Targeting endoplasmic reticulum (ER) stress is being investigated for its anticancer
effect in various cancers, including cervical cancer. However, the molecular pathways
whereby ER stress mediates cell death remain to be fully elucidated. In this study, we
confirmed that ER stress triggered by compounds such as brefeldin A (BFA), tunicamycin
(TM), and thapsigargin (TG) leads to the induction of the unfolded protein response (UPR)
in cervical cancer cell lines, which is characterized by elevated levels of
inositol-requiring kinase 1α, glucose-regulated protein-78, and C/EBP
homologous protein, and swelling of the ER observed by transmission electron microscope
(TEM). We found that BFA significantly increased autophagy in tumor cells and induced TC-1
tumor cell death in a dose-dependent manner. BFA increased punctate staining of LC3 and
the number of autophagosomes observed by TEM in TC-1 and HeLa cells. The autophagic flux
was also assessed. Bafilomycin, which blocked degradation of LC3 in lysosomes, caused both
LC3I and LC3II accumulation. BFA initiated apoptosis of TC-1 tumor cells through
activation of the caspase-12/caspase-3 pathway. At the same time, BFA enhanced the
phosphorylation of IκBα protein and translocation into the
nucleus of NF-κB p65. Quinazolinediamine, an NF-κB
inhibitor, attenuated both autophagy and apoptosis induced by BFA; meanwhile, it partly
enhances survival of cervical cancer cells following BFA treatment. In conclusion, our
results indicate that the cross-talk between ER stress, autophagy, apoptosis, and the
NF-κB pathways controls the fate of cervical cancer cells. Careful
evaluation should be given to the addition of an NF-κB pathway inhibitor to
treat cervical cancer in combination with drugs that induce ER stress-mediated cell
death.
Oleracein E (OE), a tetrahydroisoquinoline possessing potent antioxidant activity, was first isolated from a traditional Chinese medicine, Portulaca oleraea L., and is hypothesized to be a neuroprotectant. In the present study, we evaluated the effects of racemic OE on rotenone-induced toxicity in Parkinson's disease (PD) cell and animal models. Pretreatment with OE (10 μM, 2 h) decreased lactic acid dehydrogenase (LDH) release and the apoptosis rate in rotenone (5 μM, 24 h)-treated SH-SY5Y human neuroblastoma cells. Further mechanistic study indicated that OE reduced reactive oxygen species (ROS) levels, inhibited extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, reduced rotenone-induced up-regulation of the proapoptotic protein Bax, and prevented cytochrome C release and caspase-3 activation. In a rotenone-treated (intragastric 30 mg/(kg·d), 56 d) C57BL-6J mouse model, OE (intragastric 15 mg/(kg·d), 56 d) improved motor function, as indicated by an increased moving distance in the spontaneous activity test and sustained time on the rota-rod test. OE also elevated superoxide dismutase (SOD) activity, decreased malonaldehyde content, and reduced ERK1/2 phosphorylation in the midbrain and striatum of mice treated with rotenone. Furthermore, OE preserved tyrosine hydroxylase-positive neurons and maintained the density of dopaminergic (DAergic) fibers in the substantia nigra pars compacta (SNpc). Some of the effects of OE on PD models were similar to those of the positive control selegiline hydrochloride. Our results demonstrated that OE protects DAergic neurons against rotenone toxicity through reducing oxidative stress and down-regulating stress-related molecules. OE is worth exploring further for its neuroprotectant properties in the prevention and treatment of PD.
The propeller–duct interaction on the wake dynamics of a ducted propeller is numerically investigated via detached eddy simulations. The blade–blade interference and blade–duct interaction are analyzed through different configurations under non-ducted and ducted conditions. It is found that the blade–blade interference benefits the loading stability, and the duct leads to a faster efficiency decrease in a single blade with the increasing blade number. The short-wave instability dominates the wake as the unstable secondary vortices accelerates the vortex evolution. The multi-induction effect stabilizes the two tip vortices system in a two-bladed configuration, while the tip vortex grouping occurs early in a four-bladed propeller due to the combined effect of the duct retardation and smaller spiral-to-spiral distance. Additionally, the enhanced wake instability leads to the fast decline of the power spectral density peaks of kinetic energy at blade passing frequency and shaft frequency harmonics toward the far field under ducted conditions.
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