scholarly journals Flutamide Induces Hepatic Cell Death and Mitochondrial Dysfunction via Inhibition of Nrf2-Mediated Heme Oxygenase-1

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Li Zhang ◽  
Jiabin Guo ◽  
Qiang Zhang ◽  
Wei Zhou ◽  
Jin Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Liver Injury ◽  
Mitochondrial Dysfunction ◽  
Heme Oxygenase ◽  
Hepatic Cell ◽  
Atp Depletion ◽  
Heme Oxygenase 1 ◽  
Hydrogen Peroxide Accumulation

Flutamide is a widely used nonsteroidal antiandrogen for prostate cancer therapy, but its clinical application is restricted by the concurrent liver injury. Increasing evidence suggests that flutamide-induced liver injury is associated with oxidative stress, though the precise mechanism is poorly understood. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription factor regulating endogenous antioxidants including heme oxygenase-1 (HO-1). This study was designed to delineate the role of Nrf2/HO-1 in flutamide-induced hepatic cell injury. Our results showed that flutamide concentration dependently induced cytotoxicity, hydrogen peroxide accumulation, and mitochondrial dysfunction as indicated by mitochondrial membrane potential loss and ATP depletion. The protein expression of Nrf2 and HO-1 was induced by flutamide at 12.5 μM but was downregulated by higher concentrations of flutamide. Silencing either Nrf2 or HO-1 was found to aggravate flutamide-induced hydrogen peroxide accumulation and mitochondrial dysfunction as well as inhibition of the Nrf2 pathway. Moreover, preinduction of HO-1 by Copp significantly attenuated flutamide-induced oxidative stress and mitochondrial dysfunction, while inhibition of HO-1 by Snpp aggravated these deleterious effects. These findings suggest that flutamide-induced hepatic cell death and mitochondrial dysfunction is assoicated with inhibition of Nrf2-mediated HO-1. Pharmacologic intervention of Nrf2/HO-1 may provide a promising therapeutic approach in flutamide-induced liver injury.

scholarly journals Resveratrol Protects C6 Astrocyte Cell Line against Hydrogen Peroxide-Induced Oxidative Stress through Heme Oxygenase 1

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e64372 ◽  
Author(s):  
André Quincozes-Santos ◽  
Larissa Daniele Bobermin ◽  
Alexandra Latini ◽  
Moacir Wajner ◽  
Diogo Onofre Souza ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cell Line ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1

scholarly journals Mitochondria-targeted heme oxygenase-1 decreases oxidative stress in renal epithelial cells

2013 ◽  
Vol 305 (3) ◽  
pp. F255-F264 ◽  
Author(s):  
Subhashini Bolisetty ◽  
Amie Traylor ◽  
Abolfazl Zarjou ◽  
Michelle S. Johnson ◽  
Gloria A. Benavides ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Heme Oxygenase ◽  
Manganese Superoxide Dismutase ◽  
Negative Impact ◽  
Tricarboxylic Acid Cycle ◽  
Mitochondrial Fraction ◽  
Hek293 Cells ◽  
Heme Oxygenase 1 ◽  
Protective Mechanism

Mitochondria are both a source and target of the actions of reactive oxygen species and possess a complex system of inter-related antioxidants that control redox signaling and protect against oxidative stress. Interestingly, the antioxidant enzyme heme oxygenase-1 (HO-1) is not present in the mitochondria despite the fact that the organelle is the site of heme synthesis and contains multiple heme proteins. Detoxification of heme is an important protective mechanism since the reaction of heme with hydrogen peroxide generates pro-oxidant ferryl species capable of propagating oxidative stress and ultimately cell death. We therefore hypothesized that a mitochondrially localized HO-1 would be cytoprotective. To test this, we generated a mitochondria-targeted HO-1 cell line by transfecting HEK293 cells with a plasmid construct containing the manganese superoxide dismutase mitochondria leader sequence fused to HO-1 cDNA (Mito-HO-1). Nontargeted HO-1-overexpressing cells were generated by transfecting HO-1 cDNA (HO-1) or empty vector (Vector). Mitochondrial localization of HO-1 with increased HO activity in the mitochondrial fraction of Mito-HO-1 cells was observed, but a significant decrease in the expression of heme-containing proteins occurred in these cells. Both cytosolic HO-1- and Mito-HO-1-expressing cells were protected against hypoxia-dependent cell death and loss of mitochondrial membrane potential, but these effects were more pronounced with Mito-HO-1. Furthermore, decrement in production of tricarboxylic acid cycle intermediates following hypoxia was significantly mitigated in Mito-HO-1 cells. These data suggest that specific mitochondrially targeted HO-1 under acute pathological conditions may have beneficial effects, but the selective advantage of long-term expression is constrained by a negative impact on the synthesis of heme-containing mitochondrial proteins.

scholarly journals Neurons Overexpressing Heme Oxygenase-1 Resist Oxidative Stress-Mediated Cell Death

2001 ◽  
Vol 75 (1) ◽  
pp. 304-313 ◽  
Author(s):  
Kai Chen ◽  
Karlene Gunter ◽  
Mahin D. Maines
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1

Resveratrol increases vascular oxidative stress resistance

2007 ◽  
Vol 292 (5) ◽  
pp. H2417-H2424 ◽  
Author(s):  
Zoltan Ungvari ◽  
Zsuzsanna Orosz ◽  
Aracelie Rivera ◽  
Nazar Labinskyy ◽  
Zhao Xiangmin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Cell Death ◽  
Endothelial Cell ◽  
Glutathione Peroxidase ◽  
Heme Oxygenase ◽  
Stress Resistance ◽  
Heme Oxygenase 1 ◽  
Resveratrol Treatment ◽  
Vascular Oxidative Stress

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its vasculoprotective effects are not completely understood. Because oxidative stress and endothelial cell injury play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits oxidative stress-induced endothelial apoptosis. We found that oxidized LDL and TNF-α elicited significant increases in caspase-3/7 activity in endothelial cells and cultured rat aortas, which were prevented by resveratrol pretreatment (10−6–10−4 mol/l). The protective effect of resveratrol was attenuated by inhibition of glutathione peroxidase and heme oxygenase-1, suggesting a role for antioxidant systems in the antiapoptotic action of resveratrol. Indeed, resveratrol treatment protected cultured aortic segments and/or endothelial cells against increases in intracellular H2O2 levels and H2O2-mediated apoptotic cell death induced by oxidative stressors (exogenous H2O2, paraquat, and UV light). Resveratrol treatment also attenuated UV-induced DNA damage (comet assay). Resveratrol treatment upregulated the expression of glutathione peroxidase, catalase, and heme oxygenase-1 in cultured arteries, whereas it had no significant effect on the expression of SOD isoforms. Resveratrol also effectively scavenged H2O2 in vitro. Thus resveratrol seems to increase vascular oxidative stress resistance by scavenging H2O2 and preventing oxidative stress-induced endothelial cell death. We propose that the antioxidant and antiapoptotic effects of resveratrol, together with its previously described anti-inflammatory actions, are responsible, at least in part, for its cardioprotective effects.

scholarly journals Exacerbation of Oxidative Stress-Induced Cell Death and Differentiation in Induced Pluripotent Stem Cells Lacking Heme Oxygenase-1

2012 ◽  
Vol 21 (10) ◽  
pp. 1675-1687 ◽  
Author(s):  
Chen-Yu Lin ◽  
Chiu-Ying Peng ◽  
Tzu-Ting Huang ◽  
Meng-Ling Wu ◽  
Yan-Liang Lai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Cell Death ◽  
Induced Pluripotent Stem Cells ◽  
Heme Oxygenase ◽  
Pluripotent Stem Cells ◽  
Heme Oxygenase 1 ◽  
Induced Pluripotent

scholarly journals Induction of heme oxygenase-1 shifts the balance from proinjury to prosurvival in the placentas of pregnant rats with reduced uterine perfusion pressure

2012 ◽  
Vol 302 (5) ◽  
pp. R620-R626 ◽  
Author(s):  
Eric M. George ◽  
Istvan Arany
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Caspase 3 ◽  
Perfusion Pressure ◽  
Atp Depletion ◽  
Heme Oxygenase 1 ◽  
Pregnant Rats ◽  
Intracellular Atp ◽  
Uterine Perfusion ◽  
The Impact

Placental hypoxia/ischemia has been implicated as a central factor in the development of preeclampsia. One particularly useful animal model to study the impact of placental ischemia is the reduced uterine perfusion pressure (RUPP) model. We have previously demonstrated that RUPP animals exhibit elevated placental oxidative stress, which plays an important role in the development of the associated maternal hypertension. Recently, we have demonstrated that cobalt protoporphyrin (CoPP)-mediated induction of heme oxygenase-1 (HO-1) attenuates RUPP-induced oxidative stress and consequent hypertension. However, signaling pathways that are involved in this process are virtually unknown. Here, we show that placentas from RUPP animals exhibit increased phosphorylation of JNK, STAT1, STAT3, and p52shc with a concomitant increase in caspase-3 activation and depletion of intracellular ATP. Treatment with CoPP decreased RUPP-induced phosphorylation of JNK and STAT1, while it increased phosphorylation of ERK and STAT3, leading to decreased caspase-3 activation and restoration of intracellular ATP content. Our data imply that RUPP induces oxidative stress and the consequent injurious state by increasing phosphorylation of mediators of injury (STAT1, JNK) and, to a lesser extent, survival (STAT3, p52shc) in placentas of pregnant rats. HO-1 induction shifts this balance to a prosurvival phenotype by augmenting phosphorylation of the prosurvival ERK and STAT3, while suppressing phosphorylation of JNK and STAT1. This attenuates the resulting injury, as indicated by caspase-3 activation and ATP depletion. These results demonstrate a novel therapeutic activity of HO-1 induction in placental cell survival during ischemia and support the HO-1 pathway as a promising therapeutic target for the management of preeclampsia.

Cilostazol attenuates murine hepatic ischemia and reperfusion injury via heme oxygenase-dependent activation of mitochondrial biogenesis

2015 ◽  
Vol 309 (1) ◽  
pp. G21-G29 ◽  
Author(s):  
Yeonsoo Joe ◽  
Min Zheng ◽  
Hyo Jeong Kim ◽  
Md. Jamal Uddin ◽  
Seul-Ki Kim ◽  
...  
Keyword(s):  
Liver Injury ◽  
Mitochondrial Dysfunction ◽  
Heme Oxygenase ◽  
Mitochondrial Biogenesis ◽  
Ischemia Reperfusion ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Hepatocellular Injury ◽  
Primary Hepatocytes ◽  
Hepatic Ischemia

Hepatic ischemia-reperfusion (I/R) can cause hepatocellular injury associated with the inflammatory response and mitochondrial dysfunction. We studied the protective effects of the phosphodiesterase inhibitor cilostazol in hepatic I/R and the roles of mitochondria and the Nrf2/heme oxygenase-1 (HO-1) system. Wild-type, Hmox1 −/−, or Nrf2 −/− mice were subjected to hepatic I/R in the absence or presence of cilostazol followed by measurements of liver injury. Primary hepatocytes were subjected to cilostazol with the HO-1 inhibitor ZnPP, or Nrf2-specific siRNA, followed by assessment of mitochondrial biogenesis. Preconditioning with cilostazol prior to hepatic I/R protected against hepatocellular injury and mitochondrial dysfunction. Cilostazol reduced the serum levels of alanine aminotransferase, TNF-α, and liver myeloperoxidase content relative to control I/R-treated mice. In primary hepatocytes, cilostazol increased the expression of HO-1, and markers of mitochondrial biogenesis, PGC-1α, NRF-1, and TFAM, induced the mitochondrial proteins COX III and COX IV and increased mtDNA and mitochondria content. Pretreatment of primary hepatocytes with ZnPP inhibited cilostazol-induced PGC-1α, NRF-1, and TFAM mRNA expression and reduced mtDNA and mitochondria content. Genetic silencing of Nrf2 prevented the induction of HO-1 and mitochondrial biogenesis by cilostazol in HepG2 cells. Cilostazol induced hepatic HO-1 production and mitochondrial biogenesis in wild-type mice, but not in Hmox1 −/− or Nrf2 −/− mice, and failed to protect against liver injury in Nrf2 −/− mice. These results suggest that I/R injury can impair hepatic mitochondrial function, which can be reversed by cilostazol treatment. These results also suggest that cilostazol-induced mitochondrial biogenesis was mediated by an Nrf-2- and HO-1-dependent pathway.

Sign in / Sign up

Export Citation Format

Share Document