scholarly journals Valproic acid disables the Nrf2 anti-oxidant response in acute myeloid leukaemia cells enhancing reactive oxygen species-mediated killing

2021 ◽  
Author(s):  
Yao Jiang ◽  
Andrew D. Southam ◽  
Sandro Trova ◽  
Flavio Beke ◽  
Bader Alhazmi ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Valproic Acid ◽  
Low Dose ◽  
De Novo ◽  
Safety Data ◽  
Reactive Oxygen ◽  
Lipid Lowering ◽  
High Dose ◽  
Oxygen Species ◽  
Refractory Aml

Abstract Background We previously demonstrated the in vitro killing of AML cells by the combination of the lipid-lowering agent bezafibrate (BEZ) and the contraceptive hormone medroxyprogesterone acetate (MPA). A phase II trial demonstrated in vivo safety and efficacy of BEZ and MPA (BaP) in elderly, relapsed/refractory AML and high-risk myelodysplastic syndrome (MDS) patients. However, we observed dose-limiting toxicities in a second trial that attempted to improve outcomes via escalation of BaP doses. Thus we sought to identify a third repurposed drug that potentiates activity of low dose BaP (BaP 0.1 mM). Methods and Results We demonstrate that addition of a commonly used anti-epileptic, valproic acid (VAL) to low dose BaP (BaP 0.1 mM)(VBaP) enhanced killing of AML cell lines/primary AML cells to levels similar to high dose BaP (BaP 0.5 mM). Similarly, addition of VAL to BaP 0.1 mM enhanced reactive oxygen species (ROS), lipid peroxidation and inhibition of de novo fatty acid synthesis. Overexpression of Nrf2 in K562 and KG1a completely inhibited ROS production and rescued cells from VAL/BaP 0.1 mM/VBaP killing. Conclusions Given the good safety data of low-dose BaP in elderly/relapsed/refractory AML patients, and that VAL alone is well-tolerated, we propose VBaP as a novel therapeutic combination for AML.

scholarly journals Qizhi Jiangtang Jiaonang Improves Insulin Signaling and Reduces Inflammatory Cytokine Secretion and Reactive Oxygen Species Formation in Insulin Resistant HepG2 Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-8
Author(s):  
Xiao-Tian Zhang ◽  
Chun-Jiang Yu ◽  
Jian-Wei Liu ◽  
Yan-Ping Zhang ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Palmitic Acid ◽  
Hepg2 Cells ◽  
Reactive Oxygen ◽  
Glucose Consumption ◽  
Control Group ◽  
High Dose ◽  
Oxygen Species ◽  
Insulin Resistant

We analyzed the effects of a traditional Chinese medicine, Qizhi Jiangtang Jiaonang (QJJ), on insulin resistance (IR) in vitro. After an in vitro model of IR was established by treating human liver cancer cells (HepG2 cells) with palmitic acid, the cells were then treated with various concentrations of QJJ. Treatment with 400 µM palmitic acid for 24 h induced IR in HepG2 cells. The survival rate for HepG2 cells in the IR group was significantly lower than that of the untreated control group (P< 0.001); however, QJJ restored HepG2 cell survival (P< 0.001). As compared with HepG2 cells in the IR group, QJJ at all doses analyzed significantly increased glucose consumption (allP< 0.05). Moreover, treatment with all the QJJ doses significantly reduced the mean intracellular reactive oxygen species levels as compared with the IR group (allP< 0.05). Furthermore, high-dose QJJ reduced both TNF-αand IL-6 levels as compared to the IR group (allP< 0.05). QJJ ameliorated the altered PI3K, GLUT4, and RAGE expression observed with IR. In conclusion, QJJ can improve IR in HepG2 cells, which may be mediated through the IRS-1/PI3K/GLUT4 signaling pathway as well as regulation of NF-κB-mediated inflammation and oxidative stress.

scholarly journals Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism

2020 ◽  
Vol 117 (18) ◽  
pp. 9964-9972 ◽  
Author(s):  
Di Yu ◽  
Yang Liu ◽  
Yiqiang Zhou ◽  
Victor Ruiz-Rodado ◽  
Mioara Larion ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
De Novo ◽  
Synthetic Lethality ◽  
Reactive Oxygen ◽  
Metabolic Reprogramming ◽  
Glutathione Metabolism ◽  
Oxygen Species ◽  
Genetic Abnormality

Isocitrate dehydrogenase (IDH) mutation is a common genetic abnormality in human malignancies characterized by remarkable metabolic reprogramming. Our present study demonstrated that IDH1-mutated cells showed elevated levels of reactive oxygen species and higher demands on Nrf2-guided glutathione de novo synthesis. Our findings showed that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, served as a potent Nrf2 inhibitor, which exhibited selective cytotoxicity to patient-derived IDH1-mutated glioma cells in vitro and in vivo. Mechanistically, triptolide compromised the expression of GCLC, GCLM, and SLC7A11, which disrupted glutathione metabolism and established synthetic lethality with reactive oxygen species derived from IDH1 mutant neomorphic activity. Our findings highlight triptolide as a valuable therapeutic approach for IDH1-mutated malignancies by targeting the Nrf2-driven glutathione synthesis pathway.

scholarly journals Low-DoseAronia melanocarpaConcentrate Attenuates Paraquat-Induced Neurotoxicity

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
A. J. Case ◽  
D. Agraz ◽  
I. M. Ahmad ◽  
M. C. Zimmerman
Keyword(s):  
Reactive Oxygen Species ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Reactive Oxygen ◽  
High Dose ◽  
Low Doses ◽  
Oxygen Species ◽  
High Doses

Herbicides containing paraquat may contribute to the pathogenesis of neurodegenerative disorders such as Parkinson’s disease. Paraquat induces reactive oxygen species-mediated apoptosis in neurons, which is a primary mechanism behind its toxicity. We sought to test the effectiveness of a commercially available polyphenol-richAronia melanocarpa(aronia berry) concentrate in the amelioration of paraquat-induced neurotoxicity. Considering the abundance of antioxidants in aronia berries, we hypothesized that aronia berry concentrate attenuates the paraquat-induced increase in reactive oxygen species and protects against paraquat-mediated neuronal cell death. Using a neuronal cell culture model, we observed that low doses of aronia berry concentrate protected against paraquat-mediated neurotoxicity. Additionally, low doses of the concentrate attenuated the paraquat-induced increase in superoxide, hydrogen peroxide, and oxidized glutathione levels. Interestingly, high doses of aronia berry concentrate increased neuronal superoxide levels independent of paraquat, while at the same time decreasing hydrogen peroxide. Moreover, high-dose aronia berry concentrate potentiated paraquat-induced superoxide production and neuronal cell death. In summary, aronia berry concentrate at low doses restores the homeostatic redox environment of neurons treated with paraquat, while high doses exacerbate the imbalance leading to further cell death. Our findings support that moderate levels of aronia berry concentrate may prevent reactive oxygen species-mediated neurotoxicity.

scholarly journals Humic Substances Mitigate the Impact of Tritium on Luminous Marine Bacteria. Involvement of Reactive Oxygen Species

2020 ◽  
Vol 21 (18) ◽  
pp. 6783 ◽  
Author(s):  
Tatiana V. Rozhko ◽  
Olga V. Kolesnik ◽  
Gennadii A. Badun ◽  
Devard I. Stom ◽  
Nadezhda S. Kudryasheva
Keyword(s):  
Reactive Oxygen Species ◽  
Humic Substances ◽  
Marine Bacteria ◽  
Low Dose ◽  
Tritiated Water ◽  
Reactive Oxygen ◽  
Physiological Parameter ◽  
Oxygen Species ◽  
Luminous Bacteria ◽  
The Impact

The paper studies the combined effects of beta-emitting radionuclide tritium and Humic Substances (HS) on the marine unicellular microorganism—luminous bacteria—under conditions of low-dose radiation exposures (<0.04 Gy). Tritium was used as a component of tritiated water. Bacterial luminescence intensity was considered as a tested physiological parameter. The bioluminescence response of the marine bacteria to tritium corresponded to the “hormesis” model: it included stages of bioluminescence inhibition and activation, as well as the absence of the effect. HS were shown to decrease the inhibition and activation effects of tritium, similar to those of americium-241, alpha-emitting radionuclide, studied earlier. Correlations between the bioluminescence intensity and the content of Reactive Oxygen Species (ROS) were found in the radioactive bacterial suspensions. The results demonstrate an important role of HS in natural processes in the regions of low radioactive contamination: HS can mitigate radiotoxic effects and adaptive response of microorganisms to low-dose radioactive exposures. The involvement of ROS in these processes was demonstrated.

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