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  • In conclusion our results provide a new mechanistic insight


    In conclusion, our results provide a new mechanistic insight into the signaling pathways mediating TDCIPP-induced apoptosis in cultured neuronal cells. We showed that TDCIPP-induced neuronal cell cytotoxicity and death are mediated via the ER stress-regulated apoptotic pathway, wherein the induction of p-eIF2a, GRP 78, ATF-4, and CHOP expression and the subsequent increase in the apoptotic ratio and caspase-3 activation are critical events. Moreover, these adverse outcomes could be attenuated by the antioxidant NAC. Therefore, the ROS-triggered ER stress signaling pathway plays an important role in TDCIPP-induced neuronal cell apoptosis. Although the present study represents a significant contribution to our understanding of the toxicity and the apoptotic pathways of TDCIPP in cultured neuronal Reserpine hydrochloride in vitro, it is likely that general populations are subject to chronic exposure. Moreover, recent studies suggest that infants are commonly exposed to TDCIPP, potentially at levels higher than adults (Hoffman et al., 2015); further, TDCIPP has been detected in human placenta (Ding et al., 2016). Hence, more work is necessary to determine if the levels of exposure are associated with adverse health impacts among the general population, and particularly whether there are effects on the developing nervous system in children.
    Declaration of interest
    Acknowledgments This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences [grant number XDB14040103] and the National Natural Science Foundation of China [grant numbers 21237005, 21577168].
    Introduction Chronic cerebral hypoperfusion (CCH) can result from disorders affecting the cerebral vascular system, including hypertension, diabetes, generalized atherosclerosis, and smoking (Meyer et al., 2000; Valerio Romanini et al., 2013). It is a critical risk factor for both Alzheimer disease (AD) and vascular dementia (VaD) (Pimentel-Coelho et al., 2013; Zhao and Gong, 2015). The mechanisms underlying the cognitive impairment caused by CCH have recently been widely reported, including neuron damage, white matter lesions and the inflammatory response (Zou et al., 2017). Autophagy and the energy sensing AMPK signaling pathways are both associated with this type of cognitive dysfunction (Zou et al., 2017). However, the effect of these two mechanisms together in a rat model of vascular dementia is not well understood. Additionally, little is known about the relationship between the autophagy and the energy sensing AMPK signal pathway. CCH induced progressive degeneration of nerve cells eventually leading to dementia. Bilateral common carotid artery occlusion (2VO) has been widely used in rodents to replicate CCH as well as progressive neuronal degeneration. 2VO leads to early CBF reductions, approximately 66% in the cortex and 48% in the hippocampus after 2.5 h (Neto et al., 2005). This animal model exhibits many features resembling those of human AD and VaD (He et al., 2012). Now, we found that degenerating neurons after CCH likely resulted from proteasomal dysfunction. In addition, metabolic alterations, excitotoxicity, and oxidative stress are often described. All of the latter could participate in the deregulation of AMP-activated protein kinase (AMPK) that was reported to occur in some neurodegenerative diseases including Alzheimer’s (AD), Parkinson’s (PD) and amyotrophic lateral sclerosis (ALS) (Domise and Vingtdeux, 2016), while its function in CCH is largely unknown. Interestingly, accumulating reports have shown that lysosomal-dependent catabolic program, autophagy, plays important roles in macromolecular nutrient degradation related to CCH, such as glycogen and lipid droplets. Autophagy is an evolutionarily conserved process that regulates the turnover of cellular constituents through an autophagosomal-lysosomal pathway, which is an intracellular bulk degradation process whereby long-lived cytosolic proteins and organelles are degraded and recycled (Levine and Klionsky, 2004). Autophagy is also rapidly activated in neurons exposed to hypoxic (Zhu et al., 2005) or excitotoxic stimuli (Wang et al., 2008) and after closed head injury or focal cerebral ischemia (Rami et al., 2008). Although autophagy is considered primarily a homeostatic response, excessive autophagic activity may destroy portions of the cytosol and organelles, leading to a total collapse of all cellular functions. Because of its dual role in cell survival and death, whether enhanced autophagy is part of the death or survival mechanism(s) is still a matter of debate (Li et al., 2013). AMPK and eIF2α/ATF4 pathway are major regulator/activators of autophagy responding to energy deficit (Takagi et al., 2007). Activation of AMPK and eIF2α/ATF4 pathway results in decreased mTOR activity and increased autophagy (Jung et al., 2010). In this study, we examined the involvement of energy sensing AMPK signal and autophagy in neuronal degeneration after 2VO.