ALBERT

Description: Advanced glycation end products (AGE) accumulate in diabetic patients and aged persons due to high amounts of 3- or 4-carbon derivatives of glucose. Understanding the mechanism of AGE-mediated signaling leading to these consequences, like oxidative stress, inflammation, apoptosis, etc. and its regulation would be a viable strategy to control diabetic complication and age-related diseases. We have detected the probable mechanism by which AGE increases lipogenesis, the cause of fatty liver in diabetic patients. AGE increased lipid accumulation in different cells as shown by Oil Red O staining. AGE-mediated regulation of several transcription factors was determined by gel shift assay. Antioxidants like NAC, PDTC, and vitamin C, except mangiferin, were unable to protect AGE-induced activation of SREBP and subsequent lipid accumulation. AGE increased the phosphorylation of ERK, and IKK and also DNA binding ability of SREBP, thereby its dependent gene transcription. AGE induces NF-κB which might suppress PPARγ activity, in turn reducing lipid breakdown and mobilization. Mangiferin not only inhibits AGE-mediated ROI generation that requires NF-κB activation, but also inhibits ERK and IKK activity, thereby suppression of SREBP activity and lipogenesis. Mangiferin has shown a double-edged sword effect to suppress AGE-mediated ailments by reducing ROI-mediated responses as antioxidant and inhibiting SREBP activation thereby lipogenesis, suggesting its potential efficacy against diabetes and obesity-related diseases. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.

Description: Accumulation of advanced glycation end products (AGE) in diabetic patients and ageing people due to excess availability of simple 3- or 4-carbon sugars, is well-known. AGE has multiple deleterious effects including age-related disorders, apoptosis, inflammation and obesity. We have found that AGE increases autophagy but the sustained amount of autophagosomes is observed till 3 days without maturation. It is important to understand the underlying mechanism of AGE-mediated signaling responsible for impairment of autophagy and its correlation to the induction of several adverse effects. We have identified cross talk between autophagy and apoptosis upon AGE stimulation, specifically in p53 negative cells. AGE impairs autophagosomes' clearance in p53 negative cells as observed with an autophagosome maturation blocker- bafilomycinA1 treated cells. This autophagy impairment is well supported by upregulation and overexpression of NF-κB in these p53 negative cells. Autophagy impairment acts as a switch to initiate apoptosis via regulation of NF-κB and its dependent genes. Increase in the expression of NF-κB-dependent NEDD4, an E3 ubiquitin ligase, which targets Beclin1 for cleavage is also evident. Beclin1 interacts with Bcl-2, an anti-apoptotic protein thereby engaging it to facilitate apoptosis upon AGE stimulation. For the first time, we are providing data that NF-κB targeted cell signaling is involved in AGE-mediated autophagy impairment in p53 negative/null cells. The p53 acts antagonistically to prevent this impairment. This study will help to control the AGE-mediated detrimental effects associated with ageing and lysosomal storage disorders. This article is protected by copyright. All rights reserved