Increase in intracellular free/bound NAD[P]H as a cause of Cd-induced oxidative stress in the HepG2 cells

Yang, M. S.; Li, D.; Lin, Tao; Zheng, Jianping; Zheng, Wei; Qu, Jianan Y.

doi:10.1016/j.tox.2008.01.021

Cited by 15 publications

(6 citation statements)

References 30 publications

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“…Oxidative stress often occurs due to an imbalance in intracellular levels of oxidants (e.g., ROS) and reducing agents (e.g., GSH). Previous studies demonstrated a cadmium-mediated oxidative stress by decreasing cellular GSH and/or increasing cellular ROS (44,45). Supporting these findings, we previously demonstrated that cadmium rapidly lowers cellular GSH and the GSH reduction is important for the metal-mediated expression of MAPK phosphatase-1 in C6 cells (36).…”

Section: Discussionsupporting

confidence: 79%

Transcriptional and translational regulation of COX-2 expression by cadmium in C6 glioma cells

Park

Hong

Jang

2012

International Journal of Molecular Medicine

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High exposure to cadmium is a risk factor for many neuronal diseases. Overexpression of cyclooxygenase (COX)-2 is linked to many neuroinflammatory and neoplastic diseases. We, herein, investigated the effect of cadmium on the expression of COX-2 in C6 rat glioma cells. Treatment with cadmium sulfate (cadmium) increased the expression of COX-2 mRNA. Remarkably, cadmium treatment further increased expression of not only the N-glycosylated COX-2 protein of 72 kDa but also the unglycosylated COX-2 of 66 kDa, as assessed by the unglycosylated COX-2 induced by tunicamycin or glucosamine, known inhibitors of COX-2 N-glycosylation. Of note, when translation was blocked in the presence of cycloheximide (CHX), levels of both N-glycosylated and unglycosylated COX-2 proteins induced by cadmium rapidly declined but the decline was prevented by MG132, a 26S proteasomal inhibitor. However, in the absence of CHX, cadmium induced and maintained expression of the unglycosylated COX-2 proteins. Pharmacological inhibition studies importantly demonstrated that the cadmium-mediated COX-2 transcriptional upregulation in C6 cells was not shown by exogenous glutathione (GSH) supplementation or treatment with inhibitors of extracellular signal-regulated protein kinase-1/2 (ERK-1/2), p38 MAPK and c-Jun N-terminal protein kinase-1/2 (JNK-1/2), respectively. Expression of COX-2 was not noted in C6 cells exposed to other heavy metals (cobalt or manganese). These results demonstrate that cadmium specifically induces expression of COX-2 through both transcriptional and co-translational (N-glycosylation) regulation in C6 cells in which the cadmium-induced COX-2 transcriptional upregulation is closely related to oxidative stress-dependent activation of the family of MAPKs and the cadmium-induced expression of both N-glycosylated and unglycosylated COX-2 proteins is proteasome- and translation-dependent.

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Section: Discussionsupporting

confidence: 79%

Transcriptional and translational regulation of COX-2 expression by cadmium in C6 glioma cells

Park

Hong

Jang

2012

International Journal of Molecular Medicine

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“…Our in vitro data suggest that Cd, which is taken up by ECs via solute carriers or ion channels clustering on the luminal side of ECs (see Figure 2), causes DNA strand brakes. An involvement of oxidative stress, as has been suggested by others 27,28 seems unlikely in our model because we were not able to detect oxidative stress by various methods (eg, 123 Di-hydro-rhodamine, H2-DCF-DA staining, Oxyblotting, and no shift in the GSH:GSSG ratio toward GSSG; data not shown). The phosphorylation of ATM on serine 1981 clearly indicates that ECs sense DNA damage and react by upregulation and stabilization of p53 and its downstream target, cell cycle inhibitor p21/WAF1/Cip1 (note the drop in the number of viable cells in the absence of cell death after 24 and 48 hours in response to Cd treatment; Figure 3A and 3B).…”

Section: Discussionmentioning

confidence: 54%

Cadmium Is a Novel and Independent Risk Factor for Early Atherosclerosis Mechanisms and In Vivo Relevance

Meßner

Knoflach

Seubert

et al. 2009

ATVB

260

178

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Objectives-Although cadmium (Cd) is an important and common environmental pollutant and has been linked to cardiovascular diseases, little is known about its effects in initial stages of atherosclerosis. Methods and Results-In the 195 young healthy women of the Atherosclerosis Risk Factors in Female Youngsters(ARFY) study, cadmium (Cd) level was independently associated with early atherosclerotic vessel wall thickening (intima-media thickness exceeding the 90th percentile of the distribution; multivariable OR 1.6[1.1.-2.3], Pϭ0.016). In line, Cd-fed ApoE knockout mice yielded a significantly increased aortic plaque surface compared to controls (9.5 versus 26.0 mm 2 , PϽ0.004). In vitro results indicate that physiological doses of Cd increase vascular endothelial permeability up to 6-fold by (1) inhibition of endothelial cell proliferation, and (2) induction of a caspase-independent but Bcl-xL-inhibitable form of cell death more than 72 hours after Cd addition. Both phenomena are preceded by Cd-induced DNA strand breaks and a cellular DNA damage response. Zinc showed a potent protective effect against deleterious effects of Cd both in the in vitro and human studies. Conclusion-Our research suggests Cd has promoting effects on early human and murine atherosclerosis, which were partly offset by high Zn concentrations. Key Words: cadmium, zinc Ⅲ endothelial Ⅲ dysfunction Ⅲ injury Ⅲ permeability Ⅲ necrosis Ⅲ ApoE Ⅲ atherosclerosis Ⅲ vascular Ⅲ pathophysiology Ⅲ risk factor Ⅲ intima media thickness Ⅲ apoptosis Ⅲ cell death S ince the use of Cd in manifold industrial applications, sources for and the amount of Cd uptake by humans has increased dramatically. Cd is, for example, released into the air through the burning of fossil fuels (coal, oil) and the incineration of municipal waste (Environmental Protection Agency, 2000). The most relevant sources for Cd uptake by humans are, however, cigarette smoking (one cigarette contains Ϸ1 to 2 g; daily uptake of Cd Ϸ1 to 3 g per pack smoked) and food for nonsmokers (daily intake Ϸ30 g; daily uptake Ϸ1 to 3 g), as well as exhaust gases (Agency for Toxic Substances and Disease Registry, 1999). After inhalation or ingestion of Cd, it is transferred into the bloodstream (whole blood and serum Cd concentrations range between Ϸ0.2 and Ϸ20 nmol/L 1,2 ), where Cd is transported either as a free ion or protein-bound, eg, attached to albumin or metallothioneins. Cd is taken up by cells of Cd target organs (liver, kidneys, and testis) via solute carriers, calcium and manganese channels, and iron transporters. [3][4][5] In 2001, Abu-Hayyeh et al 6 demonstrated that the aortic vessel wall is another under-recognized target organ for Cd accumulation (aortic wall concentrations of Cd are up to 20 mol/ L). Epidemiologically, high Cd level was found to be associated with hypertension, stroke, and cardiac arrest, 7-9 but confirmatory data are sparse and the mechanistic basis for these interactions remains unclear. Houtman et al observed a higher than expected frequency of atherosclerosis in a...

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“…As we have described, NADPH oxidase is involved in the development of hepatic damages in response to exposure to various chemicals, including several environmental contaminants (Straub et al, 2008;Yang et al, 2008). Thus, understanding the transcriptional regulation of p40 phox expression by AhR may provide additional insight into how environmental contaminants increase cellular ROS levels in the liver.…”

Section: Ahr Regulates P40mentioning

confidence: 86%

Aryl Hydrocarbon Receptor Modulates NADPH Oxidase Activity via Direct Transcriptional Regulation of p40^phoxExpression

et al. 2013

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A member of the NADPH oxidase subunits, p40phox plays an important role in the regulation of NADPH oxidase activity and the subsequent production of reactive oxygen species (ROS). In this study, we show that mouse p40 phox is a novel transcriptional target of the aryl hydrocarbon receptor (AhR), known as a dioxin receptor or xenobiotic receptor, in the liver. Treatment of mice with 3-methylcholanthrene (3MC) increased p40 phox gene expression in the liver, but this induction of p40 phox gene expression was diminished by the deletion of the AhR gene in the liver. Consistent with the in vivo results, the expression of the p40 phox gene was increased in 3MC-treated Hepa1c1c7 cells in an AhR-dependent manner. In addition, promoter analysis established p40 phox as a transcriptional target of AhR. Studies using the RNA-interference technique revealed that p40 phox is involved in the increase of NADPH oxidase activity and the subsequent ROS production in AhR-activated Hepa1c1c7 cells. Consequently, the results obtained here may provide a novel molecular mechanism for ROS production after exposure to dioxins.

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Increase in intracellular free/bound NAD[P]H as a cause of Cd-induced oxidative stress in the HepG2 cells

Cited by 15 publications

References 30 publications

Transcriptional and translational regulation of COX-2 expression by cadmium in C6 glioma cells

Transcriptional and translational regulation of COX-2 expression by cadmium in C6 glioma cells

Cadmium Is a Novel and Independent Risk Factor for Early Atherosclerosis Mechanisms and In Vivo Relevance

Aryl Hydrocarbon Receptor Modulates NADPH Oxidase Activity via Direct Transcriptional Regulation of p40^phoxExpression

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Increase in intracellular free/bound NAD[P]H as a cause of Cd-induced oxidative stress in the HepG2 cells

Cited by 15 publications

References 30 publications

Transcriptional and translational regulation of COX-2 expression by cadmium in C6 glioma cells

Transcriptional and translational regulation of COX-2 expression by cadmium in C6 glioma cells

Cadmium Is a Novel and Independent Risk Factor for Early Atherosclerosis Mechanisms and In Vivo Relevance

Aryl Hydrocarbon Receptor Modulates NADPH Oxidase Activity via Direct Transcriptional Regulation of p40phoxExpression

Contact Info

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Aryl Hydrocarbon Receptor Modulates NADPH Oxidase Activity via Direct Transcriptional Regulation of p40^phoxExpression