Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autophagy is the process by which cytosolic components and organelles are delivered to the lysosome for degradation. Autophagy plays important roles in cellular homeostasis and disease pathogenesis. Small chemical molecules that can modulate autophagy activity may have pharmacological value for treating diseases. Using a GFP-LC3-based high content screening assay we identified a novel chemical that is able to modulate autophagy at both initiation and degradation levels. This molecule, termed as Autophagy Modulator with Dual Effect-1 (AMDE-1), triggered autophagy in an Atg5-dependent manner, recruiting Atg16 to the pre-autophagosomal site and causing LC3 lipidation. AMDE-1 induced autophagy through the activation of AMPK, which inactivated mTORC1 and activated ULK1. AMDE-1did not affect MAP kinase, JNK or oxidative stress signaling for autophagy induction. Surprisingly, treatment with AMDE-1 resulted in impairment in autophagic flux and inhibition of long-lived protein degradation. This inhibition was correlated with a reduction in lysosomal degradation capacity but not with autophagosome-lysosome fusion. Further analysis indicated that AMDE-1 caused a reduction in lysosome acidity and lysosomal proteolytic activity, suggesting that it suppressed general lysosome function. AMDE-1 thus also impaired endocytosis-mediated EGF receptor degradation. The dual effects of AMDE-1 on autophagy induction and lysosomal degradation suggested that its net effect would likely lead to autophagic stress and lysosome dysfunction, and therefore cell death. Indeed, AMDE-1 triggered necroptosis and was preferentially cytotoxic to cancer cells. In conclusion, this study identified a new class of autophagy modulators with dual effects, which can be explored for potential uses in cancer therapy.
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PMID:AMDE-1 is a dual function chemical for autophagy activation and inhibition. 2589 44

Ethyl carbamate (EC) is an environmental toxin, commonly present in various fermented foods and beverages, as well as tobacco and polluted ambient air. However, studies on the effects of EC-induced toxicity on the intestines and potential protection methods are limited. In this study, we show that EC could cause severe toxicity in intestinal epithelial cells (IECs) triggering the induction of decreased cell viability, ROS accumulation and glutathione (GSH) depletion in a dose-dependent manner. Based on these results, we established an EC-treated IEC model to screen the potential protective effects of 12 kinds of anthocyanins extracted from blueberry. Interestingly, we found that malvidin-3-O-arabinoside (M3A) significantly reversed the oxidative damage caused by EC exposure by stimulating autophagy flux, which was determined by the LC3-II level and GFP-RFP-LC3 transfection experiment. Enhancement of autophagy was mainly ascribed to the regulation of lysosomes. M3A pretreatment remarkably upregulated LAMP-1 expression, which indicated elevated lysosomal mass. Besides, M3A also successfully restored lysosomal acidity and subsequently strengthened lysosomal functions. Furthermore, M3A stimulated phosphorylation of AMP-activated protein kinase (AMPK), a master regulator of autophagy. Furthermore, our study indicated the possibility of EC-caused oxidative damage to the intestines and unveiled the remarkably protective benefits of M3A-induced AMPK-mediated autophagy against this toxicity.
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PMID:Malvidin-3-O-arabinoside ameliorates ethyl carbamate-induced oxidative damage by stimulating AMPK-mediated autophagy. 3321 19