bims-noxint 2021-07-04 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2021–07–04
ten papers selected by
Laia Caja Puigsubira, Uppsala University

NADPH Oxidases (NOX): An Overview from Discovery, Molecular Mechanisms to Physiology and Pathology.
Targeting MicroRNA-192-5p, a Downstream Effector of NOXs (NADPH Oxidases), Reverses Endothelial DHFR (Dihydrofolate Reductase) Deficiency to Attenuate Abdominal Aortic Aneurysm Formation.
NADPH Oxidase (NOX) Targeting in Diabetes: A Special Emphasis on Pancreatic β-Cell Dysfunction.
NADPH Oxidases: Redox Regulators of Stem Cell Fate and Function.
The Role of Oxidative Stress in NAFLD-NASH-HCC Transition-Focus on NADPH Oxidases.
NOX4 Signaling Mediates Cancer Development and Therapeutic Resistance through HER3 in Ovarian Cancer Cells.
Oxidative stress in corneal stromal cells contributes to the development of keratoconus in a rabbit model.
Upregulation of miR-210-5p impairs dead cell clearance by macrophages through the inhibition of Sp1-and HSCARG-dependent NADPH oxidase pathway.
Exosomes from human umbilical cord mesenchymal stem cells inhibit ROS production and cell apoptosis in human articular chondrocytes via the miR-100-5p/NOX4 axis.
DRD4 (Dopamine D4 Receptor) Mitigate Abdominal Aortic Aneurysm via Decreasing P38 MAPK (mitogen-activated protein kinase)/NOX4 (NADPH Oxidase 4) Axis-Associated Oxidative Stress.

Antioxidants (Basel). 2021 Jun 01. pii: 890. [Epub ahead of print]10(6):

NADPH Oxidases (NOX): An Overview from Discovery, Molecular Mechanisms to Physiology and Pathology.

Annelise Vermot, Isabelle Petit-Härtlein, Susan M E Smith, Franck Fieschi.

  The reactive oxygen species (ROS)-producing enzyme NADPH oxidase (NOX) was first identified in the membrane of phagocytic cells. For many years, its only known role was in immune defense, where its ROS production leads to the destruction of pathogens by the immune cells. NOX from phagocytes catalyzes, via one-electron trans-membrane transfer to molecular oxygen, the production of the superoxide anion. Over the years, six human homologs of the catalytic subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the NOX2/gp91phox component present in the phagocyte NADPH oxidase assembly itself, the homologs are now referred to as the NOX family of NADPH oxidases. NOX are complex multidomain proteins with varying requirements for assembly with combinations of other proteins for activity. The recent structural insights acquired on both prokaryotic and eukaryotic NOX open new perspectives for the understanding of the molecular mechanisms inherent to NOX regulation and ROS production (superoxide or hydrogen peroxide). This new structural information will certainly inform new investigations of human disease. As specialized ROS producers, NOX enzymes participate in numerous crucial physiological processes, including host defense, the post-translational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. These diversities of physiological context will be discussed in this review. We also discuss NOX misregulation, which can contribute to a wide range of severe pathologies, such as atherosclerosis, hypertension, diabetic nephropathy, lung fibrosis, cancer, or neurodegenerative diseases, giving this family of membrane proteins a strong therapeutic interest.

Keywords:  electron transfer; membrane protein; modular proteins; oxidative stress; reactive oxygen species; signaling molecule

DOI:  https://doi.org/10.3390/antiox10060890
Hypertension. 2021 Jun 28. HYPERTENSIONAHA12015070

Targeting MicroRNA-192-5p, a Downstream Effector of NOXs (NADPH Oxidases), Reverses Endothelial DHFR (Dihydrofolate Reductase) Deficiency to Attenuate Abdominal Aortic Aneurysm Formation.

Kai Huang, Taro Narumi, Yixuan Zhang, Qiang Li, Priya Murugesan, Yusi Wu, Norika Mengchia Liu, Hua Cai.

  We have shown that endothelial-specific DHFR (dihydrofolate reductase) deficiency underlies eNOS (endothelial NO synthase) uncoupling and formation of abdominal aortic aneurysm (AAA). Here, we examined a novel role of microRNA-192-5p in mediating NOX (NADPH oxidase)-dependent DHFR deficiency and AAA formation. microRNA-192-5p is predicted to target DHFR. Intriguingly, homo sapiens-microRNA-192-5p expression was substantially upregulated in human patients with AAA. In human aortic endothelial cells exposed to hydrogen peroxide (H2O2), homo sapiens-microRNA-192-5p expression was significantly upregulated. This was accompanied by a marked downregulation in DHFR mRNA and protein expression, which was restored by homo sapiens-microRNA-192-5p-specific inhibitor. Of note, microRNA-192-5p expression was markedly upregulated in Ang II (angiotensin II)-infused hph-1 (hyperphenylalaninemia 1) mice, which was attenuated in hph-1-NOX1, hph-1-NOX2, hph-1-neutrophil cytosol factor 1, and hph-1-NOX4 double mutant mice where AAA incidence was also abrogated, indicating a downstream effector role of microRNA-192-5p following NOX activation. In vivo treatment with mus musculus-microRNA-192-5p inhibitor attenuated expansion of abdominal aortas in Ang II-infused hph-1 mice as defined by ultrasound and postmortem inspection. It also reversed features of vascular remodeling including matrix degradation, adventitial hypertrophy, and formation of intraluminal thrombi. These animals had restored DHFR mRNA and protein expression, attenuated superoxide production, recoupled eNOS, and preserved NO bioavailability. In conclusion, our data for the first time demonstrate a critical role of microRNA-192-5p in mediating NOX-dependent DHFR deficiency and AAA formation, inhibition of which is robustly effective in attenuating development of AAA. Since the mouse and human microRNA-192-5p sequences are identical, the microRNA-192-5p inhibitors may be readily translatable into novel therapeutics for the treatment of AAA.

Keywords:  NADPH oxidase; angiotensin II; aortic aneurysm, abdominal; dihydrofolate reductase; endothelial nitric oxide synthase; microRNA; oxidative stress

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.120.15070
Cells. 2021 Jun 22. pii: 1573. [Epub ahead of print]10(7):

NADPH Oxidase (NOX) Targeting in Diabetes: A Special Emphasis on Pancreatic β-Cell Dysfunction.

Suma Elumalai, Udayakumar Karunakaran, Jun-Sung Moon, Kyu-Chang Won.

  In type 2 diabetes, metabolic stress has a negative impact on pancreatic β-cell function and survival (T2D). Although the pathogenesis of metabolic stress is complex, an imbalance in redox homeostasis causes abnormal tissue damage and β-cell death due to low endogenous antioxidant expression levels in β-cells. Under diabetogenic conditions, the susceptibility of β-cells to oxidative damage by NADPH oxidase has been related to contributing to β-cell dysfunction. Here, we consider recent insights into how the redox response becomes deregulated under diabetic conditions by NADPH oxidase, as well as the therapeutic benefits of NOX inhibitors, which may provide clues for understanding the pathomechanisms and developing strategies aimed at the treatment or prevention of metabolic stress associated with β-cell failure.

Keywords:  NADPH oxidase; diabetes mellitus; insulin-secreting cells; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.3390/cells10071573
Antioxidants (Basel). 2021 Jun 17. pii: 973. [Epub ahead of print]10(6):

NADPH Oxidases: Redox Regulators of Stem Cell Fate and Function.

Tullia Maraldi, Cristina Angeloni, Cecilia Prata, Silvana Hrelia.

  One of the major sources of reactive oxygen species (ROS) generated within stem cells is the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes (NOXs), which are critical determinants of the redox state beside antioxidant defense mechanisms. This balance is involved in another one that regulates stem cell fate: indeed, self-renewal, proliferation, and differentiation are decisive steps for stem cells during embryo development, adult tissue renovation, and cell therapy application. Ex vivo culture-expanded stem cells are being investigated for tissue repair and immune modulation, but events such as aging, senescence, and oxidative stress reduce their ex vivo proliferation, which is crucial for their clinical applications. Here, we review the role of NOX-derived ROS in stem cell biology and functions, focusing on positive and negative effects triggered by the activity of different NOX isoforms. We report recent findings on downstream molecular targets of NOX-ROS signaling that can modulate stem cell homeostasis and lineage commitment and discuss the implications in ex vivo expansion and in vivo engraftment, function, and longevity. This review highlights the role of NOX as a pivotal regulator of several stem cell populations, and we conclude that these aspects have important implications in the clinical utility of stem cells, but further studies on the effects of pharmacological modulation of NOX in human stem cells are imperative.

Keywords:  NADPH oxidases; reactive oxygen species; stem cells

DOI:  https://doi.org/10.3390/antiox10060973
Biomedicines. 2021 Jun 17. pii: 687. [Epub ahead of print]9(6):

The Role of Oxidative Stress in NAFLD-NASH-HCC Transition-Focus on NADPH Oxidases.

Daniela Gabbia, Luana Cannella, Sara De Martin.

  A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.

Keywords:  NADPH oxidases; NAFLD; NASH; NOX; hepatocellular carcinoma HCC; oxidative stress

DOI:  https://doi.org/10.3390/biomedicines9060687
Cells. 2021 Jun 30. pii: 1647. [Epub ahead of print]10(7):

NOX4 Signaling Mediates Cancer Development and Therapeutic Resistance through HER3 in Ovarian Cancer Cells.

Wen-Jing Liu, Ying-Xue Huang, Wei Wang, Ye Zhang, Bing-Jie Liu, Jian-Ge Qiu, Bing-Hua Jiang, Ling-Zhi Liu.

  Development of resistance to therapy in ovarian cancer is a major hinderance for therapeutic efficacy; however, new mechanisms of the resistance remain to be elucidated. NADPH oxidase 4 (NOX4) is responsible for higher NADPH activity to increase reactive oxygen species (ROS) production. In this study, we showed that higher levels of NOX4 were detected in a large portion of human ovarian cancer samples. To understand the molecular mechanism of the NOX4 upregulation, we showed that NOX4 expression was induced by HIF-1α and growth factor such as IGF-1. Furthermore, our results indicated that NOX4 played a pivotal role in chemotherapy and radiotherapy resistance in ovarian cancer cells. We also demonstrated that NOX4 knockdown increased sensitivity of targeted therapy and radiotherapy through decreased expression of HER3 (ERBB3) and NF-κB p65. Taken together, we identified a new HIF-1α/NOX4 signal pathway which induced drug and radiation resistance in ovarian cancer. The finding may provide a new option to overcome the therapeutic resistance of ovarian cancer in the future.

Keywords:  HER3; HIF-1α; NOX4; ovarian cancer; therapeutic resistance

DOI:  https://doi.org/10.3390/cells10071647
Eur J Ophthalmol. 2021 Jul 02. 11206721211028745

Oxidative stress in corneal stromal cells contributes to the development of keratoconus in a rabbit model.

Ruixing Liu, Xiaoming Yan.

   PURPOSE: To investigate the role of oxidative stress in keratocytes in the pathogenesis of keratoconus (KC) using the rabbit cornea as a model.
METHODS: Immerse the rabbit cornea in collagenase type II solution at room temperature for 30 min in the KC group. The central cornea thickness (CCT), and mean keratometry (Km) were examined before and after the procedure. Reactive oxygen species (ROS), the nuclear translocation of nuclear factor E2-related factor 2 (NRF-2), the expression of heme oxygenase-1 (HO-1) protein, and nicotinamide adenine dinucleotide phosphate (NADPH) Oxidase (NOX) family members NOX-2 and NOX-4 protein levels were examined by immunohistochemistry analysis and Western Blot. The expression levels of HO-1, NOX-2, NOX-4, and NRF-2 mRNA were quantitatively detected by Real-time PCR.
RESULTS: A significant increase in Km and a significant decrease in CCT were observed in the KC group compared with the control group after the surgery (both p < 0.001). Immunofluorescence staining showed the rabbit KC model induced a significant increase in ROS production (p < 0.001). The expression of HO-1, NOX-2, NOX-4, and NRF-2 proteins in the KC group were significantly higher than those in the control group (all p < 0.001). RT-PCR results showed the levels of HO-1, NOX-2, NOX-4, and NRF-2 mRNA in KC groups were all significantly increased compared with control groups (all p < 0.05).
CONCLUSIONS: Oxidative stress and compensatory activation of antioxidant proteins suggest oxidative stress injury in corneal stromal cells plays an important role in the development of KC in a rabbit model.

Keywords:  Keratoconus rabbits; NADPH oxidase; corneal stromal cells; heme oxygenase-1; oxidative stress

DOI:  https://doi.org/10.1177/11206721211028745
Free Radic Biol Med. 2021 Jun 28. pii: S0891-5849(21)00394-4. [Epub ahead of print]

Upregulation of miR-210-5p impairs dead cell clearance by macrophages through the inhibition of Sp1-and HSCARG-dependent NADPH oxidase pathway.

Yi-Hsuan Wu, Chang-Fu Kuo, Ao-Ho Hsieh, Hsi-Lung Hsieh, Yen-Fan Chan, Tsong-Long Hwang.

  The deficiency of dead cell clearance is a prominent pathogenic factor in systemic lupus erythematosus (SLE). In this study, the overexpression of miR-210-5p resulted in the accumulation of secondary necrotic cells (SNECs) in macrophages through the reduction of protein degradation. The upreguation of miR-210-5p inhibited NADPH oxidase (NOX) activation, reactive oxygen species (ROS) generation, and SNEC clearance. miR-210-5p overexpression suppressed Sp1 and HSCARG expression, and the knockdown of SP1 and HSCARG inhibited NOX expression and superoxide production in macrophages. Furthermore, patients with active SLE expressed a higher level of miR-210-5p and lower expression of SP1 and HSCARG in peripheral blood mononuclear cells. In summary, our findings indicate that the upregulation of miR-210-5p increases the accumulation of SNECs through a decrease in the Sp1-and HSCARG-mediated NOX activity and ROS generation in macrophages. Our results also suggest that targeting miR-210-5p may have therapeutic potential for SLE.

Keywords:  Dead cell clearance; NOX signaling; Systemic lupus erythematosus; miR-210–5p

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.06.029
Cell Biol Int. 2021 Jul 01.

Exosomes from human umbilical cord mesenchymal stem cells inhibit ROS production and cell apoptosis in human articular chondrocytes via the miR-100-5p/NOX4 axis.

Xiang Li, Yuanyuan Wang, Zhuyun Cai, Qi Zhou, Lexiang Li, Peiliang Fu.

  Cyclic strain-induced chondrocyte damage is actively involved in the pathogenesis of osteoarthritis and arthritis. MicroRNAs (miRNAs) carried by exosomes have been implicated in various diseases. However, the role of miR-100-5p in cyclic strain-induced chondrocyte damage remains to be elucidated. miR-100-5p and NADPH oxidase 4 (NOX4) were silenced or overexpressed in human primary articular chondrocytes. PKH-67 Dye was used to trace exosome endocytosis. Reactive oxygen species (ROS) production was monitored using DCFH-DA. Cell apoptosis was measured using a flow cytometer. Quantitative RT-PCR and western blots were used to evaluate gene expression. Cyclic strain promoted ROS production and apoptosis in primary articular chondrocytes in a time-dependent manner. HucMSCs-derived exosomal miR-100-5p inhibited cyclic strain-induced ROS production and apoptosis in primary articular chondrocytes. miR-100-5p directly targeted NOX4. Overexpressing NOX4 attenuated hucMSCs-derived exosomes-mediated protective effects in primary articular chondrocytes. Cyclic strain promotes ROS production and apoptosis in primary articular chondrocytes which was abolished by hucMSCs-derived exosomal miR-100-5p through its target NOX4. The findings highlight the importance of miR-100-5p/NOX4 axis in primary articular chondrocytes injury and provide new insights into therapeutic strategies for articular chondrocytes injury and osteoarthritis. This article is protected by copyright. All rights reserved.

Keywords:  arthritis; cartilage; cyclic strain; exosome; miR-100-5p; oxidative stress

DOI:  https://doi.org/10.1002/cbin.11657
Hypertension. 2021 Jun 28. HYPERTENSIONAHA12016738

DRD4 (Dopamine D4 Receptor) Mitigate Abdominal Aortic Aneurysm via Decreasing P38 MAPK (mitogen-activated protein kinase)/NOX4 (NADPH Oxidase 4) Axis-Associated Oxidative Stress.

Xuesong Liu, Yansong Guo, Yuxue Yang, Chunlei Qi, Ting Xiong, Yue Chen, Gengze Wu, Chunyu Zeng, Daxin Wang.

  Oxidative stress plays a vital role in the development of abdominal aortic aneurysm (AAA). DRD4 (dopamine D4 receptor) is involved in oxidative stress. Here, we reasoned that DRD4 may mitigate AAA by its antioxidative effect. Currently, in vivo, DRD4 expression was reduced in AAA patients and experimental models determined by quantitative polymerase chain reaction and Western blot. Reactive oxygen species (ROS) was increased in elastase perfused aorta from Drd4-/- mice compared with elastase perfused wild-type (WT) aorta determined by dihydroethidium staining and malondialdehyde, accompanying with more apoptotic vascular smooth muscle cells, inflammatory infiltration, and ECM (extracellular matrix) degradation determined by terminal deoxynucleotidyl transferase-mediated nick end labeling assay, immunohistochemistry, Van Gieson staining, and zymography, respectively. However, pharmacological activation of DRD4 reduced the ROS production and mitigated pathological characteristics of AAA. In vitro, activated DRD4 alleviated ROS production and apoptosis determined by 2,7-dichlorodihydrofluorescein diacetate, dihydroethidium, malondialdehyde, and flow cytometry, whereas DRD4 deficiency or inhibited DRD4 exerted the opposite effect in vascular smooth muscle cells. In terms of mechanism, in vivo, DRD4 deficiency upregulated NOX4 (NADPH oxidase 4) expression instead of other subunits, meanwhile, phosphorylated P38 mitogen-activated protein kinase was also augmented instead of other mitogen-activated protein kinase pathways. In vitro, pharmacological activation of DRD4 downregulated phosphorylated P38 and NOX4 in vascular smooth muscle cells, vice versa. Interestingly, DRD4 mediated the expression of NOX4 through a P38 mitogen-activated protein kinase pathway-dependent manner, which regulated ROS production. DRD4 mitigated AAA progression by downregulating P38 mitogen-activated protein kinase/NOX4 axis mediated ROS production in vascular smooth muscle cells. Therefore, DRD4 may serve as a novel therapeutic target for AAA treatment.

Keywords:  NADPH oxidase 4; aortic aneurysm, abdominal; dopamine D4 receptor; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.120.16738