bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2020‒06‒07
ten papers selected by
Laia Caja Puigsubira
Uppsala University


  1. Redox Biol. 2020 May 23. pii: S2213-2317(20)30120-8. [Epub ahead of print]34 101512
    Schröder K.
      Reactive oxygen species (ROS) have been shown or at least suggested to play an essential role for cellular signaling as second messengers. NADPH oxidases represent a source of controlled ROS formation. Accordingly, understanding the role of individual NADPH oxidases bears potential to interfere with intracellular signaling cascades without disturbing the signaling itself. Many tools have been developed to study or inhibit the functions and roles of the NADPH oxidases. This short review summarizes diseases, potentially associated with NADPH oxidases, genetically modified animals, and inhibitors.
    DOI:  https://doi.org/10.1016/j.redox.2020.101512
  2. Hypertension. 2020 Jun 01. HYPERTENSIONAHA12015058
    Kumar V, Kurth T, Zheleznova NN, Yang C, Cowley AW.
      We have reported that a high-salt (4.0% NaCl) dietary intake activates mTORC1 and inhibition of this pathway with rapamycin blunts the chronic phase of salt-induced hypertension and renal injury in Dahl salt-sensitive (SS) rats. In SS rats, high-salt intake is known to increase the renal production of H2O2 by NOX4, the most abundant NOX isoform in the kidney, and the global knockout of NOX4 blunts salt-sensitivity in these rats. Here, we explored the hypothesis that elevations of H2O2 by NOX4 in high-salt fed SS rat stimulate mTORC1 for the full development of salt-induced hypertension and renal injury. Our in vitro studies found that H2O2 activates mTORC1 independent of PI3K/AKT and AMPK pathways. To determine the in vivo relevance of NOX4/H2O2/mTORC1 in the salt-induced hypertension, SS-Nox4 knockout (SSNox4-/-) rats were daily administrated with vehicle/rapamycin fed a high-salt diet for 21 days. Rapamycin treatment of SSNox4-/- rats had shown no augmented effect on the salt-induced hypertension nor upon indices of renal injury. Significant reductions of renal T lymphocyte and macrophage together with inhibition of cell proliferation were observed in rapamycin treated rats suggesting a role of mTORC1 independent of NOX4 in the proliferation of immune cell. Given the direct activation of mTORC1 by H2O2 and absence of any further protection from salt-induced hypertension in rapamycin-treated SSNox4-/- rats, we conclude that NOX4-H2O2 is a major upstream activator of mTORC1 that contributes importantly to salt-induced hypertension and renal injury in the SS rat model.
    Keywords:  amino acid; glucose; insulin; rapamycin; reactive oxygen species
    DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.120.15058
  3. Eur J Pharmacol. 2020 Jun 02. pii: S0014-2999(20)30320-4. [Epub ahead of print] 173228
    Liu Y, Shen W, Chen Q, Cao Q, Di W, Lan R, Chen Z, Bai J, Han Z, Xu W.
      The current study was designed to examine the protection of RAGE-specific inhibitor FPS-ZM1 against renal injury in spontaneously hypertensive rats (SHR) and investigate the underlying mechanism. The adult male SHR were treated with FPS-ZM1 via oral gavages for 12 weeks, and age-matched male Wistar-Kyoto rats (WKY) were used as control. Treatment of SHR with FPS-ZM1 slightly reduced blood pressure, and significantly improved baroreflex sensitivity in SHR. Treatment of SHR with FPS-ZM1 improved renal function, evidenced by increased glomerular filtration rate and renal blood flow, and reduced plasma creatinine, blood urea nitrogen and urine albumin excretion rate. Histology results revealed that treatment of SHR with FPS-ZM1 alleviated renal injury and reduced tubulointerstitial fibrosis. Treatment of SHR with FPS-ZM1 suppressed activation of NF-κB and reduced expression of pro-inflammatory cytokines including Tnf, Il6, and Il1b. Treatment of SHR with FPS-ZM1 abated oxidative stress and downregulated mRNA levels of components of NADPH oxidase (Nox) including Cyba, Nox1, Nox2, Nox4 and Ncf1 in kidneys. In addition, treatment of SHR with FPS-ZM1 reduced renal AngII levels, downregulated mRNA expression of Ace and upregulated expression of Agtr2. In conclusion, treatment with FPS-ZM1 alleviated hypertension-related renal dysfunction, possibly by suppressing NF-κB-mediated inflammation, abating Nox-mediated oxidative stress, and improving local renal renin-angiotensin system (RAS).
    Keywords:  FPS-ZM1; Hypertension; Inflammation; Kidney; Oxidative stress
    DOI:  https://doi.org/10.1016/j.ejphar.2020.173228
  4. eNeuro. 2020 Jun 03. pii: ENEURO.0024-20.2020. [Epub ahead of print]
    Arias-Cavieres A, Khuu MA, Nwakudu CU, Barnard JE, Dalgin G, Garcia AJ.
      Sleep apnea causes cognitive deficits and is associated with several neurologic diseases. Intermittent hypoxia (IH) is recognized as a principal mediator of pathophysiology associated with sleep apnea, yet the basis by which IH contributes to impaired cognition remains poorly defined. Using a mouse model exposed to IH, this study examines how the transcription factor, Hypoxia Inducible Factor 1a (HIF1a), contributes to disrupted synaptic physiology and spatial memory. In wildtype mice, impaired performance in the Barnes maze caused by IH coincided with a loss of NMDA receptor dependent Long Term Potentiation (LTP) in area CA1 and increased nuclear HIF1a within the hippocampus. IH-dependent HIF1a signaling caused a two-fold increase in expression of the reactive oxygen species generating enzyme NADPH oxidase 4 (NOX4). These changes promoted a pro-oxidant state and the downregulation of GLUN1 within the hippocampus. The IH-dependent effects were not present in either mice heterozygous for Hif1a (HIF1a+/-) or wild type mice treated with the antioxidant MnTMPyP. Our findings indicate that HIF1a dependent changes in redox state are central to the mechanism by which IH disrupts hippocampal synaptic plasticity and impairs spatial memory. This mechanism may enhance the vulnerability for cognitive deficit and lower the threshold for neurologic diseases associated untreated sleep apnea.Significance: Sleep apnea is associated with cognitive decline and neurological disease. Intermittent hypoxia, a hallmark consequence of sleep apnea, yet the mechanisms by which IH affects cognition is poorly understood. We show that a pro-oxidant state produced by HIF1a is a central factor causing IH-dependent impairment to spatial memory and synaptic plasticity. This work identifies potential targets for intervention in mitigating cognitive decline associated with sleep apnea.
    Keywords:  Hypoxia inducible facto; NADPH oxidas; NMDA recepto; Oxidative stres; sleep apnea
    DOI:  https://doi.org/10.1523/ENEURO.0024-20.2020
  5. Commun Biol. 2020 Jun 05. 3(1): 292
    Lee JE, Kwon HJ, Choi J, Seo JS, Han PL.
      Brain aging proceeds with cellular and molecular changes in the limbic system. Aging-dependent changes might affect emotion and stress coping, yet the underlying mechanisms remain unclear. Here, we show aged (18-month-old) mice exhibit upregulation of NADPH oxidase and oxidative stress in the hippocampus, which mirrors the changes in young (2-month-old) mice subjected to chronic stress. Aged mice that lack p47phox, a key subunit of NADPH oxidase, do not show increased oxidative stress. Aged mice exhibit depression-like behavior following weak stress that does not produce depressive behavior in young mice. Aged mice have reduced expression of the epigenetic factor SUV39H1 and its upstream regulator p-AMPK, and increased expression of Ppp2ca in the hippocampus-changes that occur in young mice exposed to chronic stress. SUV39H1 mediates stress- and aging-induced sustained upregulation of p47phox and oxidative stress. These results suggest that aging increases susceptibility to stress by upregulating NADPH oxidase in the hippocampus.
    DOI:  https://doi.org/10.1038/s42003-020-1010-5
  6. J Mol Neurosci. 2020 Jun 03.
    Tan X, Li T, Zhu S, Zhong W, Li F, Wang Y.
      Secreted protein acidic and rich in cysteine (SPARC) has a close association with inflammatory response and oxidative stress in tissues and is widely expressed in intracranial aneurysms (IAs), especially in smooth muscle cells. Therefore, it is inferred that SPARC might be involved in the formation and development of IAs through the inflammatory response pathway or oxidative stress pathway. The aim of this study is to investigate the pathological mechanism of SPARC in oxidative stress, inflammation, and apoptosis during the formation of IAs, as well as the involvement of TGF-β1 and NOX4 molecules. Human brain vascular smooth muscle cells (HBVSMCs) were selected as experimental objects. After the cells were stimulated by recombinant human SPARC protein in vitro, the ROS level in the cells was measured using an ID/ROS fluorescence analysis kit combined with fluorescence microscope and flow cytometry. The related protein expression in HBVSMCs was measured using western blotting. The mitochondrial membrane potential change was detected using a mitochondrial membrane potential kit and laser confocal microscope. The mechanism was explored by intervention with reactive oxygen scavengers N-acetylcysteine (NAC), TGF-β1 inhibitor (SD-208), and siRNA knockout. The results showed that SPARC upregulated the expression of NOX4 through the TGF-β1-dependent signaling pathway, leading to oxidative stress and pro-inflammatory matrix behavior and apoptosis in HBVSMCs. These findings demonstrated that SPARC may promote the progression of IAs.
    Keywords:  Human brain smooth muscle cells; Intracranial aneurysms; Oxidative stress; Phenotype transformation; SPARC; TGF-β1-NOX4 pathway
    DOI:  https://doi.org/10.1007/s12031-020-01566-z
  7. Transl Res. 2020 May 31. pii: S1931-5244(20)30112-2. [Epub ahead of print]
    Kaushik D, Ashcraft KA, Wang H, Shanmugasundaram K, Shah P, Gonzalez G, Nazarullah A, Tye CB, Liss MA, Pruthi D, Mansour AM, Chowdhury W, Bacich D, Zhang H, Watson AL, Block K, O'Keefe D, Rodriguez R.
      Nuclear NADPH oxidase-4 (Nox4) is a key component of metabolic reprogramming and is often overexpressed in renal cell carcinoma (RCC). However, its prognostic role in RCC remains unclear. Here we examined the significance of nuclear Nox4 on disease progression and development of drug resistance in advanced RCC. We analyzed human RCC tissue from multiple regions in the primary index tumor, cancer-associated normal adjacent parenchyma, intravascular tumor in locally advanced cancer patients. We found that the higher nuclear Nox4 expression was significantly associated with progression and death. These findings were consistent after controlling for other competing clinical variables. In contrast, patients with lower nuclear Nox4, even in higher stage RCC had better prognosis. We identified a subset of patients with high nuclear Nox4 who had rapid disease progression or died within 6 months of surgery. In addition, higher nuclear Nox4 level correlated with resistance to targeted therapy and immunotherapy. Western blotting performed on fresh human RCC tissue as well as cell-lines revealed increased nuclear Nox4 expression. Our data support an important prognostic role of Nox4 mediated regulation of RCC independent of other competing variables. Nox4 localizes to the nucleus in high-grade, high-stage RCC. Higher nuclear Nox4 has prognostic significance for disease progression, poor survival and development of drug resistance in RCC.
    Keywords:  NADPH oxidase-4; Nuclear localization; Renal cell carcinoma; Renal intravascular tumor extension; Tumor thrombus
    DOI:  https://doi.org/10.1016/j.trsl.2020.05.009
  8. Am J Hypertens. 2020 Jun 05. pii: hpaa089. [Epub ahead of print]
    Lamb FS, Choi H, Miller MR, Stark RJ.
      Hypertension and atherosclerosis, the predecessors of stroke and myocardial infarction, are chronic vascular inflammatory reactions. Tumor necrosis factor alpha (TNFα), the "master" pro-inflammatory cytokine, contributes to both the initiation and maintenance of vascular inflammation. TNFα induces reactive oxygen species (ROS) production which drives the redox reactions that constitute "ROS signaling". However, these ROS may also cause oxidative stress which contributes to vascular dysfunction. Mice lacking TNFα or its receptors are protected against both acute and chronic cardiovascular injury. Humans suffering from TNFα-driven inflammatory conditions such as rheumatoid arthritis and psoriasis are at increased cardiovascular risk. When treated with highly specific biologic agents that target TNFα signaling (Etanercept etc.) they display marked reductions in that risk1. The ability of TNFα to induce endothelial dysfunction, often the first step in a progression towards serious vasculopathy, is well recognized and has been reviewed elsewhere2,3. However, TNFα also has profound effects on vascular smooth muscle cells (VSMCs) including a fundamental change from a contractile to a secretory phenotype. This "phenotypic switching" promotes proliferation and production of extracellar matrix proteins which are associated with medial hypertrophy. Additionally, it promotes lipid storage and enhanced motility, changes that support the contribution of VSMCs to neointima and atherosclerotic plaque formation. This review focuses on the role of TNFα in driving the inflammatory changes in VSMC biology that contribute to cardiovascular disease. Special attention is given to the mechanisms by which TNFα promotes ROS production at specific subcellular locations, and the contribution of these ROS to TNFα signaling.
    Keywords:  Atherosclerosis; Hypertension; LRRC8A; Nox1; Reactive Oxygen Signaling; TNFα; Vascular Smooth Muscle
    DOI:  https://doi.org/10.1093/ajh/hpaa089
  9. Trials. 2020 Jun 03. 21(1): 459
    De Livera AM, Reutens A, Cooper M, Thomas M, Jandeleit-Dahm K, Shaw JE, Salim A.
      BACKGROUND: The investigational medicinal product GKT137831 is a selective inhibitor of NOX 1 and 4 isoforms of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes, which has the potential to ameliorate diabetic kidney disease. An investigator-initiated, double-blind, randomised, placebo-controlled, multicentre phase 2 clinical trial started recruitment in December 2017, with the aim of evaluating the efficacy and safety of GKT13783, in adults with type 1 diabetes mellitus and persistently elevated urinary albumin excretion over a period of 48 weeks.METHODS/DESIGN: The trial is currently recruiting in Australia and New Zealand, with recruitment expected to end on 30 June 2020. The primary outcome measure of the trial is the urinary albumin excretion level measured at 48 weeks of treatment. This statistical analysis plan presents an update to the published trial protocol and provides a comprehensive description of the statistical methods that will be used for the analysis of the data from this trial. In doing so, we follow the "Guidelines for the content of statistical analysis plans in clinical trials" to support transparency and reproducibility of the trial findings.
    DISCUSSION: With the use of this prior statistical analysis plan, we aim to minimise bias in the reporting of the findings of this trial, which evaluates the investigational medicinal product GKT137831. The results of the trial are expected to be published in 2022.
    TRIAL REGISTRATION: ANZCTR registry: ACTRN12617001187336. Registered on 14 July 2017. Universal Trial Number: U1111-1187-2609; Protocol number: T1DGKT137831; Genkyotex trial number: GSN000241.
    Keywords:  Albuminuria; GKT137831; Randomised controlled trial; Statistical analysis plan; Type 1 diabetes
    DOI:  https://doi.org/10.1186/s13063-020-04404-0
  10. Nat Commun. 2020 Jun 01. 11(1): 2709
    Wolf A, Herb M, Schramm M, Langmann T.
      Aberrant immune responses including reactive phagocytes are implicated in the etiology of age-related macular degeneration (AMD), a major cause of blindness in the elderly. The translocator protein (18 kDa) (TSPO) is described as a biomarker for reactive gliosis, but its biological functions in retinal diseases remain elusive. Here, we report that tamoxifen-induced conditional deletion of TSPO in resident microglia using Cx3cr1CreERT2:TSPOfl/fl mice or targeting the protein with the synthetic ligand XBD173 prevents reactivity of phagocytes in the laser-induced mouse model of neovascular AMD. Concomitantly, the subsequent neoangiogenesis and vascular leakage are prevented by TSPO knockout or XBD173 treatment. Using different NADPH oxidase-deficient mice, we show that TSPO is a key regulator of NOX1-dependent neurotoxic ROS production in the retina. These data define a distinct role for TSPO in retinal phagocyte reactivity and highlight the protein as a drug target for immunomodulatory and antioxidant therapies for AMD.
    DOI:  https://doi.org/10.1038/s41467-020-16400-8