Hyperglycemia-induced activation of human T-lymphocytes with de novo emergence of insulin receptors and generation of reactive oxygen species

Doxorubicin (DOX), a widely used antitumour drug, causes dose-dependent cardiotoxicity. Cardiac mitochondria represent a critical target organelle of toxicity during DOX chemotherapy. Proposed mechanisms include generation of ROS (reactive oxygen species) and disturbances in mitochondrial calcium homoeostasis. In the present study, we probed the mechanistic link between mitochondrial ROS and calcium in the embryonic rat heart-derived H9c2 cell line and in adult rat cardiomyocytes. The results show that DOX stimulates calcium/calcineurin-dependent activation of the transcription factor NFAT (nuclear factor of activated T-lymphocytes). Pre-treatment of cells with an intracellular calcium chelator abrogated DOX-induced nuclear NFAT translocation, Fas L (Fas ligand) expression and caspase activation, as did pre-treatment of cells with a mitochondria-targeted antioxidant, Mito-Q (a mitochondria-targeted antioxidant consisting of a mixture of mitoquinol and mitoquinone), or with adenoviral-over-expressed antioxidant enzymes. Treatment with GPx-1 (glutathione peroxidase 1), MnSOD (manganese superoxide dismutase) or a peptide inhibitor of NFAT also inhibited DOX-induced nuclear NFAT translocation. Pre-treatment of cells with a Fas L neutralizing antibody abrogated DOX-induced caspase-8- and -3-like activities during the initial stages of apoptosis. We conclude that mitochondria-derived ROS and calcium play a key role in stimulating DOX-induced ‘intrinsic and extrinsic forms’ of apoptosis in cardiac cells with Fas L expression via the NFAT signalling mechanism. Implications of ROS- and calcium-dependent NFAT signalling in DOX-induced apoptosis are discussed.

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Decrease in generation of reactive oxygen species by neutrophils from patients with infectious mononucleosis: role of suppressor T lymphocytes

Blood ◽

10.1182/blood.v64.5.994.bloodjournal645994 ◽

1984 ◽

Vol 64 (5) ◽

pp. 994-999

Author(s):

Y Niwa ◽

T Sakane ◽

Y Miyachi ◽

T Kanoh ◽

K Somiya

Keyword(s):

Reactive Oxygen Species ◽

T Lymphocytes ◽

Infectious Mononucleosis ◽

Disease Onset ◽

Reactive Oxygen ◽

Control Group ◽

Ros Generation ◽

Oxygen Species ◽

Suppressor T Lymphocytes ◽

Subsets Of T Lymphocytes

We assessed the generation of reactive oxygen species (ROS: O2-, H2O2, OH . , chemiluminescence) by neutrophils and monocytes from six patients with infectious mononucleosis, ten patients with other viral diseases, and ten normal controls. Neutrophils from infectious mononucleosis patients showed markedly decreased generation of all reactive oxygen species, compared with the two control groups; this abnormality persisted for four to eight weeks after disease onset. Monocytes from these patients generated normal levels of ROS. Normal neutrophils incubated with T lymphocytes from infectious mononucleosis patients generated significantly less of each ROS than did those incubated with T cells from either control group. T cell-mediated suppression of ROS generation required both OKT4+ cells from infectious mononucleosis patients and OKT8+ cells from either patients or normals. We conclude that the generation of reaction oxygen species in neutrophils is suppressed in patients with infectious mononucleosis, at least in part, by interacting subsets of T lymphocytes.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1913633117 ◽

2020 ◽

Vol 117 (18) ◽

pp. 9964-9972 ◽

Cited By ~ 12

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.

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Rap1 Signaling Is Required for Suppression of Ras-Generated Reactive Oxygen Species and Protection Against Oxidative Stress in T Lymphocytes

The Journal of Immunology ◽

10.4049/jimmunol.173.2.920 ◽

2004 ◽

Vol 173 (2) ◽

pp. 920-931 ◽

Cited By ~ 44

Author(s):

Philip H. J. Remans ◽

Sonja I. Gringhuis ◽

Jacob M. van Laar ◽

Marjolein E. Sanders ◽

Ellen A. M. Papendrecht-van der Voort ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

T Lymphocytes ◽

Reactive Oxygen ◽

Oxygen Species

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Reactive Oxygen Species Selectively Deplete Normal T Lymphocytes Via a Hydroxyl Radical Dependent Mechanism

Scandinavian Journal of Immunology ◽

10.1111/j.1365-3083.1987.tb02233.x ◽

1987 ◽

Vol 26 (1) ◽

pp. 47-53 ◽

Cited By ~ 21

Author(s):

I. M. ALLAN ◽

J. LUNEC ◽

M. SALMON ◽

P. A. BACON

Keyword(s):

Reactive Oxygen Species ◽

T Lymphocytes ◽

Hydroxyl Radical ◽

Reactive Oxygen ◽

Oxygen Species ◽

Dependent Mechanism

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Reactive Oxygen Species Target the Degradation of the EVI1 Oncoprotein.

Blood ◽

10.1182/blood.v110.11.651.651 ◽

2007 ◽

Vol 110 (11) ◽

pp. 651-651

Author(s):

David Shackelford ◽

You Wang ◽

Samuel Waxman ◽

Ruibao Ren

Keyword(s):

Reactive Oxygen Species ◽

De Novo ◽

Bone Marrow Cells ◽

Reactive Oxygen ◽

Myelogenous Leukemia ◽

Leukemic Cells ◽

Mouse Bone Marrow ◽

Oxygen Species ◽

Aberrant Expression

Abstract Aberrant expression of EVI1 has been frequently found in myeloid malignancies as well as in cancers of the ovary, lung, head and neck, cervix, and breast, and is associated with a poor patient survival. Targeted degradation of oncoproteins is an effective strategy for cancer therapy. The AML1/MDS1/EVI1 (AME) transcription factor fusion protein is a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of CML during the blast phase (CML-BP) and in patients with de novo and therapy-related myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Expression of AME in mouse bone marrow cells by retroviral transduction impairs hematopoiesis and eventually induces an acute myeloid leukemia (AML)-like disease in mice. Arsenic Trioxide (ATO) has been found to be an effective treatment for patients suffering from acute promyelocytic leukemia (APL). This is, at least in part, mediated by degradation of the PML/RARα oncoprotein that is associated with over 90% of APL. We have recently shown that ATO used at therapeutic levels also degrades AME. The ATO treatment induces differentiation and apoptosis in AME leukemic cells in vitro and causes decrease in peripheral leukemic cells and splenomegaly in vivo. ATO appears to target AME at both the EVI1 and MDS moieties of the protein for degradation via the ubiquitin-proteasome pathway and proteasome-independent mechanism, respectively. To investigate the mechanism of ATO induced degradation of EVI1 oncoproteins, we examined the effect of reactive oxygen species (ROS), on EVII expression, one of the downstream effectors of ATO-induced apoptosis. We found that EVI1 degradation correlates with the amount of ROS generated in cells. EVI1 can also be targeted for degradation by doxorubicin, a chemotherapeutic agent that is effective in treating AML and ovarian cancer and a strong ROS inducer. Interestingly, the antioxidant N-acetyl cysteine (NAC) abrogates the degradation of the EVI1 protein in the presence of doxorubicin. These results demonstrate that EVI1 can be targeted for degradation by ROS. ROS inducing agents could be used as a part of targeted therapy for EVI1-positive malignancies.

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Increased Reactive Oxygen Species Induced by NUP98-HOXD13 Fusion Gene in MDS Mouse Model

Blood ◽

10.1182/blood.v112.11.3631.3631 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3631-3631

Author(s):

Yang Jo Chung ◽

Peter D. Aplan

Keyword(s):

Reactive Oxygen Species ◽

Mouse Model ◽

Disease Progression ◽

Cell Lines ◽

Oxidative Dna Damage ◽

De Novo ◽

Fusion Gene ◽

Reactive Oxygen ◽

Bone Marrow Mononuclear Cell ◽

Oxygen Species

Abstract The myelodysplastic syndromes (MDSs) comprise a group of pre-malignant hematologic disorders characterized by ineffective hematopoiesis, dysplasia, and transformation to acute myeloid leukemia (AML). The causative agents for de novo or therapy-related MDS (t-MDS) include exposure to known genotoxins, such as benzene and other solvents, anti-cancer chemotherapy, and ionizing radiation. It is known that MDS is closely related to chromosomal aberrations including deletions, amplifications, inversions, and translocations, however, the molecular mechanism of disease progression from MDS to AML not been completely elucidated. Recently, several studies have reported that oxidative stress contributes to the disease progression mechanism in MDS. Reactive oxygen species (ROS) play a role in regulating several biologic phenomena involving activation of signaling pathways in response to cytokines, and the gene expression induced by this signaling. ROS is also known to induce oxidative DNA damage which generates DNA base modifications and DNA helix alterations. Therefore, increased intracellular levels of ROS can induce mutations which lead to transformation of MDS to AML. A mouse model for MDS, generated by expressing a NUP98-HOXD13 (NHD13) fusion gene was exploited to investigate ROS levels in this study. Lineage negative (Linneg) bone marrow mononuclear cell (BMNC) from NHD13 mice with MDS had a 7.8±5.6 fold increased level of ROS compared with wild-type (WT) Linneg BMNC, while ROS levels of unfractionated BMNC were similar in NHD13 and WT mice. The increase ROS level in NHD13 Linneg BMNC was associated with an increase in G2/M phase (2 fold). Interleukin 3 (IL-3) dependent NHD13 ‘knock-in’ cell lines also showed an increased level of ROS (3 to 5 fold), in comparison with other IL-3 dependent cell lines, BaF3 and 32D. To determine if the increase in ROS could be generated by an NHD13 fusion, BaF3 and 32D cell were transfected with an NHD13 expression vector. The BaF3 and 32D transfectant showed 2 fold (2.1±0.3 and 1.9±0.6 fold) increase ROS level compared to controls transfected with an empty vector. These findings suggest that expression of an NHD13 fusion gene can induce ROS in hematopoietic progenitor cells, which may contribute to the development of MDS and subsequent disease progression to AML through DNA damages.

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