bims-noxint 2022-06-26 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2022–06–26
nine papers selected by
Laia Caja Puigsubira, Uppsala University

NADPH Oxidases in Pain Processing.
Inhibiting NADPH Oxidases to Target Vascular and Other Pathologies: An Update on Recent Experimental and Clinical Studies.
Yin and Yang of NADPH Oxidases in Myocardial Ischemia-Reperfusion.
NADPH oxidase-2 is necessary for chronic intermittent hypoxia-induced sternohyoid muscle weakness in adult male mice.
The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity.
NADPH Oxidases Connecting Fatty Liver Disease, Insulin Resistance and Type 2 Diabetes: Current Knowledge and Therapeutic Outlook.
Toxic effects of nanoplastics with different sizes and surface charges on epithelial-to-mesenchymal transition in A549 cells and the potential toxicological mechanism.
ROS and miRNA Dysregulation in Ovarian Cancer Development, Angiogenesis and Therapeutic Resistance.
Activation of the MAC1-ERK1/2-NOX2 Pathway Is Required for LPS-Induced Sustaining Reactive Microgliosis, Chronic Neuroinflammation and Neurodegeneration.

Antioxidants (Basel). 2022 Jun 14. pii: 1162. [Epub ahead of print]11(6):

NADPH Oxidases in Pain Processing.

Wiebke Kallenborn-Gerhardt, Katrin Schröder, Achim Schmidtko.

  Inflammation or injury to the somatosensory nervous system may result in chronic pain conditions, which affect millions of people and often cause major health problems. Emerging lines of evidence indicate that reactive oxygen species (ROS), such as superoxide anion or hydrogen peroxide, are produced in the nociceptive system during chronic inflammatory and neuropathic pain and act as specific signaling molecules in pain processing. Among potential ROS sources in the somatosensory system are NADPH oxidases, a group of electron-transporting transmembrane enzymes whose sole function seems to be the generation of ROS. Interestingly, the expression and relevant function of the Nox family members Nox1, Nox2, and Nox4 in various cells of the nociceptive system have been demonstrated. Studies using knockout mice or specific knockdown of these isoforms indicate that Nox1, Nox2, and Nox4 specifically contribute to distinct signaling pathways in chronic inflammatory and/or neuropathic pain states. As selective Nox inhibitors are currently being developed and investigated in various physiological and pathophysiological settings, targeting Nox1, Nox2, and/or Nox4 could be a novel strategy for the treatment of chronic pain. Here, we summarize the distinct roles of Nox1, Nox2, and Nox4 in inflammatory and neuropathic processing and discuss the effectiveness of currently available Nox inhibitors in the treatment of chronic pain conditions.

Keywords:  NADPH oxidase; Nox; Nox inhibition; inflammation; neuropathy; nociception; pain; peripheral injury

DOI:  https://doi.org/10.3390/antiox11061162
Biomolecules. 2022 Jun 13. pii: 823. [Epub ahead of print]12(6):

Inhibiting NADPH Oxidases to Target Vascular and Other Pathologies: An Update on Recent Experimental and Clinical Studies.

Anthony L Sylvester, David X Zhang, Sophia Ran, Natalya S Zinkevich.

  Reactive oxygen species (ROS) can be beneficial or harmful in health and disease. While low levels of ROS serve as signaling molecules to regulate vascular tone and the growth and proliferation of endothelial cells, elevated levels of ROS contribute to numerous pathologies, such as endothelial dysfunctions, colon cancer, and fibrosis. ROS and their cellular sources have been extensively studied as potential targets for clinical intervention. Whereas various ROS sources are important for different pathologies, four NADPH oxidases (NOX1, NOX2, NOX4, and NOX5) play a prominent role in homeostasis and disease. NOX1-generated ROS have been implicated in hypertension, suggesting that inhibition of NOX1 may be a promising therapeutic approach. NOX2 and NOX4 oxidases are of specific interest due to their role in producing extra- and intracellular hydrogen peroxide (H2O2). NOX4-released hydrogen peroxide activates NOX2, which in turn stimulates the release of mitochondrial ROS resulting in ROS-induced ROS release (RIRR) signaling. Increased ROS production from NOX5 contributes to atherosclerosis. This review aims to summarize recent findings on NOX enzymes and clinical trials inhibiting NADPH oxidases to target pathologies including diabetes, idiopathic pulmonary fibrosis (IPF), and primary biliary cholangitis (PBC).

Keywords:  NADPH oxidase; NOX; ROS

DOI:  https://doi.org/10.3390/biom12060823
Antioxidants (Basel). 2022 May 27. pii: 1069. [Epub ahead of print]11(6):

Yin and Yang of NADPH Oxidases in Myocardial Ischemia-Reperfusion.

Shouji Matsushima, Junichi Sadoshima.

  Oxidative stress is critically involved in the pathophysiology of myocardial ischemic-reperfusion (I/R) injury. NADPH oxidase (Nox) 2 and 4, major sources of reactive oxygen species (ROS) in cardiomyocytes, are upregulated in response to I/R. Suppression of Nox-derived ROS prevents mitochondrial dysfunction and endoplasmic reticulum (ER) stress, leading to attenuation of myocardial I/R injury. However, minimal levels of ROS by either Nox2 or Nox4 are required for energy metabolism during I/R in the heart, preserving hypoxia-inducible factor-1α (HIF-1α) and peroxisome proliferator-activated receptor-α (PPARα) levels. Furthermore, extreme suppression of Nox activity induces reductive stress, leading to paradoxical increases in ROS levels. Nox4 has distinct roles in organelles such as mitochondria, ER, and ER-mitochondria contact sites (MAMs). Mitochondrial Nox4 exerts a detrimental effect, causing ROS-induced mitochondrial dysfunction during I/R, whereas Nox4 in the ER and MAMs is potentially protective against I/R injury through regulation of autophagy and MAM function, respectively. Although Nox isoforms are potential therapeutic targets for I/R injury, to maximize the effect of intervention, it is likely important to optimize the ROS level and selectively inhibit Nox4 in mitochondria. Here, we discuss the 'Yin and Yang' functions of Nox isoforms during myocardial I/R.

Keywords:  NADPH oxidase; endoplasmic reticulum; energy metabolism; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/antiox11061069
Exp Physiol. 2022 Jun 21.

NADPH oxidase-2 is necessary for chronic intermittent hypoxia-induced sternohyoid muscle weakness in adult male mice.

Sarah E Drummond, David P Burns, Sarah El Maghrani, Oscar Ziegler, Vincent Healy, Ken D O'Halloran.

   NEW FINDINGS: What is the central question of this study? Exposure to chronic intermittent hypoxia (CIH) evokes redox changes, culminating in impaired upper airway muscle function. However, there is a paucity of information pertaining to the specific source of CIH-induced reactive active oxygen species (ROS). What is the main finding and its importance? Profound sternohyoid muscle dysfunction following exposure to CIH was entirely prevented by apocynin co-treatment or NOX2 deletion. Our results have implications for human obstructive sleep apnoea syndrome and point to antioxidant intervention, potentially targeting NOX2 blockade, as a therapeutic strategy.
ABSTRACT: Exposure to chronic intermittent hypoxia (CIH) evokes redox changes, culminating in impaired upper airway muscle function. We sought to determine if NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS) underpin CIH-induced maladaptive changes in upper airway (sternohyoid) muscle performance. Adult male mice (C57BL/6J) were assigned to one of three groups: normoxic controls (sham); chronic intermittent hypoxia-exposed (CIH, 12 cycles/hour, 8h/day for 14 days); and CIH + apocynin (NOX2 inhibitor, 2mM) given in the drinking water throughout exposure to CIH. In addition, we studied sham and CIH-exposed NOX2-null mice (B6.129S-CybbTM1Din /J ). Profound sternohyoid muscle dysfunction following exposure to CIH was entirely prevented by apocynin co-treatment or NOX2 deletion. Exposure to CIH increased sternohyoid muscle NOX enzyme activity, with no alteration to the gene or protein expression of NOX subunits. There was no evidence of overt oxidative stress, muscle regeneration, inflammation or atrophy following exposure to CIH. We suggest that NOX-dependent CIH-induced upper airway muscle weakness increases vulnerability to upper airway obstruction. Our results have implications for human obstructive sleep apnoea syndrome and point to antioxidant intervention, potentially targeting NOX2 blockade, as a therapeutic strategy. This article is protected by copyright. All rights reserved.

Keywords:  NADPH oxidase; chronic intermittent hypoxia; sternohyoid; upper airway

DOI:  https://doi.org/10.1113/EP090536
Cells. 2022 Jun 17. pii: 1951. [Epub ahead of print]11(12):

The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity.

Thaonhi Cung, Haibo Wang, M Elizabeth Hartnett.

  Retinopathy of prematurity (ROP) is a leading cause of vision impairment and blindness in premature infants. Oxidative stress is implicated in its pathophysiology. NADPH oxidase (NOX), a major enzyme responsible for reactive oxygen species (ROS) generation in endothelial cells, has been studied for its involvement in physiologic and pathologic angiogenesis. Erythropoietin (EPO) has gained interest recently due to its tissue protective and angiogenic effects, and it has been shown to act as an antioxidant. In this review, we summarize studies performed over the last five years regarding the role of various NOXs in physiologic and pathologic angiogenesis. We also discuss the effect of EPO in tissue and vasoprotection, and the intersection of EPO and NOX-mediated oxidative stress in angiogenesis and the pathophysiology of ROP.

Keywords:  EPOR; NADPH oxidase; NOX; ROP; ROS; angiogenesis; erythropoietin; oxidative stress

DOI:  https://doi.org/10.3390/cells11121951
Antioxidants (Basel). 2022 Jun 09. pii: 1131. [Epub ahead of print]11(6):

NADPH Oxidases Connecting Fatty Liver Disease, Insulin Resistance and Type 2 Diabetes: Current Knowledge and Therapeutic Outlook.

Alberto Nascè, Karim Gariani, François R Jornayvaz, Ildiko Szanto.

  Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic fat accumulation in hepatocytes, is closely linked to insulin resistance and is the most frequent complication of type 2 diabetes mellitus (T2DM). One of the features connecting NAFLD, insulin resistance and T2DM is cellular oxidative stress. Oxidative stress refers to a redox imbalance due to an inequity between the capacity of production and the elimination of reactive oxygen species (ROS). One of the major cellular ROS sources is NADPH oxidase enzymes (NOX-es). In physiological conditions, NOX-es produce ROS purposefully in a timely and spatially regulated manner and are crucial regulators of various cellular events linked to metabolism, receptor signal transmission, proliferation and apoptosis. In contrast, dysregulated NOX-derived ROS production is related to the onset of diverse pathologies. This review provides a synopsis of current knowledge concerning NOX enzymes as connective elements between NAFLD, insulin resistance and T2DM and weighs their potential relevance as pharmacological targets to alleviate fatty liver disease.

Keywords:  NADPH oxidase; NAFLD; NOX; ROS; diabetes; hepatosteatosis; insulin resistance; nonalcoholic fatty liver disease; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox11061131
J Hazard Mater. 2022 May 15. pii: S0304-3894(22)00273-4. [Epub ahead of print]430 128485

Toxic effects of nanoplastics with different sizes and surface charges on epithelial-to-mesenchymal transition in A549 cells and the potential toxicological mechanism.

Gulinare Halimu, Qianru Zhang, Li Liu, Zhichun Zhang, Xiujuan Wang, Wu Gu, Bowen Zhang, Yumeng Dai, Huiwen Zhang, Chenggang Zhang, Mingkai Xu.

  As a newly emerging hazardous material, airborne nanoplastics are easily inhaled and accumulated in human and animal alveoli. We previously found that polystyrene nanoplastics (PS-NPs) induced apoptosis and inflammation of human alveolar epithelial A549 cells, implying they increase the risk of pulmonary fibrosis. In this study, we investigated whether PS-NPs induce epithelial-to-mesenchymal transition (EMT), the prelude to lung fibrosis, in A549 cells. A549 cells treated with PS-NPs of different sizes and surface charges exhibited increased migration and EMT markers accompanied with up-regulation of reactive oxygen species (ROS) and NADPH oxidase 4 (NOX4), an ROS generator located in the mitochondria and endoplasmic reticulum (ER). Moreover, PS-NPs caused mitochondrial dysfunction as demonstrated by membrane potential changes and impaired cellular energy metabolism. PS-NPs also activated ER stress as indicated by the up-regulated ER stress markers. As expected, smaller PS-NPs with a positive surface charge had stronger effects. Furthermore, the effects of PS-NPs on A549 cells were reversed by NOX4 gene knock-down, which verified the involvement of NOX4. Our results suggest that PS-NPs induce EMT in A549 cells through multiple mechanisms, and NOX4 is a key mediator in this process. Our findings contribute to understanding the toxicological mechanisms of nanoplastics on the respiratory system.

Keywords:  Epithelial-to-mesenchymal transition; Nanoplastics; Newly-emerging hazardous material; Toxicologic mechanism

DOI:  https://doi.org/10.1016/j.jhazmat.2022.128485
Int J Mol Sci. 2022 Jun 16. pii: 6702. [Epub ahead of print]23(12):

ROS and miRNA Dysregulation in Ovarian Cancer Development, Angiogenesis and Therapeutic Resistance.

David C Stieg, Yifang Wang, Ling-Zhi Liu, Bing-Hua Jiang.

  The diverse repertoires of cellular mechanisms that progress certain cancer types are being uncovered by recent research and leading to more effective treatment options. Ovarian cancer (OC) is among the most difficult cancers to treat. OC has limited treatment options, especially for patients diagnosed with late-stage OC. The dysregulation of miRNAs in OC plays a significant role in tumorigenesis through the alteration of a multitude of molecular processes. The development of OC can also be due to the utilization of endogenously derived reactive oxygen species (ROS) by activating signaling pathways such as PI3K/AKT and MAPK. Both miRNAs and ROS are involved in regulating OC angiogenesis through mediating multiple angiogenic factors such as hypoxia-induced factor (HIF-1) and vascular endothelial growth factor (VEGF). The NAPDH oxidase subunit NOX4 plays an important role in inducing endogenous ROS production in OC. This review will discuss several important miRNAs, NOX4, and ROS, which contribute to therapeutic resistance in OC, highlighting the effective therapeutic potential of OC through these mechanisms.

Keywords:  HER3; HIF1-α; NOX4; ROS; VEGF; angiogenesis; miRNA dysregulation; ovarian cancer; therapeutic resistance

DOI:  https://doi.org/10.3390/ijms23126702
Antioxidants (Basel). 2022 Jun 20. pii: 1202. [Epub ahead of print]11(6):

Activation of the MAC1-ERK1/2-NOX2 Pathway Is Required for LPS-Induced Sustaining Reactive Microgliosis, Chronic Neuroinflammation and Neurodegeneration.

Shih-Heng Chen, Shuangyu Han, Chih-Fen Hu, Ran Zhou, Yun Gao, Dezhen Tu, Huiming Gao, Jing Feng, Yubao Wang, Ru-Band Lu, Jau-Shyong Hong.

  Recent studies suggest that improper resolution of acute neuroinflammation may lead to long-lasting low-grade chronic neuroinflammation and drive progressive neurodegeneration. However, the molecular mechanism underlying the transition from acute to chronic neuroinflammation remains unclear. The main purpose of this study was to search for potential pathways mediating LPS-elicited chronic neuroinflammation and resultant neurodegeneration. Using microglia cultures prepared from C57BL/6J, MAC1-deficient, and MyD88-deficient mice, the initial study showed that activation of TLR-4 is not sufficient for maintaining chronic neuroinflammation despite its essential role in LPS-initiated acute neuroinflammation. Opposite to TLR-4, our studies showed significantly reduced intensity of chronic neuroinflammation, oxidative stress, and progressive loss of nigral dopaminergic neurons in MAC1-deficient neuron/glial cultures or mice stimulated with LPS. Mechanistic studies revealed the essential role ERK1/2 activation in chronic neuroinflammation-elicited neurodegeneration, which was demonstrated by using an ERK1/2 inhibitor in neuron-glial cultures. Taken together, we propose a key role of the MAC1-NOX2-ERK1/2 signaling pathway in the initiation and maintenance of low-grade chronic neuroinflammation. Continuing ERK1/2 phosphorylation and NOX2 activation form a vicious feedforward cycle in microglia to maintain the low-grade neuroinflammation and drive neurodegeneration.

Keywords:  ERK1/2; MAC1 receptor; NADPH oxidase; TLR4; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.3390/antiox11061202