bims-noxint 2021-12-26 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2021‒12‒26
seven papers selected by
Laia Caja Puigsubira
Uppsala University

NOX4: a potential therapeutic target for pancreatic cancer and its mechanism.
Implication of type 4 NADPH oxidase (NOX4) in tauopathy.
Pharmacological Inhibition of NOX4 Improves Mitochondrial Function and Survival in Human Beta-Cells.
Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress.
NOX4 promotes mucosal barrier injury in inflammatory bowel disease by mediating macrophages M1 polarization through ROS.
Upregulation of NADPH Oxidase 2 Contributes to Renal Fibrosis in pcy Mice: An Experimental Model of Nephronophthisis.
NADPH Oxidase and Epidermal Growth Factor Receptor Are Promising Targets of Phytochemicals for Ultraviolet-Induced Skin Carcinogenesis.

J Transl Med. 2021 Dec 20. 19(1): 515

NOX4: a potential therapeutic target for pancreatic cancer and its mechanism.

Yawei Bi, Xiao Lei, Ningli Chai, Enqiang Linghu.

  Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is one of the seven isoforms of NOX family, which is upregulated in pancreatic cancer cell, mouse model of pancreatic cancer and human pancreatic cancer tissue. NOX4 is a constitutively active enzyme that primarily produces hydrogen peroxide, which exhibits completely different properties from other subtypes of NOX family. More importantly, recent studies illuminate that NOX4 promotes pancreatic cancer occurrence and development in different ways. This review summarizes the potential roles and its mechanism of NOX4 in pancreatic cancer and explores NOX4 as the potential therapeutic target in pancreatic cancer.

Keywords:  NADPH Oxidase 4; Pancreatic cancer; Reactive oxygen species

DOI:  https://doi.org/10.1186/s12967-021-03182-w
Redox Biol. 2021 Dec 10. pii: S2213-2317(21)00370-0. [Epub ahead of print]49 102210

Implication of type 4 NADPH oxidase (NOX4) in tauopathy.

Enrique Luengo, Paula Trigo-Alonso, Cristina Fernández-Mendívil, Ángel Nuñez, Marta Del Campo, César Porrero, Nuria García-Magro, Pilar Negredo, Sergio Senar, Cristina Sánchez-Ramos, Juan A Bernal, Alberto Rábano, Jeroen Hoozemans, Ana I Casas, Harald H H W Schmidt, Manuela G López.

  Aggregates of the microtubule-associated protein tau are a common marker of neurodegenerative diseases collectively termed as tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia. Therapeutic strategies based on tau have failed in late stage clinical trials, suggesting that tauopathy may be the consequence of upstream causal mechanisms. As increasing levels of reactive oxygen species (ROS) may trigger protein aggregation or modulate protein degradation and, we had previously shown that the ROS producing enzyme NADPH oxidase 4 (NOX4) is a major contributor to cellular autotoxicity, this study was designed to evaluate if NOX4 is implicated in tauopathy. Our results show that NOX4 is upregulated in patients with frontotemporal lobar degeneration and AD patients and, in a humanized mouse model of tauopathy induced by AVV-TauP301L brain delivery. Both, global knockout and neuronal knockdown of the Nox4 gene in mice, diminished the accumulation of pathological tau and positively modified established tauopathy by a mechanism that implicates modulation of the autophagy-lysosomal pathway (ALP) and, consequently, improving the macroautophagy flux. Moreover, neuronal-targeted NOX4 knockdown was sufficient to reduce neurotoxicity and prevent cognitive decline, even after induction of tauopathy, suggesting a direct and causal role for neuronal NOX4 in tauopathy. Thus, NOX4 is a previously unrecognized causative, mechanism-based target in tauopathies and blood-brain barrier permeable specific NOX4 inhibitors could have therapeutic potential even in established disease.

Keywords:  Alzheimer's disease; Autophagy; NADPH oxidases; NOX4; Tauopathy

DOI:  https://doi.org/10.1016/j.redox.2021.102210
Biomedicines. 2021 Dec 08. pii: 1865. [Epub ahead of print]9(12):

Pharmacological Inhibition of NOX4 Improves Mitochondrial Function and Survival in Human Beta-Cells.

Andris Elksnis, Jing Cen, Per Wikström, Per-Ola Carlsson, Nils Welsh.

  Previous studies have reported beneficial effects of NADPH oxidase 4 (NOX4) inhibition on beta-cell survival in vitro and in vivo. The mechanisms by which NOX4 inhibition protects insulin producing cells are, however, not known. The aim of the present study was to investigate the effects of a pharmacological NOX4 inhibitor (GLX7013114) on human islet and EndoC-βH1 cell mitochondrial function, and to correlate such effects with survival in islets of different size, activity, and glucose-stimulated insulin release responsiveness. We found that maximal oxygen consumption rates, but not the rates of acidification and proton leak, were increased in islets after acute NOX4 inhibition. In EndoC-βH1 cells, NOX4 inhibition increased the mitochondrial membrane potential, as estimated by JC-1 fluorescence; mitochondrial reactive oxygen species (ROS) production, as estimated by MitoSOX fluorescence; and the ATP/ADP ratio, as assessed by a bioluminescent assay. Moreover, the insulin release from EndoC-βH1 cells at a high glucose concentration increased with NOX4 inhibition. These findings were paralleled by NOX4 inhibition-induced protection against human islet cell death when challenged with high glucose and sodium palmitate. The NOX4 inhibitor protected equally well islets of different size, activity, and glucose responsiveness. We conclude that pharmacological alleviation of NOX4-induced inhibition of beta-cell mitochondria leads to increased, and not decreased, mitochondrial ROS, and this was associated with protection against cell death occurring in different types of heterogeneous islets. Thus, NOX4 inhibition or modulation may be a therapeutic strategy in type 2 diabetes that targets all types of islets.

Keywords:  NOX4; beta-cell; cell death; mitochondria

DOI:  https://doi.org/10.3390/biomedicines9121865
Cells. 2021 Nov 26. pii: 3328. [Epub ahead of print]10(12):

Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress.

Eloisa Aparecida Vilas-Boas, Davidson Correa Almeida, Leticia Prates Roma, Fernanda Ortis, Angelo Rafael Carpinelli.

  A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β-cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress.

Keywords:  ER stress; NADPH oxidase; lipotoxicity; oxidative stress; pancreatic β-cell; type 2 diabetes

DOI:  https://doi.org/10.3390/cells10123328
Int Immunopharmacol. 2021 Dec 20. pii: S1567-5769(21)00997-8. [Epub ahead of print] 108361

NOX4 promotes mucosal barrier injury in inflammatory bowel disease by mediating macrophages M1 polarization through ROS.

Chenyang Han, Yongjia Sheng, Jin Wang, Xiaohong Zhou, Wenyan Li, Caiqun Zhang, Li Guo, Yi Yang.

  NADPH oxidase 4 (NOX4) plays an important role in transporting electrons in the mitochondrial respiratory chain, which is also one major source of ROS. This study investigates the mechanism by which NOX4 promotes the M1 polarization of intestinal macrophages in inflammatory bowel disease (IBD) through ROS. Dextran sulfate sodium (DSS) was used to induce the inflammatory bowel disease (IBD) in wild-type (C57BL/6N, WT) and NOX4 knockout (C57BL/6N-NOX4em1cyagen, KO) mice. Body weights of mice were dynamically monitored and the disease active index (DAI) scores were assessed. H&E staining was performed to examine pathological changes, and immunohistochemical (IHC) staining was conducted to measure the expressions of TJ proteins (ZO-1, Occludin) and CD11c. Tissue ROS labeling was accomplished with ROS probe. More ucosal permeability was assessed by FITC-D. Tissue inflammatory cytokines were detected by enzyme-linked immunosorbent assay (ELISA), while the expressions of TJ proteins (ZO-1, Occludin) were measured through Western Blotting. After NOX4 inhibitor pretreatment of intestinal macrophages in vitro, polarization was induced by lipopolysaccharide (LPS) and IFN-γ, followed by determination of polarization degree. The polarized intestinal macrophages were co-cultured with Caco-2 cells, and their effect on the monolayer cell permeability was evaluated. DSS can induce the intestinal inflammation and mucosal barrier injury in mice. Besides, it can enhance the FITC-D permeability, reduce the TJ protein levels, and promote the CD11c and ROS expressions. In KO mice, intestinal inflammation was alleviated and barrier permeability was reduced. Moreover, the TJ protein levels were higher than those of WT mice, while the CD11c and ROS were down-regulated. In WT mice, the intestinal inflammation and barrier permeability could also be reduced after treatment with NOX4 inhibitor. Overexpression of NOX4 in intestinal macrophages could promote the macrophage M1 polarization while improving the barrier integrity of Caco-2 monolayer cells. NOX4 is capable of promoting M1 polarization of intestinal macrophages through ROS, thereby further aggravating the intestinal inflammation and mucosal barrier injury in IBD. NOX4 has potential as a novel therapeutic target for IBD.

Keywords:  IBD; Intestinal macrophages; M1 polarization; NADPH oxidase 4; ROS

DOI:  https://doi.org/10.1016/j.intimp.2021.108361
Nephron. 2021 Dec 23. 1-11

Upregulation of NADPH Oxidase 2 Contributes to Renal Fibrosis in pcy Mice: An Experimental Model of Nephronophthisis.

Yuya Hoshino, Hiroko Sonoda, Nobuyuki Mikoda, Masahiro Ikeda.

  BACKGROUND: DBA/2FG-pcy (pcy) mice harbor a homozygous Nphp3 missense mutation and develop nephronophthisis with renal interstitial fibrosis. Previous studies have shown that aberrant oxygen homeostasis contributes to the renal pathology in pcy mice, but the underlying molecular mechanism remains largely unknown.METHODS: pcy mice and a control strain, DBA/2N (DBA) mice, were used. Renal levels of 62 mRNAs involved in oxygen homeostasis were investigated by real-time PCR, and the resulting data were used for extraction of pathological pathways. On the basis of the genes found to be upregulated and pathway analysis, further studies were performed using immunoblotting, immunohistochemistry, and pharmacological intervention.
RESULTS: In comparison with DBA mice, the levels of 18 mRNAs were altered by >2-fold in pcy mice. Pathway analysis extracted molecular pathways related to oxidative stress, inflammation, and cell adhesion. As the levels of mRNAs relevant to the NADPH oxidase 2 (NOX2) pathway were prominently (4 genes >5-fold) increased in pcy mice, we further analyzed the molecules related to this pathway. A time course study suggested that the pathway was gradually activated in pcy mice from at least 5 weeks of age. Immunohistochemistry study revealed that NOX2 protein was colocalized with a macrophage marker protein in the renal interstitium. Moreover, treatment of pcy mice with apocynin, an inhibitor of the NOX2 pathway, ameliorated the renal fibrosis.
CONCLUSION: Our findings suggest that the activation of the NOX2 pathway, possibly mediated by macrophage infiltration, plays a pivotal role in progressive renal fibrosis in pcy mice.

Keywords:  DBA/2FG-pcy mouse; NADPH oxidase 2; Nephronophthisis; Oxidative stress; Pathway analysis

DOI:  https://doi.org/10.1159/000520697
Antioxidants (Basel). 2021 Nov 29. pii: 1909. [Epub ahead of print]10(12):

NADPH Oxidase and Epidermal Growth Factor Receptor Are Promising Targets of Phytochemicals for Ultraviolet-Induced Skin Carcinogenesis.

Min Jeong Kim, Su Jeong Ha, Bo Ram So, Chang-Kil Kim, Kyung-Min Kim, Sung Keun Jung.

  The skin acts as the primary defense organ that protects the body from the external environment. Skin cancer is one of the most common cancers in the world. Skin carcinogenesis is usually caused by cell degeneration due to exposure to ultraviolet (UV) radiation, which causes changes in various signaling networks, disrupting the homeostasis of single skin cells. In this review, we summarize the roles of nicotinamide adenine dinucleotide phosphate oxidase (NOX) and epidermal growth factor receptor (EGFR) in UV-induced skin carcinogenesis. Furthermore, we describe the crosstalk that exists between NOX, EGFR, and protein tyrosine phosphatase κ and its oncogenic downstream signaling pathways. Chemoprevention is the use of chemical compounds to recover the healthy status of the skin or delay cancer development. Current evidence from in vitro and in vivo studies on chemopreventive phytochemicals that target NOX, EGFR, or both, as major regulators of skin carcinogenesis will also be discussed.

Keywords:  epidermal growth factor receptor (EGFR); nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase); protein tyrosine phosphatase κ (PTPκ); reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/antiox10121909