Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: Involvement of JNK and ERK MAP kinases

Rosa, Laura Conde de la; Schoemaker, Marieke H.; Vrenken, Titia E.; Buist‐Homan, Manon; Havinga, Rick; Jansen, Petér L. M.; Moshage, Han

doi:10.1016/j.jhep.2005.07.034

Cited by 198 publications

(176 citation statements)

References 55 publications

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“…We did not observe neuroprotection with SOD in solution, which could be due to its rapid degradation in the culture prior to completely detoxifying free radicals. PEG-SOD in solution was also ineffective in our studies, although several previous studies have reported better antioxidant efficacy of PEG-SOD over free SOD enzyme in different cell lines such as hepatocytes and cardiac myocytes, and also in animal experiments [24,25]. However, McKinney et al [26] reported the protective effect of PEG-SOD on endothelial cells, yet no protective effect on astrocytes or neuronal plus glial cells in a model of oxidative stress mediated by stretch injury.…”

Section: Discussioncontrasting

confidence: 48%

Superoxide Dismutase-Loaded PLGA Nanoparticles Protect Cultured Human Neurons Under Oxidative Stress

Reddy

Kou

et al. 2008

Appl Biochem Biotechnol

131

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The objective of the present study was to investigate the neuroprotective efficacy of superoxide dismutase (SOD), loaded in poly(D,L-lactide co-glycolide) (PLGA) nanoparticles (NPs), in cultured human neurons challenged with hydrogen peroxide (H 2 O 2 )-induced oxidative stress. We hypothesized that the protected and sustained intracellular delivery of SOD encapsulated in NPs would demonstrate better neuroprotection from oxidative stress than either with SOD or pegylated SOD (PEG-SOD) in solution. SOD-NPs (~81 ± 4 nm in diameter, 0.9% w/w SOD loading) released the encapsulated SOD in an active form in vitro, with 8.2% cumulative release during the first 24 hrs, followed by a slower release thereafter. The results demonstrated that PLGA-NPs are compatible with human neurons and the neuroprotective effect of SOD-NPs is dose-dependent, with efficacy seen at >100 U SOD, with less significant effects at lower doses. Neither SOD (25-200 U) nor PEG-SOD (100 U) in solution demonstrated the neuroprotective effect under similar conditions. The neuroprotective effect of SOD-NPs was seen up to 6 hrs following H 2 O 2 -induced oxidative stress, but the effect diminished thereafter. Confocal microscopic studies demonstrated better intracellular neuronal uptake of the encapsulated model protein (FITC-labeled BSA) than the protein in solution. Thus, the mechanism of efficacy of SOD-NPs appears to be due to the stability of the encapsulated enzyme and its better neuronal uptake following encapsulation.

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Section: Discussioncontrasting

confidence: 48%

Superoxide Dismutase-Loaded PLGA Nanoparticles Protect Cultured Human Neurons Under Oxidative Stress

Reddy

Kou

et al. 2008

Appl Biochem Biotechnol

131

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“…Two independent factors, JNK and CHOP, are activated in response to ER stress, 9 and JNK transduces hepatocyte cell death caused by reactive oxygen species or bile acids. 30,31 We found that although JNK activation was induced in the liver of BDL mice, the extent of JNK phosphorylation did not differ between control and LIGFREKO mice ( Figure 5A). Likewise, the expression of GRP78, a key molecular chaperone promoting recovery from ER stress, was induced to the same degree in BDL control and LIGFREKO livers ( Figure 5B).…”

Section: Igf-1r Induces Cellular Stress Pathways After Bile Duct Ligamentioning

confidence: 90%

IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

Cadoret

Rey

Wendum

et al. 2009

The American Journal of Pathology

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The insulin-like growth factor type 1 receptor (IGF-1R) controls aging and cellular stress, both of which play major roles in liver disease. Stimulation of insulin-like growth factor signaling can generate cell death in vitro. Here, we tested whether IGF-1R contributes to stress insult in the liver. Cholestatic liver injury was induced by bile duct ligation in control and liver-specific IGF-1R knockout (LIGFREKO) mice. LIGFREKO mice displayed less bile duct ligation-induced hepatocyte damage than controls, while no differences in bile acid serum levels or better adaptation to cholestasis by efflux transporters were found. We therefore tested whether stress pathways contributed to this phenomenon; oxidative stress, ascertained by both malondialdehyde content and heme oxygenase-1 expression, was similar in knockout and control animals. However, together with a lower level of eukaryotic initiation factor-2 ␣ phosphorylation, the endoplasmic reticulum stress protein CHOP and its downstream pro-apoptotic target Bax were induced to lesser extents in LIGFREKO mice than in controls. Expression levels of cytokeratin 19, transforming growth factor-␤1, ␣-smooth muscle actin, and collagen ␣1(I) in LIGFREKO mice were all lower than in controls, indicating reduced ductular and fibrogenic responses and increased cholestasis tolerance in these mutants. This stress resistance phenotype was also evidenced by longer post-bile duct ligation survival in mutants than controls. These results indicate that IGF-1R contributes to cholestatic liver injury , and suggests the involvement of both CHOP and

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“…However, many recent studies have demonstrated that the activation of signal transduction pathways is important in mediating ROS-induced cell death. In various cell lines, ROS-induced apoptosis has been shown to be modulated by altered signaling pathways involving JNK, PKC, and Akt (PKB) (9,11,38,55,58). Therefore, understanding the signaling pathways involved in mediating ROSinduced cell death may have important implications in understanding many diseases associated with ROS-induced injury.…”

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confidence: 99%

Regulation of H₂O₂-induced necrosis by PKC and AMP-activated kinase signaling in primary cultured hepatocytes

Saberi

Shinohara

Ybanez

et al. 2008

American Journal of Physiology-Cell Physiology

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Recent studies have suggested that, in certain cases, necrosis, like apoptosis, may be programmed, involving the activation and inhibition of many signaling pathways. In this study, we examined whether necrosis induced by H2O2 is regulated by signaling pathways in primary hepatocytes. A detailed time course revealed that H2O2 treated to hepatocytes is consumed within minutes, but hepatocytes undergo necrosis several hours later. Thus, H2O2 treatment induces a “lag phase” where signaling changes occur, including PKC activation, Akt (PKB) downregulation, activation of JNK, and downregulation of AMP-activated kinase (AMPK). Investigation of various inhibitors demonstrated that PKC inhibitors were effective in reducing necrosis caused by H2O2 (∼80%). PKC inhibitor treatment decreased PKC activity but, surprisingly, also upregulated Akt and AMPK, suggesting that various PKC isoforms negatively regulate Akt and AMPK. Akt did not appear to play a significant role in H2O2-induced necrosis, since PKC inhibitor treatment protected hepatocytes from H2O2 even when Akt was inhibited. On the other hand, compound C, a selective AMPK inhibitor, abrogated the protective effect of PKC inhibitors against necrosis induced by H2O2. Furthermore, AMPK activators protected against H2O2-induced necrosis, suggesting that much of the protective effect of PKC inhibition was mediated through the upregulation of AMPK. Work with PKC inhibitors suggested that atypical PKC downregulates AMPK in response to H2O2. Knockdown of PKC-α using antisense oligonucleotides also slightly protected (∼22%) against H2O2. Taken together, our data demonstrate that the modulation of signaling pathways involving PKC and AMPK can alter H2O2-induced necrosis, suggesting that a signaling “program” is important in mediating H2O2-induced necrosis in primary hepatocytes.

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Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: Involvement of JNK and ERK MAP kinases

Cited by 198 publications

References 55 publications

Superoxide Dismutase-Loaded PLGA Nanoparticles Protect Cultured Human Neurons Under Oxidative Stress

Superoxide Dismutase-Loaded PLGA Nanoparticles Protect Cultured Human Neurons Under Oxidative Stress

IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

Regulation of H₂O₂-induced necrosis by PKC and AMP-activated kinase signaling in primary cultured hepatocytes

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Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: Involvement of JNK and ERK MAP kinases

Cited by 198 publications

References 55 publications

Superoxide Dismutase-Loaded PLGA Nanoparticles Protect Cultured Human Neurons Under Oxidative Stress

Superoxide Dismutase-Loaded PLGA Nanoparticles Protect Cultured Human Neurons Under Oxidative Stress

IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

Regulation of H2O2-induced necrosis by PKC and AMP-activated kinase signaling in primary cultured hepatocytes

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Regulation of H₂O₂-induced necrosis by PKC and AMP-activated kinase signaling in primary cultured hepatocytes