RESUMO
Microglia are neuroglia in the brain with an innate immune function and participate in the progress of neurodegenerative diseases. Osthole (OST) is a coumarin derivative extracted from Cnidium monnieri and bears a microglia-antagonizing ability. However, the underlying mechanism of the antagonism is not clear. The lipopolysaccharides-induced microglial BV2 cell line and amyloid-overexpressing fruit fly were used as models to study OST treatment. We found that OST treatment is sufficient to evoke NRF2 cascade under an LPS-induced inflammatory environment, and silencing NRF2 is sufficient to abolish the process. Moreover, we found that OST is sufficient to antagonize microglial activation in both LPS-induced BV2 cells and Aß-overexpressing fruit flies, and silencing NRF2 abolishes OST's antagonism. Furthermore, OST treatment rescued survival, climbing, and the learning ability of Aß-overexpressing fruit flies and relieved oxidative stress. In conclusion, we proved that OST antagonizes microglial activation induced by either LPS or Aß and that NRF2 is necessary for OST's antagonism.
Assuntos
Cumarínicos , Microglia , Cumarínicos/farmacologia , Lipopolissacarídeos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Camundongos , Linhagem Celular , DrosophilaRESUMO
Ergosta-7,9(11),22-trien-3ß-ol (EK100) was isolated from the Taiwan-specific medicinal fungus Antrodia camphorata, which is known for its health-promotion and anti-aging effects in folk medicine. Alzheimer's disease (AD) is a major aging-associated disease. We investigated the efficacy and potential mechanism of ergosta-7,9(11),22-trien-3ß-ol for AD symptoms. Drosophila with the pan-neuronal overexpression of human amyloid-ß (Aß) was used as the AD model. We compared the life span, motor function, learning, memory, oxidative stress, and biomarkers of microglia activation and inflammation of the ergosta-7,9(11),22-trien-3ß-ol-treated group to those of the untreated control. Ergosta-7,9(11),22-trien-3ß-ol treatment effectively improved the life span, motor function, learning, and memory of the AD model compared to the untreated control. Biomarkers of microglia activation and inflammation were reduced, while the ubiquitous lipid peroxidation, catalase activity, and superoxide dismutase activity remained unchanged. In conclusion, ergosta-7,9(11),22-trien-3ß-ol rescues AD deficits by modulating microglia activation but not oxidative stress.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Drosophila , Humanos , Microglia/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Polyporales/químicaRESUMO
Resistance to the current therapies is the main clinical challenge in the treatment of lethal metastatic prostate cancer (mPCa). Developing novel therapeutic approaches with effective regimes and minimal side effects for this fatal disease remain a priority in prostate cancer study. In the present study, we demonstrated that a traditional Chinese medicine, quality-assured Ganoderma tsugae ethanol extract (GTEE), significantly suppressed cell growth and metastatic capability and caused cell cycle arrest through decreasing expression of cyclins in mPCa cells, PC-3 and DU145 cells. GTEE also induced caspase-dependent apoptosis in mPCa cells. We further showed the potent therapeutic efficacy of GTEE by inhibiting subcutaneous PC-3 tumor growth in a xenograft model. The in vitro and in vivo efficacies on mPCa cells were due to blockade of the PI3K/Akt and MAPK/ERK signaling pathways associated with cancer cell growth, survival and apoptosis. These preclinical data provide the molecular basis for a new potential therapeutic approach toward the treatment of lethal prostate cancer progression.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Ganoderma/química , Animais , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Medicina Tradicional Chinesa , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Bis(2-ethylhexyl) phthalate (DEHP) is the most common plasticizer. Previous studies have shown DEHP treatment accelerates neurological degeneration, suggesting that DEHP may impact retinal sensitivity to light, neurotransmission, and copulation behaviors. Although its neurotoxicity and antifertility properties have been studied, whether DEHP exposure disrupts vision and how DEHP influences neuromuscular junction (NMJ) have not been reported yet. Moreover, the impact of DEHP on insect courtship behavior is still elusive. Fruit flies (Drosophila melanogaster) were treated with series concentrations of DEHP and observed for lifespan, motor function, electroretinogram (ERG), electrophysiology of neuromuscular junction (NMJ), courtship behaviors, and relevant gene expression. Our results confirmed the DEHP toxicity on lifespan and capacity of motor function and updated its effect on copulation behaviors. Additionally, we report for the first time that DEHP exposure may harm vision by affecting the synaptic signaling between the photoreceptor and the laminar neurons. Further, DEHP treatment altered both spontaneous and evoked neurotransmission properties. Noteworthy, the effect of DEHP exposure on the copulation behavior is sex-dependent, and we proposed potential mechanisms for future investigation.