bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2019‒08‒18
ten papers selected by
Laia Caja Puigsubira
Uppsala University

  1. Redox Biol. 2019 Aug 02. pii: S2213-2317(19)30657-3. [Epub ahead of print]26 101288
    Canugovi C, Stevenson MD, Vendrov AE, Hayami T, Robidoux J, Xiao H, Zhang YY, Eitzman DT, Runge MS, Madamanchi NR.
      Aging is characterized by increased aortic stiffness, an early, independent predictor and cause of cardiovascular disease. Oxidative stress from excess reactive oxygen species (ROS) production increases with age. Mitochondria and NADPH oxidases (NOXs) are two major sources of ROS in cardiovascular system. We showed previously that increased mitochondrial ROS levels over a lifetime induce aortic stiffening in a mouse oxidative stress model. Also, NADPH oxidase 4 (NOX4) expression and ROS levels increase with age in aortas, aortic vascular smooth muscle cells (VSMCs) and mitochondria, and are correlated with age-associated aortic stiffness in hypercholesterolemic mice. The present study investigated whether young mice (4 months-old) with increased mitochondrial NOX4 levels recapitulate vascular aging and age-associated aortic stiffness. We generated transgenic mice with low (Nox4TG605; 2.1-fold higher) and high (Nox4TG618; 4.9-fold higher) mitochondrial NOX4 expression. Young Nox4TG618 mice showed significant increase in aortic stiffness and decrease in phenylephrine-induced aortic contraction, but not Nox4TG605 mice. Increased mitochondrial oxidative stress increased intrinsic VSMC stiffness, induced aortic extracellular matrix remodeling and fibrosis, a leftward shift in stress-strain curves, decreased volume compliance and focal adhesion turnover in Nox4TG618 mice. Nox4TG618 VSMCs phenocopied other features of vascular aging such as increased DNA damage, increased premature and replicative senescence and apoptosis, increased proinflammatory protein expression and decreased respiration. Aortic stiffening in young Nox4TG618 mice was significantly blunted with mitochondrial-targeted catalase overexpression. This demonstration of the role of mitochondrial oxidative stress in aortic stiffness will galvanize search for new mitochondrial-targeted therapeutics for treatment of age-associated vascular dysfunction.
  2. J Cell Mol Med. 2019 Aug 11.
    Emrich F, Penov K, Arakawa M, Dhablania N, Burdon G, Pedroza AJ, Koyano TK, Kim YM, Raaz U, Connolly AJ, Iosef C, Fischbein MP.
      Marfan syndrome (MFS) is a connective tissue disorder that results in aortic root aneurysm formation. Reactive oxygen species (ROS) seem to play a role in aortic wall remodelling in MFS, although the mechanism remains unknown. MFS Fbn1C1039G/+ mouse root/ascending (AS) and descending (DES) aortic samples were examined using DHE staining, lucigenin-enhanced chemiluminescence (LGCL), Verhoeff's elastin-Van Gieson staining (elastin breakdown) and in situ zymography for protease activity. Fbn1C1039G/+ AS- or DES-derived smooth muscle cells (SMC) were treated with anti-TGF-β antibody, angiotensin II (AngII), anti-TGF-β antibody + AngII, or isotype control. ROS were detected during early aneurysm formation in the Fbn1C1039G/+ AS aorta, but absent in normal-sized DES aorta. Fbn1C1039G/+ mice treated with the unspecific NADPH oxidase inhibitor, apocynin reduced AS aneurysm formation, with attenuated elastin fragmentation. In situ zymography revealed apocynin treatment decreased protease activity. In vitro SMC studies showed Fbn1C1039G/+ -derived AS SMC had increased NADPH activity compared to DES-derived SMC. AS SMC NADPH activity increased with AngII treatment and appeared TGF-β dependent. In conclusion, ROS play a role in MFS aneurysm development and correspond anatomically with aneurysmal aortic segments. ROS inhibition via apocynin treatment attenuates MFS aneurysm progression. AngII enhances ROS production in MFS AS SMCs and is likely TGF-β dependent.
    Keywords:  Marfan syndrome; aneurysm; reactive oxygen species
  3. Arch Biochem Biophys. 2019 Aug 12. pii: S0003-9861(19)30447-3. [Epub ahead of print] 108076
    Meitzler JL, Konaté MM, Doroshow JH.
      The cellular microenvironment plays a critical role in cancer initiation and progression. Exposure to oxidative stress, specifically hydrogen peroxide (H2O2), has been linked to aberrant cellular signaling through which the development of cancer may be promoted. Three members of the NADPH oxidase family (NOX4, DUOX1 and DUOX2) explicitly generate this non-radical oxidant in a wide range of tissues, often in support of the inflammatory response. This review summarizes the contributions of each H2O2-producing NOX to the invasive behaviors of tumors and/or the epithelial-mesenchymal transition (EMT) in cancer that plays an essential role in metastasis. Tissue localization in tumorigenesis is also highlighted, with patient-derived TCGA microarray data profiled across 31 cancer cohorts to provide a comprehensive guide to the relevance of NOX4/DUOX1/DUOX2 in cancer studies.
    Keywords:  Dual oxidase; EMT; Hydrogen peroxide; Metastasis; NOX4
  4. Exp Cell Res. 2019 Aug 12. pii: S0014-4827(19)30404-5. [Epub ahead of print] 111552
    Wang Y, Wang XJ, Zhao LM, Pang ZD, She G, Song Z, Cheng X, Du XJ, Deng XL.
      Elevated plasma free fatty acids level has been implicated in the development of insulin resistance, inflammation, and endothelial dysfunction in diabetic and nondiabetic individuals. However, the underlying mechanisms still remain to be defined. Herein, we investigated the effect of palmitic acid (PA), the most abundant saturated fatty acid in the human body, on small-conductance Ca2+-activated potassium channels (KCa2.3)-mediated relaxation in rodent resistance arteries and the underlying molecular mechanism. The effect of PA on KCa2.3 in endothelium was evaluated using real-time PCR, Western blotting, whole-cell patch voltage-clamp, wire and pressure myograph system, and reactive oxygen species (ROS) were measured by using dihydroethidium and 2', 7'-dichlorofluorescein diacetate. KCa2.3-mediated vasodilatation responses to acetylcholine and NS309 (agonist of KCa2.3 and KCa3.1) were impaired by incubation of normal mesenteric arteries with 100 μM PA for 24 h. In cultured human umbilical vein endothelial cells (HUVECs), PA decreased KCa2.3 current and expression at mRNA and protein levels. Incubation with the NADPH oxidase (Nox) inhibitor dibenziodolium (DPI) partly inhibited the PA-induced ROS production and restored KCa2.3 expression. Inhibition of either p38-MAPK or NF-κB using specific inhibitors (SB203580, SB202190 or Bay11-7082, pyrrolidinedithiocarbamate) attenuated PA-induced downregulation of KCa2.3 and inhibition of p38-MAPK also attenuated PA-induced phosphorylation of NF-κB p65. Furthermore, DPI reversed the increment of phospho-p38-MAPK by PA. These results demonstrated that PA downregulated KCa2.3 expressions via Nox/ROS/p38-MAPK/NF-κB signaling leading to endothelial vasodilatory dysfunction.
    Keywords:  Endothelial cells; Palmitic acid; Reactive oxygen species; Resistance arteries; Small-conductance Ca(2+)-activated potassium channels
  5. Am J Physiol Gastrointest Liver Physiol. 2019 Aug 14.
    Li X, Wei X, Sun Y, Du J, Li X, Xun Z, Li YC.
      Diets high in animal fats are associated with increased risks of inflammatory bowel disease (IBD), but the mechanism remains unclear. In this study we investigated the effect of high fat diet (HFD) on the development of experimental colitis in mice. Relative to mice fed low fat diet (LFD), HFD feeding for 4 weeks increased the levels of triglyceride, cholesterol and free fatty acids in the plasma as well as within the colonic mucosa. In an experimental colitis model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS), mice on 4-week HFD exhibited more severe colonic inflammation and developed more severe colitis compared to the LFD counterparts. HFD feeding resulted in higher production of mucosal pro-inflammatory cytokines, greater activation of the myosin light chain kinase (MLCK) tight junction regulatory pathway, and greater increases in mucosal barrier permeability in mice following TNBS induction. HFD feeding also induced gp91, a NADPH oxidase subunit, and promoted reactive oxygen species (ROS) production in both colonic epithelial cells and lamina propria cells. In HCT116 cell culture, palmitic acid or palmitic acid and TNF-α combination markedly increased ROS production and induced the MLCK pathway, and these effects were markedly diminished in the presence of a ROS scavenger. Taken together, these data suggest that HFD promotes colitis by aggravating mucosal oxidative stress, which rapidly drives mucosal inflammation and increases intestinal mucosal barrier permeability.
    Keywords:  Colitis; Hight fat diet; Intestinal epithelial barrier; Oxidative stress
  6. Aging (Albany NY). 2019 Aug 12. 11
    Wang C, Zhang Y, Li F, Wei Y.
      Carbohydrate overconsumption increases blood glucose levels, which contributes to the development of various diseases including obesity and diabetes. It is generally believed that high glucose metabolism increases cellular reactive oxygen species (ROS) levels, damages insulin-secreting cells and leads to age-associated diabetic phenotypes. Here we find that in contrast, high glucose suppresses ROS production induced by paraquat in both mammalian cells and the round worm C. elegans. The role of glucose in suppressing ROS is further supported by glucose's ability to alleviate paraquat's toxicity on C. elegans development. Consistently, we find that the ROS-regulated transcription factor SKN-1 is inactivated by glucose. As a result, the ROS/SKN-1-dependent lifespan extension observed in paraquat-treated animals, mitochondrial respiration mutant isp-1 and germline-less mutant glp-1 are all suppressed by glucose. Our study reveals an unprecedented interaction of glucose with ROS, which could have significant impact on our current understanding of glucose- and ROS-related diseases.
    Keywords:  SKN-1/Nrf2; aging; glucose; hyperglycemia; reactive oxygen species (ROS)
  7. Acta Neurochir Suppl. 2020 ;127 47-54
    Wang J, Liu Y, Shen H, Li H, Wang Z, Chen G.
      BACKGROUND: Previously studies have shown that Nox2 and Nox4, as members of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, Nox), participate in brain damage caused by ischemia-reperfusion (I/R). The aim of this study is to investigate the effects of specific chemical inhibitors of Nox2 and Nox4 on cerebral I/R-induced brain injury in rats.METHODS: At 0.5 h before MCAO surgery, the rats were pretreated with vehicle, Nox2 inhibitor (gp91ds-tat), and Nox4 inhibitor (GKT137831), respectively. After reperfusion for 24 h, the infarct sizes of brain tissues in rats in various groups are determined. The penumbra (ischemic) tissues are collected to measure ROS levels, neuronal apoptosis, and degeneration, as well as the integrity of the blood-brain barrier (BBB) in brain tissues of rats.
    RESULTS: gp91ds-tat and GKT137831 pretreatment significantly reduced the infarct sizes in brain tissues of rats, effectively suppressed I/R-induced increase in ROS levels, neuronal apoptosis and degeneration, and obviously alleviated BBB damage.
    CONCLUSION: Under cerebral I/R conditions, Nox2 inhibitor (gp91ds-tat) and Nox4 inhibitor (GKT137831) can effectively play a protective role in the brain tissues of rats.
    Keywords:  Cerebral ischemia-reperfusion; Middle cerebral artery occlusion; Nox2; Nox4; Reactive oxygen species
  8. Front Physiol. 2019 ;10 956
    Zhang W, Gan D, Jian J, Huang C, Luo F, Wan S, Jiang M, Wan Y, Wang A, Li B, Zhu X.
      Oxidative stress mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) plays an important role in intestinal mucosal barrier damage in various disease states. Recent evidence suggests that intestinal mucosal barrier damage and intestinal dysbiosis occur in mice with hepatic fibrosis induced by CCl4 or bile duct ligation. Another study showed that ursolic acid (UA) attenuates experimental colitis via its anti-inflammatory and antioxidant activities. The goal of this study was to investigate the effects of UA on the intestinal mucosal barrier in CCl4-induced hepatic fibrosis in rats and identify its associated mechanisms. Male Sprague-Dawley rats were randomly divided into the following 3 groups (n = 10/group): the control, CCl4 model and UA treatment groups. Rats were sacrificed at 72 h after the hepatic fibrosis model was established and assessed for liver fibrosis, intestinal injury, enterocyte apoptosis, bacterial translocation, system inflammation, intestinal oxidative stress, and tight junction protein and NOX protein expression. The results demonstrated that UA attenuated the following: (i) liver and intestinal pathological injury; (ii) cleaved caspase-3 expression in the ileal epithelial cells; (iii) serum lipopolysaccharide and procalcitonin levels; (iv) intestinal malondialdehyde levels; and (v) the expression of the NOX protein components NOX2 and P67phox in ileal tissues. Furthermore, our results suggested that UA improved intestinal dysbiosis and the expression of the tight junction proteins Claudin 1 and Occludin in the ileum of rats. These results indicate that UA has protective effects on the intestinal mucosal barrier in rats with CCl4-induced liver fibrosis by inhibiting intestinal NOX-mediated oxidative stress. Our findings may provide a basis for further clinical studies of UA as a novel and adjuvant treatment to cure liver fibrosis.
    Keywords:  NOX; hepatic fibrosis; intestinal microbiota; intestinal mucosal barrier function; ursolic acid
  9. Biomolecules. 2019 Aug 14. pii: E369. [Epub ahead of print]9(8):
    Hamam HJ, Palaniyar N.
      : Neutrophils undergo a unique form of cell death that generates neutrophil extracellular traps (NETs) that may help to neutralize invading pathogens and restore homeostasis. However, uncontrolled NET formation (NETosis) can result in numerous diseases that adversely affect health. Recent studies further elucidate the mechanistic details of the different forms of NETosis and their common end structure, as NETs were constantly found to contain DNA, modified histones and cytotoxic enzymes. In fact, emerging evidence reveal that the post translational modifications (PTMs) of histones in neutrophils have a critical role in regulating neutrophil death. Histone citrullination is shown to promote a rapid form of NET formation independent of NADPH oxidase (NOX), which relies on calcium influx. Interestingly, few studies suggest an association between histone citrullination and other types of PTMs to control cell survival and death, such as histone methylation. Even more exciting is the finding that histone acetylation has a biphasic effect upon NETosis, where histone deacetylase (HDAC) inhibitors promote baseline, NOX-dependent and -independent NETosis. However, increasing levels of histone acetylation suppresses NETosis, and to switch neutrophil death to apoptosis. Interestingly, in the presence of NETosis-promoting stimuli, high levels of HDACis limit both NETosis and apoptosis, and promote neutrophil survival. Recent studies also reveal the importance of the PTMs of neutrophils in influencing numerous pathologies. Histone modifications in NETs can act as a double-edged sword, as they are capable of altering multiple types of neutrophil death, and influencing numerous NET-mediated diseases, such as acute lung injury (ALI), thrombosis, sepsis, systemic lupus erythematosus, and cancer progression. A clear understanding of the role of different PTMs in neutrophils would be important for an understanding of the molecular mechanisms of NETosis, and to appropriately treat NETs-mediated diseases.
    Keywords:  apoptosis; epigenetics; histone acetylation; histone citrullination; histone deacetylase inhibitors; histone methylation; neutrophil extracellular trap formation; neutrophils; post translational modification
  10. Biomolecules. 2019 Aug 14. pii: E365. [Epub ahead of print]9(8):
    Ravindran M, Khan MA, Palaniyar N.
      Neutrophil extracellular traps (NETs), a unique DNA framework decorated with antimicrobial peptides, have been in the scientific limelight for their role in a variety of pathologies ranging from cystic fibrosis to cancer. The formation of NETs, as well as relevant regulatory mechanisms, physiological factors, and pharmacological agents have not been systematically discussed in the context of their beneficial and pathological aspects. Novel forms of NET formation including vital NET formation continue to be uncovered, however, there remain fundamental questions around established mechanisms such as NADPH-oxidase (Nox)-dependent and Nox-independent NET formation. Whether NET formation takes place in the tissue versus the bloodstream, internal factors (e.g. reactive oxygen species (ROS) production and transcription factor activation), and external factors (e.g. alkaline pH and hypertonic conditions), have all been demonstrated to influence specific NET pathways. Elements of neutrophil biology such as transcription and mitochondria, which were previously of unknown significance, have been identified as critical mediators of NET formation through facilitating chromatin decondensation and generating ROS, respectively. While promising therapeutics inhibiting ROS, transcription, and gasdermin D are being investigated, neutrophil phagocytosis plays a critical role in host defense and any therapies targeting NET formation must avoid impairing the physiological functions of these cells. This review summarizes what is known in the many domains of NET research, highlights the most relevant challenges in the field, and inspires new questions that can bring us closer to a unified model of NET formation.
    Keywords:  Neutrophil extracellular traps; Nox-dependent/Nox-independent/suicidal/vital NETs; autoimmunity; cancer metastasis; cystic fibrosis; diabetes