scholarly journals Antcin C fromAntrodia cinnamomeaProtects Liver Cells Against Free Radical-Induced Oxidative Stress and ApoptosisIn VitroandIn Vivothrough Nrf2-Dependent Mechanism

2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
M. Gokila Vani ◽  
K. J. Senthil Kumar ◽  
Jiunn-Wang Liao ◽  
Shih-Chang Chien ◽  
Jeng-Leun Mau ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Transcriptional Activation ◽  
Liver Cells ◽  
Ros Generation ◽  
Antioxidant Genes ◽  
Pi3k Activation ◽  
Mice Liver ◽  
Induced Apoptosis

In this study, we investigated the cytoprotective effects of antcin C, a steroid-like compound isolated from Antrodia cinnamaomea against AAPH-induced oxidative stress and apoptosis in human hepatic HepG2 cells. Pretreatment with antcin C significantly protects hepatic cells from AAPH-induced cell death through the inhibition of ROS generation. Furthermore, AAPH-induced lipid peroxidation, ALT/AST secretion and GSH depletion was significantly inhibited by antcin C. The antioxidant potential of antcin C was correlated with induction of antioxidant genes including, HO-1, NQO-1,γ-GCLC, and SODviatranscriptional activation of Nrf2. The Nrf2 activation by antcin C is mediated by JNK1/2 and PI3K activation, whereas pharmacologic inhibition of JNK1/2 and PI3K abolished antcin C-induced Nrf2 activity. In addition, AAPH-induced apoptosis was significantly inhibited by antcin C through the down-regulation of pro-apoptotic factors including, Bax, cytochrome c, capase 9, -4, -12, -3, and PARP.In vivostudies also show that antcin C significantly protected mice liver from AAPH-induced hepatic injury as evidenced by reduction in hepatic enzymes in circulation. Further, immunocytochemistry analyses showed that antcin C significantly increased HO-1 and Nrf2 expression in mice liver tissues. These results strongly suggest that antcin C could protect liver cells from oxidative stress and cell deathviaNrf2/ARE activation.

scholarly journals In Vitro and In Vivo Protective Effects of Lentil (Lens culinaris) Extract against Oxidative Stress-Induced Hepatotoxicity

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 59
Author(s):  
Yeon-Seop Jung ◽  
So-Hee Lee ◽  
So Young Chun ◽  
Dae Hwan Kim ◽  
Byung Ik Jang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Serum Levels ◽  
Liver Cells ◽  
Dependent Manner ◽  
Protective Effects ◽  
H2o2 Treatment ◽  
Antioxidant Genes ◽  
Hepatic Diseases

Excessive oxidative stress plays a role in hepatotoxicity and the pathogenesis of hepatic diseases. In our previous study, the phenolic extract of beluga lentil (BLE) showed the most potent in vitro antioxidant activity among extracts of four common varieties of lentils; thus, we hypothesized that BLE might protect liver cells against oxidative stress-induced cytotoxicity. BLE was evaluated for its protective effects against oxidative stress-induced hepatotoxicity in AML12 mouse hepatocytes and BALB/c mice. H2O2 treatment caused a marked decrease in cell viability; however, pretreatment with BLE (25–100 μg/mL) for 24 h significantly preserved the viability of H2O2-treated cells up to about 50% at 100 μg/mL. As expected, BLE dramatically reduced intracellular reactive oxygen species (ROS) levels in a dose-dependent manner in H2O2-treated cells. Further mechanistic studies demonstrated that BLE reduced cellular ROS levels, partly by increasing expression of antioxidant genes. Furthermore, pretreatment with BLE (400 mg/kg) for 2 weeks significantly reduced serum levels of alanine transaminase and triglyceride by about 49% and 40%, respectively, and increased the expression and activity of glutathione peroxidase in CCl4-treated BALB/c mice. These results suggest that BLE protects liver cells against oxidative stress, partly by inducing cellular antioxidant system; thus, it represents a potential source of nutraceuticals with hepatoprotective effects.

scholarly journals Old Yellow Enzymes, Highly Homologous FMN Oxidoreductases with Modulating Roles in Oxidative Stress and Programmed Cell Death in Yeast

2007 ◽  
Vol 282 (49) ◽  
pp. 36010-36023 ◽  
Author(s):  
Osama Odat ◽  
Samer Matta ◽  
Hadi Khalil ◽  
Sotirios C. Kampranis ◽  
Raymond Pfau ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Antioxidant Activities ◽  
Ros Generation ◽  
Oxidized Glutathione ◽  
Wild Type ◽  
Antioxidant Genes ◽  
Knock Out ◽  
Chronological Aging

In a genetic screen to identify modifiers of Bax-dependent lethality in yeast, the C terminus of OYE2 was isolated based on its capacity to restore sensitivity to a Bax-resistant yeast mutant strain. Overexpression of full-length OYE2 suppresses Bax lethality in yeast, lowers endogenous reactive oxygen species (ROS), increases resistance to H2O2-induced programmed cell death (PCD), and significantly lowers ROS levels generated by organic prooxidants. Reciprocally, Δoye2 yeast strains are sensitive to prooxidant-induced PCD. Overexpression and knock-out analysis indicate these OYE2 antioxidant activities are opposed by OYE3, a highly homologous heterodimerizing protein, which functions as a prooxidant promoting H2O2-induced PCD in wild type yeast. To exert its effect OYE3 requires the presence of OYE2. Deletion of the 12 C-terminal amino acids and catalytic inactivation of OYE2 by a Y197F mutation enhance significantly survival upon H2O2-induced PCD in wild type cells, but accelerate PCD in Δoye3 cells, implicating the oye2p-oye3p heterodimer for promoting cell death upon oxidative stress. Unexpectedly, a strain with a double knock-out of these genes (Δoye2 oye3) is highly resistant to H2O2-induced PCD, exhibits increased respiratory capacity, and undergoes less cell death during the adaptive response in chronological aging. Simultaneous deletion of OYE2 and other antioxidant genes hyperinduces endogenous levels of ROS, promoting H2O2-induced cell death: in Δoye2 glr1 yeast high levels of oxidized glutathione elicited gross morphological aberrations involving the actin cytoskeleton and defects in organelle partitioning. Altering the ratio of reduced to oxidized glutathione by exogenous addition of GSH fully reversed these alterations. Based on this work, OYE proteins are firmly placed in the signaling network connecting ROS generation, PCD modulation, and cytoskeletal dynamics in yeast.

scholarly journals Pomegranate juice and punicalagin attenuate oxidative stress and apoptosis in human placenta and in human placental trophoblasts

2012 ◽  
Vol 302 (9) ◽  
pp. E1142-E1152 ◽  
Author(s):  
Baosheng Chen ◽  
Methodius G. Tuuli ◽  
Mark S. Longtine ◽  
Joong Sik Shin ◽  
Russell Lawrence ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Human Placenta ◽  
Apple Juice ◽  
Kinase Inhibitor ◽  
Pomegranate Juice ◽  
Control Group ◽  
Induced Apoptosis

The human placenta is key to pregnancy outcome, and the elevated oxidative stress present in many complicated pregnancies contributes to placental dysfunction and suboptimal pregnancy outcomes. We tested the hypothesis that pomegranate juice, which is rich in polyphenolic antioxidants, limits placental trophoblast injury in vivo and in vitro. Pregnant women with singleton pregnancies were randomized at 35∼38 wk gestation to 8 oz/day of pomegranate juice or apple juice (placebo) until the time of delivery. Placental tissues from 12 patients (4 in the pomegranate group and 8 in the control group) were collected for analysis of oxidative stress. The preliminary in vivo results were extended to oxidative stress and cell death assays in vitro. Placental explants and cultured primary human trophoblasts were exposed to pomegranate juice or glucose (control) under defined oxygen tensions and chemical stimuli. We found decreased oxidative stress in term human placentas from women who labored after prenatal ingestion of pomegranate juice compared with apple juice as control. Moreover, pomegranate juice reduced in vitro oxidative stress, apoptosis, and global cell death in term villous explants and primary trophoblast cultures exposed to hypoxia, the hypoxia mimetic cobalt chloride, and the kinase inhibitor staurosporine. Punicalagin, but not ellagic acid, both prominent polyphenols in pomegranate juice, reduced oxidative stress and stimulus-induced apoptosis in cultured syncytiotrophoblasts. We conclude that pomegranate juice reduces placental oxidative stress in vivo and in vitro while limiting stimulus-induced death of human trophoblasts in culture. The polyphenol punicalagin mimics this protective effect. We speculate that antenatal intake of pomegranate may limit placental injury and thereby may confer protection to the exposed fetus.

scholarly journals EF24 Suppresses Cholangiocellular Carcinoma Progression, Inhibits STAT3 Phosphorylation, and Induces Apoptosis via ROS-Mediated Oxidative Stress

2019 ◽  
Vol 2019 ◽  
pp. 1-13
Author(s):  
Savita Bisht ◽  
Jens Nolting ◽  
Jörg Wenzel ◽  
Peter Brossart ◽  
Georg Feldmann
Keyword(s):  
Oxidative Stress ◽  
Immunohistochemical Analysis ◽  
Cholangiocellular Carcinoma ◽  
Ros Generation ◽  
Nuclear Staining ◽  
Curcumin Analog ◽  
Ki 67 ◽  
Stat3 Phosphorylation ◽  
Induced Apoptosis

Therapeutic options for advanced stage cholangiocellular carcinoma (CCC) are very limited as of today and patients carry an exceptionally poor overall prognosis. In recent years, increasing evidence has been accumulated to suggest that malignant cells widely show increased intrinsic ROS levels and exhibit altered redox profiles as compared to normal counterparts, opening up potential avenues for therapeutic intervention. This study provides preclinical experimental evidence of therapeutic activity of the curcumin analog EF24 in cholangiocarcinoma models. In CCC cell lines, EF24 inhibited cell viability and induced apoptosis through excessive ROS generation. Moreover, administration of EF24 led to depletion of total intracellular GSH levels, induced mitochondrial depolarization, and abrogated STAT3 phosphorylation. Of interest, these effects were readily averted by treating the cells with exogenous antioxidants such as N-acetyl cysteine (NAC) or glutathione monoethyl ester (GEE). In vivo, EF24, solubilized using a cyclodextrin formulation, significantly suppressed the growth of tumor xenografts without exhibiting any toxic adverse effects. Immunohistochemical analysis of extracted tumor tissues demonstrated reduced nuclear staining for Ki-67 and downregulation of phospho-STAT3 as well as strong staining for oxidative stress biomarker 8-OHdG. Therefore, the data presented here suggest EF24 as potential therapeutic compound against CCC which might act at least to some extent through ROS-induced oxidative damage, subsequently inducing apoptosis. Further evaluation of this approach should be carried out in future follow-up studies.

scholarly journals Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Gang Wang ◽  
Yanan Wang ◽  
Qinzhi Yang ◽  
Chunrong Xu ◽  
Youkun Zheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Apoptosis ◽  
Vascular Complications ◽  
Tunel Staining ◽  
Ros Generation ◽  
Dependent Manner ◽  
Diabetic Vascular Complications ◽  
Induced Apoptosis

AbstractMethylglyoxal (MGO) is an active metabolite of glucose and plays a prominent role in the pathogenesis of diabetic vascular complications, including endothelial cell apoptosis induced by oxidative stress. Metformin (MET), a widely prescribed antidiabetic agent, appears to reduce excessive reactive oxygen species (ROS) generation and limit cell apoptosis. However, the molecular mechanisms underlying this process are still not fully elucidated. We reported here that MET prevents MGO-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Protein expression and protein phosphorylation were investigated using western blotting, ELISA, and immunohistochemical staining, respectively. Cell viability and apoptosis were assessed by the MTT assay, TUNEL staining, and Annexin V-FITC and propidium iodide double staining. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results revealed that MET prevented MGO-induced HUVEC apoptosis, inhibited apoptosis-associated biochemical changes such as loss of MMP, the elevation of the Bax/Bcl-2 ratio, and activation of cleaved caspase-3, and attenuated MGO-induced mitochondrial morphological alterations in a dose-dependent manner. MET pretreatment also significantly suppressed MGO-stimulated ROS production, increased signaling through the ROS-mediated PI3K/Akt and Nrf2/HO-1 pathways, and markedly elevated the levels of its downstream antioxidants. Finally, similar results were obtained in vivo, and we demonstrated that MET prevented MGO-induced oxidative damage, apoptosis, and inflammation. As expected, MET reversed MGO-induced downregulation of Nrf2 and p-Akt. In addition, a PI3K inhibitor (LY-294002) and a Nrf2 inhibitor (ML385) observably attenuated the protective effects of MET on MGO-induced apoptosis and ROS generation by inhibiting the Nrf2/HO-1 pathways, while a ROS scavenger (NAC) and a permeability transition pores inhibitor (CsA) completely reversed these effects. Collectively, these findings broaden our understanding of the mechanism by which MET regulates apoptosis induced by MGO under oxidative stress conditions, with important implications regarding the potential application of MET for the treatment of diabetic vascular complications.

Glial cytotoxicity of low doses of cadmium as a model of heavy metal pollution influence on vertebrates

2020 ◽  
Vol 31 (1) ◽  
pp. 3-10
Author(s):  
V. S. Nedzvetsky ◽  
V. Ya. Gasso ◽  
A. M. Hahut ◽  
I. A. Hasso
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Oxidative Damage ◽  
Cadmium Chloride ◽  
Glioma Cells ◽  
Low Doses ◽  
Genotoxic Effects ◽  
Cadmium Ions

Cadmium is a common transition metal that entails an extremely wide range of toxic effects in humans and animals. The cytotoxicity of cadmium ions and its compounds is due to various genotoxic effects, including both DNA damage and chromosomal aberrations. Some bone diseases, kidney and digestive system diseases are determined as pathologies that are closely associated with cadmium intoxication. In addition, cadmium is included in the list of carcinogens because of its ability to initiate the development of tumors of several forms of cancer under conditions of chronic or acute intoxication. Despite many studies of the effects of cadmium in animal models and cohorts of patients, in which cadmium effects has occurred, its molecular mechanisms of action are not fully understood. The genotoxic effects of cadmium and the induction of programmed cell death have attracted the attention of researchers in the last decade. In recent years, the results obtained for in vivo and in vitro experimental models have shown extremely high cytotoxicity of sublethal concentrations of cadmium and its compounds in various tissues. One of the most studied causes of cadmium cytotoxicity is the development of oxidative stress and associated oxidative damage to macromolecules of lipids, proteins and nucleic acids. Brain cells are most sensitive to oxidative damage and can be a critical target of cadmium cytotoxicity. Thus, oxidative damage caused by cadmium can initiate genotoxicity, programmed cell death and inhibit their viability in the human and animal brains. To test our hypothesis, cadmium cytotoxicity was assessed in vivo in U251 glioma cells through viability determinants and markers of oxidative stress and apoptosis. The result of the cell viability analysis showed the dose-dependent action of cadmium chloride in glioma cells, as well as the generation of oxidative stress (p <0.05). Calculated for 48 hours of exposure, the LD50 was 3.1 μg×ml-1. The rates of apoptotic death of glioma cells also progressively increased depending on the dose of cadmium ions. A high correlation between cadmium concentration and apoptotic response (p <0.01) was found for cells exposed to 3–4 μg×ml-1 cadmium chloride. Moreover, a significant correlation was found between oxidative stress (lipid peroxidation) and induction of apoptosis. The results indicate a strong relationship between the generation of oxidative damage by macromolecules and the initiation of programmed cell death in glial cells under conditions of low doses of cadmium chloride. The presented results show that cadmium ions can induce oxidative damage in brain cells and inhibit their viability through the induction of programmed death. Such effects of cadmium intoxication can be considered as a model of the impact of heavy metal pollution on vertebrates.

scholarly journals iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1446
Author(s):  
Tingting Jin ◽  
Jun Lin ◽  
Yingchao Gong ◽  
Xukun Bi ◽  
Shasha Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

miR-187 modulates cardiomyocyte apoptosis and oxidative stress in myocardial infarction mice via negatively regulating DYRK2

2021 ◽  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Protective Effect ◽  
Myocardial Infarct ◽  
Annexin V ◽  
Cardiomyocyte Apoptosis ◽  
Ros Generation ◽  
Downstream Target

Myocardial infarction is a serious representation of cardiovescular disease, MicroRNAs play a role in modifying I/R injury and myocardial infarct remodeling. The present study therefore examined the potential role of miR-187 in cardiac I/R injury and its underlying mechanisms. miR-187 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with miR-187 mimic or inhibitor to confirm the function of miR-187 in H/R. DYRK2 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with DYRK2 inhibitor. A myocardium I/R mouse model was established. Circulating levels of miR-187 or DYRK2 was detected by quantitative realtime PCR and protein expression was detected by western blotting. The cell viability in all groups was determined by MTT assay and the apoptosis ratio was detected by flow cytometry after staining with Annexin V-FITC. The effect of miR-187 on cellular ROS generation was examined by DCFH-DA. The level of lipid peroxidation and SOD expression were determined by MDA and SOD assay. The findings indicated that miR-187 may be a possible regulator in the protective effect of H/R-induced cardiomyocyte apoptosis, cellular oxidative stress and leaded to DYRK2 suppression at a posttranscriptional level. Moreover, the improvement of miR-187 on H/R-induced cardiomyocyte injury contributed to the obstruction of DYRK2 expression. In addition, these results identified DYRK2 as the functional downstream target of miR-187 regulated myocardial infarction and oxidative stress.These present work provided the first insight into the function of miR-187 in successfully protect cardiomyocyte both in vivo and in vitro, and such a protective effect were mediated through the regulation of DYRK2 expression.

Integrated control of cell proliferation and cell death by the c- myc oncogene

1994 ◽  
Vol 345 (1313) ◽  
pp. 269-275 ◽  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Transcriptional Activation ◽  
Dynamic Equilibrium ◽  
Growth Arrest ◽  
Deletion Mapping ◽  
Potent Inducer ◽  
Cellular Environment ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis

Regulation of multicellular architecture involves a dynamic equilibrium between cell proliferation, differentiation with consequent growth arrest, and cell death. Apoptosis is one particular form of active cell death that is extremely rapid and characterized by auto-destruction of chromatin, cellular blebbing and condensation, and vesicularization of internal components. The c- myc proto-oncogene encodes an essential component of the cell’s proliferative machinery and its deregulated expression is implicated in most neoplasms. Intriguingly, c- myc can also act as a potent inducer of apoptosis. Myc-induced apoptosis occurs only in cells deprived of growth factors or forcibly arrested with cytostatic drugs. Myc-induced apoptosis is dependent upon the level at which it is expressed and deletion mapping shows that regions of c-Myc required for apoptosis overlap with regions necessary for co-transformation, autoregulation, inhibition of differentiation, transcriptional activation and sequence-specific DNA binding. Moreover, induction of apoptosis by c-Myc requires association with c-Myc’s heterologous partner, Max. All of this strongly implies that c-Myc drives apoptosis through a transcriptional mechanism: presumably by modulation of target genes. Two simple models can be invoked to explain the induction of apoptosis by c-Myc. One holds that death arises from a conflict in growth signals which is generated by the inappropriate or unscheduled expression of c-Myc under conditions that would normally promote growth arrest. In this ‘Conflict’ model, induction of apoptosis is not a normal function of c-Myc but a pathological manifestation of its deregulation. It thus has significance only for models of carcinogenic progression in which myc genes are invariably disrupted. The other model holds that induction of apoptosis is a normal obligate function of c-Myc which is modulated by specific survival factors. Thus, every cell that enters the cycle invokes an obligate abort suicide pathway which must be continuously suppressed by signals from the immediate cellular environment for the proliferating cell to survive. Evidence will be presented supporting this second ‘Dual Signal’ model for cell growth and survival, and its widespread implications will be discussed.

scholarly journals MDM2 Suppresses p73 Function without Promoting p73 Degradation

1999 ◽  
Vol 19 (5) ◽  
pp. 3257-3266 ◽  
Author(s):  
Xiaoya Zeng ◽  
Lihong Chen ◽  
Christine A. Jost ◽  
Ruth Maya ◽  
David Keller ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Feedback Loop ◽  
Human Lung ◽  
Activation Function ◽  
Wild Type ◽  
Mdm2 Protein ◽  
Induced Apoptosis ◽  
P53 Inactivation

ABSTRACT The newly identified p53 homolog p73 can mimic the transcriptional activation function of p53. We investigated whether p73, like p53, participates in an autoregulatory feedback loop with MDM2. p73 bound to MDM2 both in vivo and in vitro. Wild-type but not mutant MDM2, expressed in human p53 null osteosarcoma Saos-2 cells, inhibited p73- and p53-dependent transcription driven by the MDM2 promoter-derived p53RE motif as measured in transient-transfection and chloramphenicol acetyltransferase assays and also inhibited p73-induced apoptosis in p53-null human lung adenocarcinoma H1299 cells. MDM2 did not promote the degradation of p73 but instead disrupted the interaction of p73, but not of p53, with p300/CBP by competing with p73 for binding to the p300/CBP N terminus. Both p73α and p73β stimulated the expression of the endogenous MDM2 protein. Hence, MDM2 is transcriptionally activated by p73 and, in turn, negatively regulates the function of this activator through a mechanism distinct from that used for p53 inactivation.

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