Comparative impacts of glutathione peroxidase-1 gene knockout on oxidative stress induced by reactive oxygen and nitrogen species in mouse hepatocytes

2001 ◽  
Vol 359 (3) ◽  
pp. 687-695 ◽  
Author(s):  
Yangxin FU ◽  
Jesus M. PORRES ◽  
Xin Gen LEI
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Glutathione Peroxidase ◽  
Apoptotic Cell ◽  
Gene Knockout ◽  
Reactive Oxygen ◽  
Nitrogen Species ◽  
Sod Activity ◽  
Glutathione Peroxidase 1 ◽  
Synergistic Cytotoxicity

Selenium-dependent glutathione peroxidase-1 (GPX1) protects against reactive-oxygen-species (ROS)-induced oxidative stress in vivo, but its role in coping with reactive nitrogen species (RNS) is unclear. Our objective was to compare the protection of GPX1 against cytotoxicity of superoxide generator diquat (DQ), NO donor S-nitroso-N-acetyl-penicillamine (SNAP) and peroxynitrite generator 3-morpholinosydnonimine (SIN-1). Primary hepatocytes were isolated from GPX1-knockout (KO) and wild-type (WT) mice and cultured in complete Williams's medium E with various levels of these agents alone or in combination for up to 12h. While the KO cells were more susceptible to cell death, DNA fragmentation and protein carbonyl formation induced by 0.25–1mM DQ, these cells were as tolerant as the WT cells to cytotoxicity of 0.1–1mM SNAP or 0.5–2mM SIN-1. Treating cells with SNAP (0.1 or 0.25mM) in addition to DQ produced synergistic cytotoxicity that minimized differences in apoptotic cell death and oxidative injuries between the KO and WT cells. Less protein nitrotyrosine was induced by 0.05–0.5mM DQ+0.25mM SNAP in the KO than in the WT cells. Total GPX activity in the WT cells was reduced by 65 and 25% by 0.5mM DQ+0.1mM SNAP and 0.5mM DQ, respectively. Decreases in Cu,Zn-superoxide dismutase (SOD) activity and increases in Mn-SOD activity in response to DQ or DQ+SNAP were greater in the KO cells than in the WT cells. In conclusion, GPX1 was more effective in protecting hepatocytes against oxidative injuries mediated by ROS alone than by ROS and RNS together. Knockout of GPX1 did not enhance cell susceptibility to RNS-associated cytotoxicity. Instead, it attenuated protein nitration induced by DQ+SNAP.

scholarly journals Low levels of glutathione peroxidase 1 activity in selenium-deficient mouse liver affect c-Jun N-terminal kinase activation and p53 phosphorylation on Ser-15 in pro-oxidant-induced aponecrosis

2003 ◽  
Vol 370 (3) ◽  
pp. 927-934 ◽  
Author(s):  
Wen-Hsing CHENG ◽  
Xinmin ZHENG ◽  
Fred R. QUIMBY ◽  
Carol A. RONEKER ◽  
Xin Gen LEI
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Glutathione Peroxidase ◽  
Intraperitoneal Injection ◽  
Mouse Liver ◽  
Deficient Mouse ◽  
Kinase Activation ◽  
Glutathione Peroxidase 1 ◽  
Low Levels ◽  
Apoptosis And Necrosis

Low levels of hepatic selenium (Se)-dependent glutathione peroxidase 1 (GPX1) activity have been shown to protect against oxidative liver injury in Se-deficient mice. The objective of the present study was to determine if the GPX1 protection was associated with phosphorylations of c-Jun N-terminal kinase (JNK) and p53 on Ser-15, two key signalling events in oxidative-stress-mediated cell death. Both Se-deficient GPX1 knockout (GPX1-/-) and wild-type (WT) mice (n = 64) were pretreated with an intraperitoneal injection of Se (as sodium selenite, 50μg/kg body weight) 6h before an intraperitoneal injection of paraquat (12.5mg/kg). Liver aponecrosis, a mixed form of cell death sharing apoptosis and necrosis, was induced by paraquat in both groups of mice. However, its appearance was remarkably delayed and the severity was decreased by the repletion of hepatic GPX1 activity to <4% of the normal level by the Se injection in the WT mice, compared with that in the GPX1-/- mice. Consistently, the WT mice had lower levels of hepatic phospho-JNK, p53 and phospho-p53 (Ser-15) when compared with the GPX1-/- mice at 1—10h after paraquat injection. Incubating liver homogenates with antibodies raised against JNK or phospho-JNK resulted in co-immunoprecipitation of phospho-p53 (Ser-15), and the amounts of the precipitated phospho-p53 were greater in the GPX1-/- mice when compared with that in the WT mice. The co-precipitated complex by the anti-phospho-JNK antibody was capable of phosphorylating intrinsic or extrinsic p53 on Ser-15. In conclusion, phospho-JNK may catalyse phosphorylation of p53 on Ser-15 in Se-deficient mouse liver under moderate oxidative stress, and attenuation of that cascade by low levels of GPX1 activity is associated with its protection against the pro-oxidant-induced liver aponecrosis.

scholarly journals 4-Hydroxychalcone Induces Cell Death via Oxidative Stress in MYCN-Amplified Human Neuroblastoma Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Amnah M. Alshangiti ◽  
Eszter Tuboly ◽  
Shane V. Hegarty ◽  
Cathal M. McCarthy ◽  
Aideen M. Sullivan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Cytotoxic Effect ◽  
Neuroblastoma Cells ◽  
Reactive Oxygen ◽  
Prognostic Indicator ◽  
Oxygen Species ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma

Neuroblastoma is an embryonal malignancy that arises from cells of sympathoadrenal lineage during the development of the nervous system. It is the most common pediatric extracranial solid tumor and is responsible for 15% of childhood deaths from cancer. Fifty percent of cases are diagnosed as high-risk metastatic disease with a low overall 5-year survival rate. More than half of patients experience disease recurrence that can be refractory to treatment. Amplification of the MYCN gene is an important prognostic indicator that is associated with rapid disease progression and a poor prognosis, highlighting the need for new therapeutic approaches. In recent years, there has been an increasing focus on identifying anticancer properties of naturally occurring chalcones, which are secondary metabolites with variable phenolic structures. Here, we report that 4-hydroxychalcone is a potent cytotoxin for MYCN-amplified IMR-32 and SK-N-BE (2) neuroblastoma cells, when compared to non-MYCN-amplified SH-SY5Y neuroblastoma cells and to the non-neuroblastoma human embryonic kidney cell line, HEK293t. Moreover, 4-hydroxychalcone treatment significantly decreased cellular levels of the antioxidant glutathione and increased cellular reactive oxygen species. In addition, 4-hydroxychalcone treatment led to impairments in mitochondrial respiratory function, compared to controls. In support of this, the cytotoxic effect of 4-hydroxychalcone was prevented by co-treatment with either the antioxidant N-acetyl-L-cysteine, a pharmacological inhibitor of oxidative stress-induced cell death (IM-54) or the mitochondrial reactive oxygen species scavenger, Mito-TEMPO. When combined with the anticancer drugs cisplatin or doxorubicin, 4-hydroxychalcone led to greater reductions in cell viability than was induced by either anti-cancer agent alone. In summary, this study identifies a cytotoxic effect of 4-hydroxychalcone in MYCN-amplified human neuroblastoma cells, which rationalizes its further study in the development of new therapies for pediatric neuroblastoma.

scholarly journals Antioxidants of Natural Products

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 612
Author(s):  
Mee Ree Kim
Keyword(s):  
Oxidative Stress ◽  
Health Promotion ◽  
Natural Products ◽  
Disease Prevention ◽  
Biological Systems ◽  
Reactive Oxygen ◽  
Nitrogen Species ◽  
Beneficial Effects

Antioxidant ingredients are known to contribute to the beneficial effects of natural products in health promotion as well as disease prevention by reducing oxidative stress, caused by reactive oxygen or nitrogen species, in biological systems [...]

scholarly journals Overexpression of Transcripts Coding for Renin-b but Not for Renin-a Reduce Oxidative Stress and Increase Cardiomyoblast Survival under Starvation Conditions

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1204
Author(s):  
Heike Wanka ◽  
Philipp Lutze ◽  
Alexander Albers ◽  
Janine Golchert ◽  
Doreen Staar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
B Cells ◽  
Apoptotic Cell ◽  
Renin Angiotensin System ◽  
Glucose Deprivation ◽  
Protective Effects ◽  
Glucose Depletion ◽  
A Cells ◽  
Apoptosis And Necrosis

A stimulated renin-angiotensin system is known to promote oxidative stress, apoptosis, necrosis and fibrosis. Renin transcripts (renin-b; renin-c) encoding a cytosolic renin isoform have been discovered that may in contrast to the commonly known secretory renin (renin-a) exert protective effects Here, we analyzed the effect of renin-a and renin-b overexpression in H9c2 cardiomyoblasts on apoptosis and necrosis as well as on potential mechanisms involved in cell death processes. To mimic ischemic conditions, cells were exposed to glucose starvation, anoxia or combined oxygen–glucose deprivation (OGD) for 24 h. Under OGD, control cells exhibited markedly increased necrotic and apoptotic cell death accompanied by enhanced ROS accumulation, loss of mitochondrial membrane potential and decreased ATP levels. The effects of OGD on necrosis were exaggerated in renin-a cells, but markedly diminished in renin-b cells. However, with respect to apoptosis, the effects of OGD were almost completely abolished in renin-b cells but interestingly also moderately diminished in renin-a cells. Under glucose depletion we found opposing responses between renin-a and renin-b cells; while the rate of necrosis and apoptosis was aggravated in renin-a cells, it was attenuated in renin-b cells. Based on our results, strategies targeting the regulation of cytosolic renin-b as well as the identification of pathways involved in the protective effects of renin-b may be helpful to improve the treatment of ischemia-relevant diseases.

scholarly journals Autophagy impairment as a key feature for acetaminophen-induced ototoxicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tong Zhao ◽  
Tihua Zheng ◽  
Huining Yu ◽  
Bo Hua Hu ◽  
Bing Hu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Lysosomal Enzymes ◽  
Apoptotic Cell ◽  
Cell Damage ◽  
Treatment Strategies ◽  
Explant Culture ◽  
Apoptotic Cell Death ◽  
Lysosomal Dysfunction ◽  
Autophagic Degradation

AbstractMacroautophagy/autophagy is a highly conserved self-digestion pathway that plays an important role in cytoprotection under stress conditions. Autophagy is involved in hepatotoxicity induced by acetaminophen (APAP) in experimental animals and in humans. APAP also causes ototoxicity. However, the role of autophagy in APAP-induced auditory hair cell damage is unclear. In the present study, we investigated autophagy mechanisms during APAP-induced cell death in a mouse auditory cell line (HEI-OC1) and mouse cochlear explant culture. We found that the expression of LC3-II protein and autophagic structures was increased in APAP-treated HEI-OC1 cells; however, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence, and the activity of lysosomal enzymes decreased in APAP-treated HEI-OC1 cells. The degradation of p62 protein and the expression of lysosomal enzymes also decreased in APAP-treated mouse cochlear explants. These data indicate that APAP treatment compromises autophagic degradation and causes lysosomal dysfunction. We suggest that lysosomal dysfunction may be directly responsible for APAP-induced autophagy impairment. Treatment with antioxidant N-acetylcysteine (NAC) partially alleviated APAP-induced autophagy impairment and apoptotic cell death, suggesting the involvement of oxidative stress in APAP-induced autophagy impairment. Inhibition of autophagy by knocking down of Atg5 and Atg7 aggravated APAP-induced ER and oxidative stress and increased apoptotic cell death. This study provides a better understanding of the mechanism responsible for APAP ototoxicity, which is important for future exploration of treatment strategies for the prevention of hearing loss caused by ototoxic medications.

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