bims-noxint 2020-12-27 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2020–12–27
six papers selected by
Laia Caja Puigsubira, Uppsala University

Enriched conditioning expands the regenerative ability of sensory neurons after spinal cord injury via neuronal intrinsic redox signaling.
ABCG1 Attenuates Oxidative Stress Induced by H2O2 through the Inhibition of NADPH Oxidase and the Upregulation of Nrf2-Mediated Antioxidant Defense in Endothelial Cells.
Role of NADPH oxidase in MAPK signaling activation by a 50 Hz magnetic field in human neuroblastoma cells.
Miro1-mediated mitochondrial positioning supports subcellular redox status.
Human placental mesenchymal stem cells improve stroke outcomes via extracellular vesicles-mediated preservation of cerebral blood flow.
The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens.

Nat Commun. 2020 Dec 21. 11(1): 6425

Enriched conditioning expands the regenerative ability of sensory neurons after spinal cord injury via neuronal intrinsic redox signaling.

Francesco De Virgiliis, Thomas H Hutson, Ilaria Palmisano, Sarah Amachree, Jian Miao, Luming Zhou, Rositsa Todorova, Richard Thompson, Matt C Danzi, Vance P Lemmon, John L Bixby, Ilka Wittig, Ajay M Shah, Simone Di Giovanni.

Overcoming the restricted axonal regenerative ability that limits functional repair following a central nervous system injury remains a challenge. Here we report a regenerative paradigm that we call enriched conditioning, which combines environmental enrichment (EE) followed by a conditioning sciatic nerve axotomy that precedes a spinal cord injury (SCI). Enriched conditioning significantly increases the regenerative ability of dorsal root ganglia (DRG) sensory neurons compared to EE or a conditioning injury alone, propelling axon growth well beyond the spinal injury site. Mechanistically, we established that enriched conditioning relies on the unique neuronal intrinsic signaling axis PKC-STAT3-NADPH oxidase 2 (NOX2), enhancing redox signaling as shown by redox proteomics in DRG. Finally, NOX2 conditional deletion or overexpression respectively blocked or phenocopied enriched conditioning-dependent axon regeneration after SCI leading to improved functional recovery. These studies provide a paradigm that drives the regenerative ability of sensory neurons offering a potential redox-dependent regenerative model for mechanistic and therapeutic discoveries.

DOI: https://doi.org/10.1038/s41467-020-20179-z
Anal Cell Pathol (Amst). 2020 ;2020 2095645

ABCG1 Attenuates Oxidative Stress Induced by H2O2 through the Inhibition of NADPH Oxidase and the Upregulation of Nrf2-Mediated Antioxidant Defense in Endothelial Cells.

Jiahong Xue, Jiali Fan, Yuan Li, Wenhuan Wu, Qing Yan, Qiangsun Zheng.

Summary. Oxidative stress is an important factor that is related to endothelial dysfunction. ATP-binding cassette transporter G1 (ABCG1), a regulator of intracellular cholesterol efflux, has been found to prevent endothelial activation in vessel walls. To explore the role of ABCG1 in oxidative stress production in endothelial cells, HUAECs were exposed to H2O2 and transfected with the specific ABCG1 siRNA or ABCG1 overexpression plasmid. The results showed that overexpression of ABCG1 by ABCG1 plasmid or liver X receptor (LXR) agonist T0901317 treatment inhibited ROS production and MDA content induced by H2O2 in HUAECs. Furthermore, ABCG1 upregulation blunted the activity of prooxidant NADPH oxidase and the expression of Nox4, one of the NADPH oxidase subunits. Moreover, the increased migration of Nrf2 from the cytoplasm to the nucleus and antioxidant HO-1 expression were detected in HUAECs with upregulation of ABCG1. Conversely, ABCG1 downregulation by ABCG1 siRNA increased NADPH oxidase activity and Nox4 expression and abrogated the increase at Nrf2 nuclear protein levels. In addition, intracellular cholesterol load interfered with the balance between NADPH oxidase activity and HO-1 expression. It was suggested that ABCG1 attenuated oxidative stress induced by H2O2 in endothelial cells, which might be involved in the balance between decreased NADPH oxidase activity and increased Nrf2/OH-1 antioxidant defense signaling via its regulation for intracellular cholesterol accumulation.

DOI: https://doi.org/10.1155/2020/2095645
Electromagn Biol Med. 2020 Dec 19. 1-14

Role of NADPH oxidase in MAPK signaling activation by a 50 Hz magnetic field in human neuroblastoma cells.

María Antonia Martínez, Alejandro Úbeda, María Ángeles Trillo.

  Our previous studies have shown that intermittent exposure to a 50-Hz, 100-µT sine wave magnetic field (MF) promotes human NB69 cell proliferation, mediated by activation of the epidermal growth factor receptor (EGFR) and pathways MAPK-ERK1/2 and p38; being the effects on proliferation and p38 activation blocked by the chelator N-acetylcysteine. The present work investigates the MF effects on free radical (FR) production, and the potential involvement of NADPH oxidase, the main source of reactive oxygen species (ROS), in the MF-induced activation of MAPK pathways. To this end, the field effects on MAPK-ERK1/2, -p38 and -JNK activation in the presence or absence of the NADPH oxidase inhibitor, diphenyleneiodonium chloride (DPI), as well as the expression of the p67phox subunit, were analyzed. The results revealed that field exposure increases FR production and induces early, transient expression of the cytosolic component of the NADPH oxidase, p67phox. Also, the MF-induced activation of the MAPK-JNK pathway, but not that of -ERK1/2 or -p38 pathways, was prevented in the presence of the DPI, which has been shown to significantly reduce p67phox expression. These data, together with those from previous studies, identify various, FR-dependent or -independent mechanisms, involved in the MF-induced proliferative response mediated by MAPK signaling activation.

Keywords:  ELF; MAPK; NB69; ROS; magnetic field; p67phox

DOI:  https://doi.org/10.1080/15368378.2020.1851250
Redox Biol. 2020 Nov 29. pii: S2213-2317(20)31023-5. [Epub ahead of print]38 101818

Miro1-mediated mitochondrial positioning supports subcellular redox status.

Haya Alshaabi, Nathaniel Shannon, Randi Gravelle, Stephanie Milczarek, Terri Messier, Brian Cunniff.

  Mitochondria are strategically trafficked throughout the cell by the action of microtubule motors, the actin cytoskeleton and adapter proteins. The intracellular positioning of mitochondria supports subcellular levels of ATP, Ca2+ and reactive oxygen species (ROS, i.e. hydrogen peroxide, H2O2). Previous work from our group showed that deletion of the mitochondrial adapter protein Miro1 leads to perinuclear clustering of mitochondria, leaving the cell periphery devoid of mitochondria which compromises peripheral energy status. Herein, we report that deletion of Miro1 significantly restricts subcellular H2O2 levels to the perinuclear space which directly affects intracellular responses to elevated mitochondrial ROS. Using the genetically encoded H2O2-responsive fluorescent biosensor HyPer7, we show that the highest levels of subcellular H2O2 map to sites of increased mitochondrial density. Deletion of Miro1 or disruption of microtubule dynamics with Taxol significantly reduces peripheral H2O2 levels. Following inhibition of mitochondrial complex 1 with rotenone we observe elevated spikes of H2O2 in the cell periphery and complementary oxidation of mitochondrial peroxiredoxin 3 (PRX3) and cytosolic peroxiredoxin 2 (PRX2). Conversely, in cells lacking Miro1, rotenone did not increase peripheral H2O2 or PRX2 oxidation but rather lead to increased nuclear H2O2 and an elevated DNA-damage response. Lastly, local levels of HyPer7 oxidation correlate with the size and abundance of focal adhesions (FAs) in MEFs and cells lacking Miro1 have significantly smaller focal adhesions and reduced phosphorylation levels of vinculin and p130Cas compared to Miro1+/+ MEFs. Together, we present evidence that the intracellular distribution of mitochondria influences subcellular H2O2 levels and local cellular responses dependent on mitochondrial ROS.

Keywords:  Cell migration; Hydrogen peroxide; Miro1; Mitochondrial trafficking; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2020.101818
EBioMedicine. 2020 Dec 18. pii: S2352-3964(20)30537-5. [Epub ahead of print]63 103161

Human placental mesenchymal stem cells improve stroke outcomes via extracellular vesicles-mediated preservation of cerebral blood flow.

Mansoureh Barzegar, Yuping Wang, Randa S Eshaq, J Winny Yun, Christen J Boyer, Sergio G Cananzi, Luke A White, Oleg Chernyshev, Roger E Kelley, Alireza Minagar, Karen Y Stokes, Xiao-Hong Lu, Jonathan S Alexander.

   BACKGROUND: Besides long-term trans-differentiation into neural cells, benefits of stem cell therapy (SCT) in ischemic stroke may include secretion of protective factors, which partly reflects extracellular vesicle (EVs) released by stem cell. However, the mechanism(s) by which stem cells/EVs limit stroke injury have yet to be fully defined.
METHODS: We evaluated the protection effect of human placenta mesenchymal stem cells (hPMSC) as a potential form of SCT in experimental ischemic stroke 'transient middle cerebral artery occusion (MCAO)/reperfusion' mice model.
FINDINGS: We found for the first time that intraperitoneal administration of hPMSCs or intravenous hPMSC-derived EVs, given at the time of reperfusion, significantly protected the ipsilateral hemisphere from ischemic injury. This protection was associated with significant restoration of normal blood flow to the post-MCAO brain. More importantly, EVs derived from hPMSC promote paracrine-based protection of SCT in the MCAO model in a cholesterol/lipid-dependent manner.
INTERPRETATION: Together, our results demonstrated beneficial effects of hPMSC/EVs in experimental stroke models which could permit the rapid "translation" of these cells into clinical trials in the near-term.

Keywords:  Blood brain barrier; Cerebral blood flow; Extracellular vesicles; Human placental mesenchymal stem cells; Infarction; Ischemic stroke

DOI:  https://doi.org/10.1016/j.ebiom.2020.103161
Nat Immunol. 2020 Dec 21.

The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens.

Johnathan Canton, Hanna Blees, Conor M Henry, Michael D Buck, Oliver Schulz, Neil C Rogers, Eleanor Childs, Santiago Zelenay, Hefin Rhys, Marie-Charlotte Domart, Lucy Collinson, Andres Alloatti, Cara J Ellison, Sebastian Amigorena, Venizelos Papayannopoulos, David C Thomas, Felix Randow, Caetano Reis E Sousa.

Type 1 conventional dendritic (cDC1) cells are necessary for cross-presentation of many viral and tumor antigens to CD8+ T cells. cDC1 cells can be identified in mice and humans by high expression of DNGR-1 (also known as CLEC9A), a receptor that binds dead-cell debris and facilitates XP of corpse-associated antigens. Here, we show that DNGR-1 is a dedicated XP receptor that signals upon ligand engagement to promote phagosomal rupture. This allows escape of phagosomal contents into the cytosol, where they access the endogenous major histocompatibility complex class I antigen processing pathway. The activity of DNGR-1 maps to its signaling domain, which activates SYK and NADPH oxidase to cause phagosomal damage even when spliced into a heterologous receptor and expressed in heterologous cells. Our data reveal the existence of innate immune receptors that couple ligand binding to endocytic vesicle damage to permit MHC class I antigen presentation of exogenous antigens and to regulate adaptive immunity.

DOI: https://doi.org/10.1038/s41590-020-00824-x