bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2019‒06‒02
four papers selected by
Laia Caja Puigsubira
Uppsala University


  1. Neurochem Int. 2019 May 23. pii: S0197-0186(19)30119-6. [Epub ahead of print]129 104466
    Kumar S, Singh AK, Vinayak M.
      Reactive oxygen species (ROS) have a key role in different etiologies of pain. At sub-cellular level, mitochondria and plasma membranes have been identified as endogenous sources of ROS required for pain generation. NADPH oxidase (NOX) is the main contributor of membrane associated ROS generation. Out of 7 isozymes, NOX1, NOX2 and NOX4 are reported to be associated with nociceptive sensitization. Therefore, it has been hypothesized that specific inhibition of the NOX isozymes could be putative strategy for treatment of pain. However, unavailability of specific inhibitors was the biggest obstacle to test this hypothesis. Here, we investigated anti-nociceptive potential of a newly identified specific NOX1 inhibitor ML171 in formalin induced inflammatory pain. ML171 administration decreased the paw lickings and flinching response in both phases of formalin test. Behavioral response was supported with decreased activation of c-Fos in spinal dorsal horn. The increased level of total NOX activity, ROS and pERK1/2 in dorsal root ganglion (DRG) and spinal dorsal horn of formalin induced nociception were reversed by ML171 administration. ML171 also inhibited the upregulated Tumor necrosis factor receptor 1 (TNFR1) expression in DRG, whereas did not show any effect in spinal dorsal horn which was unaltered after formalin insult. The study for the first time depicts anti-nociceptive potential of ML171 via regulation of ROS mediated ERK1/2 signaling by inhibition of NOX1 activity.
    Keywords:  ERK1/2; ML171; NOX1; ROS; TNFR1; c-Fos
    DOI:  https://doi.org/10.1016/j.neuint.2019.104466
  2. Front Immunol. 2019 ;10 1085
    Emmi G, Becatti M, Bettiol A, Hatemi G, Prisco D, Fiorillo C.
      Behçet's syndrome (BS) is a systemic vasculitis, clinically characterized by different organ involvement and often complicated by thrombosis which occurs in vessels of all sizes. Thrombosis is more frequent in male patients with active disease and represents an important cause of morbidity and mortality. Neutrophil involvement in BS has been repeatedly suggested in the last few years. Indeed, neutrophils have been shown to be hyperactivated in BS patients, probably with a HLAB51 related contribution, and represent the main cells infiltrating not only oral and genital ulcers or erythema nodosum, but also other sites. Besides being deputed to host defense against micro-organisms, neutrophils display fundamental roles both in inflammation and tissue damage becoming inappropriately activated by cytokines, chemokines and autoantibodies and subsequently producing large amounts of superoxide anion ( O 2 . ) via NADPH oxidase (NOX2). The strict relationship between inflammation and hemostasis has been already demonstrated. Indeed, inflammation and immune-mediated disorders increase the risk of thrombosis, but the pathways that link these processes have not been completely elucidated. In this regard, we recently demonstrated, in a large population of BS patients, a new neutrophil-dependent pathogenetic mechanism of thrombosis. In particular, it was shown that neutrophils, mainly through NADPH oxidase, produce excessive amounts of reactive oxygen species (ROS), which are able to markedly modify the secondary structure of fibrinogen and hence the overall architecture of the fibrin clot that becomes less susceptible to plasmin-induced lysis. These data point out that BS represents "per se" a model of inflammation-induced thrombosis and suggest that neutrophils specifically contribute to thrombo-inflammation in this rare disease. In particular, it is suggested that an alteration in fibrinogen structure and function are associated with enhanced ROS production via neutrophil NADPH oxidase. Altogether, these findings improve our understanding of the intricate pathogenetic mechanisms of thrombo-inflammation and may indicate potential new therapeutic targets.
    Keywords:  Behçet's syndrome; fibrinogen; neutrophils; oxidative stress; thrombosis
    DOI:  https://doi.org/10.3389/fimmu.2019.01085
  3. Aging (Albany NY). 2019 May 30.
    You W, Hong Y, He H, Huang X, Tao W, Liang X, Zhang Y, Li X.
      Formation of aortic aneurysms as a consequence of augmented transforming growth factor β (TGF-β) signaling and vascular smooth muscle cell (VSMC) dysfunction is a potentially lethal complication of Marfan syndrome (MFS). Here, we examined VSMC senescence in patients with MFS and explored the potential mechanisms that link VSMC senescence and TGF-β. Tissue was harvested from the ascending aorta of control donors and MFS patients, and VSMCs were isolated. Senescence-associated β-galactosidase (SA-β-gal) activity and expression of senescence-related proteins (p53, p21) were significantly higher in aneurysmal tissue from MFS patients than in healthy aortic tissue from control donors. Compared to control-VSMCs, MFS-VSMCs were larger with higher levels of both SA-β-gal activity and mitochondrial reactive oxygen species (ROS). In addition, TGF-β1 levels were much higher in MFS- than control-VSMCs. TGF-β1 induced VSMC senescence through excessive ROS generation. This effect was suppressed by Mito-tempo, a mitochondria-targeted antioxidant, or SC-514, a NF-κB inhibitor. This suggests TGF-β1 induces VSMC senescence through ROS-mediated activation of NF-κB signaling. It thus appears that a TGF-β1/ROS/NF-κB axis may mediate VSMC senescence and aneurysm formation in MFS patients. This finding could serve as the basis for a novel strategy for treating aortic aneurysm in MFS.
    Keywords:  Marfan syndrome; reactive oxygen species; senescence; transforming growth factor β; vascular smooth muscle cells
    DOI:  https://doi.org/10.18632/aging.101998
  4. Front Pharmacol. 2019 ;10 431
    Huang C, Gan D, Luo F, Wan S, Chen J, Wang A, Li B, Zhu X.
      Background: Studies have shown that both NOX4 and RhoA play essential roles in fibrosis and that they regulate each other. In lung fibrosis, NOX4/ROS is located upstream of the RhoA/ROCK1 signaling pathway, and the two molecules are oppositely located in renal fibrosis. Currently, no reports have indicated whether the above mechanisms or other regulatory mechanisms exist in liver fibrosis.Objectives: To investigate the effects of the NOX4/ROS and RhoA/ROCK1 signaling pathways on hepatic stellate cell (HSC)-T6 cells, the interaction mechanisms of the two pathways, and the impact of UA on the two pathways to elucidate the role of UA in the reduction of hepatic fibrosis and potential mechanisms of HSC-T6 cell proliferation, migration, and activation.
    Methods: Stable cell lines were constructed using the lentiviral transduction technique. Cell proliferation, apoptosis, migration, and invasion were examined using the MTS, TdT-mediated dUTP nick-end labeling, cell scratch, and Transwell invasion assays, respectively. The DCFH-DA method was used to investigate the ROS levels in each group. RT-qPCR and western blotting techniques were utilized to assess the mRNA and protein expression in each group. CoIP and the Biacore protein interaction analysis systems were used to evaluate protein interactions.
    Results: The NOX4/ROS and RhoA/ROCK1 signaling pathways promoted the proliferation, migration, and activation of HSCs. UA inhibited cell proliferation, migration, and activation by inhibiting the activation of the two signaling pathways, but the mechanism of apoptosis was independent of these two pathways. The NOX4/ROS pathway was upstream of and positively regulated the RhoA/ROCK1 pathway in HSCs. No direct interaction between the NOX4 and RhoA proteins was detected.
    Conclusion: The NOX4/ROS and RhoA/ROCK1 signaling pathways are two critical signaling pathways in a series of behavioral processes in HSCs, and NOX4/ROS regulates RhoA/ROCK1 through an indirect pathway to control the activation of HSCs. Additionally, NOX4/ROS and RhoA/ROCK1 constitute a new target for UA antifibrosis treatment.
    Keywords:  NOX4; RhoA; cytoskeleton; hepatic stellate cells; ursolic acid
    DOI:  https://doi.org/10.3389/fphar.2019.00431