Induction of Oxidative Stress and Glutathione Depletion by ABT-737, a Novel Small Molecule Inhibitor of Bcl-2, Contributes to Cytotoxicity in Leukemia Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4336-4336
Author(s):  
Joya Chandra ◽  
Adrienne Howard ◽  
Kathleen Jensen ◽  
Ray Meyn
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Small Molecule ◽  
Buthionine Sulfoximine ◽  
Redox Status ◽  
Lymphocytic Leukemia ◽  
Glutathione Depletion ◽  
Dose Dependent Increase ◽  
Dose Dependent

Abstract The Bcl-2 family of proteins regulate the process of cell death. Bcl-2 and Bcl-xL are potent anti-apoptotic members that are overexpressed in a number of malignancies, providing a means to evade cell death, which has been described as a characteristic hallmark of cancer. Several lines of evidence suggest that Bcl-2 and Bcl-xL possess anti-oxidant properties. Overexpression of Bcl-2 is protective against menadione and hydrogen peroxide induced cell death and causes an increase in intracellular levels of glutathione (GSH), the most abundant antioxidant defense. In the present study, we utilized a novel small molecule to test effects of Bcl-2 inhibition on intracellular redox status. ABT-737 is a first generation inhibitor of Bcl-2, Bcl-xL and Bcl-w and and acts as a mimic of the BH3-only antagonists of these family members. Exposure of acute lymphocytic leukemia (ALL) cells to ABT-737 caused a dose dependent increase in intracellular levels reactive oxygen species (ROS), namely superoxide and hydrogen peroxide. This dose dependent increase in intracellular oxidants was significantly less pronounced in cells treated with the less active enantiomer of ABT-737. A greater than 50% decrease in intracellular GSH levels was seen with similar doses of ABT-737 and the combination of buthionine sulfoximine, an agent that depletes GSH levels further, with ABT-737, caused synergistic cell death. These data were verified using cells transfected with a tetracycline repressable Bcl-2 expression plasmid. Taken together, our data identifies a novel sequelae for Bcl-2 inhibition: the induction of oxidative stress. Combination therapies utilizing ABT-737 or its analogs may be devised based on the observed effects on the redox environment.

Dietary Taurine Attenuates Hydrogen Peroxide-Impaired Growth Performance and Meat Quality of Broilers via Modulating Redox Status and Cell Death Signaling

2021 ◽  
Author(s):  
Tong Xing ◽  
Xiangxing Chen ◽  
Jiaolong Li ◽  
Lin Zhang ◽  
Feng Gao
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Growth Performance ◽  
Meat Quality ◽  
Redox Status ◽  
Breast Muscle ◽  
Breast Meat ◽  
Cell Death Signaling

Abstract Oxidative stress seriously affects poultry production. Nutritional manipulations have been effectively used to alleviate the negative effects caused by oxidative stress. This study investigated the attenuating effects and potential mechanisms of dietary taurine on growth performance and meat quality of broiler chickens challenged with hydrogen peroxide (H2O2). Briefly, a total of 192 male Arbor Acres broilers (28-day-old) were randomly categorized into 3 groups: non-injection of birds on basal diets (control), 10.0% H2O2-injection of birds on basal diets (H2O2), and 10.0% H2O2-injection of birds on basal diets supplemented with 5 g/kg taurine (H2O2+taurine). Each group consisted of 8 cages of 8 birds each. Results indicated that H2O2 administration significantly reduced growth performance and impaired breast meat quality by decreasing ultimate pH and increasing shear force value (P < 0.05). Dietary taurine improved the body weight gain and feed intake, and decreased feed/gain ratio of H2O2-challenged broilers. Meanwhile, oxidative stress induced by intraperitoneal injection of H2O2 suppressed the nuclear factor-κB (NF-κB) signaling and initiated autophagy and apoptosis. Compared with the H2O2 group, taurine supplementation restored the redox status in breast muscle by decreasing levels of reactive oxygen species and contents of oxidative products and increasing antioxidant capacity (P < 0.05). Moreover, upregulated mRNA expression of NF-κB signaling-related genes including p50 and Bcl-2, as well as enhanced protein expression of NF-κB were observed in the H2O2+taurine group (P < 0.05). Additionally, dietary taurine decreased expression of caspase family, beclin-1 and LC3-II (P < 0.05), thereby rescuing autophagy and apoptosis in breast muscle induced by H2O2. Collectively, dietary supplementation with taurine effectively improves growth performance and breast meat quality of broilers challenged with H2O2, possibly by protecting against oxidative injury and modulating cell death signaling.

scholarly journals The Antioxidant Enzymes Activity From the Poly-extromophilic Yarrowia lipolytica Yeast Under Oxidative Stress During Long-lasting Cultivation

2020 ◽  
Vol 6 (12) ◽  
pp. 23-35
Author(s):  
V. Sekova ◽  
E. Bobrova ◽  
E. Isakova ◽  
Yu. Deryabina
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Yarrowia Lipolytica ◽  
Growth Stage ◽  
Redox Status ◽  
Stationary Growth ◽  
Signaling Mechanisms ◽  
The Impact ◽  
Dose Dependent ◽  
Logarithmic Growth

Hydrogen peroxide is one of the most widespread reactive oxygen species, which can diffuse through cell membranes, causing changes in the redox status of cells and the development of oxidative stress. The results show that the effects caused by hydrogen peroxide are dose-dependent and can lead to both damage to cells and an increase in their resistance to oxidative stress. In this study, we assayed the effect of various concentrations of H2O2 on the redox status of the Yarrowia lipolytica yeast during long-lasting cultivation. The oxidant application to the cells in the logarithmic growth stage was shown to delay the impact on the ROS level in the late stationary growth stage. In this case, the dependence of the injected concentration on the redox status is not linear, which suggests triggering different signaling mechanisms by various concentrations of the oxidant.

scholarly journals Redox Status in Women with Rheumathoid Arthritis

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Aleksandra Vranic ◽  
Aleksandra Antovic ◽  
Nevena Draginic ◽  
Marijana Andjic ◽  
Marko Ravic ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Lipid Peroxidation ◽  
Superoxide Dismutase ◽  
Cartilage Damage ◽  
Thiobarbituric Acid ◽  
Antioxidant Defense System ◽  
Redox Status ◽  
Female Population

Abstract The aim of this study was to assess oxidative status and to set baseline characteristics for female population with established rheumatoid arthritis. Total of 42 patients with rheumatoid arthritis and 48 age- and sex-matched controls were included in the study. Clinical examination was performed and assessed disease activity. Peripheral blood samples were used for all the assays. The markers of oxidative stress were assessed, including plasma levels of index of lipid peroxidation - thiobarbituric acid reactive substances, hydrogen peroxide, superoxide anion radical, nitrites and activity of superoxide dismutase, catalase and reduced glutathione levels as antioxidant parameters. In the patients group, levels of hydrogen peroxide and index of lipid peroxidation were higher than in controls. Patients with rheumatoid arthritis had decreased superoxide dismutase and catalase activity compared to healthy subjects. Interestingly, controls had higher levels of nitrites compared to patients. Patients showed a marked increase in reactive oxygen species formation and lipid peroxidation as well as decrease in the activity of antioxidant defense system leading to oxidative stress which may contribute to tissue and cartilage damage and hence to the chronicity of the disease.

Epicatechin and its in vivo metabolite, 3′-O-methyl epicatechin, protect human fibroblasts from oxidative-stress-induced cell death involving caspase-3 activation

2001 ◽  
Vol 354 (3) ◽  
pp. 493-500 ◽  
Author(s):  
Jeremy P. E. SPENCER ◽  
Hagen SCHROETER ◽  
Gunter KUHNLE ◽  
S. Kaila S. SRAI ◽  
Rex M. TYRRELL ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Caspase 3 ◽  
Cell Damage ◽  
Protective Action ◽  
Human Fibroblasts ◽  
Membrane Damage ◽  
Antioxidant Properties

There is considerable current interest in the cytoprotective effects of natural antioxidants against oxidative stress. In particular, epicatechin, a major member of the flavanol family of polyphenols with powerful antioxidant properties in vitro, has been investigated to determine its ability to attenuate oxidative-stress-induced cell damage and to understand the mechanism of its protective action. We have induced oxidative stress in cultured human fibroblasts using hydrogen peroxide and examined the cellular responses in the form of mitochondrial function, cell-membrane damage, annexin-V binding and caspase-3 activation. Since one of the major metabolites of epicatechin in vivo is 3′-O-methyl epicatechin, we have compared its protective effects with that of epicatechin. The results provide the first evidence that 3′-O-methyl epicatechin inhibits cell death induced by hydrogen peroxide and that the mechanism involves suppression of caspase-3 activity as a marker for apoptosis. Furthermore, the protection elicited by 3′-O-methyl epicatechin is not significantly different from that of epicatechin, suggesting that hydrogen-donating antioxidant activity is not the primary mechanism of protection.

scholarly journals Effects of Carbazole Derivatives on Neurite Outgrowth and Hydrogen Peroxide-Induced Cytotoxicity in Neuro2a Cells

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1366 ◽  
Author(s):  
Yoshiko Furukawa ◽  
Atsushi Sawamoto ◽  
Mizuki Yamaoka ◽  
Makiko Nakaya ◽  
Yuhzo Hieda ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Neurite Outgrowth ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Anti Oxidant ◽  
Neuro2a Cells ◽  
Cerebral Ischemic

Many studies have demonstrated that oxidative stress plays an important role in several ailments including neurodegenerative diseases and cerebral ischemic injury. Previously we synthesized some carbazole compounds that have anti-oxidant ability in vitro. In this present study, we found that one of these 22 carbazole compounds, compound 13 (3-ethoxy-1-hydroxy-8- methoxy-2-methylcarbazole-5-carbaldehyde), had the ability to protect neuro2a cells from hydrogen peroxide-induced cell death. It is well known that neurite loss is one of the cardinal features of neuronal injury. Our present study revealed that compound 13 had the ability to induce neurite outgrowth through the PI3K/Akt signaling pathway in neuro2a cells. These findings suggest that compound 13 might exert a neurotrophic effect and thus be a useful therapy for the treatment of brain injury.

Quercetin protects rat hepatocytes from oxidative damage induced by ethanol and iron by maintaining intercellular liable iron pool

2013 ◽  
Vol 33 (5) ◽  
pp. 534-541 ◽  
Author(s):  
Y Li ◽  
Y Deng ◽  
Y Tang ◽  
H Yu ◽  
C Gao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Iron Overload ◽  
Combined Treatment ◽  
Rat Hepatocytes ◽  
Redox Status ◽  
Glutathione Depletion ◽  
Labile Iron Pool ◽  
Iron Pool ◽  
And Oxidative Stress

Accumulating evidence has shown that ethanol-induced iron overload plays a crucial role in the development and progression of alcoholic liver disease. We designed the present study to investigate the potential protective effect of quercetin, a naturally occurring iron-chelating antioxidant on alcoholic iron overload and oxidative stress. Ethanol-incubated (100 mmol/L) rat primary hepatocytes were co-treated by quercetin (100 µmol/L) and different dose of ferric nitrilotriacetate (Fe-NTA) for 24 h. When the hepatic enzyme releases in the culture medium, redox status of hepatocytes and the intercellular labile iron pool (LIP) level were assayed. Our data showed that Fe-NTA dose dependently induced cellular leakage of aspartate transaminase and lactate dehydrogenase, glutathione depletion, superoxide dismutase inactivation, and overproduction of malondialdehyde) and reactive oxygen species (ROS) of intact and especially ethanol-incubated hepatocytes. The oxidative damage resulted from ethanol, Fe-NTA, and especially their combined treatment was substantially alleviated by quercetin, accompanying the corresponding normalization of intercellular LIP level. Iron in excess, thus, may aggravate ethanol hepatotoxicity through Fenton-active LIP, and quercetin attenuated ethanol-induced iron and oxidative stress. To maintain intercellular LIP contributes to the hepatoprotective effect of quercetin besides its direct ROS-quenching activity.

scholarly journals Oxidative stress stimulates skeletal muscle glucose uptake through a phosphatidylinositol 3-kinase-dependent pathway

2008 ◽  
Vol 294 (5) ◽  
pp. E889-E897 ◽  
Author(s):  
Yasuki Higaki ◽  
Toshio Mikami ◽  
Nobuharu Fujii ◽  
Michael F. Hirshman ◽  
Katsuhiro Koyama ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Intracellular Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Maximal Increase ◽  
Skeletal Muscle Glucose Uptake ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Phosphatidylinositol 3

We determined the acute effects of oxidative stress on glucose uptake and intracellular signaling in skeletal muscle by incubating muscles with reactive oxygen species (ROS). Xanthine oxidase (XO) is a superoxide-generating enzyme that increases ROS. Exposure of isolated rat extensor digitorum longus (EDL) muscles to Hx/XO (Hx/XO) for 20 min resulted in a dose-dependent increase in glucose uptake. To determine whether the mechanism leading to Hx/XO-stimulated glucose uptake is associated with the production of H2O2, EDL muscles from rats were preincubated with the H2O2 scavenger catalase or the superoxide scavenger superoxide dismutase (SOD) prior to incubation with Hx/XO. Catalase treatment, but not SOD, completely inhibited the increase in Hx/XO-stimulated 2-deoxyglucose (2-DG) uptake, suggesting that H2O2 is an intermediary leading to Hx/XO-stimulated glucose uptake with incubation. Direct H2O2 also resulted in a dose-dependent increase in 2-DG uptake in isolated EDL muscles, and the maximal increase was threefold over basal levels at a concentration of 600 μmol/l H2O2. H2O2-stimulated 2-DG uptake was completely inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, but not the nitric oxide inhibitor N G-monomethyl-l-arginine. H2O2 stimulated the phosphorylation of Akt Ser473 (7-fold) and Thr308 (2-fold) in isolated EDL muscles. H2O2 at 600 μmol/l had no effect on ATP concentrations and did not increase the activities of either the α1 or α2 catalytic isoforms of AMP-activated protein kinase. These results demonstrate that acute exposure of muscle to ROS is a potent stimulator of skeletal muscle glucose uptake and that this occurs through a PI3K-dependent mechanism.

Chemopreventive Agent Resveratrol, a Natural Product Derived From Grapes, Triggers CD95 Signaling-Dependent Apoptosis in Human Tumor Cells

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 996-1002 ◽  
Author(s):  
Marie-Véronique Clément ◽  
Jayshreekumari L. Hirpara ◽  
Sanaul-Haq Chawdhury ◽  
Shazib Pervaiz
Keyword(s):  
Cell Death ◽  
Natural Product ◽  
Tumor Cells ◽  
Leukemia Cell ◽  
Human Tumor ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
Resveratrol Treatment ◽  
Dose Dependent Increase ◽  
Dose Dependent

Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity. © 1998 by The American Society of Hematology.

Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4512-4519 ◽  
Author(s):  
Joya Chandra ◽  
Jennifer Hackbarth ◽  
Son Le ◽  
David Loegering ◽  
Nancy Bone ◽  
...  
Keyword(s):  
Cell Lines ◽  
Buthionine Sulfoximine ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Glutathione Depletion ◽  
Leukemia Cells ◽  
Clinical Samples ◽  
Human Leukemia ◽  
Lymphoid Leukemia

Abstract Adaphostin (NSC 680410), an analog of the tyrphostin AG957, was previously shown to induce Bcr/abl down-regulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/abl- cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wild-type p53, a typical DNA damage response consisting of p53 phosphorylation and up-regulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned. (Blood. 2003;102:4512-4519)

scholarly journals Song Bu Li Decoction, a Traditional Uyghur Medicine, Protects Cell Death by Regulation of Oxidative Stress and Differentiation in Cultured PC12 Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Maitinuer Maiwulanjiang ◽  
Kevin Y. Zhu ◽  
Jianping Chen ◽  
Abudureyimu Miernisha ◽  
Sherry L. Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Pc12 Cells ◽  
Stress Proteins ◽  
Antioxidant Response ◽  
Scientific Basis ◽  
Herbal Extract ◽  
Dependent Manner ◽  
Protein Marker ◽  
Dose Dependent

Song Bu Li decoction (SBL) is a traditional Uyghur medicinal herbal preparation, containing Nardostachyos Radix et Rhizoma. Recently, SBL is being used to treat neurological disorders (insomnia and neurasthenia) and heart disorders (arrhythmia and palpitation). Although this herbal extract has been used for many years, there is no scientific basis about its effectiveness. Here, we aimed to evaluate the protective and differentiating activities of SBL in cultured PC12 cells. The pretreatment of SBL protected the cell against tBHP-induced cell death in a dose-dependent manner. In parallel, SBL suppressed intracellular reactive oxygen species (ROS) formation. The transcriptional activity of antioxidant response element (ARE), as well as the key antioxidative stress proteins, was induced in dose-dependent manner by SBL in the cultures. In cultured PC12 cells, the expression of neurofilament, a protein marker for neuronal differentiation, was markedly induced by applied herbal extract. Moreover, the nerve growth factor- (NGF-) induced neurite outgrowth in cultured PC12 cells was significantly potentiated by the cotreatment of SBL. In accord, the expression of neurofilament was increased in the treatment of SBL. These results therefore suggested a possible role of SBL by its effect on neuron differentiation and protection against oxidative stress.

Sign in / Sign up

Export Citation Format

Share Document