br Conclusions br Acknowledgments br Introduction

Conclusions
Acknowledgments
Introduction To die or not to die – that is the question. Christian de Duve created the word “autophagy” in 1960’s for the first time (Klionsky et al., 2016). The word “autophagy” was derived from the Greek roots “auto” (self) and “phagy” (eating) and referred to as the cellular catabolic processes in which cytoplasmic proteins and organelles are “eaten” by itself. In the mid 1950’s, a new specialized membrane-bound organelle was found in animal cells, which always contain fragmentized cellular compartments. It was found that the organelle functions as a workstation for degradation of cellular constituents and called it as “lysosome”. Dr. Christian de Duve was awarded the Nobel Prize in 1974 for the discovery of the lysosome. Upon nutrition limitation, Iodophenpropit dihydrobromide australia resort to breaking down their compartment-proteins, lipids and even whole organelles in lysosomes to recycle the metabolites. Thus, the cell may develop a mechanism to deliver intracellular cargo to the lysosome for preserving materials and energy. This new type of vesicle transporting cellular cargo, were named autophagosomes, which then fuse with the lysosome in order for its contents to be degraded. It has been widely accepted that autophagy is a self-protecting cellular catabolic pathway, through which some long-lived or misfolded proteins and damaged organelles are degraded into metabolic elements and recycled for the maintenance of cellular homeostasis. Autophagy is activated in response to nutrient starvation or metabolic stress to maintain tissue homeostasis through updating dysfunctional proteins and organelles. In brief, after sequestration of the cytoplasmic materials into autophagosomes and fusing with lysosomes, autolysosomes are formed. The whole process of autophagy is evolutionarily conserved from yeast to mammals (He and Klionsky, 2009; Schultz et al., 2017). Importantly, the 2016 Nobel Prize in medicine or physiology has been awarded to Yoshinori Ohsumi for his work uncovering the processes of cell autophagy (Van Noorden and Ledford, 2016). According to the mode of cargo delivery to the lysosomal lumen and physiological functions, three different kinds of autophagy have been described, namely microautophagy, chaperone-mediated autophagy (CMA) and macroautophagy (Fig. 1). Microautophagy is a non-selective lysosomal degradative process referring to as the engulfment of cytoplasmic constituents through invagination of the lysosomal/vacuolar membranes (de Waal et al., 1986; Mortimore et al., 1983). It was shown that several functions are attributed to microautophagy, including basal degradation of long-lived proteins and membrane proteins as well as maintenance and regulation of membrane homeostasis and size of lysosomes through the consumption of superfluous membranes (Kalachev and Yurchenko, 2017). CMA is a type of autophagy that allows the degradation of cytosolic proteins depending on chaperones. It is recognized as the only autophagy process that allows selective degradation of soluble cytosolic proteins in lysosomes (Dice, 2007). CMA degradation largely demands the presence of a targeting motif in the substrate protein, a set of cytosolic and lysosomal chaperones, and a receptor protein at the lysosomal membrane for the transportation into lysosome assisted by a chaperone located in the lysosomal lumen (Martinet and De Meyer, 2008). Macroautophagy is a catabolic process characterized by sequestration of cytoplasmic material in double-membrane vacuoles called autophagosomes, which are then delivered to the lysosome for degradation (Cadwell, 2016; Mizushima et al., 1998; Su et al., 2017). Since macroautophagy is the main and best studied form of autophagy, our review will primarily focus on its mechanisms and effects in ischemic stroke, and we will refer to macroautophagy as “autophagy” thereafter. Of note, since the discovery of autophagy process, it has been reported to be vital in the pathogenesis and progression as well as the treatment of numerous kinds of diseases. In cardiovascular system, it has been demonstrated that autophagy contributes to the alleviation of inflammasome-related inflammatory response in the lesional macrophage and the reduction of macrophage apoptosis, thus attenuating the pathogenesis and development of atherosclerosis (Liao et al., 2012; Razani et al., 2012). Autophagy was also shown to be vital for the maintenance of cholesterol efflux in vascular plaque macrophage, thus effectively regulating the cellular metabolism of lipids (Fu et al., 2013). In cardiac ischemia, autophagy was widely believed to protect myocardiocyte from ischemic damage or apoptosis from ischemic stress (Gustafsson and Gottlieb, 2009). In central nervous system, it was recently demonstrated that autophagy produced protective effects both in an OGD-treated neuronal model and a mouse cerebral ischemia model, via inhibiting neuronal apoptosis (Papadakis et al., 2013; Wang et al., 2012; Wu et al., 2017). In neurodegenerative diseases like Alzheimer’s disease or autistic disease, it was already proven that the induction of autophagy contributes to the modulation of symptoms and severity of diseases (Lee et al., 2010; Li et al., 2017b; Pickford et al., 2008; Tang et al., 2014). In endocrine system, autophagy process has been proven to be effective in the attenuation of the severity of diabetes and obesity (Ebato et al., 2008; Lee et al., 2014; Park et al., 2014; Yang et al., 2010). As a result, it seems that the induction of autophagy process may become a potential therapeutic strategy in the treatment of various kinds of disorders. However, some researchers also pointed out that the over-induction of autophagy could lead to cellular death, the so-called “autophagic cellular death”, indicating that the induction of autophagy for the treatment of diseases is not without its problems, and to get rid of those negative factors, further studies are demanded on this issue (Clarke and Puyal, 2012; Kroemer and Levine, 2008). We proposed that, there may be a flexible adaptive capacity in the cells that face the exogenous and endogenous stress. In normal condition, autophagy process is activated upon the stress and helps cells to survive by controlling the clearance and re-use of intracellular constituents (Fig. 2A). In this case, autophagy leads to a series of restorative events not only by its contribution to the re-establishment of the baseline physiological status, but also the achieving an internal homeostasis via improving the recovery action. If the autophagy is impaired due to some reasons such as mutation in autophagy-related genes (Atg), the cellular adaptive capacity becomes smaller than that in normal condition, and the cells may be more vulnerable to the same degree of stimulation (Fig. 2B). In contrary, if the persistent stress induces excessive or prolonged autophagy, which exceeds the maximal cellular adaptive capacity, the autophagy-induced effects may facilitate the necrotic and apoptotic cascades, and thereby result in a cell death (Fig. 2C). So, autophagy appears to be a double-sword in the mechanisms of cellular adaptive system. Whether autophagy is beneficial or detrimental depends on the rate of autophagy induction and the duration of autophagy activation.