Apoptosis induced by oxidized lipids is associated with up-regulation of p66Shc in intestinal Caco-2 cells: protective effects of phenolic compounds

Giovannini, Claudio; Scazzocchio, Beatrice; Matarrese, Paola; Varı̀, Rosaria; D’Archivio, Massimo; Benedetto, Roberta Di; Casciani, Stefania; Dessı̀, Mariarita; Straface, Elisabetta; Malorni, Walter; Masella, Roberta

doi:10.1016/j.jnutbio.2007.01.010

Cited by 40 publications

(33 citation statements)

References 45 publications

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“…Therefore, these results support the important role of the induction of cytoprotective enzymes exhibited by some polyphenols as an additional mechanism of action to better defend against AA insult. Similar results have been recently shown with phenolic compounds increasing glutathione related enzymes in intestine to protect against oxidative stress induced by lipid peroxidation [40].…”

Section: Discussionsupporting

confidence: 85%

Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway

Rodríguez-Ramiro¹,

Ramos²,

Bravo³

et al. 2011

The Journal of Nutritional Biochemistry

123

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Humans are exposed to dietary acrylamide (AA) during their lifetime, it is therefore necessary to investigate the mechanisms associated with AA induced toxic effects.Accumulating evidence indicates that oxidative stress may contribute to AA cytotoxicity but the link between oxidative stress and AA cytotoxicity in the gastrointestinal tract, the primary organ in contact with dietary AA, has not been described. In this study, we evaluate the alterations of the redox balance induced by AA in Caco-2 intestinal cells as well as the potential protective role of natural antioxidants such as a well-standardized cocoa polyphenolic extract (CPE) and its main polyphenol components epicatechin (EC) and procyanidin B2 (PB2). We found that AA-induced oxidative stress in Caco-2 cells is evidenced by glutathione (GSH) depletion and reactive oxygen species (ROS) overproduction. AA also activated the extracellular-regulated kinases (ERKs) and the c-jun N-amino terminal kinases (JNKs) leading to an increase in caspase-3 activity and cell death. Studies with appropriate inhibitors confirmed the implication of oxidative stress and JNKs activation in AA-induced apoptosis. Additionally, AA cytotoxicity was counteracted by CPE or PB2 by inhibiting GSH consumption and ROS generation, increasing the levels of gamma-glutamyl cysteine synthase (γ-GCS) and glutathione-S-transferase (GST) and blocking the apoptotic pathways activated by AA. Therefore, AA-induced cytotoxicity and apoptosis are closely related to oxidative stress in Caco-2 cells. Interestingly, natural dietary antioxidant such as PB2 and CPE were able to suppress AA toxicity by improving the redox status of Caco-2 cells and by blocking the apoptotic pathway activated by AA.3

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Section: Discussionsupporting

confidence: 85%

Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway

Rodríguez-Ramiro¹,

Ramos²,

Bravo³

et al. 2011

The Journal of Nutritional Biochemistry

123

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“…However, we can exclude the implication of oxidative stress in oxLDL-treated 3T3-L1. In fact, although oxLDL have been demonstrated to induce an intracellular redox imbalance in several cell kinds (101,102), in our experimental system this did not occur as supported by the lack of ROS production and of GSH consumption following oxLDL treatment, and by the inability of the antioxidant vitamin E to restore glucose uptake. Finally, cell treatment with anti-CD36 antibody, which blocks the main scavenger receptor for oxLDL present on the cell membrane, counteracted the effect of lipoproteins, clearly demonstrating that oxLDL must be internalized to affect glucose uptake.…”

Section: Oxldl Impair Insulin Signaling In Adipocytes 839mentioning

confidence: 61%

Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases

Scazzocchio

Varı̀

D’Archivio

et al. 2009

Journal of Lipid Research

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Oxidized LDL (oxLDL) increase in patients affected by type-2 diabetes, obesity, and metabolic syndrome. Likewise, insulin resistance, an impaired responsiveness of target tissues to insulin, is associated with those pathological conditions. To investigate a possible causal relationship between oxLDL and the onset of insulin resistance, we evaluated the response to insulin of 3T3-L1 adipocytes treated with oxLDL. We observed that oxLDL inhibited glucose uptake (240%) through reduced glucose transporter 4 (GLUT4) recruitment to the plasma membrane (270%), without affecting GLUT4 gene expression. These findings were associated to the impairment of insulin signaling. Specifically, in oxLDL-treated cells insulin receptor (IR) substrate-1 (IRS-1) was highly degraded likely because of the enhanced Ser 307 phosphorylation. This process was largely mediated by the activation of the inhibitor of kB-kinase b (IKKb) and the c-Jun NH 2 -terminal kinase ( JNK). Moreover, the activation of IKKb positively regulated the nuclear content of nuclear factor kB (NF-kB), by inactivating the inhibitor of NF-kB (IkBa). The activated NF-kB further impaired per se GLUT4 functionality. Specific inhibitors of IKKb, JNK, and NF-kB restored insulin sensitivity in adipocytes treated with oxLDL. These data provide the first evidence that oxLDL, by activating serine/threonine kinases, impaired adipocyte response to insulin affecting pathways involved in the recruitment of GLUT4 to plasma membranes (PM). This suggests that oxLDL might participate in the development of insulin resistance.-Scazzocchio, B., R. Varì, M. DʼArchivio, C. Santangelo, C. Filesi, C. Giovannini, and R. Masella. Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases. J. Lipid Res. 2009. 50: 832-845.

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“…p66 Shc has been linked not only to diabetic nephropathy, but also to various other conditions, such as other glomerulopathies, cardiomyopathy, ischemia/reperfusion injury, neurodegenerative diseases, and in vitro models of intestinal cell dysfunction (27)(28)(29)(30). Likewise, aPC has evolved as a panacea, ameliorating a broad array of experimental diseases, including experimental cardiac or renal ischemia reperfusion injury, neurodegenerative diseases, inflammatory bowel disease, and diabetic glomerulopathy (1,31).…”

Section: Discussionmentioning

confidence: 99%

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc

Bock

Shahzad

Wang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

178

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The coagulation protease activated protein C (aPC) confers cytoprotective effects in various in vitro and in vivo disease models, including diabetic nephropathy. The nephroprotective effect may be related to antioxidant effects of aPC. However, the mechanism through which aPC may convey these antioxidant effects and the functional relevance of these properties remain unknown. Here, we show that endogenous and exogenous aPC prevents glomerular accumulation of oxidative stress markers and of the redox-regulating protein p66 Shc in experimental diabetic nephropathy. These effects were predominately observed in podocytes. In vitro, aPC inhibited glucose-induced expression of p66 Shc mRNA and protein in podocytes (via PAR-1 and PAR-3) and various endothelial cell lines, but not in glomerular endothelial cells. Treatment with aPC reversed glucose-induced hypomethylation and hyperacetylation of the p66 Shc promoter in podocytes. The hyperacetylating agent sodium butyrate abolished the suppressive effect of aPC on p66 Shc expression both in vitro and in vivo. Moreover, sodium butyrate abolished the beneficial effects of aPC in experimental diabetic nephropathy. Inhibition of p66 Shc expression and mitochondrial translocation by aPC normalized mitochondrial ROS production and the mitochondrial membrane potential in glucose-treated podocytes. Genetic ablation of p66 Shc compensated for the loss of protein C activation in vivo, normalizing markers of diabetic nephropathy and oxidative stress. These studies identify a unique mechanism underlying the cytoprotective effect of aPC. Activated PC epigenetically controls expression of the redox-regulating protein p66 Shc , thus linking the extracellular protease aPC to mitochondrial function in diabetic nephropathy.

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Apoptosis induced by oxidized lipids is associated with up-regulation of p66Shc in intestinal Caco-2 cells: protective effects of phenolic compounds

Cited by 40 publications

References 45 publications

Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway

Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway

Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc

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Apoptosis induced by oxidized lipids is associated with up-regulation of p66Shc in intestinal Caco-2 cells: protective effects of phenolic compounds

Cited by 40 publications

References 45 publications

Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway

Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway

Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 Shc

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Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc