bims-noxint 2021-02-21 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2021–02–21
ten papers selected by
Laia Caja Puigsubira, Uppsala University

USP7 Inhibition Alleviates H2O2-Induced Injury in Chondrocytes via Inhibiting NOX4/NLRP3 Pathway.
Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.
Neuroprotective roles of HAX-1 in ischemic neuronal injury.
Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages.
Immune cell - produced ROS and their impact on tumor growth and metastasis.
The glyco-redox interplay: Principles and consequences on the role of reactive oxygen species during protein glycosylation.
Activation of NADPH oxidase mediates mitochondrial oxidative stress and atrial remodeling in diabetic rabbits.
Redox signaling as a modulator of germline stem cell behavior: Implications for regenerative medicine.
In the right place at the right time: ROS and Ca2+ are allies in the battle for survival.
Neutrophil Extracellular Traps: New Aspects.

Front Pharmacol. 2020 ;11 617270

USP7 Inhibition Alleviates H2O2-Induced Injury in Chondrocytes via Inhibiting NOX4/NLRP3 Pathway.

Gang Liu, Qingbai Liu, Bin Yan, Ziqiang Zhu, Yaozeng Xu.

  Osteoarthritis (OA), the most common form of arthritis, is a very common joint disease that often affects middle-aged to elderly people. However, current treatment options for OA are predominantly palliative. Thus, understanding its pathological process and exploring its potential therapeutic approaches are of great importance. Rat chondrocytes were isolated and exposed to hydrogen peroxide (H2O2) to mimic OA. The effects of H2O2 on ubiquitin-specific protease 7 (USP7) expression, reactive oxygen species (ROS) levels, proliferation, inflammatory cytokine release, and pyroptosis were measured. USP7 was knocked down (KD) or overexpressed to investigate the role of USP7 in OA. Co-immunoprecipitation (Co-IP) was used to study the interaction between USP7 and NAD(P)H oxidases (NOX)4 as well as NOX4 ubiquitination. NOX4 inhibitor was applied to study the involvement of NOX4 in USP7-mediated OA development. USP7 inhibitor was given to OA animals to further investigate the role of USP7 in OA in vivo. Moreover, H2O2 treatment significantly increased USP7 expression, enhanced ROS levels, and inhibited proliferation in rat chondrocytes. The overexpression of USP7 enhanced pyroptosis, ROS production, interleukin (IL)-1β and IL-18 levels, and the expression level of NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, matrix metalloproteinases (MMP) 1, and MMP13, which was abolished by ROS inhibition. The USP7 KD protected rat chondrocytes against H2O2-induced injury. Co-IP results showed that USP7 interacted with NOX4, and USP7 KD enhanced NOX4 ubiquitinylation. The inhibition of NOX4 blocked the pro-OA effect of USP7. Moreover, the USP7 inhibitor given to OA animals suppressed OA in vivo. USP7 inhibited NOX4 ubiquitination for degradation which leads to elevated ROS production. ROS subsequently activates NLPR3 inflammasome, leading to enhanced production of IL-1β and IL-18, GSDMD-N-dependent pyroptosis, and extracellular matrix remodeling. Thus, UPS7 contributes to the progression of OA via NOX4/ROS/NLPR3 axis.

Keywords:  Pyroptosis; inflammation; osteoarthritis; reactive oxygen species; ubiquitin-specific proteases

DOI:  https://doi.org/10.3389/fphar.2020.617270
Cell Death Dis. 2021 Feb 16. 12(2): 189

Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.

Muyun Liu, Dan Wang, Yongde Luo, Lianghao Hu, Yawei Bi, Juntao Ji, Haojie Huang, Guoqiang Wang, Liang Zhu, Jianjia Ma, Eunice Kim, Catherine K Luo, James L Abbruzzese, Xiaokun Li, Vincent W Yang, Zhaoshen Li, Weiqin Lu.

Oncogenic RAS is a critical driver for the initiation and progression of several types of cancers. However, effective therapeutic strategies by targeting RAS, in particular RASG12D and RASG12V, and associated downstream pathways have been so far unsuccessful. Treatment of oncogenic RAS-ravaged cancer patients remains a currently unmet clinical need. Consistent with a major role in cancer metabolism, oncogenic RAS activation elevates both reactive oxygen species (ROS)-generating NADPH oxidase (NOX) activity and ROS-scavenging glutathione biosynthesis. At a certain threshold, the heightened oxidative stress and antioxidant capability achieve a higher level of redox balance, on which cancer cells depend to gain a selective advantage on survival and proliferation. However, this prominent metabolic feature may irrevocably render cancer cells vulnerable to concurrent inhibition of both NOX activity and glutathione biosynthesis, which may be exploited as a novel therapeutic strategy. In this report, we test this hypothesis by treating the HRASG12V-transformed ovarian epithelial cells, mutant KRAS-harboring pancreatic and colon cancer cells of mouse and human origins, as well as cancer xenografts, with diphenyleneiodonium (DPI) and buthionine sulfoximine (BSO) combination, which inhibit NOX activity and glutathione biosynthesis, respectively. Our results demonstrate that concomitant targeting of NOX and glutathione biosynthesis induces a highly potent lethality to cancer cells harboring oncogenic RAS. Therefore, our studies provide a novel strategy against RAS-bearing cancers that warrants further mechanistic and translational investigation.

DOI: https://doi.org/10.1038/s41419-021-03473-6
Exp Neurol. 2021 Feb 15. pii: S0014-4886(21)00047-9. [Epub ahead of print] 113642

Neuroprotective roles of HAX-1 in ischemic neuronal injury.

Xin Sui, Hideyuki Yoshioka, Yuichiro Fukumoto, Kazuya Kanemaru, Hiroyuki Kinouchi.

  Hematopoietic cell-specific protein 1 associated protein X-1 (HAX-1) is a novel mitochondrial protein that regulates oxidative stress-induced apoptosis. However, the roles of HAX-1 in ischemic neuronal injury have not been thoroughly elucidated. In this study, the expression and roles of HAX-1 after ischemic stress were investigated using in vivo and in vitro models. The effect of oxidative stress on the regulation of HAX-1 was examined using knockout mice lacking nicotinamide-adenine dinucleotide phosphate oxidase 2 (NOX2), which is a major source of reactive oxygen species (ROS) after cerebral ischemia. Male C57BL/6 J mice were subjected to transient forebrain ischemia induced by 22-min occlusion of the bilateral common carotid arteries, and striatum samples were analyzed. For in vitro ischemic experiments, oxygen and glucose deprivation (OGD) in a rat pheochromocytoma cell line was utilized. Western blotting and immunofluorescence analysis revealed HAX-1 expression in neuronal mitochondria, which was significantly decreased after ischemia in vivo and in vitro. In NOX2 knockout mice, ischemia-induced decrease in HAX-1 expression and ischemic neuronal injury was significantly alleviated compared to those in wild-type mice. Inhibition of HAX-1 using small interfering RNA significantly increased injury in cultured cells after OGD. These findings suggest that HAX-1 has a neuroprotective effect against ischemic neuronal injury, and downregulation of HAX-1 by NOX2-produced ROS induces apoptosis after cerebral ischemia.

Keywords:  Apoptosis; Brain ischemia; HAX-1; Mitochondria; NADPH oxidase

DOI:  https://doi.org/10.1016/j.expneurol.2021.113642
Antioxidants (Basel). 2021 Jan 25. pii: 172. [Epub ahead of print]10(2):

Novel and Converging Ways of NOX2 and SOD3 in Trafficking and Redox Signaling in Macrophages.

Steen Vang Petersen, Nanna Bach Poulsen, Cecilie Linneberg Matthiesen, Frederik Vilhardt.

  Macrophages and related tissue macrophage populations use the classical NADPH oxidase (NOX2) for the regulated production of superoxide and derived oxidants for pathogen combat and redox signaling. With an emphasis on macrophages, we discuss how sorting into secretory storage vesicles, agonist-responsive membrane trafficking, and segregation into sphingolipid and cholesterol-enriched microdomains (lipid rafts) determine the subcellular distribution and spatial organization of NOX2 and superoxide dismutase-3 (SOD3). We discuss how inflammatory activation of macrophages, in part through small GTPase Rab27A/B regulation of the secretory compartments, mediates the coalescence of these two proteins on the cell surface to deliver a focalized hydrogen peroxide output. In interplay with membrane-embedded oxidant transporters and redox sensitive target proteins, this arrangement allows for the autocrine and paracrine signaling, which govern macrophage activation states and transcriptional programs. By discussing examples of autocrine and paracrine redox signaling, we highlight why formation of spatiotemporal microenvironments where produced superoxide is rapidly converted to hydrogen peroxide and conveyed immediately to reach redox targets in proximal vicinity is required for efficient redox signaling. Finally, we discuss the recent discovery of macrophage-derived exosomes as vehicles of NOX2 holoenzyme export to other cells.

Keywords:  NOX2; Rab27; SOD3; cellular sorting; hydrogen peroxide; macrophages; membrane trafficking; redox signaling; superoxide

DOI:  https://doi.org/10.3390/antiox10020172
Redox Biol. 2021 Feb 05. pii: S2213-2317(21)00039-2. [Epub ahead of print] 101891

Immune cell - produced ROS and their impact on tumor growth and metastasis.

Kilian B Kennel, Florian R Greten.

  Reactive oxygen species (ROS) are derivatives of molecular oxygen (O2) involved in various physiological and pathological processes. In immune cells, ROS are mediators of pivotal functions such as phagocytosis, antigen presentation and recognition, cytolysis as well as phenotypical differentiation. Furthermore, ROS exert immunosuppressive effects on T and natural killer (NK) cells which is of particular importance in the so-called "tumor microenvironment" (TME) of solid tumors. This term describes the heterogenous group of non-malignant cells including tumor-associated fibroblasts and immune cells, vascular cells, bacteria etc. by which cancer cells are surrounded and with whom they engage in functional crosstalk. Importantly, pharmacological targeting of the TME and, specifically, tumor-associated immune cells utilizing immune checkpoint inhibitors - monoclonal antibodies that mitigate immunosuppression - turned out to be a major breakthrough in the treatment of malignant tumors. In this review, we aim to give an overview of the role that ROS produced in tumor-associated immune cells play during initiation, progression and metastatic outgrowth of solid cancers. Finally, we summarize findings on how ROS in the TME could be targeted therapeutically to increase the efficacy of cancer immunotherapy and discuss factors determining therapeutic success of redox modulation in tumors.

Keywords:  Immune cells; ROS; TME

DOI:  https://doi.org/10.1016/j.redox.2021.101891
Redox Biol. 2021 Feb 10. pii: S2213-2317(21)00036-7. [Epub ahead of print] 101888

The glyco-redox interplay: Principles and consequences on the role of reactive oxygen species during protein glycosylation.

Fawzi Khoder-Agha, Thomas Kietzmann.

  Reactive oxygen species (ROS) carry out prime physiological roles as intracellular signaling agents, yet pathologically high concentrations of ROS cause irreversible damage to biomolecules, alter cellular programs and contribute to various diseases. While decades of intensive research have identified redox-related patterns and signaling pathways, very few addressed how the glycosylation machinery senses and responds to oxidative stress. A common trait among ROS and glycans residing on glycoconjugates is that they are both highly dynamic, as they are quickly fine-tuned in response to stressors such as inflammation, cancer and infectious diseases. On this account, the delicate balance of the redox potential, which is tightly regulated by dozens of enzymes including NOXs, and the mitochondrial electron transport chain as well as the fluidity of glycan biosynthesis resulting from the cooperation of glycosyltransferases, glycosidases, and nucleotide sugar transporters, is paramount to cell survival. Here, we review the broad spectrum of the interplay between redox changes and glycosylation with respect to their principle consequences on human physiology.

Keywords:  CGD; Endoplasmic reticulum; Glycosylation; Golgi; Hypoxia; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2021.101888
Life Sci. 2021 Feb 15. pii: S0024-3205(21)00225-3. [Epub ahead of print] 119240

Activation of NADPH oxidase mediates mitochondrial oxidative stress and atrial remodeling in diabetic rabbits.

Lingling Zhou, Yang Liu, Zhaojia Wang, Daiqi Liu, Bingxin Xie, Yue Zhang, Meng Yuan, Gary Tse, Guangping Li, Gang Xu, Tong Liu.

   AIMS: The mechanisms of atrial fibrillation (AF) in diabetes mellitus (DM) involve a complex interplay between increased oxidative stress, mitochondrial dysfunction and atrial remodeling. In this study, we examined the effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation on mitochondrial oxidative stress and atrial remodeling in a rabbit model of diabetes mellitus (DM).
MAIN METHODS: Healthy rabbits were selected and randomly divided into control, diabetic and apocynin administration group. Parameters of echocardiography, atrial electrophysiology, oxidative stress and mitochondrial function were compared between the different groups.
KEY FINDINGS: Compared to the control group, the DM group showed higher activity of NADPH oxidase, increased oxidative stress, larger left atrial diameter, a reduction in atrial mean conduction velocity. These findings were associated with increased interstitial fibrosis of the atria and higher atrial fibrillation (AF) inducibility. Moreover, atrial ultrastructure and mitochondrial function such as the mitochondrial respiratory control rate (RCR) were impaired. NADPH oxidase inhibition using the pharmacological agent apocynin improved these changes.
SIGNIFICANCE: NADPH oxidase activity plays an important role in mitochondrial oxidative stress, which is associated with AF inducibility by promoting adverse atrial remodeling. The NADPH oxidase inhibitor apocynin can prevent these pathological changes and may be a potential drug for AF treatment.

Keywords:  Apocynin; Atrial remodeling; Diabetes mellitus; Mitochondrial oxidative stress; NADPH oxidase

DOI:  https://doi.org/10.1016/j.lfs.2021.119240
Free Radic Biol Med. 2021 Feb 13. pii: S0891-5849(21)00074-5. [Epub ahead of print]

Redox signaling as a modulator of germline stem cell behavior: Implications for regenerative medicine.

Rafael Sênos Demarco, D Leanne Jones.

  Germline stem cells (GSCs) are crucial for the generation of gametes and propagation of the species. Both intrinsic signaling pathways and environmental cues are employed in order to tightly control GSC behavior, including mitotic divisions, the choice between self-renewal or onset of differentiation, and survival. Recently, oxidation-reduction (redox) signaling has emerged as an important regulator of GSC and gamete behavior across species. In this review, we will highlight the primary mechanisms through which redox signaling acts to influence GSC behavior in different model organisms (Caenorhabditis elegans, Drosophila melanogaster and Mus musculus). In addition, we will summarize the latest research on the use of antioxidants to support mammalian spermatogenesis and discuss potential strategies for regenerative medicine in humans to enhance reproductive fitness.

Keywords:  ROS; germline stem cells; reactive oxygen species; redox; spermatogonial stem cells

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.02.001
Cell Calcium. 2021 Feb 06. pii: S0143-4160(21)00008-7. [Epub ahead of print]95 102354

In the right place at the right time: ROS and Ca2+ are allies in the battle for survival.

Cristina Mammucari.

  Both Ca2+ and reactive oxygen species (ROS) are double face entities, acting as signaling messengers or cell fate determinants according to their concentration and to spatial temporal restrictions. Recently, Beretta and colleagues found that ROS generated at ER-mitochondria contact sites (MAMs) support cell survival in stress conditions by decreasing inter-organelle Ca2+ transfer.

Keywords:  Akt; Calcium; Endoplasmic reticulum; I/R injury; IP3R; Mitochondria; Nox4; PP2a; ROS

DOI:  https://doi.org/10.1016/j.ceca.2021.102354
Moscow Univ Biol Sci Bull. 2020 ;75(4): 173-188

Neutrophil Extracellular Traps: New Aspects.

N V Vorobjeva.

  Neutrophils are the "first line" of defense against pathogens in the locus of inflammation, where they use effector functions such as phagocytosis, degranulation, and formation of reactive oxygen species (ROS). In 2004, Artuto Zychlinsky characterized one more neutrophil effector function-the release of neutrophil extracellular traps (or NETs). NETs are a modified chromatin "decorated" by bactericidal proteins of granules, nucleus, and cytoplasm. The release of NETs can be activated by diverse physiological and pharmacological stimuli and depends on ROS, for which NADPH oxidase is the main source. In the process of NET formation, the release of bactericidal components of granules into the cytoplasm, modification of histones leading to chromatin decondensation, destruction of the nuclear envelope and cytoplasmic membrane with the involvement of gasdermin D protein, and, finally, the release of chromatin outside the cell occurs. At the same time, uncontrolled formation of NETs is a provoking factor in the development of many inflammatory and autoimmune diseases. NETs were found at autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and vasculitis; NETs are involved in the pathogenesis of cardiovascular, pulmonary, and oncological diseases. In this review, the main ideas about the mechanisms of NET formation, as well as their role in physiological processes and pathogenesis of a number of diseases (including COVID-19), are discussed.

Keywords:  NADPH oxidase; NETosis; neutrophil; neutrophil extracellular traps; reactive oxygen species; sepsis; thrombosis

DOI:  https://doi.org/10.3103/S0096392520040112