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The key features of type 2 diabetes mellitus (T2DM) caused by high fat diet (HFD) in combination with arsenic (As) exposure (pronounced glucose intolerance despite a significant decrease in insulin resistance) are different from those expected for T2DM. Autophagy has been considered as a possible link between insulin resistance and obesity. Therefore in this study, we utilized autophagy gene expression profiling via real-time RT-PCR array analysis in livers of NMRI mice exposed to an environmentally relevant and minimally cytotoxic concentration of arsenite (50 ppm) in drinking water while being fed with a HFD for 20 weeks. Out of 84 genes associated with autophagy under study, 21 genes were related to autophagy machinery components of which 13 genes were downregulated when HDF diet was applied. In this study, for the first time, it was shown that the exposure to arsenic in the livers of mice chronically fed with HFD along with increased oxidative stress resulted in the restoration of autophagy [upregulation of genes involved in the early phase of phagophore formation, phagophore expansion and autophagosome-lysosome linkage stages]. Considering the role of arsenic in the induction of autophagy; it can be argued that reduced insulin resistance in HFD − As induced diabetes may be mediated by autophagy upregulation.

Autophagy, the molecular machinery of self-eating, plays a dual role of a tumor promoter and tumor suppressor. This mechanism affects different clinical responses in cancer cells. Autophagy is targeted for treating patients resistant to chemotherapy or radiation. Limited reports investigate the significance of autophagy in cancer therapy, the regulation of hematopoietic and leukemic stem cells and leukemia formation. In the current review, the role of autophagy is discussed in various stages of hematopoiesis including quiescence, self-renewal, and differentiation. K E Y W O R D S autophagy, hematopoiesis, leukemia 1 | INTRODUCTION Autophagy plays a crucial role in removing damaged organelles and protein aggregates from the cytoplasm through lysosomal pathways. To date, autophagy includes three main types: Macroautophagy, in which cytoplasmic components are engulfed by autophagosome, whereas both microautophagy and chaperone-mediated autophagy are characterized by having proteins that directly fuse to the lysosomes (Chen & White, 2011; Levine & Kroemer, 2008).Autophagy is upregulated by inhibiting mammalian targets of rapamycin (mTOR) when cells require nutrients and energy production (Tanaka et al., 2012). Autophagy has been originally identified in yeasts as a group of autophagy-related (Atg) genes and is a wellconserved evolutionary pathway in eukaryotes that has been shown to be implicated in degradation and recycling. These proteins are essential for membrane isolation and the formation of autophagosome ( Figure 1). In conditions of poor nutrients, increased AMP/ATP ratio activates AMPK, which inhibits mTORC1 and induces autophagy. In this setting, uncoordinated 51-like kinase 1 (ULK1), binds to dephosphorylated ATG13, which is normally hyperphosphorylated by mTOR and other kinases, ATG101 and FIP200, forming a tetrameric complex called ATG1/ULK1 complex. Upon the activation of ULK1, Beclin1 is phosphorylated and forms the class III PI3K complex containing ATG14, VPS15, Ambra1, and VPS34. The formation of these two complexes is essential for induction of autophagy nucleation. In fact, phosphatidylinositol 3-phosphate [PI(3)P] is generated by the PI3K complex at the nucleation site of a doublemembraned structure, called phagophore or isolated membrane, F I G U R E 1 Autophagic machinery in leukemia. The PI3K/AKT/mTORC1 pathway plays an important role in the regulation of HSC quiescence and the incidence of leukemia. Incorrect initiation of this process can lead to the inhibition of autophagy. Many factors, such as RTKs stimulate PI3K activity and form PIP3 from PIP2. PIP3 activates PDK and AKT. Activated AKT inhibits the FOXO activity in RTKs expression. In addition, AKT stimulates phosphorylation of TSC2 and leads to inhibition of the TSC1/TSC2 complex function. The containment of the TSC1/TSC2 complex causes Rheb to accumulate in the form of Rheb-GTP, which stimulates and activates mTORC1. The mTORC1 targets three major factors in cell translation including p70s6k, 4E-BP1, and Eif4e. P70S6K controls the PI3K...

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Previous studies have demonstrated the toxic impacts of zinc oxide nanoparticles (ZO‐NPs) on male reproductive cells. The effect of quercetin (QCT) on ZO‐NPs‐induced mouse Sertoli cell (TM4 cell line) toxicity and its underlying mechanisms were investigated in this study. The TM4 cells were exposed to ZO‐NPs or QCT in different groups for 24 hr. The TM4 cells pre‐treated with 3MA (3‐Methyladenine, an autophagy inhibitor) to evaluate the autophagy role of QCT and ZO‐NPs in the TM4 cells. ZO‐NPs significantly reduced the viability percentage of the TM4 cells. The apoptosis percentage and Bax/Bcl‐2 ratio of the ZO‐NPs group were significantly increased, while the expression of autophagy‐related genes was considerably downregulated. ZO‐NPs also induced oxidative stress in the TM4 cells through increasing malondialdehyde contents and reactive oxygen species levels (ROS) and reducing antioxidant factors including superoxide dismutase, catalase, glutathione and glutathione peroxidase. In QCT + ZO‐NPs group, these events were considerably reversed. 3MA could significantly decrease the cell viability of TM4 cells exposed to the QCT and ZO‐NPs in comparison with the untreated 3MA groups. According to these results, the protective effects of QCT on ZO‐NPs‐exposed TM4 cells are related to inducing autophagy, prevention apoptosis and suppressing oxidative stress.