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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.

No abstract

α-Lipoic acid administration activates a coordinated cytoprotective response against diabetes-induced oxidative injury in kidney tissue through an O-GlcNAc-dependent mechanism.

Pancreatic b-cell death or dysfunction mediated by oxidative stress underlies the development and progression of diabetes mellitus. In the present study, we tested extracts from the edible mushroom Lactarius deterrimus and the chestnut Castanea sativa, as well as their mixture (MIX Ld/Cs), for potential beneficial effects on streptozotocin (STZ)-induced pancreatic b-cell death. Analysis of chelating effects, reducing power and radical-scavenging assays revealed strong antioxidant effects of the C. sativa extract and MIX Ld/Cs, while the L. deterrimus extract displayed a weak to moderate effect. The antioxidative effect of the chestnut extract corresponds with the high content of phenolics and flavonoids identified by HPLC analysis. In contrast, the mushroom extract contains relatively small amounts of phenols and flavonoids. However, both extracts, and especially their combination MIX Ld/Cs, increased cell viability after the STZ treatment as a result of a significant reduction of DNA damage and improved redox status. The chestnut extract and MIX Ld/Cs significantly lowered the STZ-induced increases in superoxide dismutase and catalase activities, while the mushroom extract had no impact on the activities of these antioxidant enzymes. However, the L. deterrimus extract exhibited good NO-scavenging activity. Different mechanisms that underlie antioxidant effects of the mushroom and chestnut extracts were discussed. When combined as in the MIX Ld/Cs, the extracts exhibited diverse but synergistic actions that ultimately exerted beneficial and protective effects against STZ-induced pancreatic b-cell death.Key words: Lactarius deterrimus: Castanea sativa: Rin-5F cells: Cytoprotection: Antioxidant activity Reactive oxygen (ROS) and nitrogen (RNS) species are products of normal aerobic metabolism and are continuously produced under physiological conditions. However, when they rise above their physiological concentrations, ROS and RNS are extremely toxic due to their ability to induce protein and DNA damage and lipid peroxidation. Consequently, organisms have developed antioxidant defence systems, i.e. antioxidative enzymes that work in synergy with nonenzymatic antioxidant systems that are produced in cells or ingested through the diet. In healthy individuals, there is a balance between ROS and RNS production and antioxidant defences. An imbalance provoked by either overproduction of reactive species or attenuation of the antioxidative system leads to a process called oxidative stress. Oxidative stress is implicated in the development of many diseases such as CVD, atherosclerosis, neurodegenerative diseases and diabetes mellitus (1) . Diabetes mellitus is a chronic metabolic disorder that continues to present a major health problem worldwide. It is characterised by hyperglycaemia resulting from deficiencies in insulin secretion, insulin action or both. Multiple biochemical pathways and mechanisms for glucose toxicity have been (2) . All of these pathways have in common the formation of ROS that when in excess...