RESUMO
A prominent characteristic of Alzheimer's disease (AD) is the deposition of both amyloid-ß (Aß) peptide and tau protein in the brain. Aß and tau not only induce toxicity through self-aggregation but also induce more potent toxicity through the synergistic action of Aß and tau. In particular, neurotoxic aggregates of Aß and tau directly affect several AD pathologies including neuroinflammation and cognitive decline. Therefore, there is increasing interest in strategies to modulate the aggregation and dissociation of Aß and tau for treatment of AD. Our recent study found that Uncaria rhynchophylla (UR) has a therapeutic effect on AD via the inhibition of Aß aggregation and attenuating Aß-mediated pathogenesis of AD. However, no studies have investigated whether UR has anti- and disaggregation effects on both Aß and tau. In this study, we showed the significant effects of UR on aggregation and dissociation of Aß42 and tau K18 using a thioflavin T (ThT) assay. In addition, histological study revealed an inhibitory effect of UR on the accumulation of Aß and tau and AD-related pathologies in 3xTg mice with both Aß and tau pathology. Furthermore, we found that rhynchophylline and corynoxeine, bioactive components of UR, could modulate the aggregation and dissociation of both Aß and tau using molecular docking simulation, isothermal titration calorimetry, and ThT assays. In conclusion, our results demonstrate that UR can inhibit the aggregation of Aß and tau and promote the degradation of their aggregates in AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Animais , Camundongos , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Simulação de Acoplamento Molecular , Camundongos Transgênicos , Doença de Alzheimer/metabolismoRESUMO
Oncostatin M is a muscle-secreted myokine that has various effects on neuronal function, however, the underlying molecular mechanism has been poorly defined. In this study, we showed that Oncostatin M increased the phosphorylation of Akt and ERK, proteins crucial for neuron cell survival and proliferation. Furthermore, Oncostatin M increased the expression of c-Fos, a protein with significant involvement in neuronal cell proliferation and survival, through both Akt and ERK. Oncostatin M also increased intracellular calcium concentrations that act upstream of Akt and ERK. Treatment with Oncostatin M led to the recovery of high-glucose-induced impairment of Akt phosphorylation. Thus, Oncostatin M can protect neuronal cell damage related to high-glucose conditions, showing potential as a therapeutic agent.
Assuntos
Glucose/administração & dosagem , Hipocampo/metabolismo , Neurônios/metabolismo , Oncostatina M/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Células Cultivadas , Hipocampo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Oncostatina M/administração & dosagem , FosforilaçãoRESUMO
Inflammation is a common cause of cardiac arrhythmia. Angiotensin ÐÐ (Ang ÐÐ) is a major contributing factor in the pathogenesis of cardiac inflammation; however, its underlying molecular mechanism remains unclear. Here, we explored the effect of Ang ÐÐ on inflammatory mechanisms and oxidative stress using HL-1 atrial myocytes. We showed that Ang ÐÐ activated c-Jun N-terminal kinase (JNK) phosphorylation and other inflammatory markers, such as transforming growth factor-ß1 (TGF-ß1) and tumor necrosis factor-α (TNF-α). Ang ÐÐ decreased oxygen consumption rate, which resulted in reactive oxygen species (ROS) generation and inhibition of ROS blocked Ang II-mediated JNK phosphorylation and TGF-ß1 induction. Ang ÐÐ induced the expression of its specific receptor, AT1R. Ang II-induced intracellular calcium production associated with Ang ÐÐ-mediated signalling pathways. In addition, the generated ROS and calcium stimulated AMPK phosphorylation. Inhibiting AMPK blocked Ang II-mediated JNK and TGF-ß signalling pathways. Ang ÐÐ concentration, along with TGF-ß1 and tumor necrosis factor-α levels, was slightly increased in plasma of patients with atrial fibrillation. Taken together, these results suggest that Ang ÐÐ induces inflammation mechanisms through an AMPK-related signalling pathway. Our results provide new molecular targets for the development of therapeutics for inflammation-related conditions, such as atrial fibrillation.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Angiotensina II/metabolismo , Miocardite/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Cálcio/metabolismo , Sobrevivência Celular/genética , Átrios do Coração/citologia , Átrios do Coração/metabolismo , Humanos , Mitocôndrias/metabolismo , Miocardite/etiologia , Estresse Oxidativo , Oxigênio/metabolismo , Consumo de Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismoRESUMO
Oxytocin is a mammalian hormone that is released mainly after distension of the uterine cervix. In this study, we report that oxytocin stimulates intracellular release of calcium, and also activates AMPK (AMP-activated protein kinase) in C2C12 myoblast cells in a time/dose-dependent manner. Oxytocin receptor mRNA was detected in C2C12 cells. In addition, oxytocin stimulated glucose uptake and, moreover, inhibition of either CaMKK (Ca(2+)/calmodulin-dependent protein kinase kinase) or AMPK blocked oxytocin-mediated AMPK activation and glucose uptake. Taken together, our findings suggest that oxytocin may serve a peripheral metabolic function in skeletal muscle cells through the calcium-CaMKK-AMPK pathway.