RESUMO
Inhibition of the excessive NO production has been recognized as a potential means for the treatment of rheumatoid arthritis (RA). In order to discover more potent inhibitors and explore the preliminary structure activity relationship, a series of unique stereodimers of sinomenine analogues were designed and synthesized. Their inhibitory activity on NO production and cytotoxicity were evaluated using LPS-activated murine macrophages RAW264.7 assay and MTT method, respectively. Among these compounds, 1a, 2, 2a, 2b, and 4 showed potent inhibitory activity on NO production without obvious cytotoxicity. Furthermore, 2, 2a, and 2b significantly suppressed mRNA expression of iNOS. Interestingly, (S)-dimers displayed a better bioactivity than (R)-dimers. These compounds may sever as lead candidates in the development of novel therapeutic drugs for RA treatment.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Morfinanos/química , Morfinanos/farmacologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Animais , Artrite Reumatoide/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dimerização , Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Morfinanos/síntese química , Óxido Nítrico Sintase Tipo II/genética , RNA Mensageiro/genética , EstereoisomerismoRESUMO
SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis. It can specifically methylate histone H3 at lysine 4 and activate the transcription of a set of downstream genes, including several oncogenes (e.g., N-myc, CrkL, Wnt10b, RIZ and hTERT) and genes involved in the control of cell cycle (e.g., CyclinG1 and CDK2) and signal transduction (e.g., STAT1, MAP3K11 and PIK3CB). To determine the effects of SMYD3 over-expression on cell proliferation, we transfected SMYD3 into MDA-MB-231 cells and found that these cells showed several transformed phenotypes as demonstrated by colony growth in soft agar. Besides, we show here that down-regulation of SMYD3 could induce G1-phase cell cycle arrest, indicating the potent induction of apoptosis by SMYD3 knockdown. These results suggest the regulatory mechanisms of SMYD3 on the acceleration of cell cycle and facilitate the development of strategies that may inhibit the progression of cell cycle in breast cancer cells.
Assuntos
Neoplasias da Mama/metabolismo , Proliferação de Células , Pontos de Checagem da Fase G1 do Ciclo Celular/fisiologia , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Feminino , HumanosRESUMO
Ursolic acid (UA), a pentacyclic triterpenoid compound, is widely distributed in the plant kingdom and has a broad range of biological effects. This study was carried out for the first time to investigate the potential role of UA in the differentiation of human leukemia HL60 cells and the underlying mechanisms in it. UA could induce differentiation of HL60 cells into the monocytic lineage, as assessed by the morphological change, nitroblue tetrazolium reduction assay, and expression of CD14 and CD11b surface antigens. Moreover, UA activated the extracellular signal-regulated kinase (ERK) pathway in both dose-dependent and time-dependent manners. Inhibiting ERK pathway activation with PD98059 could significantly block the differentiation induced by UA. Consistent with the induced differentiation, the upregulation of CCAAT/enhancer-binding protein ß by UA was also eliminated by PD98059. Taken together, the results reported here show that UA can promote the monocytic differentiation of HL60 cells and increase the expression of CCAAT/enhancer-binding protein ß by activating the ERK pathway, suggesting that UA could be a potential candidate as a differentiation-inducing agent for the therapeutic treatment of leukemia.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteína beta Intensificadora de Ligação a CCAAT/biossíntese , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Triterpenos/farmacologia , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Diferenciação Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Flavonoides/farmacologia , Células HCT116 , Células HL-60 , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas Proto-Oncogênicas c-myc/genética , Triterpenos/antagonistas & inibidores , Células U937 , Regulação para Cima/efeitos dos fármacos , Ácido UrsólicoRESUMO
In a continuing study on discovery of more potent derivatives of sinomenine (1), a clinically available alkaloid for rheumatoid arthritis (RA) treatment, oxidation of sinomenine provided two unique stereoisomers, disinomenines 2 and 3. The structure of 3 was determined by MS, NMR, and X-ray analysis. The formation of 2 and 3 via oxidation of sinomenine by potassium permanganate (KMnO4) exhibited a pH-dependent stereoselectivity. The bioassay results using human synovial sarcoma cells (SW982) showed that 2 inhibited, while 3 stimulated, IL-6 production.