bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2020‒12‒20
six papers selected by
Laia Caja Puigsubira
Uppsala University


  1. J Cell Mol Med. 2020 Dec 17.
    Liang Y, Liu H, Fang Y, Lin P, Lu Z, Zhang P, Jiao X, Teng J, Ding X, Dai Y.
      Podocyte injury is associated with albuminuria and the progression of diabetic nephropathy (DN). NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and NOX4 is up-regulated in podocytes in response to high glucose. In the present study, the effects of Salvianolate on DN and its underlying mechanisms were investigated in diabetic db/db mice and human podocytes. We confirmed that the Salvianolate administration exhibited similar beneficial effects as the NOX1/NOX4 inhibitor GKT137831 treated diabetic mice, as reflected by attenuated albuminuria, reduced podocyte loss and mesangial matrix accumulation. We further observed that Salvianolate attenuated the increase of Nox4 protein, NOX4-based NADPH oxidase activity and restored podocyte loss in the diabetic kidney. In human podocytes, NOX4 was predominantly localized to mitochondria and Sal B treatment blocked HG-induced mitochondrial NOX4 derived superoxide generation and thereby ameliorating podocyte apoptosis, which can be abrogated by AMPK knockdown. Therefore, our results suggest that Sal B possesses the reno-protective capabilities in part through AMPK-mediated control of NOX4 expression. Taken together, our results identify that Salvianolate could prevent glucose-induced oxidative podocyte injury through modulation of NOX4 activity in DN and have a novel therapeutic potential for DN.
    Keywords:  AMPK; NADPH oxidases 4; Salvianolate; diabetes nephropathy; mitochondria; podocyte injury; reactive oxygen species
    DOI:  https://doi.org/10.1111/jcmm.16165
  2. Antioxidants (Basel). 2020 Dec 09. pii: E1253. [Epub ahead of print]9(12):
    Sha'fie MSA, Rathakrishnan S, Hazanol IN, Dali MHI, Khayat ME, Ahmad S, Hussin Y, Alitheen NB, Jiang LH, Syed Mortadza SA.
      Microglial cells are the primary immune cell resident in the brain. Growing evidence indicates that microglial cells play a prominent role in alcohol-induced brain pathologies. However, alcohol-induced effects on microglial cells and the underlying mechanisms are not fully understood, and evidence exists to support generation of oxidative stress due to NADPH oxidases (NOX_-mediated production of reactive oxygen species (ROS). Here, we investigated the role of the oxidative stress-sensitive Ca2+-permeable transient receptor potential melastatin-related 2 (TRPM2) channel in ethanol (EtOH)-induced microglial cell death using BV2 microglial cells. Like H2O2, exposure to EtOH induced concentration-dependent cell death, assessed using a propidium iodide assay. H2O2/EtOH-induced cell death was inhibited by treatment with TRPM2 channel inhibitors and also treatment with poly(ADP-ribose) polymerase (PARP) inhibitors, demonstrating the critical role of PARP and the TRPM2 channel in EtOH-induced cell death. Exposure to EtOH, as expected, led to an increase in ROS production, shown using imaging of 2',7'-dichlorofluorescein fluorescence. Consistently, EtOH-induced microglial cell death was suppressed by inhibition of NADPH oxidase (NOX) as well as inhibition of protein kinase C. Taken together, our results suggest that exposure to high doses of ethanol can induce microglial cell death via the NOX/ROS/PARP/TRPM2 signaling pathway, providing novel and potentially important insights into alcohol-induced brain pathologies.
    Keywords:  NOX; PARP; ROS; TRPM2; alcoholism; cell death; microglia; oxidative stress
    DOI:  https://doi.org/10.3390/antiox9121253
  3. Ann Transl Med. 2020 Nov;8(21): 1376
    Hong Y, Woo S, Kim Y, Lee JJ, Hong JY.
      Background: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) enzymes play important roles in generating reactive oxygen species (ROS); in particular, NOX4 plays a distinct role in regulating lung inflammation and apoptosis.Methods: We determined whether plasma NOX4 level can be used as a prognostic biomarker to guide weaning from mechanical ventilation and to predict mortality in intubated patients. Plasma levels of NOX4 were measured at days 1 (NOX4 D1) and 7 (NOX4 D7) after initiation of mechanical ventilation in 184 patients.
    Results: With increase in day 7 NOX4 quartile, the success of weaning tended to decrease and 28-day mortality tended to increase. On multivariate logistic regression, Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) [odds ratio (OR): 1.10; 95% CI, 1.02-1.18], duration of mechanical ventilation (OR: 1.12; 95% CI: 1.06-1.18), and NOX4 D7 levels >18.2 ng/mL (OR: 4.40; 95% CI: 1.91-10.06) were independently associated with weaning failure. Also, Cox-hazard proportional model showed that NOX4 D7 level >18.2 ng/mL (hazard ratio [HR], 2.29; 95% CI, 1.26-4.16), APACHE II (HR: 1.07; 95% CI: 1.02-1.14), Sequential Organ Failure Assessment (SOFA) (HR: 1.10; 95% CI: 1.01-1.20) and coexisting cancer (HR: 1.99; 95% CI, 1.01-3.94), were independently associated with 28-day mortality. The longitudinal trend of NOX4 level varied according to the clinical outcomes.
    Conclusions: An increased plasma NOX4 D7 level was associated with weaning failure and 28-day mortality in patients with mechanical ventilation. Our results suggest that NOX4-directed management may lead to improved outcomes in patients with mechanical ventilation.
    Keywords:  Biomarker; NOX4; mechanical ventilation; mechanical ventilation weaning; mortality
    DOI:  https://doi.org/10.21037/atm-20-4252
  4. Oxid Med Cell Longev. 2020 ;2020 7095902
    Grauers Wiktorin H, Aydin E, Hellstrand K, Martner A.
      The formation of reactive oxygen species (ROS) by the myeloid cell NADPH oxidase NOX2 is critical for the destruction of engulfed microorganisms. However, recent studies imply that ROS, formed by NOX2+ myeloid cells in the malignant microenvironment, exert multiple actions of relevance to the growth and spread of neoplastic cells. By generating ROS, tumor-infiltrating myeloid cells and NOX2+ leukemic myeloid cells may thus (i) compromise the function and viability of adjacent cytotoxic lymphocytes, including natural killer (NK) cells and T cells, (ii) oxidize DNA to trigger cancer-promoting somatic mutations, and (iii) affect the redox balance in cancer cells to control their proliferation and survival. Here, we discuss the impact of NOX2-derived ROS for tumorigenesis, tumor progression, regulation of antitumor immunity, and metastasis. We propose that NOX2 may be a targetable immune checkpoint in cancer.
    DOI:  https://doi.org/10.1155/2020/7095902
  5. Biochem Biophys Res Commun. 2020 Dec 10. pii: S0006-291X(20)32114-8. [Epub ahead of print]534 59-66
    Zhang X, Ibi M, Haga R, Iwata K, Matsumoto M, Asaoka N, Liu J, Katsuyama M, Yabe-Nishimura C.
      Autism spectrum disorder (ASD) is a neurodevelopmental disorder caused by genetic and environmental factors. Among the environmental factors, maternal infection is known as one of the principal risk factors for ASD. On the other hand, postmortem studies suggested the relationship of oxidative stress with ASD etiology. However, the role of oxidative stress in the development of ASD remains unclear. Here, we report the involvement of NOX1/NADPH oxidase, an enzyme generating reactive oxygen species (ROS), in behavioral and anatomical abnormalities in a maternal immune activation (MIA) model. In the MIA model of gestational polyinosinic-polycytidylic acid (poly(I:C)) exposure, increased serum levels of IL-6 were observed in both wild-type (WT) and Nox1-deficient mice (Nox1KO). Following the comparable induction of MIA in the two genotypes, impairment of social preference and defects in motor coordination were observed in WT offspring but not in offspring deficient in Nox1. MIA up-regulated NOX1 mRNA in the cerebral cortex and cerebellum of the fetus but not in the adult offspring. Although the development of cortical neurons was unaffected by MIA in either genotype, the dropout of Purkinje cells in lobule VII of MIA-affected offspring was significantly ameliorated in Nox1KO. Taken together, these results suggested that NOX1/NADPH oxidase plays an essential role in some behavioral phenotypes observed in ASD, possibly by promoting the loss of Purkinje cells in the cerebellum.
    Keywords:  Autism spectrum disorder (ASD); Maternal immune activation (MIA); NADPH oxidase; NOX1; Polyinosinic-polycytidylic acid (poly(I:C)); Purkinje cells
    DOI:  https://doi.org/10.1016/j.bbrc.2020.11.070
  6. Int J Biochem Cell Biol. 2020 Dec 09. pii: S1357-2725(20)30219-3. [Epub ahead of print] 105902
    Li S, Li Z, Yin R, Nie J, Fu Y, Ying R.
      Fibrotic diseases account for more than 8 million deaths worldwide annually. Reactive oxygen species (ROS) has been shown to activate pyroptosis and promote the production of interleukin (IL)-1β and IL-18, leading to fibrosis development. However, the role of dual oxidase 1 (DUOX1)-induced ROS production and pyroptosis in cardiac fibrosis remains largely unknown. Activin A was used to induce ROS and pyroptosis in cardiomyocytes. ROS level, pyroptosis, and cytokine production were detected using Active Oxygen Detection Kit, flow cytometry, and enzyme-linked immunosorbent assay, respectively. Western blotting analysis was used to measure expression changes of proteins. DUOX1 was silenced or overexpressed to investigate its role in fibrosis. We found that activin A induced ROS production and pyroptosis in cardiomyocytes, which was blocked by the ROS scavenger, N-acetyl-L-cysteine (NAC). Knockdown of DUOX1 reversed activin A-induced ROS production, pyroptosis, cytokine release, and the upregulation of proinflammatory proteins. Overexpression of DUOX1 resulted in opposite effects of knockdown DUOX1. Administration of an ROS scavenger blocked the effect of DUOX1 overexpression. Supplementation of IL-1β and IL-18 caused significant fibrosis in human cardiac fibroblasts (hCFs). The knockdown of DUOX1 protected cardiomyocytes against activin A-induced fibrosis via the inhibition of ROS, cytokine release, and pyroptosis.
    Keywords:  cardiac fibrosis; cytokine release; inflammation; pyroptosis; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.biocel.2020.105902