: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood; treatments with greater effectiveness are required for NB, especially in advanced cases. This study aimed at evaluating the combined effect of anaplastic lymphoma kinase (ALK) inhibitor alectinib and histone deacetylase inhibitor vorinostat on NB cell lines harboring wild-type or mutated ALK. MATERIALS AND METHODS: Cytotoxicity was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Protein expression was analyzed using western blotting. RESULTS: Combination treatment with alectinib and vorinostat had a synergistic effect on growth inhibition of the NB cell line with ALK R1275Q mutation. Cleavage of caspase-3 and poly-(ADP-ribose) polymerase increased, indicating enhanced caspase-dependent apoptosis. In addition, this combination reduced the protein levels of MYCN proto-oncogene and nuclear factor kappa B, both of which are important for NB tumorigenesis and progression. CONCLUSION: Combined treatment with alectinib and vorinostat might be a novel therapeutic option for NB harboring the ALK R1275Q mutation.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carbazóis/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Neuroblastoma/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Vorinostat/farmacologia , Quinase do Linfoma Anaplásico/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Mutação , Proteína Proto-Oncogênica N-Myc/metabolismo , NF-kappa B/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo
3.
Eur J Med Chem ; 178: 802-817, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31252285

RESUMO

We report in this work the discovery of novel allosteric MEK inhibitors by pharmacophore modeling and virtual screening. Two out of 13 virtual hit compounds were identified as MEK kinase inhibitors using a MEK1 binding assay. Structural derivations on the hit compound M100 (IC50 = 27.2 ±â€¯4.5 µM in RAF-MEK cascading assay) by substituent transformation and bioisosterism replacement have led to the synthesis of a small library of carbazoles. The enzymatic studies revealed the preliminary structure-activity relationships and the derivative 22k (IC50 = 12.8 ±â€¯0.5 µM) showed the most potent inhibitory effect against Raf-MEK cascading. Compound 7 was discovered as toxic as M100 to tumor cells whereas safer to HEK293 cells (IC50 > 100 µM) than M100 (IC50 = 8.9 ±â€¯2.0 µM). It suggests that carbazole is a good scaffold for the design of novel MEK inhibitors for therapeutic uses. More importantly, the developed pharmacophore model can serve as a reliable criterion in novel MEK inhibitor discovery.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Descoberta de Drogas , MAP Quinase Quinase Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Regulação Alostérica/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , MAP Quinase Quinase Quinases/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
4.
J Agric Food Chem ; 67(26): 7512-7525, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31180659

RESUMO

Recent observations on the emergence of drug-resistant plant pathogenic bacteria have highlighted and elicited an acute campaign to develop novel, highly efficient antibiotic surrogates for managing bacterial diseases in agriculture. Thus, a type of racemic and chiral carbazole derivative containing an isopropanolamine pattern was systematically synthesized to discover low-cost and efficient antibacterial candidates. Screening results showed that compounds 2f, 6c, and 2j could significantly suppress the growth of tested plant pathogens, namely Xanthomonas oryzae pv oryzae, X. axonopodis pv citri, and Pseudomonas syringae pv actinidiae, and provided the corresponding EC50 values of 1.27, 0.993, and 0.603 µg/mL, which were significantly better than those of existing commercial drugs. In vivo studies confirmed their prospective applications for controlling plant bacterial diseases. Label-free quantitative proteomics analysis indicated that compound 2f could dramatically induce the up- and down-regulation of a total of 247 differentially expressed proteins, which was further validated by the parallel reaction monitoring technique. Moreover, fluorescence spectra and SEM images were obtained to further explore the antibacterial mechanism.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Doenças das Plantas/microbiologia , Propanolaminas/química , Pseudomonas syringae/efeitos dos fármacos , Xanthomonas/efeitos dos fármacos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Testes de Sensibilidade Microbiana , Proteômica , Pseudomonas syringae/química , Pseudomonas syringae/genética , Pseudomonas syringae/metabolismo , Relação Estrutura-Atividade , Xanthomonas/química , Xanthomonas/genética , Xanthomonas/metabolismo
5.
J Agric Food Chem ; 67(20): 5764-5771, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31083994

RESUMO

Clausena lansium, also known as wampee, is a species of strongly scented evergreen trees belonging to the genus Clausena (Rutaceae), which is native to southern China. Its ripe fruits have been consumed as a very popular fruit and reported to possess a range of biological activities. To study the potential health-promoting constituents from the fruits of C. lansium, a chemical investigation on its fruits was thus carried out. In this study, 16 carbazole alkaloids (1-16), including six new carbazole alkaloids, clausenalansines A-F (1-6), were separated from the fruits of C. lansium. The molecular structures of these isolated new carbazole alkaloids (1-6) were ambiguously established on the basis of comprehensive spectroscopic methods. The known analogues (7-16) were determined via comparing their experimental data with those described in the literature, which were separated from C. lansium for the first time. All these isolated alkaloids were tested in vitro for their neuroprotective effects against 6-hydroxydopamine induced cell death in human neuroblastoma SH-SY5Y cells. Carbazole alkaloids 1-16 displayed remarkable neuroprotective effects possessing the EC50 values ranging from 0.36 ± 0.02 to 10.69 ± 0.15 µM. These findings indicate that regular consumption of the fruits of C. lansium may help people prevent the occurrence of Parkinson's disease. In addition, the separation and identification of these carbazole alkaloids possessing remarkable neuroprotective effects from the fruits of C. lansium could be extremely important to the discovery of new agents for the prevention and treatment of Parkinson's disease.


Assuntos
Alcaloides/química , Carbazóis/química , Clausena/química , Medicamentos de Ervas Chinesas/química , Fármacos Neuroprotetores/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Carbazóis/isolamento & purificação , Carbazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Frutas/química , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia
6.
Chem Biol Interact ; 306: 152-162, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31063767

RESUMO

Punicalagin has been found to exert cardiac protective effects against myocardial ischemia/reperfusion (MI/R) injury, although the detailed mechanisms remain largely unknown. This experiment was performed to explore the potential involvement of silent information regulator 1 (SIRT1)-NFE2-related factor 2 (NRF-2)-heme oxygenase-1 (HO-1) pathway in the cardiac protective actions of punicalagin. Sprague-Dawley (SD) rats were subjected to MI/R operation with or without punicalagin treatment (40 mg kg-1d-1). We showed that punicalagin-treated group exhibited enhanced cardiac function, reduced myocardial infarction and decreased cleaved caspase-3 level. Furthermore, myocardial oxidative/nitrosative stress was ameliorated by punicalagin as evidenced by suppressed superoxide generation, gp91phox and iNOS expressions, NO metabolites as well as myocardial nitrotyrosine level. Additionally, punicalagin decreased myocardial IL-6, TNF-α and the levels of ICAM-1, VCAM-1 and IKK-ß expressions as well as IκB-α phosphorylation and NF-κB nuclear translocation. However, these effects were abolished by EX527 (5 mg kg-1d-1, a selective SIRT1 inhibitor). We further found that punicalagin dose-dependently enhanced SIRT1 nuclear distribution and NRF-2-HO-1 signaling. While EX527 treatment not only reduced SIRT1 activity, but also reversed the activation of NRF-2-HO-1 pathway. Collectively, these results revealed that punicalagin reduced cardiac oxidative/nitrosative stress and inflammatory response induced by MI/R operation through SIRT1-mediated activation of NRF-2-HO-1 signaling.


Assuntos
Heme Oxigenase-1/metabolismo , Taninos Hidrolisáveis/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Sirtuína 1/metabolismo , Animais , Carbazóis/química , Carbazóis/farmacologia , Relação Dose-Resposta a Droga , Heme Oxigenase-1/antagonistas & inibidores , Taninos Hidrolisáveis/química , Masculino , Estrutura Molecular , Traumatismo por Reperfusão Miocárdica/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Relação Estrutura-Atividade
7.
Molecules ; 24(7)2019 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959983

RESUMO

Many studies have demonstrated that oxidative stress plays an important role in several ailments including neurodegenerative diseases and cerebral ischemic injury. Previously we synthesized some carbazole compounds that have anti-oxidant ability in vitro. In this present study, we found that one of these 22 carbazole compounds, compound 13 (3-ethoxy-1-hydroxy-8- methoxy-2-methylcarbazole-5-carbaldehyde), had the ability to protect neuro2a cells from hydrogen peroxide-induced cell death. It is well known that neurite loss is one of the cardinal features of neuronal injury. Our present study revealed that compound 13 had the ability to induce neurite outgrowth through the PI3K/Akt signaling pathway in neuro2a cells. These findings suggest that compound 13 might exert a neurotrophic effect and thus be a useful therapy for the treatment of brain injury.


Assuntos
Carbazóis/farmacologia , Peróxido de Hidrogênio/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Animais , Carbazóis/química , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos
8.
Int J Mol Med ; 43(5): 2033-2043, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864731

RESUMO

Sirtuin 1 (Sirt1) exerts its cardioprotective effects in various cardiovascular diseases via multiple cellular activities. However, the therapeutic implications of Sirt1 in hypoxic cardiomyocytes and the underlying mechanisms remain elusive. The present study investigated whether Sirt1 regulates autophagy and apoptosis in hypoxic H9C2 cardiomyocytes and in an experimental hypoxic mouse model. Right ventricular outflow tract biopsies were obtained from patients with cyanotic or acyanotic congenital heart diseases. Adenovirus Ad­Sirt1 was used to activate Sirt1 and Ad­Sh­Sirt1 was used to inhibit Sirt1 expression in H9C2 cells, in order to investigate the effect of Sirt1 on cellular autophagy and apoptosis. SRT1720, a pharmacological activator of Sirt1 and EX­527, a Sirt1 antagonist, were administered to mice to explore the role of Sirt1 in hypoxic cardiomyocytes in vivo. The levels of autophagy and apoptosis­related proteins were evaluated using western blotting. Apoptosis was investigated by TUNEL staining and Annexin V/7­aminoactinomycin D flow cytometry analysis. Heart tissue samples from cyanotic patients exhibited increased autophagy and apoptosis, as well as elevated Sirt1 levels, compared with the noncyanotic control samples. The data from the western blot analysis revealed that Sirt1 promoted autophagic flux and reduced apoptosis in hypoxic H9C2 cells. In addition, Sirt1 activated AMP­activated protein kinase (AMPK), and the AMPK inhibitor Compound C abolished the effect of Sirt1 on autophagy activation. Further exploration of the mechanism revealed that Sirt1 protects hypoxic cardiomyocytes from apoptosis, at least in part, through inositol requiring kinase enzyme 1α (IRE1α). Consistent with the in vitro results, treatment with the Sirt1 activator SRT1720 activated AMPK, inhibited IRE1α, enhanced autophagy, and decreased apoptosis in the heart tissues of normoxic mice compared with the hypoxia control group. Opposite changes were observed in hypoxic mice treated with the Sirt1 inhibitor EX­527. These results suggested that Sirt1 promoted autophagy via AMPK activation and reduced hypoxia­induced apoptosis via the IRE1α pathway, to protect cardiomyocytes from hypoxic stress.


Assuntos
Apoptose , Autofagia , Miócitos Cardíacos/metabolismo , Substâncias Protetoras/metabolismo , Sirtuína 1/metabolismo , Estresse Fisiológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carbazóis/farmacologia , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Cianose/patologia , Modelos Animais de Doenças , Endorribonucleases/metabolismo , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Lactente , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
9.
Nat Commun ; 10(1): 1441, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926878

RESUMO

Recently we characterized a class of anti-cancer agents (curaxins) that disturbs DNA/histone interactions within nucleosomes. Here, using a combination of genomic and in vitro approaches, we demonstrate that curaxins strongly affect spatial genome organization and compromise enhancer-promoter communication, which is necessary for the expression of several oncogenes, including MYC. We further show that curaxins selectively inhibit enhancer-regulated transcription of chromatinized templates in cell-free conditions. Genomic studies also suggest that curaxins induce partial depletion of CTCF from its binding sites, which contributes to the observed changes in genome topology. Thus, curaxins can be classified as epigenetic drugs that target the 3D genome organization.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Genoma Humano , Sítios de Ligação , Fator de Ligação a CCCTC/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Elementos Facilitadores Genéticos , Humanos , Regiões Promotoras Genéticas , Ligação Proteica/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
10.
Life Sci ; 222: 140-147, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30849417

RESUMO

AIM: To investigate the cardioprotective effects of prolonged and moderate exercise training on cellular and molecular events early after myocardial infarction. MATERIALS AND METHODS: Male Wistar rats were divided in sedentary or exercised group; both groups underwent to a myocardial infarction. All the molecular and immunohistochemical analyses on hearts of sedentary and exercised rats were performed 48 h after surgical procedure. SIRT1 and SIRT3 expression were measured and two of the pathways activated by sirtuins, p53-induced apoptosis and Forkhead boxO (FOXO)3a-induced oxidative stress, were investigated. All the experiments were performed also in presence of the SIRT inhibitor, EX527. KEY FINDINGS: Fourty-eight hours post myocardial infarction, exercise training induced the activation of SIRT1 and SIRT3 pathway reducing cardiomyocytes apoptosis and oxidative damage. Molecular data were confirmed by immunohistochemical evaluations. These effects are more evident in border infarcted zone than in the remote myocardium. SIGNIFICANCE: Exercise training is a non-pharmacological prevention strategy in cardiovascular diseases and the sirtuins family seems to be as novel and attractive target in cardioprotection.


Assuntos
Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/prevenção & controle , Condicionamento Físico Animal/fisiologia , Transdução de Sinais/fisiologia , Sirtuína 1/metabolismo , Sirtuínas/metabolismo , Animais , Carbazóis/farmacologia , Masculino , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/tendências , Distribuição Aleatória , Ratos , Ratos Wistar , Comportamento Sedentário , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Fatores de Tempo
11.
Med Sci Monit ; 25: 1976-1983, 2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30877718

RESUMO

BACKGROUND Nasopharyngeal carcinoma results in high patient morbidity and mortality, due to early metastasis, and toxicity due to chemotherapy. Mukonal is plant-derived carbazole alkaloid that has been used in traditional Chinese medicine to treat several types of cancer. This study aimed to investigate the effects of mukonal on cell proliferation, apoptosis, autophagy, and the mitochondrial membrane potential of nasopharyngeal carcinoma cells in vitro. MATERIAL AND METHODS CNE1 human nasopharyngeal carcinoma cells and NP69 normal nasopharyngeal epithelial cells were cultured with and without treatment with increasing doses of mukonal. Cell viability was determined by the MTT assay. Fluorescence microscopy was used to detect reactive oxygen species (ROS), mitochondrial membrane potential, and the release of cytochrome C. Flow cytometry was used to examine changes in the cell cycle, electron microscopy examined cell autophagy, and Western blot was performed to measure levels of proteins associated with autophagy and apoptosis. RESULTS Mukonal had an antiproliferative effect on CNE1 cells, with an IC50 of 9 µM and there were effects of toxicity on normal NP69 cells. Mukonal triggered ROS-mediated changes in mitochondrial membrane potential which was also accompanied by the discharge of cytochrome C in the CNE1 cells. Mukonal activated autophagy and apoptosis in CNE1 cells, which was also associated with upregulation of the autophagy-related proteins, LC3 II and beclin-1, as well as apoptosis-associated proteins, Bax, cleaved caspase-3 and -9. Mukonal treatment also resulted in CNE1 cells cycle arrest at G2/M. CONCLUSIONS Mukonal inhibited the growth of human CNE1 nasopharyngeal carcinoma cells in vitro.


Assuntos
Carbazóis/farmacologia , Carcinoma Nasofaríngeo/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Carcinoma/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , China , Citocromos c/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Carcinoma Nasofaríngeo/patologia , Espécies Reativas de Oxigênio/metabolismo
12.
Med Sci Monit ; 25: 2002-2008, 2019 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-30879017

RESUMO

BACKGROUND Murrayanine is a carbazole alkaloid derived from Murraya koenigii, which has been used in traditional Chinese medicine in the treatment of cancer. This study aimed to investigate the effects of murrayanine on human lung adenocarcinoma cells in vitro and to investigate the mechanisms of its action. MATERIAL AND METHODS A549 human lung adenocarcinoma cells and MRC-5 human lung fibroblasts were grown in culture, and an MTT assay determined cell viability. Cells were treated for 24 h with increasing doses of murrayanine (0, 9, 18, and 36 µM). Fluorescence, using 4', 6-diamidino-2-phenylindole (DAPI), acridine orange, ethidium bromide, and propidium iodide (PI), were used for the detection of apoptosis. The cell cycle was studied with fluorescence-activated cell sorting (FACS), and Western blot evaluated protein expression. RESULTS Murrayanine treatment resulted in significant dose-dependent inhibition of the growth of A549 cells (p<0.05), with an IC50 of 9 µM, and arrested the cells at the G2/M phase of the cell cycle, reduced the expression of cyclin D and E, CDK2, 4, and 6, and increased the expression of p21 and p27. Murrayanine treatment increased apoptosis of the A549 cells and increased cleaved of caspase-3 and caspase-9, and the Bax/Bcl-2 ratio. Murrayanine treatment increased levels of reactive oxygen species (ROS), disrupted the mitochondrial membrane potential, inhibited invasion, and inhibited phosphorylation of p38 mitogen-activated protein kinase (MAPK) of the A549 cells. CONCLUSIONS Murrayanine induced cell cycle arrest, oxidative stress, and inhibited the expression of phosphorylated p38 in A549 adenocarcinoma cells.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Carbazóis/farmacologia , Células A549 , Adenocarcinoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Carbazóis/metabolismo , Caspase 3/efeitos dos fármacos , Caspase 9/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , China , Fase G2/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos
13.
J Vet Med Sci ; 81(4): 573-576, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30799325

RESUMO

We investigated the effects of tyrosol (Tyr) on anterior chamber paracentesis (ACP)-induced anterior uveitis in beagle dogs, as determined by protein and prostaglandin E2 (PGE2) concentrations in the aqueous humor (AH). Tyr at a dose of 100 or 200 mg/kg or 2.2 mg/kg of carprofen as a positive control was administered orally twice daily from 2.5 days before paracentesis. The initial ACP was performed in one eye of individual dogs and 0.5 ml AH was aspirated. The secondary AH was collected 60 min later. Pretreatment with 200 mg/kg of Tyr and carprofen significantly decreased aqueous protein and PGE2 concentrations compared to the control group. Overall, these findings suggested that Tyr was useful for the management of canine anterior uveitis.


Assuntos
Humor Aquoso/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Uveíte Anterior/veterinária , Animais , Câmara Anterior/cirurgia , Humor Aquoso/metabolismo , Carbazóis/farmacologia , Dinoprostona/metabolismo , Cães , Proteínas do Olho/metabolismo , Feminino , Masculino , Paracentese/efeitos adversos , Paracentese/veterinária , Álcool Feniletílico/farmacologia , Uveíte Anterior/tratamento farmacológico
14.
Ther Adv Respir Dis ; 13: 1753466619831906, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30786826

RESUMO

Molecular profiling of metastatic nonsquamous non-small cell lung cancer (NSCLC) is required to guide the treatment strategy. Anaplastic lymphoma kinase ( ALK) gene rearrangements are found in approximately 5% of lung adenocarcinomas and are associated with specific clinical features including a high risk of brain metastases. Crizotinib was the first ALK inhibitor developed and it demonstrated improved outcomes in patients with ALK-positive advanced NSCLC in comparison with chemotherapy. However, despite an initial response, all ALK-positive NSCLC patients develop acquired resistance to crizotinib. Because the most frequent mechanism of resistance is the development of a secondary ALK mutation, second (ceritinib, alectinib, brigatinib) and third-generation (lorlatinib) ALK inhibitors were developed. Alectinib is a second-generation ALK inhibitor and was shown to be effective for a broad spectrum of ALK rearrangements and ALK mutations. It was also shown to have high intracranial efficacy. In this article, we review clinical trial evidence of alectinib efficacy as well as publications reporting the experience of alectinib in daily practice, with a focus on brain metastases.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Carbazóis/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Piperidinas/administração & dosagem , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Carbazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia
15.
Nat Ecol Evol ; 3(3): 450-456, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778184

RESUMO

Heterogeneity in strategies for survival and proliferation among the cells that constitute a tumour is a driving force behind the evolution of resistance to cancer therapy. The rules mapping the tumour's strategy distribution to the fitness of individual strategies can be represented as an evolutionary game. We develop a game assay to measure effective evolutionary games in co-cultures of non-small cell lung cancer cells that are sensitive and resistant to the anaplastic lymphoma kinase inhibitor alectinib. The games are not only quantitatively different between different environments, but targeted therapy and cancer-associated fibroblasts qualitatively switch the type of game being played by the in vitro population from Leader to Deadlock. This observation provides empirical confirmation of a central theoretical postulate of evolutionary game theory in oncology: we can treat not only the player, but also the game. Although we concentrate on measuring games played by cancer cells, the measurement methodology we develop can be used to advance the study of games in other microscopic systems by providing a quantitative description of non-cell-autonomous effects.


Assuntos
Carbazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Fibroblastos/efeitos dos fármacos , Neoplasias Pulmonares/fisiopatologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Evolução Biológica , Células Cultivadas , Teoria do Jogo , Humanos , Modelos Biológicos
16.
Mol Pain ; 15: 1744806919832718, 2019 Jan-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30717631

RESUMO

The neuropeptide of calcitonin gene-related peptide (CGRP) plays critical roles in chronic pain, especially in migraine. Immunohistochemistry and in situ hybridization studies have shown that CGRP and its receptors are expressed in cortical areas including pain perception-related prefrontal anterior cingulate cortex. However, less information is available for the functional roles of CGRP in cortical regions such as the anterior cingulate cortex (ACC). Recent studies have consistently demonstrated that long-term potentiation is a key cellular mechanism for chronic pain in the ACC. In the present study, we used 64-electrode array field recording system to investigate the effect of CGRP on excitatory transmission in the ACC. We found that CGRP induced potentiation of synaptic transmission in a dose-dependently manner (1, 10, 50, and 100 nM). CGRP also recruited inactive circuit in the ACC. An application of the calcitonin receptor-like receptor antagonist CGRP8-37 blocked CGRP-induced chemical long-term potentiation and the recruitment of inactive channels. CGRP-induced long-term potentiation was also blocked by N-methyl-D-aspartate (NMDA) receptor antagonist AP-5. Consistently, the application of CGRP increased NMDA receptor-mediated excitatory postsynaptic currents. Finally, we found that CGRP-induced long-term potentiation required the activation of calcium-stimulated adenylyl cyclase subtype 1 (AC1) and protein kinase A. Genetic deletion of AC1 using AC1-/- mice, an AC1 inhibitor NB001 or a protein kinase A inhibitor KT5720, all reduced or blocked CGRP-induced potentiation. Our results provide direct evidence that CGRP may contribute to synaptic potentiation in important physiological and pathological conditions in the ACC, an AC1 inhibitor NB001 may be beneficial for the treatment of chronic headache.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , 2-Amino-5-fosfonovalerato/farmacologia , Adenilil Ciclases/deficiência , Adenilil Ciclases/genética , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Carbazóis/farmacologia , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Giro do Cíngulo/metabolismo , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Patch-Clamp , Pirróis/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Eur J Med Chem ; 167: 226-244, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30772606

RESUMO

A series of new pyranocarbazole derivatives were synthesized via semi-synthetic modification of koenimbine (1a) and koenidine (1b) isolated from the leaves of Murraya koenigii. Among all, compound 3bg displayed significant anti-cancer activity against MDA-MB-231, DU145 and PC3 cell lines with the IC50 values of 3.8, 7.6 and 5.8 µM, respectively. It was also observed that the halogenated-benzyl substitution at N-9 position, C-3 Methyl and C-7 methoxy group on carbazole motif are favoured for anti-cancer activity. The detailed investigation was carried out with compound 3bg and its SEDDS (self-emulsifying drug delivery systems) formulation 3bgF. The in vivo drug release behavior study showed that the formulation enhanced slow release and better bioavailability at a tumor site. Compound 3bg and its formulation (3bgF) significantly inhibited cell proliferation and colony formation, induced G2/M arrest, reduced cellular ROS generation and induced caspase-dependent apoptosis in MDA-MB-231 cells. 3bg also induced significant alteration of Bax/Bcl expression ratio suggesting involvement of mitochondrial apoptosis. Additionally, 3bg caused down-regulation of mTOR/Akt survival pathway. 3bg do not bind to DNA, but interacts with tubulin as observed with in silico molecular docking studies. This interaction results in stabilization of tubulin polymerization similar to paclitaxel as detected in cell-free assay. Oral administration of 3bgF for 30 days at dose rate of 10 and 20 mg/kg body weight significantly reduced tumor growth in syngenic rat LA-7 mammary tumor model. These results indicated that the pyranocarbazole natural product based N-substituted analogues can act as potential anti-cancer lead.


Assuntos
Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Carbazóis/química , Piranos/química , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carbazóis/farmacologia , Caspases , Linhagem Celular Tumoral , Regulação para Baixo/genética , Humanos , Concentração Inibidora 50 , Células PC-3 , Polimerização , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piranos/farmacologia , Ratos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
18.
Thromb Haemost ; 119(3): 421-430, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30616245

RESUMO

BACKGROUND: Inflammation plays an important role in thrombus formation, and Sirtuin 1 (SIRT1) negatively regulates inflammation via deacetylating nuclear factor-kappa B. However, the relationship between SIRT1-regulated inflammation and deep vein thrombosis (DVT) is still unknown. OBJECTIVE: The aim of this study was to investigate whether SIRT1 plays a critical role in inferior vena cava (IVC) stenosis-induced DVT. MATERIALS AND METHODS: Thrombus weight and histopathologic analysis of IVC were evaluated at different time points after IVC stenosis in rats. Serum levels of inflammatory cytokines and protein expressions of SIRT1, acetylated p65 (Ace-p65), phosphorylated p65 (p-p65) and tissue factor (TF) in thrombosed IVC were assessed. Besides, the effects of resveratrol (RES, a SIRT1 agonist) and EX527 (a selective SIRT1 inhibitor) on DVT were evaluated. RESULTS: Thrombus weight was increased from 1 to 3 days after IVC stenosis, and then was decreased afterwards. Leukocytes infiltration appeared and serum levels of cytokines were significantly increased in rats of IVC stenosis. SIRT1 protein expression was significantly down-regulated at 1 hour and 1 day after stenosis, while p-p65, Ace-p65 and TF protein expressions appeared a contrary trend. RES reduced thrombus weight, leukocytes infiltration, levels of tumour necrosis factor-α and interleukin-1ß and protein expressions of Ace-p65 and TF as well. Moreover, RES significantly increased the protein and messenger ribonucleic acid expressions of SIRT1, while EX527 abolished the protective effects of RES. CONCLUSION: SIRT1 activation attenuated IVC stenosis-induced DVT via anti-inflammation in rats. Therefore, SIRT1 may be a potential therapeutic target that could ameliorate DVT.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/enzimologia , Transdução de Sinais , Sirtuína 1/metabolismo , Fator de Transcrição RelA/metabolismo , Veia Cava Inferior/enzimologia , Trombose Venosa/enzimologia , Acetilação , Animais , Anti-Inflamatórios/farmacologia , Carbazóis/farmacologia , Modelos Animais de Doenças , Feminino , Fibrinolíticos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inflamação/imunologia , Inflamação/patologia , Inflamação/prevenção & controle , Mediadores da Inflamação/imunologia , Masculino , Fosforilação , Ratos Sprague-Dawley , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Fatores de Tempo , Veia Cava Inferior/efeitos dos fármacos , Veia Cava Inferior/imunologia , Veia Cava Inferior/patologia , Trombose Venosa/imunologia , Trombose Venosa/patologia , Trombose Venosa/prevenção & controle
19.
Int J Mol Sci ; 20(3)2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30691004

RESUMO

Hemp seed (Fructus cannabis) is rich in lignanamides, and initial biological screening tests showed their potential anti-inflammatory and anti-oxidative capacity. This study investigated the possible effects and underlying mechanism of cannabisin F, a hempseed lignanamide, against inflammatory response and oxidative stress in lipopolysaccharide (LPS)-stimulated BV2 microglia cells. Cannabisin F suppressed the production and the mRNA levels of pro-inflammatory mediators such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in a concentration-dependent manner in LPS-stimulated BV2 microglia cell. Furthermore, cannabisin F enhanced SIRT1 expression and blocked LPS-induced NF-κB (Nuclear factor kappa B) signaling pathway activation by inhibiting phosphorylation of IκBα (Inhibit proteins of nuclear factor kappaB) and NF-κB p65. And the SIRT1 inhibitor EX527 significantly inhibited the effect of cannabisin F on pro-inflammatory cytokines production, suggesting that the anti-inflammatory effects of cannabisin F are SIRT1-dependent. In addition, cannabisin F reduced the production of cellular reactive oxygen species (ROS) and promoted the expression of Nrf2 (Nuclear factor erythroid-2 related factor 2) and HO-1 (Heme Oxygenase-1), suggesting that the anti-oxidative effects of cannabisin F are related to Nrf2 signaling pathway. Collectively, these results suggest that the neuro-protection effect of cannabisin F against LPS-induced inflammatory response and oxidative stress in BV2 microglia cells involves the SIRT1/NF-κB and Nrf2 pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Lipopolissacarídeos/efeitos adversos , Microglia/citologia , Fenóis/farmacologia , Sirtuína 1/metabolismo , Animais , Carbazóis/farmacologia , Linhagem Celular , Sobrevivência Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Transdução de Sinais/efeitos dos fármacos
20.
Environ Toxicol ; 34(4): 539-547, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30672645

RESUMO

The mechanism of manganism caused by manganese (Mn), an important environmental risk factor for Parkinson's disease, is still unclear. Recent evidence suggested that autophagy participated in neurodegenerative diseases, in which microRNA played a crucial role. However, roles of microRNA in the aberrant autophagy that occurs in neurodegenerative diseases remains controversial. In nervous system, miRNA-138-5p is highly expressed and plays a key role in regulating memory and axon regeneration. Importantly, we also found that miR-138-5p expression decreased significantly after SH-SY5Y cells exposed to manganese chloride (MnCl2 ) in previous study. To explore the role of miR-138-5p in Mn-induced autophagy, autophagy associated indicators were detected. And we found that MnCl2 could induce autophagic dysregulation and inhibit expression of miR-138-5p. While the levels of LC3-II/LC3-I, Beclin1, and p62, the number of autophagosome formation significantly decreased after miR-138-5p over-expression, which demonstrated that miR-138-5p could clearly retard Mn-induced autophagy. In additional, we found there were classical and evolutionarily conserved miR-138-5p binding sites in 3'-UTR region of SIRT1, which was inhibited when overexpression of miR-138-5p. Therefore, it was speculated that elevated expression of SIRT1 may be resulted from inhibition of miR-138-5p after cells exposed to MnCl2 . Finally, we found that SIRT1 inhibitor EX-527 suppressed Mn-induced autophagy as well as miR-138-5p, while the suppression was reversed by SIRT1-specific activator SRT1720. These results indicated that overexpression of miR-138-5p suppressed Mn-induced autophagy by targeting SIRT1.


Assuntos
Autofagia/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Manganês/toxicidade , MicroRNAs/genética , Sirtuína 1/metabolismo , Regiões 3' não Traduzidas/genética , Autofagia/genética , Carbazóis/farmacologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Humanos , Sirtuína 1/antagonistas & inibidores
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