<i>In Vivo</i>Effect of Arsenic Trioxide on Keap1-p62-Nrf2 Signaling Pathway in Mouse Liver: Expression of Antioxidant Responsive Element-Driven Genes Related to Glutathione Metabolism

Han

Environmental Toxicology

et al. 2018

Arsenic trioxide (ATO; As O ) induces cell death in various cells via oxidative stress. Expose to chronic arsenic is involved in the development of vascular diseases. However, little is known about the cytotoxic effects of ATO on human normal vascular smooth muscle cells (VSMCs). Thus, in this study, we investigated the effects of ATO on cell growth and death in human pulmonary artery smooth muscle (HPASM) cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. ATO treatment decreased the growth of HPASM cells with an IC of ∼30-50 μM at 24 h, and ATO induced HPASM cell death via apoptosis or necrosis dependent on the doses of it at this time. Treatment with 50 μM ATO did not increase ROS levels at the early time points, but it significantly increased mitochondrial O2•- levels at 24 h. ATO also induced GSH depletion in HPASM cells. N-acetyl cysteine (NAC; a well-known antioxidant) did not significantly affect apoptotic cell death, ROS levels, or GSH depletion in ATO-treated HPASM cells. However, l-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) intensified mitochondrial O2•- levels in ATO-treated HPASM cells, and significantly increased cell death and GSH depletion in these cells as well. In summary, we provided the first evidence that ATO inhibited the growth of HPASM cells, and induced apoptotic and/or necrotic cell death in these cells, accompanied by increases in mitochondrial O2•- level and GSH depletion.

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide induces growth inhibition and death in human pulmonary artery smooth muscle cells accompanied by mitochondrial increase and GSH depletion

Han

Environmental Toxicology

et al. 2018

Journal of Neurochemistry

“…), whereas decreased GSH levels in human multiple myeloma cells increase the sensitivity of tumor cells to arsenic trioxide (Srivastava et al . ). Therefore, the GSH content of glioma cells is closely related to the overall regulation of redox status and drug response of cells (Backos et al .…”

mentioning

confidence: 97%

Glutathione reductase mediates drug resistance in glioblastoma cells by regulating redox homeostasis

Zhu

et al. 2017

138

Glutathione (GSH) and GSH-related enzymes constitute the most important defense system that protects cells from free radical, radiotherapy, and chemotherapy attacks. In this study, we aim to explore the potential role and regulatory mechanism of the GSH redox cycle in drug resistance in glioblastoma multiforme (GBM) cells. We found that temozolomide (TMZ)-resistant glioma cells displayed lower levels of endogenous reactive oxygen species and higher levels of total antioxidant capacity and GSH than sensitive cells. Moreover, the expression of glutathione reductase (GSR), the key enzyme of the GSH redox cycle, was higher in TMZ-resistant cells than in sensitive cells. Furthermore, silencing GSR in drug-resistant cells improved the sensitivity of cells to TMZ or cisplatin. Conversely, the over-expression of GSR in sensitive cells resulted in resistance to chemotherapy. In addition, the GSR enzyme partially prevented the oxidative stress caused by pro-oxidant Lbuthionine -sulfoximine. The modulation of redox state by GSH or L-buthionine -sulfoximine regulated GSR-mediated drug resistance, suggesting that the action of GSR in drug resistance is associated with the modulation of redox homeostasis. Intriguingly, a trend toward shorter progress-free survival was observed among GBM patients with high GSR expression. These results indicated that GSR is involved in mediating drug resistance and is a potential target for improving GBM treatment.

J of Applied Toxicology

“…In order to cope with this stress, the activity of the CAT enzyme which is responsible for the formation of oxygen and water by breaking down hydrogen peroxide (H 2 O 2 ) was also found to et al, 2019). Pb-induced stress may disrupt cysteine residues of Keap1, which results in release of Nrf2 from Keap1 and Nrf2 translocates into nucleus subsequently for the induction of antioxidant response pathway (Srivastava et al, 2013). Reports on Nqo1 protein expression in fish after Pb exposure is scarce.…”

Section: Discussionmentioning

confidence: 99%

Environmentally relevant lead alters nuclear integrity in erythrocytes and generates oxidative stress in liver of Anabas testudineus: Involvement of Nrf2‐Keap1 regulation and expression of biomarker genes

Dey,

Mondal,

Chattopadhyay

2023

Self Cite

Genotoxic and hepatotoxic effects of lead (Pb) on a freshwater fish, climbing perch (Anabas testudineus) were studied at an environmentally relevant concentration (43.3 ppm). The genotoxic potential of Pb was confirmed by micronucleus study, with increased frequencies of erythrocytic nuclear alterations like lobed, blebbed, notched, fragmented, and micronuclei were observed in erythrocytes in treated groups as compared to control. Inorganic Pb induces oxidative stress which is a consequence of elevated level of Reactive Oxygen Species. Hepatotoxicity was assessed both by the oxidative stress and cellular responses that emerged due to the toxic assault of Pb in the liver, the most important detoxifying organ. Upregulation of xenobiotic metabolizing enzyme like catalase was evident after 15, 30, and 90 days of exposure, and a profound effect was observed on 30th days. The level of lipid peroxidation and reduced glutathione was increased after Pb exposure. Histoarchitectural damages of liver were distinctly evident in treated fish. Western blot analysis confirmed the expressional alterations of stress‐responsive marker proteins like Nrf2, Keap1, Hsp70, and Nqo1. Pb exposure resulted in increased expression of Hsp70, Nrf2, and Nqo1, whereas Keap1 was downregulated, suggesting the involvement of Nrf2‐Keap1 regulation as a cytoprotective mechanism against Pb toxicity.