RESUMO
Disturbance in calcium (Ca2+ ) homeostasis has been involved in a variety of neuropathological conditions including Parkinson's disease (PD). The Ca2+ channel, transient receptor potential channel 1 (TRPC1), plays a protective role in regulating entry of Ca2+ activated by store depletion of Ca2+ in endoplasmic reticulum (ER). We have showed that thioredoxin-1 (Trx-1) plays a role in suppressing ER stress in PD. However, whether Trx-1 regulates TRPC1 expression in PD is still unknown. In the present study, we demonstrated that treatment of 1-methyl-4-phenylpyridinum ion (MPP+ ) significantly reduced the expression of TRPC1 in PC12 cells, which was restored by Trx-1 overexpression, and further decreased significantly by Trx-1 siRNA. Moreover, we found that Ca2+ entered into the cells was decreased by MPP+ in PC 12 cells, which was restored by Trx-1 overexpression, and further decreased by Trx-1 siRNA. MPP+ significantly increased calcium-dependent cysteine protease calpain1 expression in PC12 cells, which was suppressed by Trx-1 overexpression. Calpain1 expression was increased by Trx-1 siRNA or SKF96365, an inhibitor of TRPC1. Moreover, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreased TRPC1 expression in the substantia nigra pars compacta region (SNpc), which was restored in mice overexpressing Trx-1, and further decreased in mice of knockdown Trx-1. Inversely, the expression of calpain1 was increased by MPTP, which was suppressed in mice overexpressing Trx-1, and further increased in mice of knockdown Trx-1. In conclusion, Trx-1 regulates the Ca2+ entry through regulating TRPC1 expression after treatment of MPP+ /MPTP.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Doença de Parkinson , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Cálcio , Modelos Animais de Doenças , Homeostase , Camundongos , Camundongos Endogâmicos C57BL , Células PC12 , Ratos , Tiorredoxinas/genéticaRESUMO
Building on our previous work that discovered 1,2,4-triazole-spirodienone as a promising pharmacophore for anticancer activity, we have further diversified 1,2,4-triazole- spirodienone derivatives and synthesized a series of novel naphthalene-substituted triazole spirodienones to explore their antineoplastic activity. Of these, compound 6a possesses remarkable in vitro cytotoxic activity by arresting cell cycle and inducing apoptosis in MDA-MB-231 cells. Subsequently, acute toxicity assay showed that 6a at 20 mg/kg has no apparent toxicity to the major organ in mice. In addition, compound 6ain vivo suppressed breast cancer 4T1 tumor growth. Taken together, these results indicate that compound 6a may be a potential anticancer agent for further development.
Assuntos
Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Naftalenos/química , Triazóis/síntese química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Camundongos , Relação Estrutura-Atividade , Triazóis/farmacologiaRESUMO
The antisense transcript long non-coding RNA (lncRNA) (antisense non-coding RNA in the INK4 locus, ANRIL) is an antisense of the cyclin-dependent kinase inhibitor 2B (CDKN2B) gene on chromosome 9p21 that contains an overlapping 299-bp region and shares a bidirectional promoter with alternate open reading frame (ARF). In the context of gene regulation, ANRIL is responsible for directly recruiting polycomb group (PcG) proteins, including polycomb repressive complex-1 (PRC-1) and polycomb repressive complex-2 (PRC-2), to modify the epigenetic chromatin state and subsequently inhibit gene expression in cis-regulation. On the other hand, previous reports have indicated that ANRIL is capable of binding to a specific site or sequence, including the Alu element, E2F transcription factor 1 (E2F1), and CCCTC-binding factor (CTCF), to achieve trans-regulation functions. In addition to its function in cell proliferation, adhesion and apoptosis, ANRIL is very closely associated with atherosclerosis- related diseases. The different transcripts and the SNPs that are related to atherosclerotic vascular diseases (ASVD-SNPs) are inextricably linked to the development and progression of atherosclerosis. Linear transcripts have been shown to be a risk factor for atherosclerosis, whereas circular transcripts are protective against atherosclerosis. Furthermore, ANRIL also acts as a component of the inflammatory pathway involved in the regulation of inflammation, which is considered to be one of the causes of atherosclerosis. Collectively, ANRIL plays an important role in the formation of atherosclerosis, and the artificial modification of ANRIL transcripts should be considered following the development of this disease.
Assuntos
Aterosclerose/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Epigênese Genética , Predisposição Genética para Doença , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Processamento Alternativo , Elementos Alu , Aterosclerose/metabolismo , Aterosclerose/patologia , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Cromossomos Humanos Par 9 , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Humanos , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Transdução de SinaisRESUMO
The seeds of Raphanus sativus L., known as Lai-fu-zi in traditional Chinese Medicine, are always roasted before clinical use for avoiding nausea. During an investigation of the chemical difference between roasted and pre-roasted products, two novel sulfur-containing compounds, which mainly existed in the pre-roasted products, were isolated. Their structures and absolute configurations were established by spectroscopic and X-ray diffraction analysis.