bims-noxint 2022-08-28 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2022‒08‒28
seven papers selected by
Laia Caja Puigsubira
Uppsala University

NADPH Oxidase Isoforms in COPD Patients and Acute Cigarette Smoke-Exposed Mice: Induction of Oxidative Stress and Lung Inflammation.
SIRT7 Deficiency Protects against Aβ42-Induced Apoptosis through the Regulation of NOX4-Derived Reactive Oxygen Species Production in SH-SY5Y Cells.
Evolutionary and structural analyses of the NADPH oxidase family in eukaryotes reveal an initial calcium dependency.
Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages.
Oxidative and Inflammatory Imbalance in Placenta and Kidney of sFlt1-Induced Early-Onset Preeclampsia Rat Model.
Targeting Hydrogen Sulfide Modulates Dexamethasone-Induced Muscle Atrophy and Microvascular Rarefaction, through Inhibition of NOX4 and Induction of MGF, M2 Macrophages and Endothelial Progenitors.
UPREGULATION OF NADH/NADPH OXIDASE 4 BY ANGIOTENSIN II INDUCES PODOCYTE APOPTOSIS.

Antioxidants (Basel). 2022 Aug 08. pii: 1539. [Epub ahead of print]11(8):

NADPH Oxidase Isoforms in COPD Patients and Acute Cigarette Smoke-Exposed Mice: Induction of Oxidative Stress and Lung Inflammation.

Xinjing Wang, Priya Murugesan, Pan Zhang, Shiqing Xu, Liang Peng, Chen Wang, Hua Cai.

  Cigarette smoke (CS) is a major risk factor for chronic obstructive pulmonary disease (COPD), which represents the third leading cause of death worldwide. CS induces reactive oxygen species (ROS) production, leading to pulmonary inflammation and remodeling. NADPH oxidases (NOXs) represent essential sources of ROS production in the cardiovascular system. Whether and how NOX isoforms are activated in COPD patients and in response to acute cigarette smoke (ACS) remains incompletely understood. In the present study, the expression of NOX isoforms was examined in the lungs of end-stage COPD patients. In addition, mice silenced of NOX1 or NOX4 expression using in vivo RNA interference (RNAi), and NOX2-deficient (NOX2-/y) mice, were exposed to ACS for 1 h using a standard TE-10B smoking machine. In lung sections isolated from COPD patients undergoing lung transplantation, protein expression of NOX1, NOX2, NOX4, or NOX5 was markedly upregulated compared to non-smoking donor controls. Likewise, ACS upregulated protein expression of NOX1, NOX2, and NOX4, production of ROS, inflammatory cell infiltration, and mRNA expression of proinflammatory cytokines TNF-α and KC in the mouse lung. In vivo RNAi knockdown of NOX1 or NOX4 decreased ACS induced ROS production, inflammatory cell influx, and the expression of TNF-α and KC, which were accompanied by inhibition of the NF-κB-COX-2 axis. Although ACS induced ROS production was reduced in the lungs of NOX2-/y mice, inflammatory cell influx and expression of NF-κB/COX-2 were increased. Taken together, our results demonstrate for the first time that NOX isoforms 1, 2, 4 and 5 all remain activated in end-stage COPD patients, while NOX1 and NOX4 mediate oxidative stress and inflammatory responses in response to acute cigarette smoke. Therefore, targeting different isoforms of NOX might be necessary to treat COPD at different stages of the disease, which represents novel mechanistic insights enabling improved management of the devastating disease.

Keywords:  NADPH oxidase (NOX); NOX1; NOX2; NOX4; NOX5; acute cigarette smoke (ACS); chronic obstructive pulmonary disease (COPD); lung inflammation; oxidative stress

DOI:  https://doi.org/10.3390/antiox11081539
Int J Mol Sci. 2022 Aug 12. pii: 9027. [Epub ahead of print]23(16):

SIRT7 Deficiency Protects against Aβ42-Induced Apoptosis through the Regulation of NOX4-Derived Reactive Oxygen Species Production in SH-SY5Y Cells.

Hironori Mizutani, Yoshifumi Sato, Masaya Yamazaki, Tatsuya Yoshizawa, Yukio Ando, Mitsuharu Ueda, Kazuya Yamagata.

  Alzheimer's disease (AD) is an age-related neurodegenerative disease that is characterized by irreversible memory loss and cognitive decline. The deposition of amyloid-β (Aβ), especially aggregation-prone Aβ42, is considered to be an early event preceding neurodegeneration in AD. Sirtuins (SIRT1-7 in mammals) are nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases, and several sirtuins play important roles in AD. However, the involvement of SIRT7 in AD pathogenesis is not known. Here, we demonstrate that SIRT7 mRNA expression is increased in the cortex, entorhinal cortex, and prefrontal cortex of AD patients. We also found that Aβ42 treatment rapidly increased NADPH oxidase 4 (NOX4) expression at the post-transcriptional level, and induced reactive oxygen species (ROS) production and apoptosis in neuronal SH-SY5Y cells. In contrast, SIRT7 knockdown inhibited Aβ42-induced ROS production and apoptosis by suppressing the upregulation of NOX4. Collectively, these findings suggest that the inhibition of SIRT7 may play a beneficial role in AD pathogenesis through the regulation of ROS production.

Keywords:  Alzheimer’s disease; NADPH oxidase; SIRT7; amyloid-β; apoptosis; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms23169027
Redox Biol. 2022 Aug 12. pii: S2213-2317(22)00208-7. [Epub ahead of print]56 102436

Evolutionary and structural analyses of the NADPH oxidase family in eukaryotes reveal an initial calcium dependency.

Marta Massari, Callum R Nicoll, Sara Marchese, Andrea Mattevi, Maria Laura Mascotti.

  Reactive oxygen species are unstable molecules generated by the partial reduction of dioxygen. NADPH oxidases are a ubiquitous family of enzymes devoted to ROS production. They fuel an array of physiological roles in different species and are chemically demanding enzymes requiring FAD, NADPH and heme prosthetic groups in addition to either calcium or a various number of cytosolic mediators for activity. These activating partners are exclusive components that partition and distinguish the NOX members from one another. To gain insight into the evolution of these activating mechanisms, and in general in their evolutionary history, we conducted an in-depth phylogenetic analysis of the NADPH oxidase family in eukaryotes. We show that all characterized NOXs share a common ancestor, which comprised a fully formed catalytic unit. Regarding the activation mode, we identified calcium-dependency as the earliest form of NOX regulation. The protein-protein mode of regulation would have evolved more recently by gene-duplication with the concomitant loss of the EF-hands motif region. These more recent events generated the diversely activated NOX systems as observed in extant animals and fungi.

Keywords:  Enzyme evolution; NADPH oxidase; NOX; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2022.102436
Antioxidants (Basel). 2022 Jul 29. pii: 1488. [Epub ahead of print]11(8):

Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages.

Jonathan R Erlich, Eunice E To, Raymond Luong, Felicia Liong, Stella Liong, Osezua Oseghale, Mark A Miles, Steven Bozinovski, Robert D Brooks, Ross Vlahos, Stanley Chan, John J O'Leary, Doug A Brooks, Stavros Selemidis.

  Macrophages undergo a metabolic switch from oxidative phosphorylation to glycolysis when exposed to gram-negative bacterial lipopolysaccharide (LPS), which modulates antibacterial host defence mechanisms. Here, we show that LPS treatment of macrophages increased the classical oxidative burst response via the NADPH oxidase (NOX) 2 enzyme, which was blocked by 2-deoxyglucose (2-DG) inhibition of glycolysis. The inhibition of the pentose phosphate pathway with 6-aminonicotinamide (6-AN) also suppressed the LPS-induced increase in NOX2 activity and was associated with a significant reduction in the mRNA expression of NOX2 and its organizer protein p47phox. Notably, the LPS-dependent enhancement in NOX2 oxidase activity was independent of both succinate and mitochondrial reactive oxygen species (ROS) production. LPS also increased type I IFN-β expression, which was suppressed by 2-DG and 6-AN and, therefore, is dependent on glycolysis and the pentose phosphate pathway. The type I IFN-β response to LPS was also inhibited by apocynin pre-treatment, suggesting that NOX2-derived ROS promotes the TLR4-induced response to LPS. Moreover, recombinant IFN-β increased NOX2 oxidase-dependent ROS production, as well as NOX2 and p47phox expression. Our findings identify a previously undescribed molecular mechanism where both glycolysis and the pentose phosphate pathway are required to promote LPS-induced inflammation in macrophages.

Keywords:  LPS; NADPH oxidase; NOX2; glycolysis; inflammation; macrophages; pentose phosphate pathway; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox11081488
Antioxidants (Basel). 2022 Aug 19. pii: 1608. [Epub ahead of print]11(8):

Oxidative and Inflammatory Imbalance in Placenta and Kidney of sFlt1-Induced Early-Onset Preeclampsia Rat Model.

Álvaro Santana-Garrido, Claudia Reyes-Goya, Pablo Espinosa-Martín, Luis Sobrevia, Luis M Beltrán, Carmen M Vázquez, Alfonso Mate.

  Preeclampsia (PE) is a pregnancy-specific disorder characterized by the new onset of hypertension plus proteinuria and/or end-organ dysfunction. Here, we investigate the role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system as a major component of reactive oxygen species generation, in a rodent model of early-onset preeclampsia induced by excess sFlt1 (soluble fms-like tyrosine kinase 1). Placenta and kidney samples were obtained from normal pregnant and PE rats to measure the sFlt1/PlGF (placental growth factor) ratio in addition to oxidative stress-related parameters, including the activities and expressions of NADPH oxidase isoforms (NOX1, NOX2, and NOX4), components of nitric oxide (NO) metabolism, and antioxidant enzymes. Peroxisome proliferator-activated receptors (PPARα, PPARγ) and cytokines IL1β, IL3, IL6, IL10, and IL18 were also measured to evaluate the inflammation status in our experimental setting. Excessive O2●- production was found in rats that were treated with sFlt1; interestingly, this alteration appears to be mediated mainly by NOX2 in the placenta and by NOX4 in the kidney. Altered NO metabolism and antioxidant defense systems, together with mitochondrial dysfunction, were observed in this model of PE. Preeclamptic animals also exhibited overexpression of proinflammatory biomarkers as well as increased collagen deposition. Our results highlight the role of NADPH oxidase in mediating oxidative stress and possibly inflammatory processes in the placenta and kidney of an sFlt1-based model of early-onset preeclampsia.

Keywords:  NADPH oxidase; inflammation; kidney; nitric oxide; oxidative stress; placenta; preeclampsia; sFlt1

DOI:  https://doi.org/10.3390/antiox11081608
Cells. 2022 Aug 11. pii: 2500. [Epub ahead of print]11(16):

Targeting Hydrogen Sulfide Modulates Dexamethasone-Induced Muscle Atrophy and Microvascular Rarefaction, through Inhibition of NOX4 and Induction of MGF, M2 Macrophages and Endothelial Progenitors.

Mohamed Adel, Hassan Reda Hassan Elsayed, Mohammad El-Nablaway, Shereen Hamed, Amira Eladl, Samah Fouad, Eman Mohamad El Nashar, Mohammed Lafi Al-Otaibi, Mohammed R Rabei.

  Long-term use of Glucocorticoids produces skeletal muscle atrophy and microvascular rarefaction. Hydrogen sulfide (H2S) has a potential role in skeletal muscle regeneration. However, the mechanisms still need to be elucidated. This is the first study to explore the effect of Sodium hydrosulfide (NaHS) H2S donor, against Dexamethasone (Dex)-induced soleus muscle atrophy and microvascular rarefaction and on muscle endothelial progenitors and M2 macrophages. Rats received either; saline, Dex (0.6 mg/Kg/day), Dex + NaHS (5 mg/Kg/day), or Dex + Aminooxyacetic acid (AOAA), a blocker of H2S (10 mg/Kg/day) for two weeks. The soleus muscle was examined for contractile properties. mRNA expression for Myostatin, Mechano-growth factor (MGF) and NADPH oxidase (NOX4), HE staining, and immunohistochemical staining for caspase-3, CD34 (Endothelial progenitor marker), vascular endothelial growth factor (VEGF), CD31 (endothelial marker), and CD163 (M2 macrophage marker) was performed. NaHS could improve the contractile properties and decrease oxidative stress, muscle atrophy, and the expression of NOX4, caspase-3, Myostatin, VEGF, and CD31 and could increase the capillary density and expression of MGF with a significant increase in expression of CD34 and CD163 as compared to Dex group. However, AOAA worsened the studied parameters. Therefore, H2S can be a promising target to attenuate muscle atrophy and microvascular rarefaction.

Keywords:  H2S; MGF; Myostatin; NOX-4; NaHS; muscle atrophy

DOI:  https://doi.org/10.3390/cells11162500
J Hypertens. 2022 Jun 01. 40(Suppl 1): e251-e252

UPREGULATION OF NADH/NADPH OXIDASE 4 BY ANGIOTENSIN II INDUCES PODOCYTE APOPTOSIS.

Tae Sun Ha, Dong Soo Ha.

OBJECTIVE: Angiotensin II induces glomerular and podocyte injury via systemic and local vasoconstrictive or non-hemodynamic effects including oxidative stress. The release of free radicals from podocytes may participate in the development of glomerular injury and proteinuria. We studied the pathophysiologic roles of oxidative stress in angiotensin II-induced podocyte apoptosis.DESIGN AND METHOD: Mouse podocytes were incubated in media containing various concentrations of angiotensin II and at different incubation times and transfected by Nox4 or AT1R siRNAs or negative control scrambled siRNA for 24 h. The changes of podocyte oxidative stress and apoptosis were observed by confocal imaging, western blotting, realtime PCR, FACS and TUNEL assay according to the presence of angiotensin II.
RESULTS: Angiotensin II increased the generation of mitochondrial superoxide anions and reactive oxygen species levels but suppressed superoxide dismutase activity that was reversed by probucol, an antioxidant. Angiotensin II also increased NADH/NADPH oxidase 4 protein and expression in a transcriptional mechanism that was also reversed by probucol. In addition, the suppression of NADH/NADPH oxidase 4 by siRNA reduced the oxidative stress induced by angiotensin II. Furthermore, angiotensin II promoted podocyte apoptosis that was reduced significantly by probucol and NADH/NADPH oxidase 4 siRNA, and also recovered by angiotensin II type 1 receptor siRNA. In sum, angiotensin II induced podocyte oxidative stress and apoptosis through NADH/NADPH oxidase 4 and angiotensin II type 1 receptor.
CONCLUSIONS: These findings suggest that angiotensin II promoted podocyte mitochondrial oxidative stress resulting in apoptosis via the upregulation of NADH/NADPH oxidase 4 and angiotensin II type 1 receptor and, which could be prevented by NADH/NADPH oxidase 4 inhibition and/or antagonizing angiotensin II type 1 receptor as well as antioxidants.

DOI: https://doi.org/10.1097/01.hjh.0000838076.83665.f3