bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2021‒02‒28
five papers selected by
Laia Caja Puigsubira
Uppsala University

  1. Am J Physiol Renal Physiol. 2021 Feb 22.
      Dozens of millions of people are exposed to gadolinium-based contrast agents annually for enhanced magnetic resonance imaging. Gadolinium-based contrast agents are known nephrotoxins and can trigger the potentially fatal condition of systemic fibrosis. Risk factors are practically entirely undefined. We examined the role of NADPH oxidase 4 (Nox4) in gadolinium-induced systemic disease. Age- and weight-matched mice were randomized to experimental diabetes (streptozotocin) and control followed by systemic gadolinium-based contrast agent treatment. Nox4-deficient mice were randomized to experimental diabetes and gadolinium-based contrast agent treatment. Skin fibrosis and cellular infiltration were apparent in both the gadolinium-based contrast agent-treated and experimental diabetes groups. Similarly, both groups demonstrated renal pathologies with evidence of reactive oxygen species generation. Deletion of Nox4 abrogated both skin and renal pathology, whether from diabetes or gadolinium-based contrast agent treatment. These discoveries demonstrate the importance of Nox4 in gadolinium-based contrast agent- and diabetes-induced fibrosis.
    Keywords:  NADPH Oxidase 4; diabetes mellitus; fibrosis; gadolinium; nephrogenic fibrosing dermopathy
  2. Am J Physiol Renal Physiol. 2021 Feb 22.
      BACKGROUND: Calcineurin inhibitors (CNIs) are vital immunosuppressive therapies in the management of inflammatory conditions. A long-term consequence is nephrotoxicity. In the kidneys, the primary, catalytic calcineurin (CnA) isoforms are CnAα and CnAβ. While the renal phenotype of CnAα-/- mice substantially mirrors CNI-induced nephrotoxicity, the mechanisms downstream of CnAa are poorly understood.HYPOTHESIS: Since NADPH oxidase-2 (Nox2)-derived oxidative damage is implicated in CNI-induced nephrotoxicity, we hypothesized that CnAα inhibition drives Nox2 upregulation and promotes oxidative stress.
    EXPERIMENTAL DESIGN: To test the hypothesis, Nox2 regulation was investigated in kidneys from CnAα-/-, CnAβ-/- and WT littermate mice. To identify the downstream mediator of CnAα, NFAT and NFκB regulation was examined. To test if Nox2 is transcriptionally regulated via a NFκB pathway, CnAα-/- and WT renal fibroblasts were treated with the NFκB inhibitor, caffeic acid phenethyl ester.
    RESULTS: Our findings showed that CsA treatment induced Nox2 upregulation and oxidative stress. Further, Nox2 upregulation and elevated ROS generation occurred only in CnAα-/- mice. In these mice, NFκB but not NFAT activity was increased. In CnAα-/- renal fibroblasts, NFκB inhibition prevented Nox2 upregulation and ROS generation.
    CONCLUSIONS: These findings indicate that 1) CnAα loss stimulates Nox2 upregulation, 2) NFκB is a novel CnAα-regulated transcription factor and 3) NFκB mediates CnAα-induced Nox2 and ROS upregulation.
    SIGNIFICANCE: Our results demonstrate that CnAα plays a key role in Nox2 and ROS generation. Further, these novel findings provide evidence of divergent CnA isoform signaling pathways. Finally, this study advocates for CnAα-sparing CNIs, ultimately circumventing the CNI nephrotoxicity.
    Keywords:  NADPH oxidase; NFκB; calcineurin inhibitors; calcineurin isoforms; oxidative stress
  3. Front Mol Neurosci. 2020 ;13 131
      Depression is a common mental disorder that presents a considerable challenge for public health. The natural product geniposide has neuroprotective effects on depression, but the underlying mechanism behind these effects had remained undefined. The present study was designed to investigate the role of microRNAs (miRs) in this mechanism. It studied mice with depression-like behavior established by exposure to chronic unpredictable mild stress (CUMS) for 2 months. The CUMS mice were intragastrically fed with geniposide at a dose of 10 ml/kg daily for two consecutive weeks. We monitored the depression-like behaviors of the CUMS mice by the forced swimming test (FST) and tail suspension test (TST). Then, we measured the cerebral expression of miR-298-5p and NADPH oxidase 1 (Nox1) mRNA in the CUMS mice by the RT-qPCR. The targeting relationship between miR-298-5p and Nox1 was evaluated by dual-luciferase reporter gene assay. The concentrations of adenosine triphosphate (ATP) and reactive oxygen species (ROS) were determined by the CellTiter-Glo® and flow cytometry, respectively. The mitochondrial membrane potential (MMP) was detected using JC-1 staining. Moreover, the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6, and TGF-β) was determined by ELISA, RT-qPCR, and western blot analysis. We found that miR-298-5p was poorly-expressed while Nox1 was highly-expressed in the brain tissues of the CUMS-induced mice. Intriguingly, Geniposide treatment reversed the behavioral abnormalities of CUMS mice, including shortened immobility time. Geniposide inhibited the Nox1 expression by increasing miR-298-5p levels. There were increased ATP content and MMP and reduced contents of ROS and inflammatory cytokines in the CUMS mice receiving geniposide treatment. Hence, this study revealed an antidepressant effect of geniposide on CUMS-induced depression-like behavior in mice by down-regulating the miR-298-5p-targeted Nox1. This highlights a novel candidate target for the treatment of depression.
    Keywords:  NADPH oxidase 1; depression; geniposide; inflammation; microRNA-298-5p; mitochondria; mouse frontal cortex; reactive oxygen species
  4. Oxid Med Cell Longev. 2021 ;2021 6643171
      Background: Perinatal hypoxia is a universal cause of death and neurological deficits in neonates worldwide. Activation of microglial NADPH oxidase 2 (NOX2) leads to oxidative stress and neuroinflammation, which may contribute to hypoxic damage in the developing brain. Dexmedetomidine has been reported to exert potent neuroprotection in several neurological diseases, but the mechanism remains unclear. We investigated whether dexmedetomidine acts through microglial NOX2 to reduce neonatal hypoxic brain damage.Methods: The potential role of microglial NOX2 in dexmedetomidine-mediated alleviation of hypoxic damage was evaluated in cultured BV2 microglia and neonatal rats subjected to hypoxia. In vivo, neonatal rats received dexmedetomidine (25 μg/kg, i.p.) 30 min before or immediately after hypoxia (5% O2, 2 h). Apocynin-mediated NOX inhibition and lentivirus-mediated NOX2 overexpression were applied to further assess the involvement of microglial NOX2 activation.
    Results: Pre- or posttreatment with dexmedetomidine alleviated hypoxia-induced cognitive impairment, restored damaged synapses, and increased postsynaptic density-95 and synaptophysin protein expression following neonatal hypoxia. Importantly, dexmedetomidine treatment suppressed hypoxia-induced microglial NOX2 activation and subsequent oxidative stress and the neuroinflammatory response, as reflected by reduced 4-hydroxynonenal and ROS accumulation, and decreased nuclear NF-κB p65 and proinflammatory cytokine levels in cultured BV2 microglia and the developing hippocampus. In addition, treating primary hippocampal neurons with conditioned medium (CM) from hypoxia-activated BV2 microglia resulted in neuronal damage, which was alleviated by CM from dexmedetomidine-treated microglia. Moreover, the neuroprotective effect of dexmedetomidine was reversed in NOX2-overexpressing BV2 microglia and diminished in apocynin-pretreated neonatal rats.
    Conclusion: Dexmedetomidine targets microglial NOX2 to reduce oxidative stress and neuroinflammation and subsequently protects against hippocampal synaptic loss following neonatal hypoxia.
  5. Endocrinology. 2021 Feb 25. pii: bqab043. [Epub ahead of print]
      PURPOSE: The objectives of this study were to analyze the distribution of Dual oxidase (DUOX) system genes (containing DUOX2, DUOX1, DUOXA2 and DUOXA1) variants in children with congenital hypothyroidism and their phenotypes.METHODS: Target region sequencing technology was performed on DUOX system genes among 606 congenital hypothyroidism (CH) subjects covering all the exon and intron regions. Detailed clinical data were collected for statistical analysis.
    RESULTS: A total of 95 suspected pathogenic variants were detected in the DUOX system genes, showing a 39.11% rate in variant carrying (237/606). DUOX2 was with the highest rate in this study. There were statistical difference in maximum adjusted dose and current dose of L-T4 between the DUOX system genes non-mutated group with the mutated group (p<0.001; p<0.001). The cases in DUOX system genes mutated group were more likely to develop into transient CH (χ 2 = 23.155, p<0.001) and more likely to manifested as goiter or gland-in-situ (χ 2 = 66.139, p<0.001). In addition, there was no significant difference in clinical characteristics between DUOX system genes mono-allelic and non mono-allelic. Although 20% of the variants affected the functional domain regions (EF hand, and FAD and NADPH binding sites), there was no significant effect on the phenotype severity whether the variation is located in the functional domain regions.
    CONCLUSIONS: Our results showed the high variation rate of DUOX2 in the DUOX system genes among the Chinese CH patients. And the complex genotype-phenotype relationship of DUOX system genes broadened the understanding of CH phenotype spectrum.
    Keywords:  Clinical phenotype; Congenital hypothyroidism; DUOX system genes; Targeted region sequencing; Thyroid gland