Antioxidant Genes and Reactive Oxygen Species in Down's Syndrome

DS (Down's syndrome) is the most common human aneuploidy associated with mental retardation and early neurodegeneration. Mitochondrial dysfunction has emerged as a crucial factor in the pathogenesis of numerous neurological disorders including DS, but the cause of mitochondrial damage remains elusive. In the present study, we identified new molecular events involved in mitochondrial dysfunction which could play a role in DS pathogenesis. We analysed mitochondrial respiratory chain function in DS-HSFs (Down's syndrome human foetal skin fibroblasts; human foetal skin fibroblasts with chromosome 21 trisomy) and found a selective deficit in the catalytic efficiency of mitochondrial complex I. The complex I deficit was associated with a decrease in cAMP-dependent phosphorylation of the 18 kDa subunit of the complex, due to a decrease in PKA (protein kinase A) activity related to reduced basal levels of cAMP. Consistently, exposure of DS-HSFs to db-cAMP (dibutyryl-cAMP), a membrane-permeable cAMP analogue, stimulated PKA activity and consequently rescued the deficit of both the cAMP-dependent phosphorylation and the catalytic activity of complex I; conversely H89, a specific PKA inhibitor, suppressed these cAMP-dependent activations. Furthermore, in the present paper we report a 3-fold increase in cellular levels of ROS (reactive oxygen species), in particular superoxide anion, mainly produced by DS-HSF mitochondria. ROS accumulation was prevented by db-cAMP-dependent activation of complex I, suggesting its involvement in ROS production. Taken together, the results of the present study suggest that the drastic decrease in basal cAMP levels observed in DS-HSFs participates in the complex I deficit and overproduction of ROS by DS-HSF mitochondria.

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PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/1452696 ◽

2020 ◽

Vol 2020 ◽

pp. 1-20 ◽

Cited By ~ 21

Author(s):

Sergio Rius-Pérez ◽

Isabel Torres-Cuevas ◽

Iván Millán ◽

Ángel L. Ortega ◽

Salvador Pérez

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Metabolic Syndrome ◽

Inflammatory Response ◽

Reactive Oxygen ◽

High Energy ◽

Low Grade ◽

Oxygen Species ◽

Antioxidant Genes ◽

Integrative View

Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1α is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1α, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome. PGC-1α regulates the expression of mitochondrial antioxidant genes, including manganese superoxide dismutase, catalase, peroxiredoxin 3 and 5, uncoupling protein 2, thioredoxin 2, and thioredoxin reductase and thus prevents oxidative injury and mitochondrial dysfunction. Dysregulation of PGC-1α alters redox homeostasis in cells and exacerbates inflammatory response, which is commonly accompanied by metabolic disturbances. During inflammation, low levels of PGC-1α downregulate mitochondrial antioxidant gene expression, induce oxidative stress, and promote nuclear factor kappa B activation. In metabolic syndrome, which is characterized by a chronic low grade of inflammation, PGC-1α dysregulation modifies the metabolic properties of tissues by altering mitochondrial function and promoting reactive oxygen species accumulation. In conclusion, PGC-1α acts as an essential node connecting metabolic regulation, redox control, and inflammatory pathways, and it is an interesting therapeutic target that may have significant benefits for a number of metabolic diseases.

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Potential role of reactive oxygen species and antioxidant genes in the regulation of peach fruit development and ripening

Plant Physiology and Biochemistry ◽

10.1016/j.plaphy.2016.05.013 ◽

2016 ◽

Vol 104 ◽

pp. 294-303 ◽

Cited By ~ 51

Author(s):

Chen Huan ◽

Li Jiang ◽

Xiujuan An ◽

Mingliang Yu ◽

Yin Xu ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Fruit Development ◽

Potential Role ◽

Reactive Oxygen ◽

Oxygen Species ◽

Peach Fruit ◽

Antioxidant Genes ◽

Fruit Development And Ripening

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Protective Role of Peroxiredoxins against Reactive Oxygen Species in Neonatal Rat Testicular Gonocytes

Antioxidants ◽

10.3390/antiox9010032 ◽

2019 ◽

Vol 9 (1) ◽

pp. 32 ◽

Cited By ~ 3

Author(s):

Cristian O’Flaherty ◽

Annie Boisvert ◽

Gurpreet Manku ◽

Martine Culty

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Gene Array ◽

Reactive Oxygen ◽

Fold Increase ◽

Protective Role ◽

Neonatal Rat ◽

Oxygen Species ◽

Antioxidant Genes

Peroxiredoxins (PRDXs) are antioxidant enzymes that protect cells from oxidative stress and play a role in reactive oxygen species (ROS)-mediated signaling. We reported that PRDXs are critical for human fertility by maintaining sperm viability and regulating ROS levels during capacitation. Moreover, studies on Prdx6−/− mice revealed the essential role of PRDX6 in the viability, motility, and fertility competence of spermatozoa. Although PRDXs are abundant in the testis and spermatozoa, their potential role at different phases of spermatogenesis and in perinatal germ cells is unknown. Here, we examined the expression and role of PRDXs in isolated rat neonatal gonocytes, the precursors of spermatogonia, including spermatogonial stem cells. Gene array, qPCR analyses showed that PRDX1, 2, 3, 5, and 6 transcripts are among the most abundant antioxidant genes in postnatal day (PND) 3 gonocytes, while immunofluorescence confirmed the expression of PRDX1, 2, and 6 proteins. The role of PRDXs in gonocyte viability was examined using PRDX inhibitors, revealing that the 2-Cys PRDXs and PRDX6 peroxidases activities are critical for gonocytes viability in basal condition, likely preventing an excessive accumulation of endogenous ROS in the cells. In contrast to its crucial role in spermatozoa, PRDX6 independent phospholipase A2 (iPLA2) activity was not critical in gonocytes in basal conditions. However, under conditions of H2O2-induced oxidative stress, all these enzymatic activities were critical to maintain gonocyte viability. The inhibition of PRDXs promoted a two-fold increase in lipid peroxidation and prevented gonocyte differentiation. These results suggest that ROS are produced in neonatal gonocytes, where they are maintained by PRDXs at levels that are non-toxic and permissive for cell differentiation. These findings show that PRDXs play a major role in the antioxidant machinery of gonocytes, to maintain cell viability and allow for differentiation.

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Serine/Threonine Kinase 17A Is a Novel p53 Target Gene and Modulator of Cisplatin Toxicity and Reactive Oxygen Species in Testicular Cancer Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m111.218040 ◽

2011 ◽

Vol 286 (22) ◽

pp. 19381-19391 ◽

Cited By ~ 25

Author(s):

Pingping Mao ◽

Mary P. Hever ◽

Lynne M. Niemaszyk ◽

Jessica M. Haghkerdar ◽

Esty G. Yanco ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Testicular Cancer ◽

Cancer Cells ◽

Target Gene ◽

Reactive Oxygen ◽

Dependent Manner ◽

Oxygen Species ◽

Antioxidant Genes ◽

Ec Cells ◽

P53 Target Gene

Testicular cancer is highly curable with cisplatin-based therapy, and testicular cancer-derived human embryonal carcinoma (EC) cells undergo a p53-dominant transcriptional response to cisplatin. In this study, we have discovered that a poorly characterized member of the death-associated protein family of serine/threonine kinases, STK17A (also called DRAK1), is a novel p53 target gene. Cisplatin-mediated induction of STK17A in the EC cell line NT2/D1 was prevented with p53 siRNA. Furthermore, STK17A was induced with cisplatin in HCT116 and MCF10A cells but to a much lesser extent in isogenic p53-suppressed cells. A functional p53 response element that binds endogenous p53 in a cisplatin-dependent manner was identified 5 kb upstream of the first coding exon of STK17A. STK17A is not present in the mouse genome, but the closely related gene STK17B is induced with cisplatin in mouse NIH3T3 cells, although this induction is p53-independent. Interestingly, in human cells containing both STK17A and STK17B, only STK17A is induced with cisplatin. Knockdown of STK17A conferred resistance to cisplatin-induced growth suppression and apoptotic cell death in EC cells. This was associated with the up-regulation of detoxifying and antioxidant genes, including metallothioneins MT1H, MT1M, and MT1X that have previously been implicated in cisplatin resistance. In addition, knockdown of STK17A resulted in decreased cellular reactive oxygen species, whereas STK17A overexpression increased reactive oxygen species. In summary, we have identified STK17A as a novel direct target of p53 and a modulator of cisplatin toxicity and reactive oxygen species in testicular cancer cells.

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Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

Biomolecules ◽

10.3390/biom10020320 ◽

2020 ◽

Vol 10 (2) ◽

pp. 320 ◽

Cited By ~ 17

Author(s):

Shuya Kasai ◽

Sunao Shimizu ◽

Yota Tatara ◽

Junsei Mimura ◽

Ken Itoh

Keyword(s):

Gene Expression ◽

Reactive Oxygen Species ◽

Physiological Stress ◽

Reactive Oxygen ◽

Negative Regulator ◽

Endurance Capacity ◽

Oxygen Species ◽

Antioxidant Genes ◽

Beneficial Effects ◽

Quantity Control

Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence has shown that mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, and induce the expression of antioxidant genes and genes involved in mitochondrial quality/quantity control. Mild physiological stress, such as caloric restriction and exercise, elicits beneficial effects through a process known as “mitohormesis”. Exercise induces NOX4 expression in the heart, which activates Nrf2 and increases endurance capacity. Mice transiently depleted of SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated antioxidant gene expression and PGC1α-mediated mitochondrial biogenesis. ATF4 activation may induce a transcriptional program that enhances NADPH synthesis in the mitochondria and might cooperate with the Nrf2 antioxidant system. In response to severe oxidative stress, Nrf2 induces Klf9 expression, which represses mtROS-eliminating enzymes to enhance cell death. Nrf2 is inactivated in certain pathological conditions, such as diabetes, but Keap1 down-regulation or mtROS elimination rescues Nrf2 expression and improves the pathology. These reports aid us in understanding the roles of Nrf2 in pathophysiological alterations involving mtROS.

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Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer

BioMed Research International ◽

10.1155/2020/1269624 ◽

2020 ◽

Vol 2020 ◽

pp. 1-19

Author(s):

Chenglin Han ◽

Zilong Wang ◽

Yingkun Xu ◽

Shuxiao Chen ◽

Yuqing Han ◽

...

Keyword(s):

Prostate Cancer ◽

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Oxygen Species ◽

Antioxidant Genes ◽

Beneficial Effects ◽

Cell Functions ◽

Incidence And Mortality ◽

Intracellular Ros ◽

High Incidence

Prostate cancer (PCa), known as a heterogenous disease, has a high incidence and mortality rate around the world and seriously threatens public health. As an inevitable by-product of cellular metabolism, reactive oxygen species (ROS) exhibit beneficial effects by regulating signaling cascades and homeostasis. More and more evidence highlights that PCa is closely associated with age, and high levels of ROS are driven through activation of several signaling pathways with age, which facilitate the initiation, development, and progression of PCa. Nevertheless, excessive amounts of ROS result in harmful effects, such as genotoxicity and cell death. On the other hand, PCa cells adaptively upregulate antioxidant genes to detoxify from ROS, suggesting that a subtle balance of intracellular ROS levels is required for cancer cell functions. The current review discusses the generation and biological roles of ROS in PCa and provides new strategies based on the regulation of ROS for the treatment of PCa.

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