bims-noxint 2022-02-06 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2022–02–06
six papers selected by
Laia Caja Puigsubira, Uppsala University

Nox2 underpins microvascular inflammation and vascular contributions to cognitive decline.
Impaired p47phox phosphorylation in neutrophils from p67phox-deficient chronic granulomatous disease patients.
Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension.
The Methylglyoxal/RAGE/NOX-2 Pathway is Persistently Activated in the Hippocampus of Rats with STZ-Induced Sporadic Alzheimer's Disease.
HPV+ HNSCC-derived exosomal miR-9-5p inhibits TGFβ signaling mediated fibroblasts phenotypic transformation through NOX4.
The role of ROS in tumour development and progression.

J Cereb Blood Flow Metab. 2022 Feb 01. 271678X221077766

Nox2 underpins microvascular inflammation and vascular contributions to cognitive decline.

Alessio Alfieri, Juraj Koudelka, Mosi Li, Sanny Scheffer, Jessica Duncombe, Andrea Caporali, Rajesh N Kalaria, Colin Smith, Ajay M Shah, Karen Horsburgh.

  Chronic microvascular inflammation and oxidative stress are inter-related mechanisms underpinning white matter disease and vascular cognitive impairment (VCI). A proposed mediator is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2), a major source of reactive oxygen species (ROS) in the brain. To assess the role of Nox2 in VCI, we studied a tractable model with white matter pathology and cognitive impairment induced by bilateral carotid artery stenosis (BCAS). Mice with genetic deletion of Nox2 (Nox2 KO) were compared to wild-type (WT) following BCAS. Sustained BCAS over 12 weeks in WT mice induced Nox2 expression, indices of microvascular inflammation and oxidative damage, along with white matter pathology culminating in a marked cognitive impairment, which were all protected by Nox2 genetic deletion. Neurovascular coupling was impaired in WT mice post-BCAS and restored in Nox2 KO mice. Increased vascular expression of chemoattractant mediators, cell-adhesion molecules and endothelial activation factors in WT mice post-BCAS were ameliorated by Nox2 deficiency. The clinical relevance was confirmed by increased vascular Nox2 and indices of microvascular inflammation in human post-mortem subjects with cerebral vascular disease. Our results support Nox2 activity as a critical determinant of VCI, whose targeting may be of therapeutic benefit in cerebral vascular disease.

Keywords:  NADPH oxidase; Vascular cognitive impairment; cerebral hypoperfusion; inflammation; white matter

DOI:  https://doi.org/10.1177/0271678X221077766
Blood. 2022 Feb 02. pii: blood.2021011134. [Epub ahead of print]

Impaired p47phox phosphorylation in neutrophils from p67phox-deficient chronic granulomatous disease patients.

Sahra Amel Belambri, Viviana Marzailoli, Margarita Hurtado-Nedelec, Coralie Pintard, Shiyu Liang, Yezhou Liu, Tarek Boussetta, Marie-Anne Gougerot-Pocidalo, Richard D Ye, Pham My-Chan Dang, Jamel El Benna.

Superoxide production by the phagocyte NADPH oxidase is essential for innate immunity as shown in chronic granulomatous disease (CGD), an immunodeficiency disease due to mutations in one of its genes. The NADPH oxidase is composed of two membrane proteins (gp91phox/NOX2 and p22phox) and four cytosolic proteins (p47phox, p67phox, p40phox, and Rac1/2). The phosphorylation of p47phox is required for NADPH oxidase activation in cells. As p47phox and p67phox can form a tight complex in cells, we hypothesized that p67phox could regulate p47phox phosphorylation. To investigate this hypothesis, we used phospho-specific antibodies against five major p47phox-phosphorylated sites (Ser304, Ser315, Ser320, Ser328 and Ser345) and neutrophils from healthy donors and from p67phox-/--CGD patients. Results showed that fMLF and PMA induced the time- and concentration-dependent phosphorylation of p47phox on Ser304, Ser315, Ser320 and Ser328 in healthy human neutrophils. Interestingly, in neutrophils and Epstein-Barr virus-transformed B-lymphocytes from p67phox-/--CGD patients, phosphorylation of p47phox on serine residues was dramatically reduced. In COSphox cells, the presence of p67phox led to increased phosphorylation of p47phox. In vitro studies showed that recombinant p47phox was phosphorylated on Ser304, Ser315, Ser320 and Ser328 by different PKC isoforms and the addition of recombinant p67phox alone or in combination with p40phox potentiated this process. Thus, p67phox and p40phox are required for optimal p47phox phosphorylation on Ser304, Ser315, Ser320 and Ser328 in intact cells. Therefore, p67phox and p40phox are novel regulators of p47phox-phosphorylation.

DOI: https://doi.org/10.1182/blood.2021011134
J Clin Invest. 2022 Feb 01. pii: e146343. [Epub ahead of print]132(3):

Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension.

Paola Di Pietro, Albino Carrizzo, Eduardo Sommella, Marco Oliveti, Licia Iacoviello, Augusto Di Castelnuovo, Fausto Acernese, Antonio Damato, Massimiliano De Lucia, Fabrizio Merciai, Paola Iesu, Eleonora Venturini, Raffaele Izzo, Valentina Trimarco, Michele Ciccarelli, Giuseppe Giugliano, Roberto Carnevale, Vittoria Cammisotto, Serena Migliarino, Nicola Virtuoso, Andrea Strianese, Viviana Izzo, Pietro Campiglia, Elena Ciaglia, Bodo Levkau, Annibale A Puca, Carmine Vecchione.

  Sortilin has been positively correlated with vascular disorders in humans. No study has yet evaluated the possible direct effect of sortilin on vascular function. We used pharmacological and genetic approaches coupled with study of murine and human samples to unravel the mechanisms recruited by sortilin in the vascular system. Sortilin induced endothelial dysfunction of mesenteric arteries through NADPH oxidase 2 (NOX2) isoform activation, dysfunction that was prevented by knockdown of acid sphingomyelinase (ASMase) or sphingosine kinase 1. In vivo, recombinant sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of sphingosine-1-phosphate receptor 3 (S1P3) and gp91phox/NOX2 resulted in preservation of endothelial function and blood pressure homeostasis after 14 days of systemic sortilin administration. Translating these research findings into the clinical setting, we detected elevated sortilin levels in hypertensive patients with endothelial dysfunction. Furthermore, in a population-based cohort of 270 subjects, we showed increased plasma ASMase activity and increased plasma levels of sortilin, S1P, and soluble NOX2-derived peptide (sNOX2-dp) in hypertensive subjects, and the increase was more pronounced in hypertensive subjects with uncontrolled blood pressure. Our studies reveal what we believe is a previously unrecognized role of sortilin in the impairment of vascular function and in blood pressure homeostasis and suggest the potential of sortilin and its mediators as biomarkers for the prediction of vascular dysfunction and high blood pressure.

Keywords:  Cardiovascular disease; Hypertension; Vascular Biology

DOI:  https://doi.org/10.1172/JCI146343
Neurotox Res. 2022 Feb 02.

The Methylglyoxal/RAGE/NOX-2 Pathway is Persistently Activated in the Hippocampus of Rats with STZ-Induced Sporadic Alzheimer's Disease.

Ana Paula Moreira, Adriana Fernanda K Vizuete, Lisandra Eda Fusinato Zin, Charlanne Oliveira de Marques, Rafaela Ferreira Pacheco, Miriara B Leal, Carlos-Alberto Gonçalves.

  Alzheimer's disease (AD) is the leading cause of dementia in humans, with a high social and economic cost. AD is predominantly a sporadic disease, and the intracerebroventricular (ICV) administration of streptozotocin (STZ) has been widely used as an AD-like model of dementia. While the etiology of AD remains unknown, changes such as glucose metabolism and activation of receptors for advanced glycation end products (RAGE) seem to underlie its pathogenesis. We hypothesized that methylglyoxal, an endogenous toxin derived from the glycolytic pathway, could be the precursor of advanced glycated end products that activates RAGE and that, consequently, may activate membrane NADPH oxidase (NOX), contributing to the inflammatory status of the model and the disease. We administered ICV-STZ to Wistar rats and evaluated several neurochemical parameters in the hippocampus, particularly glyoxalase 1 (GLO-1) activity, which serves as an index of high levels of methylglyoxal, and the contents of RAGE and NOX-2, the most abundant brain NOX isoform. At the times evaluated (4 and 24 weeks after STZ), we observed cognitive deficit, increased beta-amyloid content, and increased tau phosphorylation. A persistent increase in GLO-1 activity was found, as well as increases in RAGE and NOX-2 contents, suggesting astroglial and microglial commitment. The increase in NOX-2 may reflect elevated microglial activity (confirmed by IBA-1 marker), which may contribute to the synaptic dysfunction and pruning described in the literature, both in this model and AD patients. Furthermore, reinforcing this possibility, we found a reduction in cholinergic communication in the hippocampus (as shown by decreased choline acetyltransferase), a reduction in BDNF, and an increase in TGF-β, the combination of which may result in synaptic deterioration.

Keywords:  Alzheimer; Astrocyte; Methylglyoxal; NOX-2; RAGE; STZ

DOI:  https://doi.org/10.1007/s12640-022-00476-9
Cancer Sci. 2022 Jan 31.

HPV+ HNSCC-derived exosomal miR-9-5p inhibits TGFβ signaling mediated fibroblasts phenotypic transformation through NOX4.

Bozhi Wang, Siwei Zhang, Fangjia Tong, Yan Wang, Lanlan Wei.

  Human papillomavirus (HPV) is a significant risk factor for head and neck squamous cell carcinoma (HNSCC). HPV+ HNSCC patients have a higher survival rate, which may be related to its unique tumor microenvironment. Exosomes can be emerging as a communication tool between tumor cells and the tumor microenvironment, including cancer-associated fibroblasts (CAFs). In this study, 111 clinical samples tissues and public sequencing data were analyzed. Our study found fewer CAFs infiltrated in HPV+ HNSCC, and poor CAFs infiltration level was associated with a good prognosis. HPV+ HNSCC cell-derived exosomes can significantly reduce the phenotypic transformation of fibroblasts. MiR-9-5p, as a miRNA enriched in HPV+ HNSCC cell-derived exosomes, can be transferred to fibroblasts. MiR-9-5p mimic transfection decreased the expression of NOX4 and the level of intracellular reactive oxygen species (ROS), which inhibited transforming growth factor beta 1(TGF-β1) induced increase of αSMA level. Hence, these results indicated that HPV+ HNSCC-derived exosomal miR-9-5p inhibits TGFβ signaling mediated fibroblasts phenotypic transformation through NOX4, which is related to the excellent prognosis of HPV patients.

Keywords:  Cancer-associated fibroblasts; Exosome; HPV; Head and neck squamous cell carcinoma; MiR-9-5p

DOI:  https://doi.org/10.1111/cas.15281
Nat Rev Cancer. 2022 Jan 31.

The role of ROS in tumour development and progression.

Eric C Cheung, Karen H Vousden.

Eukaryotic cells have developed complex systems to regulate the production and response to reactive oxygen species (ROS). Different ROS control diverse aspects of cell behaviour from signalling to death, and deregulation of ROS production and ROS limitation pathways are common features of cancer cells. ROS also function to modulate the tumour environment, affecting the various stromal cells that provide metabolic support, a blood supply and immune responses to the tumour. Although it is clear that ROS play important roles during tumorigenesis, it has been difficult to reliably predict the effect of ROS modulating therapies. We now understand that the responses to ROS are highly complex and dependent on multiple factors, including the types, levels, localization and persistence of ROS, as well as the origin, environment and stage of the tumours themselves. This increasing understanding of the complexity of ROS in malignancies will be key to unlocking the potential of ROS-targeting therapies for cancer treatment.

DOI: https://doi.org/10.1038/s41568-021-00435-0