α-Lipoic Acid–Induced Heme Oxygenase-1 Expression Is Mediated by Nuclear Factor Erythroid 2-Related Factor 2 and p38 Mitogen-Activated Protein Kinase in Human Monocytic Cells

Ogborne, Richard M.; Rushworth, Stuart A.; O’Connell, Maria A.

doi:10.1161/01.atv.0000183745.37161.6e

Cited by 107 publications

(67 citation statements)

References 46 publications

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“…Our results also suggested that inhibition of HO-1, Hsp72, or iNOS proteins by the inhibitors ZnPP IX, quercitin, or L-NMMA, respectively, abrogated the protective effect of 75 μM ALCAR+50 μM LA (data not shown), demonstrating that HO-1 or Hsp72 or iNOS are likely involved in the ALCAR+LA-mediated cytoprotection against HNE-induced oxidative stress. It has been recently demonstrated that LA induces HO-1 expression in THP-1 monocytic cells via Nrf2 and p38 (72). Our results are consonant with the recent studies, which shows that ALCAR is cytoprotective against inflammatory and oxidative insults in astrocytes in part by being able to up-regulate cytoprotective cellular stress responses, particularly induction of HO-1, while inhibiting induction of iNOS (73).…”

Section: Discussionsupporting

confidence: 92%

Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and α-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease

Abdul

Butterfield

2007

Free Radical Biology and Medicine

126

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Oxidative stress has been shown to underlie neuropathological aspects of Alzheimer's disease (AD). 4-Hydroxy-2-nonenal (HNE) is a highly reactive product of lipid peroxidation of unsaturated lipids. HNE-induced oxidative toxicity is a well-described model of oxidative stress-induced neurodegeneration. GSH plays a key role in antioxidant defense, and HNE exposure causes an initial depletion of GSH that leads to gradual toxic accumulation of reactive oxygen species. In the current study, we investigated whether pre-treatment of cortical neurons with acetyl-L-carnitine (ALCAR) and α-lipoic acid (LA) plays a protective role in cortical neuronal cells against HNE-mediated oxidative stress and neurotoxicity. Decreased cell survival of neurons treated with HNE correlated with increased protein oxidation (protein carbonyl, 3-nitrotyrosine) and lipid peroxidation (HNE) accumulation. Pretreatment of primary cortical neuronal cultures with ALCAR and LA significantly attenuated HNE-induced cytotoxicity, protein oxidation, lipid peroxidation and apoptosis in a dosedependent manner. Additionally, pretreatment of ALCAR and LA also led to elevated cellular GSH and heat shock proteins (HSPs) levels compared to untreated control cells. We have also determined that pretreatment of neurons with ALCAR and LA leads to the activation of phosphoinositol-3 kinase (PI3K), PKG and ERK1/2 pathways, which play essential roles in neuronal cell survival. Thus, this study demonstrates a cross talk between the PI3K, PKG and ERK1/2 pathways in cortical neuronal cultures that contributes to ALCAR and LA-mediated pro-survival signaling mechanisms. This evidence supports the pharmacological potential of co-treatment of ALCAR and LA in the management of neurodegenerative disorders associated with HNE-induced oxidative stress and neurotoxicity, including AD.

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Section: Discussionsupporting

confidence: 92%

Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and α-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease

Abdul

Butterfield

2007

Free Radical Biology and Medicine

126

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“…It is essential to determine whether their stimulatory effect on insulin signaling is dependent on Nrf2 activity. Again, the Nrf2 null mice will be the asset for these studies; (4) The AMP-dependent kinase activator metformin, PPARγ agonists and α-folic acid were shown to improve glucose control and also to attenuate oxidative stress [101][102][103][104] . Whether these existing drugs exert these effects via Nrf2 activation requires further investigations; and (5) Nrf2 can upregulate CD36 expression involved in lipid uptake.…”

Section: Resultsmentioning

confidence: 99%

Role of nuclear factor (erythroid-derived 2)-like 2 in metabolic homeostasis and insulin action: A novel opportunity for diabetes treatment?

Zhong

Li²,

Liu³

et al. 2012

WJD

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Redox balance is fundamentally important for physiological homeostasis. Pathological factors that disturb this dedicated balance may result in oxidative stress, leading to the development or aggravation of a variety of diseases, including diabetes mellitus, cardiovascular diseases, metabolic syndrome as well as inflammation, aging and cancer. Thus, the capacity of endogenous free radical clearance can be of patho-physiological importance; in this regard, the major reactive oxygen species defense machinery, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system needs to be precisely modulated in response to pathological alterations. While oxidative stress is among the early events that lead to the development of insulin resistance, the activation of Nrf2 scavenging capacity leads to insulin sensitization. Furthermore, Nrf2 is evidently involved in regulating lipid metabolism. Here we summarize recent findings that link the Nrf2 system to metabolic homeostasis and insulin action and present our view that Nrf2 may serve as a novel drug target for diabetes and its complications.

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“…In addition to its substrate heme, a variety of conditions and agents, both physiologic and nonphysiologic, including UV irradiation, hyperthermia, inflammatory cytokines, bacterial endotoxins, and heavy metals, potently stimulate HO-1 (16)(17)(18)(19)(20). This is due to the 5′-flanking region of the HO-1 gene containing binding sites for several different transcription factors that regulate inflammation and apoptosis, including NF-κB, activator protein-1 (AP-1), and NF-E2-related factor 2 (Nrf2; refs.…”

Section: Introductionmentioning

confidence: 99%

NF-κB–Inhibited Acute Myeloid Leukemia Cells Are Rescued from Apoptosis by Heme Oxygenase-1 Induction

et al. 2010

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Despite high basal NF-κB activity in acute myeloid leukemia (AML) cells, inhibiting NF-κB in these cells has little or no effect on inducing apoptosis. We previously showed that heme oxygenase-1 (HO-1) underlies this resistance of AML to tumor necrosis factor-induced apoptosis. Here, we describe a mechanism by which HO-1 is a silent antiapoptotic factor only revealed when NF-κB is inhibited, thus providing a secondary antiapoptotic mechanism to ensure AML cell survival and chemoresistance. We show that inhibition of NF-κB increased HO-1 expression in primary AML cells compared with that of nonmalignant cells. In addition, we observed this suppressed HO-1 level in AML cells compared with CD34+ nonmalignant control cells. Using chromatin immunoprecipitation assay and small interfering RNA knockdown, we showed that the NF-κB subunits p50 and p65 control this suppression of HO-1 in AML cells. Finally, we showed that inhibition of HO-1 and NF-κB in combination significantly induced apoptosis in AML cells but not in noncancerous control cells. Thus, NF-κB inhibition combined with HO-1 inhibition potentially provides a novel therapeutic approach to treat chemotherapy-resistant forms of AML. Cancer Res; 70(7); 2973-83. ©2010 AACR.

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α-Lipoic Acid–Induced Heme Oxygenase-1 Expression Is Mediated by Nuclear Factor Erythroid 2-Related Factor 2 and p38 Mitogen-Activated Protein Kinase in Human Monocytic Cells

Abstract: These results demonstrate that ALA induces HO-1 expression in THP-1 monocytic cells via Nrf2 and p38. Further studies are required to investigate whether the protective effects of ALA in monocytes are mediated by HO-1.

Cited by 107 publications

References 46 publications

Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and α-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease

Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and α-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease

Role of nuclear factor (erythroid-derived 2)-like 2 in metabolic homeostasis and insulin action: A novel opportunity for diabetes treatment?

NF-κB–Inhibited Acute Myeloid Leukemia Cells Are Rescued from Apoptosis by Heme Oxygenase-1 Induction

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