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      Oxidative stress-dependent contribution of HMGB1 to the interplay between apoptosis and autophagy in diabetic rat liver.

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          Abstract

          The progression of oxidative stress, resulting cell damage, and cell death underlies the etiology of liver damage/dysfunction as a complication of diabetes. High-mobility group box 1 (HMGB1) protein, a chromatin-binding nuclear protein and damage-associated molecular pattern molecule, is integral to oxidative stress and signaling pathways regulating cell death and cell survival. We previously found that in streptozotocin (STZ)-induced diabetic rats, reduction of oxidative stress after melatonin administration lowered necrotic cell death and increased expression of HMGB1 and hepatocellular damage. In the present study, we examined whether alleviation of diabetes-attendant oxidative stress and ensuing change in HMGB1 expression influence the dynamic equilibrium between apoptosis/autophagy and liver damage. We observed that elevated HMGB1 protein levels in diabetic rat liver accompanied increased interactions of HMGB1 with TLR4 and RAGE, and activation of the intrinsic apoptotic pathway and Beclin 1-dependent autophagy. The absence of p62 degradation in diabetic rat liver pointed to defective autophagy which was responsible for lower autophagosome/autophagolysosome formation and an increased apoptosis/autophagy ratio. Compared to diabetic rats, in melatonin-treated diabetic rats, the structure of liver cells was preserved, HMGB1/TLR4 interaction and downstream apoptotic signaling were significantly reduced, HMGB1/Beclin 1 colocalization and interactions were augmented and Beclin 1-mediated autophagy, mithophagy in particular, were increased. We concluded that in mild oxidative stress, HMGB1 is cytoprotective, whereas in intense oxidative stress, HMGB1 actions promote cell death and liver damage. Since reduced HMGB1 binds to RAGE but not to TLR4, redox modification of HMGB1 as a mechanism regulating the cross-talk between apoptosis and autophagy in diabetes is discussed.

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          Author and article information

          Journal
          J. Physiol. Biochem.
          Journal of physiology and biochemistry
          Springer Nature America, Inc
          1877-8755
          1138-7548
          Nov 2017
          : 73
          : 4
          Affiliations
          [1 ] Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar despota Stefana 142, Republic of Belgrade, 11060, Serbia.
          [2 ] Faculty of Biology, Center for Electron Microscopy, University of Belgrade, Belgrade, Serbia.
          [3 ] Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar despota Stefana 142, Republic of Belgrade, 11060, Serbia. iligri@ibiss.bg.ac.rs.
          Article
          10.1007/s13105-017-0574-0
          10.1007/s13105-017-0574-0
          28695466

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