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

Abstract Background Oxidative stress is a hallmark of many cancers. The increment in reactive oxygen species (ROS), resulting from an increased mitochondrial respiration, is the major cause of oxidative stress. Cell fate is known to be intricately linked to the amount of ROS produced. The direct generation of ROS is also one of the mechanisms exploited by common anticancer therapies, such as chemotherapy. Methods We assessed the role of NFKBIA with various approaches, including in silico analyses, RNA-silencing and xenotransplantation. Western blot analyses, immunohistochemistry and RT-qPCR were used to detect the expression of specific proteins and genes. Immunoprecipitation and pull-down experiments were used to evaluate protein-protein interactions. Results Here, by using an in silico approach, following the identification of NFKBIA (the gene encoding IκBα) amplification in various cancers, we described an inverse correlation between IκBα, oxidative metabolism, and ROS production in lung cancer. Furthermore, we showed that novel IκBα targeting compounds combined with cisplatin treatment promote an increase in ROS beyond the tolerated threshold, thus causing death by oxytosis. Conclusions NFKBIA amplification and IκBα overexpression identify a unique cancer subtype associated with specific expression profile and metabolic signatures. Through p65-NFKB regulation, IκBα overexpression favors metabolic rewiring of cancer cells and distinct susceptibility to cisplatin. Lastly, we have developed a novel approach to disrupt IκBα/p65 interaction, restoring p65-mediated apoptotic responses to cisplatin due to mitochondria deregulation and ROS-production.

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Transcriptional and post-transcriptional regulation of L-type pyruvate kinase in diabetic rat liver by insulin and dietary fructose.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)38731-8 ◽

1985 ◽

Vol 260 (26) ◽

pp. 14393-14397 ◽

Cited By ~ 17

Author(s):

T Noguchi ◽

H Inoue ◽

T Tanaka

Keyword(s):

Transcriptional Regulation ◽

Pyruvate Kinase ◽

Rat Liver ◽

Diabetic Rat ◽

Dietary Fructose ◽

Post Transcriptional Regulation

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Copper-Mediated Oxidative Stress in Rat Liver

Biological Trace Element Research ◽

10.1385/bter:96:1-3:209 ◽

2003 ◽

Vol 96 (1-3) ◽

pp. 209-216 ◽

Cited By ~ 39

Author(s):

Dervis Ozcelik ◽

Resat Ozaras ◽

Zafer Gurel ◽

Hafize Uzun ◽

Seval Aydin

Keyword(s):

Oxidative Stress ◽

Rat Liver

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Oxidative Stress in Rats After 60 Days of Hypergalactosemia or Hyperglycemia

International Journal of Toxicology ◽

10.1177/109158180302200603 ◽

2003 ◽

Vol 22 (6) ◽

pp. 423-427 ◽

Cited By ~ 17

Author(s):

Mary Otsyula ◽

Matthew S. King ◽

Tonya G. Ketcham ◽

Ruth A. Sanders ◽

John B. Watkins

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Superoxide Dismutase ◽

Glutathione Peroxidase ◽

Insulin Treatment ◽

Diabetic Rats ◽

Diabetic Rat ◽

Glutathione Disulfide ◽

Hepatic Lipid Peroxidation ◽

Streptozotocin Diabetic Rats

Two of the models used in current diabetes research include the hypergalactosemic rat and the hyperglucosemic, streptozotocin-induced diabetic rat. Few studies, however, have examined the concurrence of these two models regarding the effects of elevated hexoses on biomarkers of oxidative stress. This study compared the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase and the concentrations of glutathione, glutathione disulfide, and thiobarbituric acid reactants (as a measure of lipid peroxidation) in liver, kidney, and heart of Sprague-Dawley rats after 60 days of either a 50% galactose diet or insulin deficiency caused by streptozotocin injection. Most rats from both models developed bilateral cataracts. Blood glucose and glycosy-lated hemoglobin A1c concentrations were elevated in streptozotocin diabetic rats. Streptozotocin diabetic rats exhibited elevated activities of renal superoxide dismutase, cardiac catalase, and renal and cardiac glutathione peroxidase, as well as elevated hepatic lipid peroxidation. Insulin treatment of streptozotocin-induced diabetic rats normalized altered markers. In galactosemic rats, hepatic lipid peroxidation was increased whereas glutathione reductase activity was diminished. Glutathione levels in liver were decreased in diabetic rats but elevated in the galactosemic rats, whereas hepatic glutathione disulfide concentrations were decreased much more in diabetes than in galactosemia. Insulin treatment reversed/prevented all changes caused by streptozotocin-induced diabetes. Lack of concomitance in these data indicate that the 60-day galactose-fed rat is not experiencing the same oxidative stress as the streptozotocin diabetic rat, and that investigators must be cautious drawing conclusions regarding the concurrence of the effects of the two animal models on oxidative stress biomarkers.

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