scholarly journals NNT Regulates Mitochondrial Metabolism in NSCLC Through Maintenance of Fe-S Protein Function

2019 ◽  
Author(s):  
Nathan P. Ward ◽  
Yun Pyo Kang ◽  
Aimee Falzone ◽  
Terry A. Boyle ◽  
Gina M. DeNicola
Keyword(s):  
Oxidative Stress ◽  
Protein Function ◽  
Lung Tumor ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Reducing Power ◽  
Tumor Formation ◽  
Mitochondrial Metabolism ◽  
Mitochondrial Activity ◽  
Ros Generation ◽  
Pulmonary Tissue

AbstractHuman lung tumors exhibit robust and complex mitochondrial metabolism, likely precipitated by the highly oxygenated nature of pulmonary tissue. As ROS generation is a byproduct of this metabolism, reducing power in the form of nicotinamide adenine dinucleotide phosphate (NADPH) is required to mitigate oxidative stress in response to this heightened mitochondrial activity. Nicotinamide nucleotide transhydrogenase (NNT) is known to sustain mitochondrial antioxidant capacity through the generation of NADPH, however its function in non-small cell lung cancer (NSCLC) has not been established. We found that NNT expression significantly enhances tumor formation and aggressiveness in mouse models of lung tumor initiation and progression. We further show that NNT loss elicits mitochondrial dysfunction independent of substantial increases in oxidative stress, but rather marked by the diminished activities of proteins dependent on resident iron-sulfur clusters. These defects were associated with both NADPH availability and ROS accumulation, suggesting that NNT serves a specific role in mitigating the oxidation of these critical protein cofactors.

scholarly journals Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function

2020 ◽  
Vol 217 (6) ◽  
Author(s):  
Nathan P. Ward ◽  
Yun Pyo Kang ◽  
Aimee Falzone ◽  
Theresa A. Boyle ◽  
Gina M. DeNicola
Keyword(s):  
Oxidative Stress ◽  
Lung Tumor ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Reducing Power ◽  
Tumor Formation ◽  
Mitochondrial Metabolism ◽  
Mitochondrial Activity ◽  
Ros Generation ◽  
Pulmonary Tissue ◽  
Nicotinamide Nucleotide Transhydrogenase

Human lung tumors exhibit robust and complex mitochondrial metabolism, likely precipitated by the highly oxygenated nature of pulmonary tissue. As ROS generation is a byproduct of this metabolism, reducing power in the form of nicotinamide adenine dinucleotide phosphate (NADPH) is required to mitigate oxidative stress in response to this heightened mitochondrial activity. Nicotinamide nucleotide transhydrogenase (NNT) is known to sustain mitochondrial antioxidant capacity through the generation of NADPH; however, its function in non-small cell lung cancer (NSCLC) has not been established. We found that NNT expression significantly enhances tumor formation and aggressiveness in mouse models of lung tumor initiation and progression. We further show that NNT loss elicits mitochondrial dysfunction independent of substantial increases in oxidative stress, but rather marked by the diminished activities of proteins dependent on resident iron-sulfur clusters. These defects were associated with both NADPH availability and ROS accumulation, suggesting that NNT serves a specific role in mitigating the oxidation of these critical protein cofactors.

scholarly journals Identification, Characterization, and Stress Responsiveness of Glucose-6-phosphate Dehydrogenase Genes in Highland Barley

Plants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1800
Author(s):  
Ruijun Feng ◽  
Xiaomin Wang ◽  
Li He ◽  
Shengwang Wang ◽  
Junjie Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Redox Homeostasis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Reducing Power ◽  
Cellular Redox ◽  
E Coli ◽  
Intermediate Metabolites ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Highland Barley ◽  
Salt And Drought Stresses

G6PDH provides intermediate metabolites and reducing power (nicotinamide adenine dinucleotide phosphate, NADPH) for plant metabolism, and plays a pivotal role in the cellular redox homeostasis. In this study, we cloned five G6PDH genes (HvG6PDH1 to HvG6PDH5) from highland barley and characterized their encoded proteins. Functional analysis of HvG6PDHs in E. coli showed that HvG6PDH1 to HvG6PDH5 encode the functional G6PDH proteins. Subcellular localization and phylogenetic analysis indicated that HvG6PDH2 and HvG6PDH5 are localized in the cytoplasm, while HvG6PDH1, HvG6PDH3, and HvG6PDH4 are plastidic isoforms. Analysis of enzymatic activities and gene expression showed that HvG6PDH1 to HvG6PDH4 are involved in responses to salt and drought stresses. The cytosolic HvG6PDH2 is the major isoform against oxidative stress. HvG6PDH5 may be a house-keeping gene. In addition, HvG6PDH1 to HvG6PDH4 and their encoded enzymes responded to jasmonic acid (JA) and abscisic acid (ABA) treatments, implying that JA and ABA are probably critical regulators of HvG6PDHs (except for HvG6PDH5). Reactive oxygen species analysis showed that inhibition of cytosolic and plastidic G6PDH activities leads to increased H2O2 and O2− contents in highland barley under salt and drought stresses. These results suggest that G6PDH can maintain cellular redox homeostasis and that cytosolic HvG6PDH2 is an irreplaceable isoform against oxidative stress in highland barley.

scholarly journals LmTDRM Database: A Comprehensive Database on Thiol Metabolic Gene/Gene Products in Listeria monocytogenes EGDe

2014 ◽  
Vol 11 (1) ◽  
pp. 17-29
Author(s):  
Vanishree Srinivas ◽  
Shubha Gopal
Keyword(s):  
Oxidative Stress ◽  
Listeria Monocytogenes ◽  
Protein Function ◽  
Model Organism ◽  
Reducing Power ◽  
Major Step ◽  
Redox Metabolism ◽  
Interaction Database ◽  
Insertion Elements ◽  
Thiol Redox

Summary There are a number of databases on the Listeria species and about their genome. However, these databases do not specifically address a set of network that is important in defence mechanism of the bacteria. Listeria monocytogenes EGDe is a well-established intracellular model organism to study host pathogenicity because of its versatility in the host environment. Here, we have focused on thiol disulphide redox metabolic network proteins, specifically in L. monocytogenes EGDe. The thiol redox metabolism is involved in oxidative stress mechanism and is found in all living cells. It functions to maintain the thiol disulphide balance required for protein folding by providing reducing power. Nevertheless, they are involved in the reversible oxidation of thiol groups in biomolecules by creating disulphide bonds; therefore, the term thiol disulphide redox metabolism (TDRM). TDRM network genes play an important role in oxidative stress mechanism and during host-pathogen interaction. Therefore, it is essential to have detailed information on these proteins with regard to other bacteria and its genome analysis to understand the presence of tRNA, transposons, and insertion elements for horizontal gene transfer. LmTDRM database is a new comprehensive web-based database on thiol proteins and their functions. It includes: Description, Search, TDRM analysis, and genome viewer. The quality of these data has been evaluated before they were aggregated to produce a final representation. The web interface allows for various queries to understand the protein function and their annotation with respect to their relationship with other bacteria. LmTDRM is a major step towards the development of databases on thiol disulphide redox proteins; it would definitely help researchers to understand the mechanism of these proteins and their interaction. Database URL: www.lmtdrm.com

scholarly journals Overexpression of PRDX4 Modulates Tumor Microenvironment and Promotes Urethane-Induced Lung Tumorigenesis

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Jianbo Zheng ◽  
Xin Guo ◽  
Yuka Nakamura ◽  
Xiaolei Zhou ◽  
Reimon Yamaguchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Lung Tumor ◽  
Interleukin 1 ◽  
Tumor Development ◽  
Tumor Model ◽  
Tumor Formation ◽  
Tumor Diameter

Peroxiredoxin 4 (PRDX4), initially reported as an antioxidant, is overexpressed in lung cancer and participates in its progression. However, its role in the urethane-induced lung tumor model is undetermined. The aim of this study was to investigate the effect of PRDX4 overexpression on carcinogen-induced lung tumor development. Human PRDX4 overexpression transgenic (Tg) mice (hPRDX4+/+) and non-Tg mice were intraperitoneally injected with urethane to induce lung tumor. After 6 months, tumor formation was compared between groups and possible mechanisms for the difference in tumor development were investigated. The serum and lung PRDX4 expressions were enhanced after urethane stimulation in Tg mice. Both the average number of tumors (≥0.5 mm) and tumor diameter per mouse in the Tg group were significantly larger than in non-Tg controls, while body weight was lower in the Tg group. Compared with non-Tg controls, tumor cell proliferation was enhanced, while tumor cell apoptosis was suppressed in Tg mice. Systemic oxidative stress and oxidative stress in lung tumors were inhibited by PRDX4 overexpression. The balance of prooxidant enzymes and antioxidant enzymes was also shifted to a decreased level in Tg tumor. In lung tumor tissue, the density of microvessel penetrated into tumor was higher in the Tg group; macrophage infiltration was enhanced in Tg tumors, while there was no difference in T lymphocyte infiltration; the expressions of cytokines, including interleukin-1 beta (IL-1β) and matrix metallopeptidase 9 (MMP9), were elevated in Tg tumors, which resulted from enhanced phosphorylation of nuclear factor-κB p65 (NF-κB p65) and c-Jun, respectively. In conclusion, PRDX4 overexpression modulated tumor microenvironment and promoted tumor development in the mouse urethane-induced lung cancer model.

scholarly journals Octadecaneuropeptide prevents toxicity induced by 6-hydroxydopamine in cultured rat astrocyte: involvement of the endogenous antioxidant systems and the intrinsic apoptotic pathway

2018 ◽  
Author(s):  
Hadhemi Kaddour ◽  
Yosra Hamdi ◽  
David Vaudry ◽  
Jérôme Leprince ◽  
Hubert Vaudry ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Antioxidant Systems ◽  
Mitochondrial Activity ◽  
Ros Generation ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Antioxidant Defences ◽  
Apoptotic Pathway

AbstractOxidative stress, associated with various neurodegenerative diseases, induces imbalance in ROS generation, impairs cellular antioxidant defences and finally triggers both neurons and astroglial cell death by apoptosis. Astrocytes specifically synthesize and release endozepines, a family of regulatory peptides, including the octadecaneuropeptide (ODN). We have previously reported that ODN is a potent neuroprotective agent that prevents 6-OHDA-induced apoptotic neuronal death. The purpose of the present study was to investigate the potential glioprotective effect of ODN on 6-OHDA-induced oxidative stress and cell death in cultured rat astrocytes. Incubation of astrocytes with graded concentrations of ODN (10−14 to 10−8 M) inhibited 6-OHDA-evoked cell death in a concentration- and time-dependent manner. In addition, ODN prevented the decrease of mitochondrial activity and caspase-3 activation induced by 6-OHDA. Toxin-treated cells exhibited high level of ROS associated with a generation of H2O2 and O2°-and a reduction of both SOD and catalase activities. Co-treatment of astrocytes with low concentrations of ODN dose dependently blocked 6-OHDA-evoked ROS production and inhibition of antioxidant enzymes activities. Taken together, these data demonstrate that ODN is a potent glioprotective agent that prevents 6-OHDA-induced oxidative stress and apoptotic cell death. ODN is thus a potential candidate to delay neuronal damages in various pathological conditions involving oxidative neurodegeneration.

scholarly journals The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders

2018 ◽  
Vol 19 (12) ◽  
pp. 3824 ◽  
Author(s):  
Anuradha Tarafdar ◽  
Giordano Pula
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Ros Generation ◽  
Phagocytic Cells ◽  
Nadph Oxidases ◽  
Age Related ◽  
Recent Developments ◽  
Cerebrovascular Endothelial Cells

For a number of years, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) was synonymous with NOX2/gp91phox and was considered to be a peculiarity of professional phagocytic cells. Over the last decade, several more homologs have been identified and based on current research, the NOX family consists of NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 enzymes. NOXs are electron transporting membrane proteins that are responsible for reactive oxygen species (ROS) generation—primarily superoxide anion (O2●−), although hydrogen peroxide (H2O2) can also be generated. Elevated ROS leads to oxidative stress (OS), which has been associated with a myriad of inflammatory and degenerative pathologies. Interestingly, OS is also the commonality in the pathophysiology of neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). NOX enzymes are expressed in neurons, glial cells and cerebrovascular endothelial cells. NOX-mediated OS is identified as one of the main causes of cerebrovascular damage in neurodegenerative diseases. In this review, we will discuss recent developments in our understanding of the mechanisms linking NOX activity, OS and neurodegenerative diseases, with particular focus on the neurovascular component of these conditions. We conclude highlighting current challenges and future opportunities to combat age-related neurodegenerative disorders by targeting NOXs.

scholarly journals The impact of reactive oxygen species in the development of cardiometabolic disorders: a review

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Roland Akhigbe ◽  
Ayodeji Ajayi
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Reactive Oxygen ◽  
Acid Oxidation ◽  
Ros Generation ◽  
Metabolic Memory ◽  
Oxygen Species ◽  
Cardiometabolic Disorders ◽  
The Impact

AbstractOxidative stress, an alteration in the balance between reactive oxygen species (ROS) generation and antioxidant buffering capacity, has been implicated in the pathogenesis of cardiometabolic disorders (CMD). At physiological levels, ROS functions as signalling mediators, regulates various physiological functions such as the growth, proliferation, and migration endothelial cells (EC) and smooth muscle cells (SMC); formation and development of new blood vessels; EC and SMC regulated death; vascular tone; host defence; and genomic stability. However, at excessive levels, it causes a deviation in the redox state, mediates the development of CMD. Multiple mechanisms account for the rise in the production of free radicals in the heart. These include mitochondrial dysfunction and uncoupling, increased fatty acid oxidation, exaggerated activity of nicotinamide adenine dinucleotide phosphate oxidase (NOX), reduced antioxidant capacity, and cardiac metabolic memory. The purpose of this study is to discuss the link between oxidative stress and the aetiopathogenesis of CMD and highlight associated mechanisms. Oxidative stress plays a vital role in the development of obesity and dyslipidaemia, insulin resistance and diabetes, hypertension via various mechanisms associated with ROS-led inflammatory response and endothelial dysfunction.

Sulforaphane attenuates angiotensin II-induced human umbilical vein endothelial cell injury by modulating ROS-mediated mitochondrial signaling

2020 ◽  
Vol 39 (5) ◽  
pp. 734-747 ◽  
Author(s):  
M Zhang ◽  
Y Xu ◽  
L Jiang
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cell ◽  
Angiotensin Ii ◽  
Cell Injury ◽  
Umbilical Vein ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Specific Inhibitor ◽  
Ros Generation ◽  
Ang Ii ◽  
Human Umbilical Vein

The study aimed to investigate whether sulforaphane (SFN) protects against angiotensin II (Ang II)-mediated human umbilical vein endothelial cell (HUVEC) injury. Ang II treatment decreased HUVEC viability, increased cell apoptosis, decreased mitochondria membrane potential (MMP), impaired cytochrome c release, activated caspase 3/9, and induced reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate oxidase activity. Moreover, SFN treatment blunted Ang II-stimulated oxidative stress and mitochondria-related apoptosis in HUVECs. The ROS scavenger N-acetyl-l-cysteine reduced Ang II-induced oxidative stress and apoptosis, indicating that ROS generation is involved in the Ang II-induced mitochondria-mediated apoptotic pathway. SFN induced nuclear factor erythroid 2 (Nrf2) activation and expression in Ang II-stimulated HUVECs. Downregulation of Nrf2 expression by a target-specific siRNA revealed an Nrf2-dependent effect on the SFN-mediated attenuation of Ang II-induced apoptosis in HUVECs. Pretreatment with brusatol, an Nrf2-specific inhibitor, reversed the protective effects of SFN on Ang II-induced HUVEC injury. SFN treatment protected HUVECs from Ang II-induced damage by decreasing oxidative stress and ameliorating mitochondrial injury.

scholarly journals Metabolic Rewiring Is Essential for AML Cell Survival to Overcome Autophagy Inhibition by Loss of ATG3

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6142
Author(s):  
Fatima Baker ◽  
Ibrahim H. Polat ◽  
Khalil Abou-El-Ardat ◽  
Islam Alshamleh ◽  
Marlyn Thoelken ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Lactate Production ◽  
Mitochondrial Metabolism ◽  
Mitochondrial Activity ◽  
Ros Generation ◽  
Related Protein ◽  
Combination Therapies ◽  
Autophagy Gene ◽  
Mitochondrial Ros ◽  
Autophagy Inhibition

Autophagy is an important survival mechanism that allows recycling of nutrients and removal of damaged organelles and has been shown to contribute to the proliferation of acute myeloid leukemia (AML) cells. However, little is known about the mechanism by which autophagy- dependent AML cells can overcome dysfunctional autophagy. In our study we identified autophagy related protein 3 (ATG3) as a crucial autophagy gene for AML cell proliferation by conducting a CRISPR/Cas9 dropout screen with a library targeting around 200 autophagy-related genes. shRNA-mediated loss of ATG3 impaired autophagy function in AML cells and increased their mitochondrial activity and energy metabolism, as shown by elevated mitochondrial ROS generation and mitochondrial respiration. Using tracer-based NMR metabolomics analysis we further demonstrate that the loss of ATG3 resulted in an upregulation of glycolysis, lactate production, and oxidative phosphorylation. Additionally, loss of ATG3 strongly sensitized AML cells to the inhibition of mitochondrial metabolism. These findings highlight the metabolic vulnerabilities that AML cells acquire from autophagy inhibition and support further exploration of combination therapies targeting autophagy and mitochondrial metabolism in AML.

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