Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.064
Filtrar
1.
Eur J Cancer ; 138: 109-112, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32871524
2.
Anticancer Res ; 40(9): 4961-4968, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878784

RESUMO

BACKGROUND/AIM: Despite advances in treatment modalities, the visual prognosis of retinoblastoma still remains unsatisfactory, underscoring the need to develop novel therapeutic approaches. MATERIALS AND METHODS: The effect on the growth of six human retinoblastoma cell lines and a normal human fibroblast cell line of CEP1347, a small-molecule kinase inhibitor originally developed for the treatment of Parkinson's disease and therefore with a known safety profile in humans, was examined. The role of the P53 pathway in CEP1347-induced growth inhibition was also investigated. RESULTS: CEP1347 selectively inhibited the growth of retinoblastoma cell lines expressing murine double minute 4 (MDM4), a P53 inhibitor. Furthermore, CEP1347 reduced the expression of MDM4 and activated the P53 pathway in MDM4-expressing retinoblastoma cells, which was required for the inhibition of their growth by CEP1347. CONCLUSION: We propose CEP1347 as a promising candidate for the treatment of retinoblastomas, where functional inactivation of P53 as a result of MDM4 activation is reportedly common.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Retinoblastoma/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reposicionamento de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Retinoblastoma/metabolismo , Retinoblastoma/patologia
3.
Med Hypotheses ; 143: 110122, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32759007

RESUMO

A characteristic feature of COVID-19 disease is lymphopenia. Lymphopenia occurs early in the clinical course and is a predictor of disease severity and outcomes. The mechanism of lymphopenia in COVID-19 is uncertain. It has been variously attributed to the release of inflammatory cytokines including IL-6 and TNF-α; direct infection of the lymphocytes by the virus; and rapid sequestration of lymphocytes in the tissues. Additionally, we postulate that prostaglandin D2 (PGD2) is a key meditator of lymphopenia in COVID-19. First, SARS-CoV infection is known to stimulate the production of PGD2 in the airways, which inhibits the host dendritic cell response via the DP1 receptor signaling. Second, PGD2 is known to upregulate monocytic myeloid-derived suppressor cells (MDSC) via the DP2 receptor signaling in group 2 innate lymphoid cells (ILC2). We propose targeting PGD2/DP2 signaling using a receptor antagonist such as ramatroban as an immunotherapy for immune dysfunction and lymphopenia in COVID-19 disease.


Assuntos
Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Linfopenia/fisiopatologia , Modelos Imunológicos , Terapia de Alvo Molecular , Pandemias , Pneumonia Viral/fisiopatologia , Prostaglandina D2/fisiologia , Sistema Respiratório/metabolismo , Adulto , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Criança , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Células Dendríticas/imunologia , Humanos , Linfopenia/etiologia , Células Mieloides/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Prostaglandina D2/biossíntese , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/metabolismo , Receptores de Prostaglandina/fisiologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T/imunologia , Tromboxano A2/antagonistas & inibidores
4.
Nat Commun ; 11(1): 2814, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32499508

RESUMO

Food consumption is fundamental for life, and eating disorders often result in devastating or life-threatening conditions. Anorexia nervosa (AN) is characterized by a persistent restriction of energy intake, leading to lowered body weight, constant fear of gaining weight, and psychological disturbances of body perception. Herein, we demonstrate that SIRT1 inhibition, both genetically and pharmacologically, delays the onset and progression of AN behaviors in activity-based anorexia (ABA) models, while SIRT1 activation accelerates ABA phenotypes. Mechanistically, we suggest that SIRT1 promotes progression of ABA, in part through its interaction with NRF1, leading to suppression of a NMDA receptor subunit Grin2A. Our results suggest that AN may arise from pathological positive feedback loops: voluntary food restriction activates SIRT1, promoting anxiety, hyperactivity, and addiction to starvation, exacerbating the dieting and exercising, thus further activating SIRT1. We propose SIRT1 inhibition can break this cycle and provide a potential therapy for individuals suffering from AN.


Assuntos
Anorexia Nervosa/metabolismo , Regulação da Expressão Gênica , Fator 1 Nuclear Respiratório/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sirtuína 1/metabolismo , Animais , Peso Corporal , Carbazóis/farmacologia , Modelos Animais de Doenças , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Resveratrol/farmacologia , Estresse Mecânico , Regulação para Cima
5.
Anticancer Res ; 40(6): 3155-3161, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487610

RESUMO

BACKGROUND/AIM: The deacetylase sirtuin1 (SIRT1) inhibits tumor suppressor p53 and may promote tumorigenesis; however, SIRT1 effects on leukemia cells are controversial. The aim of this study was to clarify the activity of SIRT1 in leukemia cells. MATERIALS AND METHODS: The effects of SIRT1 inhibition or activation and SIRT1 knockdown or overexpression were examined in two T cell acute lymphoblastic leukemia (T-ALL) cell lines carrying NOTCH1 mutations and three acute myeloid leukemia (AML) cell lines. RESULTS: The growth of T-ALL cells was promoted by SIRT1 inhibition and SIRT1 knockdown but was reduced by SIRT1 activation and overexpression; however, no effects were observed in AML cells. SIRT1 activation decreased NOTCH, NF-κB, and mTOR signaling and inhibited p53, suggesting that the possible mechanisms of T-ALL growth suppression by SIRT1 are independent of p53. CONCLUSION: SIRT1 activators acting through the down-regulation of NOTCH, NF-κB, and mTOR pathways can be novel targeted drugs for NOTCH1-mutated T-ALLs.


Assuntos
NF-kappa B/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores Notch/metabolismo , Sirtuína 1/metabolismo , Carbazóis/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/biossíntese , Sirtuína 1/genética , Serina-Treonina Quinases TOR/metabolismo , Transfecção
6.
Proc Natl Acad Sci U S A ; 117(27): 15837-15845, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571957

RESUMO

Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.


Assuntos
Ácido Fólico/metabolismo , Desnutrição/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/metabolismo , Vitamina B 12/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Carbazóis/farmacologia , Anormalidades Congênitas , Feminino , Deficiência de Ácido Fólico/tratamento farmacológico , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias , Dibenzodioxinas Policloradas/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Deficiência de Vitamina B 12/tratamento farmacológico
7.
Thorac Surg Clin ; 30(2): 137-146, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32327172

RESUMO

The treatment of patients with advanced non-small cell lung cancer with anaplastic lymphoma kinase chromosomal rearrangements has been revolutionized by the development of tyrosine kinase inhibitors (TKIs). Excellent progress has been made over the past decade, with 4 TKIs now approved in the front-line setting. Alectinib is the preferred first-line option based on its efficacy and side-effect profile. The central nervous system (CNS) activity of alectinib and brigatinib has allowed for treatment of CNS metastases with TKI therapy. Once resistance inevitably develops, newer therapies such as lorlatinib can be considered.


Assuntos
Quinase do Linfoma Anaplásico , Carbazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Piperidinas/farmacologia , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Testes Farmacogenômicos , Inibidores de Proteínas Quinases/farmacologia
8.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1145-L1157, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32267731

RESUMO

We have demonstrated previously that intracellular transport is impaired in cystic fibrosis (CF) epithelial cells. This impairment is related to both growth and inflammatory regulation in CF cell and animal models. Understanding how transport in CF cells is regulated and identifying means to manipulate that regulation are key to identifying new therapies that can address key CF phenotypes. It was hypothesized that resveratrol could replicate these benefits since it interfaces with multiple pathways identified to affect microtubule regulation in CF. It was found that resveratrol treatment significantly restored intracellular transport as determined by monitoring both cholesterol distribution and the distribution of rab7-positive organelles in CF cells. This restoration of intracellular transport is due to correction of both microtubule formation rates and microtubule acetylation in cultured CF cell models and primary nasal epithelial cells. Mechanistically, the effect of resveratrol on microtubule regulation and intracellular transport was dependent on peroxisome proliferator-activated receptor-γ signaling and its ability to act as a pan-histone deacetylase (HDAC) inhibitor. Resveratrol represents a candidate compound with known anti-inflammatory properties that can restore both microtubule formation and acetylation in CF epithelial cells.


Assuntos
Fibrose Cística/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Espaço Intracelular/metabolismo , Resveratrol/farmacologia , 1-Metil-3-Isobutilxantina/farmacologia , Acetilação/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Carbazóis/farmacologia , Células Cultivadas , Colesterol/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Nariz/patologia , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Resorcinóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/metabolismo , Estilbenos/farmacologia , Tubulina (Proteína)/metabolismo
9.
Eur J Med Chem ; 191: 112181, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113125

RESUMO

Here, we formulated and investigated the structure-activity relationships of novel N-substituted carbazole sulfonamide derivatives with improved physicochemical properties. Most of these new compounds displayed good aqueous solubility. Certain molecules presented strong in vitro antiproliferative and in vivo antitumor activity. Relative to the control, 50 mg/kg compound 3v substantially reduced human HepG2 xenograft mouse tumor growth by 54.5% and its efficacy was comparable to that of CA-4P. Compound 3h demonstrated anticancer efficacy in both subcutaneous and orthotopic HepG2 xenograft mouse models. We also developed a novel synthetic method for 7-hydroxy-substituted carbazole sulfonamides. Compared with the control, 25 mg/kg compound 4c inhibited human HepG2 xenograft mouse tumor growth by 71.7% and was more potent than 50 mg/kg CA-4P with only 50% tumor shrinkage efficacy. Among the three water-soluble carbazole sulfonamide derivatives formulated in the present study, compound 4c displayed the most effective tumor growth inhibition in vivo and merit further investigation as potential antitumor agents for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Células Tumorais Cultivadas , Água/química
10.
Neoplasma ; 67(3): 547-556, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32202904

RESUMO

Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide due to the lack of effective therapy methods. Therefore, there is an urgent need to develop novel therapies for HCC. CBL0137 is a small molecule that affects p53 and nuclear factor-kappa B (NF-κB). The expression of p53 was measured by using immunohistochemistry (IHC) in tumor and adjacent tissues. Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to detect the level of p-p53, p53, Bax, and PUMA after CBL0137 administration. CCK-8 and immunofluorescence staining (IF) assays were performed to evaluate the proliferation and viability of HCC cells. Flow cytometry was used to detect the apoptosis of HCC cells. Xenograft model was established to determine the effect of CBL0137 treatment on HCC tumor growth in vivo. HE staining was used to monitor HCC cell morphology and IHC staining for Ki-67 was performed to determine the tumor cell proliferation following CBL0137 treatment. Results showed that the expression of p-p53, p53, Bax, and PUMA was upregulated after CBL0137 administration. The viability, growth, and colony formation of HCC cells were significantly inhibited by CBL0137 in the CBL group compared with the NC group (p<0.05). Meanwhile, the results revealed that the proportions of apoptotic and necrotic cells were significantly elevated in the CBL group compared to the NC group (p<0.05). And the apoptosis-related proteins including PARP, caspase-3, caspase-7, caspase-8, and caspase-9 were increased in the CBL group compared with the NC group (p<0.05), while the NF-κB, p-NF-κB and p-AKT expression levels were significantly downregulated following CBL0137 treatment (p<0.05). Additionally, the tumor volume and weight were significantly reduced in the CBL group compared with the NC group (p<0.05). Moreover, HE staining and IHC staining for Ki-67 indicated that CBL0137 treatment could obviously induce cell apoptosis and suppress cell proliferation. CBL0137 treatment could effectively inhibit HCC cell proliferation and induce cell apoptosis associated with multiple factors expression.


Assuntos
Apoptose , Carbazóis/farmacologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Proteína Supressora de Tumor p53/genética , Proteína X Associada a bcl-2/genética
11.
Anticancer Res ; 40(3): 1395-1403, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132036

RESUMO

BACKGROUND/AIM: The aim of the study was to examine the efficacy of the combination of anaplastic lymphoma kinase (ALK) inhibitors with other inhibitors for the treatment of ALK-positive lymphomas. This approach is predicted to be an alternative way for suppressing ALK-positive anaplastic large cell lymphoma (ALCL). MATERIALS AND METHODS: We treated ALK-positive ALCL cell lines, KARPAS-299 and SU-DHL-1, with the ALK inhibitor alectinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus. RESULTS: The ALK inhibitor alectinib had a selective ALK-dependent inhibitory effect on ALK-positive cancer cell proliferation. Treatment with alectinib or everolimus inhibited target molecules, and their combination augmented their inhibitory effect on the mTOR pathway. Furthermore, the combination treatment significantly inhibited cell proliferation and induced cell cycle arrest at the G0/G1 phase in ALK-positive ALCL cells. CONCLUSION: The combination of both inhibitors synergistically inhibits ALK-positive ALCL cell growth via the ALK/mTOR pathway.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carbazóis/farmacologia , Everolimo/farmacologia , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/enzimologia , Piperidinas/farmacologia , Quinase do Linfoma Anaplásico/biossíntese , Carbazóis/administração & dosagem , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Crizotinibe/administração & dosagem , Crizotinibe/farmacologia , Sinergismo Farmacológico , Everolimo/administração & dosagem , Humanos , Células Jurkat , Linfoma Anaplásico de Células Grandes/patologia , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia
12.
Biomed Res Int ; 2020: 7821913, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104704

RESUMO

Murraya koenigii is a well-known Indian medicinal herb, and a carbazole alkaloid (mahanine) from this plant causes apoptosis in cancer cells. Here, we investigated how seasonal and geographical variations influence carbazole alkaloids composition and medicinal property of this plant against cancer cells in vitro and in vivo. Leaflets were collected from various places in different seasons for three years. A mahanine-enriched fraction (MEF) was prepared in two steps using ethanol and water. The best plant was selected based on the highest percent of mahanine. MEF prepared from leaflets of nine different locations showed a different concentration of identified markers (mahanine, mahanimbine, and koenimbine) which exhibited differential reduced metabolic activity against ovarian cancer, mahanine being the best. Our systematic study revealed that mahanine content was highest during September-December. Interestingly, MEF from southern part (tropical zone) exhibited 43 ± 2.5% mahanine compared to 2.7 ± 1.3% in northeastern part (subtropical zone) with five folds higher activity against PA1. Moreover, MEF reduced metabolic activity of sixteen cancer cell lines from nine different origins and significantly reduced tumor mass in lung and ovarian cancer xenograft models. Taken together, this is the first report demonstrating the marker's content in these leaflets is highly dependent on location/season. A positive correlation between biological activity and mahanine concentration was established in MEF. Such a comprehensive study suggests that the selection of location and suitable season for collection of any plant materials with biologically active stable markers in sufficient quantity play a decisive role in determining the fate of their medicinal property.


Assuntos
Alcaloides , Antineoplásicos Fitogênicos , Carbazóis , Murraya , Neoplasias Experimentais/tratamento farmacológico , Estações do Ano , Células A549 , Alcaloides/química , Alcaloides/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Feminino , Células HCT116 , Células HeLa , Humanos , Camundongos , Camundongos Nus , Murraya/química , Murraya/crescimento & desenvolvimento , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Muscle Nerve ; 61(5): 662-670, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32083755

RESUMO

INTRODUCTION: We investigated the mechanisms underlying immobilization-induced muscle pain in rats. METHODS: In rat skeletal muscle, pressure pain threshold (PPT) of the gastrocnemius muscle was measured, and nerve growth factor (NGF) level, peripheral nerve fiber density, macrophage number, and interleukin-1ß (IL-1ß) mRNA expression were examined. An NGF receptor inhibitor was injected intramuscularly to assess the relationship between PPT and NGF levels. RESULTS: Immobilization resulted in a decrease in PPT and increases in NGF level, C-fiber density, M1 macrophage number, and IL-1ß mRNA expression. Injection of NGF receptor inhibitor reversed the decrease in PPT. DISCUSSION: NGF upregulation may be a major contributor to immobilization-induced muscle pain. The increases in C-fiber density, M1 macrophage number, and IL-1ß mRNA expression may be related to immobilization-induced muscle pain.


Assuntos
Hiperalgesia/metabolismo , Imobilização , Interleucina-1beta/genética , Macrófagos/patologia , Músculo Esquelético/metabolismo , Fator de Crescimento Neural/metabolismo , Limiar da Dor/fisiologia , RNA Mensageiro/metabolismo , Animais , Carbazóis/farmacologia , Moldes Cirúrgicos , Inibidores Enzimáticos/farmacologia , Membro Posterior , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Alcaloides Indólicos/farmacologia , Masculino , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Fibras Nervosas/patologia , Fibras Nervosas Amielínicas/patologia , Limiar da Dor/efeitos dos fármacos , Pressão , Distribuição Aleatória , Ratos , Ratos Wistar , Receptor trkA/antagonistas & inibidores
14.
Chem Biol Interact ; 317: 108972, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32017914

RESUMO

BACKGROUND: Heart failure (HF) is an epidemic disease with increased incidence annually. It has been reported that taurine can improve cardiac function. This study investigated the cardioprotective effects of taurine in pressure-loaded HF mice and elucidated the possible mechanism. METHODS: HF models were established by transverse aortic constriction (TAC). Animals were treated with either taurine for 9 weeks and/or the SIRT1 inhibitor EX527 (5 mg/kg/day, every 2days) after TAC operation. Cardiac function and geometry were revealed by echocardiography. Myocardial hypertrophy and fibrosis were assessed using Fluorescent wheat germ agglutinin (WGA) staining and Masson's trichrome staining. Western blot and RT-PCR were performed to elucidate the expression of target proteins and genes respectively. Apoptosis in cardiomyocytes was detected by TUNEL staining. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD) and malonyldialdehyde (MDA) and reactive oxygen species (ROS). Taurine concentrations and NAD+/NADH ratio were determined by taurine and NAD+/NADH assay kit. RESULTS: Taurine notably relieved cardiac dysfunction after TAC. The mechanisms were attributed to reduced myocyte hypertrophy and fibrosis, and alleviated apoptosis and oxidative stress. Meanwhile, taurine increased NAD+/NADH ratio,promoted the expression of SIRT1 and suppressed p53 acetylation. However, EX-527(inhibitor of SIRT1) decreased NAD+/NADH ratio and increased acetyl-p53 levels, and abolished the cardioprotective effects of taurine on mice subjected to TAC and increased apoptosis and oxidative stress. CONCLUSION: The mechanism responsible for cardiac-protective effects of taurine in HF induced by pressure overload is associated with the activation of the SIRT1-p53 pathway.


Assuntos
Miócitos Cardíacos/efeitos dos fármacos , Pressão , Sirtuína 1/metabolismo , Taurina/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Aorta/patologia , Apoptose/efeitos dos fármacos , Carbazóis/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Sirtuína 1/genética , Proteína Supressora de Tumor p53/genética
15.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165723, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061777

RESUMO

Aging provokes both morphological and functional changes in cells, which are accompanied by a fundamental shift in gene expression patterns. One of the characteristic alterations associated with senescence in fibroblast cells is the down-regulation of collagen type I genes. In the present study, we investigated the contribution of myocardin-related transcription factor A, or MRTF-A, in this process. In mouse embryonic fibroblast (MEF) cells and human foreskin fibroblast (HFF) cells, senescence, induced by either progressive passage or treatment with hydrogen peroxide (H2O2), led to augmented lysine acetylation of MRTF-A paralleling down-regulation of collagen type I and SIRT1, a lysine deacetylase. SIRT1 interacted with MRTF-A to promote MRTF-A deacetylation. SIRT1 over-expression or activation by selective agonists enhanced trans-activation of the collagen promoters by MRTF-A. On the contrary, SIRT1 depletion or inhibition by specific antagonists suppressed trans-activation of the collagen promoters by MRTF-A. Likewise, mutation of four lysine residues within MRTF-A rendered it more potent in terms of activating the collagen promoters but unresponsive to SIRT1. Importantly, SIRT1 activation in senescent fibroblasts mitigated repression of collagen type I expression whereas SIRT1 inhibition promoted the loss of collagen type I expression prematurely in young fibroblasts. Mechanistically, SIRT1 enhanced the affinity of MRTF-A for the collagen type I promoters. In conclusion, our data unveil a novel mechanism that underscores aging-associated loss of collagen type I in fibroblasts via SIRT1-mediated post-translational modification of MRTF-A.


Assuntos
Senescência Celular/fisiologia , Colágeno Tipo I/genética , Sirtuína 1/metabolismo , Transativadores/metabolismo , Acetilação/efeitos dos fármacos , Animais , Benzamidas/farmacologia , Carbazóis/farmacologia , Regulação para Baixo/efeitos dos fármacos , Embrião de Mamíferos , Fibroblastos , Células HEK293 , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Camundongos , Mutação , Naftóis/farmacologia , Cultura Primária de Células , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/metabolismo , Resveratrol/farmacologia , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Transativadores/genética
16.
Cell Physiol Biochem ; 54(1): 126-141, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32017483

RESUMO

BACKGROUND/AIMS: Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter and hormone with important physiological functions in many organs, including the intestine. We have previously shown that 5-HT activates the aryl hydrocarbon receptor (AhR) in intestinal epithelial cells (IECs) via a serotonin transporter (SERT)-dependent mechanism. AhR is a nuclear receptor that binds a variety of molecules including tryptophan (TRP) metabolites to regulate physiological processes in the intestine including xenobiotic detoxification and immune modulation. We hypothesized that 5-HT activates AhR indirectly by interfering with metabolic clearance of AhR ligands by cytochrome P450 1A1 (CYP1A1). METHODS: Inhibition of CYP1A1 activity by 5-HT was assessed in the human intestinal epithelial cell line Caco-2 and recombinant CYP1A1 microsomes using both luciferase and LC-MS/MS. Degradation of 5-HT by recombinant CYP1A1 was measured by LC-MS/MS. For in vitro studies, CYP1A1 and CYP1B1 mRNA expression levels were measured by RT-PCR and CYP1A1 activity was measured by ethoxyresorufin-O-deethylase (EROD) assays. For in vivo studies, AhR ligands were administered to SERT KO mice and WT littermates and intestinal mucosa CYP1A1 mRNA was measured. RESULTS: We show that 5-HT inhibits metabolism of both the pro-luciferin CYP1A1 substrate Luc-CEE as well as the high affinity AhR ligand 6-formylindolo[3,2-b] carbazole (FICZ). Recombinant CYP1A1 assays revealed that 5-HT is metabolized by CYP1A1 in an NADPH dependent manner. Treatment with 5-HT in TRP-free medium, which is devoid of trace AhR ligands, showed that 5-HT requires the presence of AhR ligands to activate AhR. Cotreatment with 5-HT and FICZ confirmed that 5-HT potentiates induction of AhR target genes by AhR ligands. However, this was only true for ligands which are CYP1A1 substrates such as FICZ. Administration of ß-napthoflavone by gavage or indole-3-carbinol via diet to SERT KO mice revealed that lack of SERT impairs intestinal AhR activation. CONCLUSION: Our studies provide novel evidence of crosstalk between serotonergic and AhR signaling where 5-HT can influence the ability of AhR ligands to activate the receptor in the intestine.


Assuntos
Citocromo P-450 CYP1A1/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Serotonina/farmacologia , Transcrição Genética/efeitos dos fármacos , Animais , Células CACO-2 , Carbazóis/farmacologia , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Humanos , Ligantes , Masculino , Camundongos , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/deficiência , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transdução de Sinais/efeitos dos fármacos , Especificidade por Substrato , beta-Naftoflavona/administração & dosagem
17.
Int J Mol Sci ; 21(4)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32074942

RESUMO

BACKGROUND: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease that manifests as progressive valvular fibrosis and calcification. An inflammatory milieu in valvular tissue promotes fibrosis and calcification. Aortic valve interstitial cell (AVIC) proliferation and the over-production of the extracellular matrix (ECM) proteins contribute to valvular thickening. However, the mechanism underlying elevated AVIC fibrogenic activity remains unclear. Recently, we observed that AVICs from diseased aortic valves express higher levels of neurotrophin 3 (NT3) and that NT3 exerts pro-osteogenic and pro-fibrogenic effects on human AVICs. HYPOTHESIS: Pro-inflammatory stimuli upregulate NT3 production in AVICs to promote fibrogenic activity in human aortic valves. METHODS AND RESULTS: AVICs were isolated from normal human aortic valves and were treated with lipopolysaccharide (LPS, 0.20 µg/mL). LPS induced TLR4-dependent NT3 production. This effect of LPS was abolished by inhibition of the Akt and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways. The stimulation of TLR4 in human AVICs with LPS resulted in a greater proliferation rate and an upregulated production of matrix metallopeptidases-9 (MMP-9) and collagen III, as well as augmented collagen deposition. Recombinant NT3 promoted AVIC proliferation in a tropomyosin receptor kinase (Trk)-dependent fashion. The neutralization of NT3 or the inhibition of Trk suppressed LPS-induced AVIC fibrogenic activity. CONCLUSIONS: The stimulation of TLR4 in human AVICs upregulates NT3 expression and promotes cell proliferation and collagen deposition. The NT3-Trk cascade plays a critical role in the TLR4-mediated elevation of fibrogenic activity in human AVICs. Upregulated NT3 production by endogenous TLR4 activators may contribute to aortic valve fibrosis associated with CAVD progression.


Assuntos
Cardiopatias Congênitas/patologia , Doenças das Valvas Cardíacas/patologia , Neurotrofina 3/metabolismo , Receptor 4 Toll-Like/metabolismo , Valva Aórtica/citologia , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Carbazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colágeno/metabolismo , Feminino , Cardiopatias Congênitas/metabolismo , Doenças das Valvas Cardíacas/metabolismo , Humanos , Alcaloides Indólicos/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Regulação para Cima/efeitos dos fármacos
18.
Nat Cell Biol ; 22(1): 74-86, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31907414

RESUMO

Collagen is the most abundant secreted protein in vertebrates and persists throughout life without renewal. The permanency of collagen networks contrasts with both the continued synthesis of collagen throughout adulthood and the conventional transcriptional/translational homeostatic mechanisms that replace damaged proteins with new copies. Here, we show circadian clock regulation of endoplasmic reticulum-to-plasma membrane procollagen transport by the sequential rhythmic expression of SEC61, TANGO1, PDE4D and VPS33B. The result is nocturnal procollagen synthesis and daytime collagen fibril assembly in mice. Rhythmic collagen degradation by CTSK maintains collagen homeostasis. This circadian cycle of collagen synthesis and degradation affects a pool of newly synthesized collagen, while maintaining the persistent collagen network. Disabling the circadian clock causes abnormal collagen fibrils and collagen accumulation, which are reduced in vitro by the NR1D1 and CRY1/2 agonists SR9009 and KL001, respectively. In conclusion, our study has identified a circadian clock mechanism of protein homeostasis wherein a sacrificial pool of collagen maintains tissue function.


Assuntos
Relógios Circadianos/fisiologia , Colágeno/metabolismo , Homeostase/fisiologia , Via Secretória/fisiologia , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/efeitos dos fármacos , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Carbazóis/farmacologia , Colágeno/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Matriz Extracelular/metabolismo , Camundongos Transgênicos , Pirrolidinas/farmacologia , Canais de Translocação SEC/efeitos dos fármacos , Canais de Translocação SEC/metabolismo , Via Secretória/genética , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Proteínas de Transporte Vesicular/efeitos dos fármacos , Proteínas de Transporte Vesicular/metabolismo
19.
Theriogenology ; 144: 132-138, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31940504

RESUMO

N-WASP is the mammalian ortholog of WASP which is an actin nucleation promoting factor and has been reported to regulate actin nucleation and polymerization for multiple cell activities. However, the expression and functions of N-WASP in porcine oocytes are still unclear. In this study, we showed that N-WASP expressed at all stages during porcine oocyte maturation, and immunofluorescence staining indicated that N-WASP mainly accumulated at the cortex in different stages of meiosis. Inhibition of N-WASP activity by Wiskostatin significantly decreased the rate of first polar body extrusion and disturbed the cell cycle progression of porcine oocytes. Further analysis indicated that cortical actin distribution was interfered by N-WASP inhibition, and this might be through its regulatory roles on the expression and localization of ARP2, a key component of actin nucleator Arp2/3 complex. Moreover, the expression of N-WASP decreased after ROCK activity inhibition, indicating a ROCK-N-WASP-ARP2/3 pathway for actin assembly in porcine oocytes. Taken together, these results suggest that N-WASP is critical for the regulation of actin filaments for cytokinesis during porcine oocyte maturation.


Assuntos
Actinas/metabolismo , Citocinese/fisiologia , Técnicas de Maturação in Vitro de Oócitos/veterinária , Oócitos/fisiologia , Suínos/fisiologia , Proteína Neuronal da Síndrome de Wiskott-Aldrich/antagonistas & inibidores , Amidas/farmacologia , Animais , Carbazóis/farmacologia , Propanolaminas/farmacologia , Piridinas/farmacologia , Proteína Neuronal da Síndrome de Wiskott-Aldrich/genética , Proteína Neuronal da Síndrome de Wiskott-Aldrich/metabolismo
20.
Leukemia ; 34(3): 682-696, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31919472

RESUMO

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in approximately one third of patients with acute myeloid leukemia (AML), either by internal tandem duplications (FLT3-ITD), or by a point mutation mainly involving the tyrosine kinase domain (FLT3-TKD). Patients with FLT3-ITD have a high risk of relapse and low cure rates. Several FLT3 tyrosine kinase inhibitors have been developed in the last few years with variable kinase inhibitory properties, pharmacokinetics, and toxicity profiles. FLT3 inhibitors are divided into first generation multi-kinase inhibitors (such as sorafenib, lestaurtinib, midostaurin) and next generation inhibitors (such as quizartinib, crenolanib, gilteritinib) based on their potency and specificity of FLT3 inhibition. These diverse FLT3 inhibitors have been evaluated in myriad clinical trials as monotherapy or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front-line, relapsed or refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. In this practical question-and-answer-based review, the main issues faced by the leukemia specialists on the use of FLT3 inhibitors in AML are addressed.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Compostos de Anilina/farmacologia , Benzimidazóis/farmacologia , Benzotiazóis/farmacologia , Carbazóis/farmacologia , Metilação de DNA , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Recidiva Local de Neoplasia , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Prognóstico , Pirazinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sorafenibe/farmacologia , Estaurosporina/análogos & derivados , Estaurosporina/farmacologia , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA