scholarly journals The Tumorigenic Roles of the Cellular REDOX Regulatory Systems

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Stéphanie Anaís Castaldo ◽  
Joana Raquel Freitas ◽  
Nadine Vasconcelos Conchinha ◽  
Patrícia Alexandra Madureira
Keyword(s):  
Oxidative Stress ◽  
Cancer Cell ◽  
Current Knowledge ◽  
Redox Homeostasis ◽  
Chemotherapeutic Agents ◽  
Antioxidant Systems ◽  
Cell Integrity ◽  
Cellular Redox ◽  
Regulatory Systems ◽  
Knowledge Of Cancer

The cellular REDOX regulatory systems play a central role in maintaining REDOX homeostasis that is crucial for cell integrity, survival, and proliferation. To date, a substantial amount of data has demonstrated that cancer cells typically undergo increasing oxidative stress as the tumor develops, upregulating these important antioxidant systems in order to survive, proliferate, and metastasize under these extreme oxidative stress conditions. Since a large number of chemotherapeutic agents currently used in the clinic rely on the induction of ROS overload or change of ROS quality to kill the tumor, the cancer cell REDOX adaptation represents a significant obstacle to conventional chemotherapy. In this review we will first examine the different factors that contribute to the enhanced oxidative stress generally observed within the tumor microenvironment. We will then make a comprehensive assessment of the current literature regarding the main antioxidant proteins and systems that have been shown to be positively associated with tumor progression and chemoresistance. Finally we will make an analysis of commonly used chemotherapeutic drugs that induce ROS. The current knowledge of cancer cell REDOX adaptation raises the issue of developing novel and more effective therapies for these tumors that are usually resistant to conventional ROS inducing chemotherapy.

scholarly journals Redox Homeostasis and Cellular Antioxidant Systems: Crucial Players in Cancer Growth and Therapy

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Barbara Marengo ◽  
Mariapaola Nitti ◽  
Anna Lisa Furfaro ◽  
Renata Colla ◽  
Chiara De Ciucis ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
Cell Damage ◽  
Redox Homeostasis ◽  
Cancer Growth ◽  
Antioxidant Systems ◽  
Ros Generation ◽  
Regulatory Systems ◽  
Cell Signaling Pathways

Reactive oxygen species (ROS) and their products are components of cell signaling pathways and play important roles in cellular physiology and pathophysiology. Under physiological conditions, cells control ROS levels by the use of scavenging systems such as superoxide dismutases, peroxiredoxins, and glutathione that balance ROS generation and elimination. Under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids, and DNA, leading to cell damage that may contribute to carcinogenesis. Several studies have shown that cancer cells display an adaptive response to oxidative stress by increasing expression of antioxidant enzymes and molecules. As a double-edged sword, ROS influence signaling pathways determining beneficial or detrimental outcomes in cancer therapy. In this review, we address the role of redox homeostasis in cancer growth and therapy and examine the current literature regarding the redox regulatory systems that become upregulated in cancer and their role in promoting tumor progression and resistance to chemotherapy.

scholarly journals Developmental Origins of Kidney Disease: Why Oxidative Stress Matters?

Antioxidants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 33
Author(s):  
Chien-Ning Hsu ◽  
You-Lin Tain
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Current Knowledge ◽  
Future Research ◽  
Antioxidant Systems ◽  
Developmental Origins ◽  
Adult Onset ◽  
Functional Changes ◽  
Health And Disease ◽  
Developing Kidney

The “developmental origins of health and disease” theory indicates that many adult-onset diseases can originate in the earliest stages of life. The developing kidney has emerged as being particularly vulnerable to adverse in utero conditions leading to morphological and functional changes, namely renal programming. Emerging evidence indicates oxidative stress, an imbalance between reactive oxygen/nitrogen species (ROS/RNS) and antioxidant systems, plays a pathogenetic role in the developmental programming of kidney disease. Conversely, perinatal use of antioxidants has been implemented to reverse programming processes and prevent adult-onset diseases. We have termed this reprogramming. The focus of this review is twofold: (1) To summarize the current knowledge on oxidative stress implicated in renal programming and kidney disease of developmental origins; and (2) to provide an overview of reprogramming effects of perinatal antioxidant therapy on renal programming and how this may prevent adult-onset kidney disease. Although early-life oxidative stress is implicated in mediating renal programming and adverse offspring renal outcomes, and animal models provide promising results to allow perinatal antioxidants applied as potential reprogramming interventions, it is still awaiting clinical translation. This presents exciting new challenges and areas for future research.

scholarly journals Endogenous formaldehyde scavenges cellular glutathione resulting in cytotoxic redox disruption

2020 ◽  
Author(s):  
Carla Umansky ◽  
Agustín Morellato ◽  
Marco Scheidegger ◽  
Matthias Rieckher ◽  
Manuela R. Martinefski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Redox Homeostasis ◽  
Thiol Group ◽  
Cellular Damage ◽  
Repair Pathway ◽  
Cellular Redox ◽  
Redox Active ◽  
Development And Aging

AbstractFormaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking. We show here that FA can cause cellular damage beyond genotoxicity by triggering oxidative stress, which is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR). Mechanistically, we determine that endogenous FA reacts with the redox-active thiol group of glutathione (GSH) forming S-hydroxymethyl-GSH, which is metabolized by ADH5 yielding reduced GSH thus preventing redox disruption. We identify the ADH5-ortholog gene in Caenorhabditis elegans and show that oxidative stress also underlies FA toxicity in nematodes. Moreover, we show that endogenous GSH can protect cells lacking the Fanconi Anemia DNA repair pathway from FA, which might have broad implications for Fanconi Anemia patients and for healthy BRCA2-mutation carriers. We thus establish a highly conserved mechanism through which endogenous FA disrupts the GSH-regulated cellular redox homeostasis that is critical during development and aging.

scholarly journals Gankyrin has an antioxidative role through the feedback regulation of Nrf2 in hepatocellular carcinoma

2016 ◽  
Vol 213 (5) ◽  
pp. 859-875 ◽  
Author(s):  
Chun Yang ◽  
Ye-xiong Tan ◽  
Guang-zhen Yang ◽  
Jian Zhang ◽  
Yu-fei Pan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Redox Homeostasis ◽  
Feedback Regulation ◽  
Cellular Redox ◽  
Intracellular Ros ◽  
Oxidative Stress Status ◽  
Kelch Domain ◽  
Cellular Stressors ◽  
Hcc Cells

Oxidative stress status has a key role in hepatocellular carcinoma (HCC) development and progression. Normally, reactive oxygen species (ROS) levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors. How HCC cells respond to excessive oxidative stress remains elusive. Here, we identified a feedback loop between gankyrin, an oncoprotein overexpressed in human HCC, and Nrf2 maintaining the homeostasis in HCC cells. Mechanistically, gankyrin was found to interact with the Kelch domain of Keap1 and effectively competed with Nrf2 for Keap1 binding. Increased expression of gankyrin in HCC cells blocked the binding between Nrf2 and Keap1, inhibiting the degradation of Nrf2 by proteasome. Interestingly, accumulation and translocation of Nrf2 increased the transcription of gankyrin through binding to the ARE elements in the promoter of gankyrin. The positive feedback regulation involving gankyrin and Nrf2 modulates a series of antioxidant enzymes, thereby lowering intracellular ROS and conferring a steadier intracellular environment, which prevents mitochondrial damage and cell death induced by excessive oxidative stress. Our results indicate that gankyrin is a regulator of cellular redox homeostasis and provide a link between oxidative stress and the development of HCC.

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 Nestin regulates cellular redox homeostasis in lung cancer through the Keap1–Nrf2 feedback loop

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jiancheng Wang ◽  
Qiying Lu ◽  
Jianye Cai ◽  
Yi Wang ◽  
Xiaofan Lai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Cancer ◽  
Feedback Loop ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Cellular Redox ◽  
Anti Cancer ◽  
Oxidative Stress Status ◽  
Kelch Domain ◽  
Antioxidant Response Elements

Abstract Abnormal cancer antioxidant capacity is considered as a potential mechanism of tumor malignancy. Modulation of oxidative stress status is emerging as an anti-cancer treatment. Our previous studies have found that Nestin-knockdown cells were more sensitive to oxidative stress in non-small cell lung cancer (NSCLC). However, the molecular mechanism by which Nestin protects cells from oxidative damage remains unclear. Here, we identify a feedback loop between Nestin and Nrf2 maintaining the redox homeostasis. Mechanistically, the ESGE motif of Nestin interacts with the Kelch domain of Keap1 and competes with Nrf2 for Keap1 binding, leading to Nrf2 escaping from Keap1-mediated degradation, subsequently promoting antioxidant enzyme generation. Interestingly, we also map that the antioxidant response elements (AREs) in the Nestin promoter are responsible for its induction via Nrf2. Taken together, our results indicate that the Nestin–Keap1–Nrf2 axis regulates cellular redox homeostasis and confers oxidative stress resistance in NSCLC.

scholarly journals 12-oxo-Phytodienoic Acid: A Fuse and/or Switch of Plant Growth and Defense Responses?

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenshan Liu ◽  
Sang-Wook Park
Keyword(s):  
Regulatory Networks ◽  
Current Knowledge ◽  
Redox Homeostasis ◽  
Defense Responses ◽  
Fine Tuning ◽  
Transcriptional Regulatory Networks ◽  
Cellular Redox ◽  
Trade Offs ◽  
Transcriptional Regulatory ◽  
Regulatory Loop

12-oxo-Phytodienoic acid (OPDA) is a primary precursor of (-)-jasmonic acid (JA), able to trigger autonomous signaling pathways that regulate a unique subset of jasmonate-responsive genes, activating and fine-tuning defense responses, as well as growth processes in plants. Recently, a number of studies have illuminated the physiol-molecular activities of OPDA signaling in plants, which interconnect the regulatory loop of photosynthesis, cellular redox homeostasis, and transcriptional regulatory networks, together shedding new light on (i) the underlying modes of cellular interfaces between growth and defense responses (e.g., fitness trade-offs or balances) and (ii) vital information in genetic engineering or molecular breeding approaches to upgrade own survival capacities of plants. However, our current knowledge regarding its mode of actions is still far from complete. This review will briefly revisit recent progresses on the roles and mechanisms of OPDA and information gaps within, which help in understanding the phenotypic and environmental plasticity of plants.

scholarly journals Understanding Cellular Redox Homeostasis: A Challenge for Precision Medicine

2021 ◽  
Vol 23 (1) ◽  
pp. 106
Author(s):  
Verena Tretter ◽  
Beatrix Hochreiter ◽  
Marie Louise Zach ◽  
Katharina Krenn ◽  
Klaus Ulrich Klein
Keyword(s):  
Oxidative Stress ◽  
Precision Medicine ◽  
Redox Homeostasis ◽  
Reactive Species ◽  
Scientific Field ◽  
Redox Systems ◽  
Cellular Redox ◽  
Redox Biology ◽  
Living Organisms ◽  
Large Repertoire

Living organisms use a large repertoire of anabolic and catabolic reactions to maintain their physiological body functions, many of which include oxidation and reduction of substrates. The scientific field of redox biology tries to understand how redox homeostasis is regulated and maintained and which mechanisms are derailed in diverse pathological developments of diseases, where oxidative or reductive stress is an issue. The term “oxidative stress” is defined as an imbalance between the generation of oxidants and the local antioxidative defense. Key mediators of oxidative stress are reactive species derived from oxygen, nitrogen, and sulfur that are signal factors at physiological concentrations but can damage cellular macromolecules when they accumulate. However, therapeutical targeting of oxidative stress in disease has proven more difficult than previously expected. Major reasons for this are the very delicate cellular redox systems that differ in the subcellular compartments with regard to their concentrations and depending on the physiological or pathological status of cells and organelles (i.e., circadian rhythm, cell cycle, metabolic need, disease stadium). As reactive species are used as signaling molecules, non-targeted broad-spectrum antioxidants in many cases will fail their therapeutic aim. Precision medicine is called to remedy the situation.

scholarly journals Synchronization and interaction of proline, ascorbate and oxidative stress pathways under abiotic stress combination in tomato plants

2020 ◽  
Author(s):  
María Lopez-Delacalle ◽  
Christian J Silva ◽  
Teresa C Mestre ◽  
Vicente Martinez ◽  
Barbara Blanco-Ulate ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Metabolic Pathways ◽  
Leucine Zipper ◽  
Redox Homeostasis ◽  
Basic Leucine Zipper ◽  
Cellular Redox ◽  
Tomato Plants ◽  
Leucine Zipper Domain ◽  
And Oxidative Stress

ABSTRACTAdverse environmental conditions have a devastating impact on plant productivity. In nature, multiple abiotic stresses occur simultaneously, and plants have evolved unique responses to cope against this combination of stresses. Here, we coupled genome-wide transcriptional profiling and untargeted metabolomics with physiological and biochemical analyses to characterize the effect of salinity and heat applied in combination on the metabolism of tomato plants. Our results demonstrate that this combination of stresses causes a unique reprogramming of metabolic pathways, including changes in the expression of 1,388 genes and the accumulation of 568 molecular features. Pathway enrichment analysis of transcript and metabolite data indicated that the proline and ascorbate pathways act synchronously to maintain cellular redox homeostasis, which was supported by measurements of enzymatic activity and oxidative stress markers. We also identified key transcription factors from the basic Leucine Zipper Domain (bZIP), Zinc Finger Cysteine-2/Histidine-2 (C2H2) and Trihelix families that are likely regulators of the identified up-regulated genes under salinity+heat combination. Our results expand the current understanding of how plants acclimate to environmental stresses in combination and unveils the synergy between key cellular metabolic pathways for effective ROS detoxification. Our study opens the door to elucidating the different signaling mechanisms for stress tolerance.HIGHLIGHTSThe combination of salinity and heat causes a unique reprogramming of tomato metabolic pathways by changing the expression of specific genes and metabolic features.Proline and ascorbate pathways act synchronously to maintain cellular redox homeostasisKey transcription factors from the basic Leucine Zipper Domain (bZIP), Zinc Finger Cysteine-2/Histidine-2 (C2H2) and Trihelix families were identified as putative regulators of the identified up-regulated genes under salinity and heat combination.

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