bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2020‒11‒01
six papers selected by
Laia Caja Puigsubira
Uppsala University
  1. Targeting feed-forward signaling of TGFβ/NOX4/DHFR/eNOS uncoupling/TGFβ axis with anti-TGFβ and folic acid attenuates formation of aortic aneurysms: Novel mechanisms and therapeutics.
  2. β-Arrestin2 deficiency attenuates oxidative stress in mouse hepatic fibrosis through modulation of NOX4.
  3. NOX2ko Mice Show Largely Increased Expression of a Mutated NOX2 mRNA Encoding an Inactive NOX2 Protein.
  4. Epithelial TLR4 signaling activates DUOX2 to induce microbiota-driven tumorigenesis.
  5. Inhibition of NOX2 contributes to the therapeutic effect of aloin on traumatic brain injury.
  6. HIF-1α-Mediated, NADPH Oxidase-Derived ROS Contributes to Laryngeal Airway Hyperreactivity Induced by Intermittent Hypoxia in Rats.
  1. Redox Biol. 2020 Oct 13. pii: S2213-2317(20)30962-9. [Epub ahead of print]38 101757
    Targeting feed-forward signaling of TGFβ/NOX4/DHFR/eNOS uncoupling/TGFβ axis with anti-TGFβ and folic acid attenuates formation of aortic aneurysms: Novel mechanisms and therapeutics.
    Kai Huang, Yongchen Wang, Kin Lung Siu, Yixuan Zhang, Hua Cai.
      In the present study we aimed to identify novel mechanisms and therapeutics for thoracic aortic aneurysm (TAA) in Fbn1C1039G/+ Marfan Syndrome (MFS) mice. The expression of mature/active TGFβ and its downstream effector NOX4 were upregulated while tetrahydrobiopterin (H4B) salvage enzyme dihydrofolate reductase (DHFR) was downregulated in Fbn1C1039G/+ mice. In vivo treatment with anti-TGFβ completely attenuated NOX4 expression, restored DHFR protein abundance, reduced ROS production, recoupled eNOS and attenuated aneurysm formation. Intriguingly, oral administration with folic acid (FA) to recouple eNOS markedly alleviated expansion of aortic roots and abdominal aortas in Fbn1C1039G/+ mice, which was attributed to substantially upregulated DHFR expression and activity in the endothelium to restore tissue and circulating levels of H4B. Notably, circulating H4B levels were accurately predictive of tissue H4B bioavailability, and negatively associated with expansion of aortic roots, indicating a novel biomarker role of circulating H4B for TAA. Furthermore, FA diet abrogated TGFβ and NOX4 expression, disrupting the feed-forward loop to inactivate TGFβ/NOX4/DHFR/eNOS uncoupling axis in vivo and in vitro, while PTIO, a NO scavenger, reversed this effect in cultured human aortic endothelial cells (HAECs). Besides, expression of the rate limiting H4B synthetic enzyme GTP cyclohydrolase 1 (GTPCHI), was downregulated in Fbn1C1039G/+ mice at baseline. In cultured HAECs, RNAi inhibition of fibrillin resulted in reduced GTPCHI expression, while this response was abrogated by anti-TGFβ, indicating TGFβ-dependent downregulation of GTPCHI in response to fibrillin deficiency. Taken together, our data for the first time reveal that uncoupled eNOS plays a central role in TAA formation, while anti-TGFβ and FA diet robustly abolish aneurysm formation via inactivation of a novel TGFβ/NOX4/DHFR/eNOS uncoupling/TGFβ feed-forward pathway. Correction of fibrillin deficiency is additionally beneficial via preservation of GTPCHI function.
    Keywords:  Abdominal aortic aneurysm (AAA); Dihydrofolate reductase (DHFR); Folic acid (FA); GTP cyclohydrolase 1 (GTPCHI); Marfan syndrome (MFS); NADPH oxidase (NOX); NOX isoform 4 (NOX4); Nitric oxide (NO); Reactive oxygen species (ROS); Tetrahydrobiopterin (H(4)B); Thoracic aortic aneurysm (TAA); Transforming growth factor–β (TGFβ); eNOS uncoupling/recoupling
    DOI:  https://doi.org/10.1016/j.redox.2020.101757
  2. Acta Pharmacol Sin. 2020 Oct 28.
    β-Arrestin2 deficiency attenuates oxidative stress in mouse hepatic fibrosis through modulation of NOX4.
    Jia-Jia Du, Jia-Chang Sun, Nan Li, Xiu-Qin Li, Wu-Yi Sun, Wei Wei.
      Hepatic fibrosis is a disease characterized by excessive deposition of extracellular matrix (ECM) in the liver. Activation of hepatic stellate cells (HSCs) is responsible for most of ECM production. Oxidative stress and reactive oxygen species (ROS) may be important factors leading to liver fibrosis. NADPH oxidase 4 (NOX4) is the main source of ROS in hepatic fibrosis, but the mechanism by which NOX4 regulates oxidative stress is not fully understood. β-Arrestin2 is a multifunctional scaffold protein that regulates receptor endocytosis, signaling and trafficking. In this study, we investigated whether β-arrestin2 regulated oxidative stress in hepatic fibrosis. Both β-arrestin2 knockout (Arrb2 KO) mice and wild-type mice were intraperitoneally injected with carbon tetrachloride (CCl4) to induce hepatic fibrosis. Arrb2 KO mice showed significantly attenuated liver fibrosis, decreased ROS levels and NOX4 expression, and reduced collagen levels in their livers. In vitro, NOX4 knockdown significantly inhibited ROS production, and decreased expression of alpha-smooth muscle actin in angiotensin II-stimulated human HSC cell line LX-2. Through overexpression or depletion of β-arrestin2 in LX-2 cells, we revealed that decreased β-arrestin2 inhibited ROS levels and NOX4 expression, and reduced collagen production; it also inhibited activation of ERK and JNK signaling pathways. These results demonstrate that β-arrestin2 deficiency protects against liver fibrosis by downregulating ROS production through NOX4. This effect appears to be mediated by ERK and JNK signaling pathways. Thus, targeted inhibition of β-arrestin2 might reduce oxidative stress and inhibit the progression of liver fibrosis.
    Keywords:  NOX4; ROS; SP600125; U0126; hepatic stellate cells; liver fibrosis; oxidative stress; α-SMA; β-arrestin2
    DOI:  https://doi.org/10.1038/s41401-020-00545-9
  3. Antioxidants (Basel). 2020 Oct 26. pii: E1043. [Epub ahead of print]9(11):
    NOX2ko Mice Show Largely Increased Expression of a Mutated NOX2 mRNA Encoding an Inactive NOX2 Protein.
    Monika Göllner, Irmgard Ihrig-Biedert, Victoria Petermann, Sabrina Saurin, Matthias Oelze, Swenja Kröller-Schön, Ksenija Vujacic-Mirski, Marin Kuntic, Andrea Pautz, Andreas Daiber, Hartmut Kleinert.
      BACKGROUND: The superoxide-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2 or gp91phox, the phagocytic isoform) was reported as a major source of oxidative stress in various human diseases. Genetic deletion is widely used to study the impact of NOX2-derived reactive oxygen species (ROS) on disease development and progression in various animal models. Here, we investigate why NOX2 knockout mice show no NOX2 activity but express NOX2 mRNA and protein.METHODS AND RESULTS: Oxidative burst (NOX2-dependent formation of ROS) was measured by L-012-based chemiluminescence and was largely absent in whole blood of NOX2 knockout mice. Protein expression was still detectable in different tissues of the NOX2 knockout mice, at the expected and a slightly lower molecular weight (determined by Western blot). The NOX2 gene was even largely enhanced at its expressional level in NOX2 knockout mice. RNA sequencing revealed a modified NOX2 mRNA in the knockout mice that is obviously translated to a truncated inactive mutant enzyme.
    CONCLUSION: Although the commercial NOX2 knockout mice display no considerable enzymatic NOX2 activity, expression of the NOX2 gene (when using standard primers) and protein (when using antibodies binding to the carboxy-terminal end) can still be detected, which may lead to confusion among investigators.
    Keywords:  next generation sequencing (NGS); nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) knockout mice; oxidative stress related disease; truncated and inactive mutant
    DOI:  https://doi.org/10.3390/antiox9111043
  4. Gastroenterology. 2020 Oct 23. pii: S0016-5085(20)35320-8. [Epub ahead of print]
    Epithelial TLR4 signaling activates DUOX2 to induce microbiota-driven tumorigenesis.
    Juan F Burgueño, Julia Fritsch, Eddy E Gonzalez, Kevin S Landau, Ana M Santander, Irina Fernández, Hajar Hazime, Julie M Davies, Rebeca Santaolalla, Matthew C Phillips, Sophia Diaz, Rishu Dheer, Nivis Brito, Judith Pignac-Kobinger, Ester Fernández, Gregory E Conner, Maria T Abreu.
      BACKGROUND & AIMS: Chronic colonic inflammation leads to dysplasia and cancer in patients with inflammatory bowel disease (IBD). We have described the critical role of innate immune signaling via toll-like receptor 4 (TLR4) in the pathogenesis of dysplasia and cancer. In the current study, we interrogate the intersection of TLR4 signaling, epithelial redox activity, and the microbiota in colitis-associated neoplasia.METHODS: IBD and colorectal cancer datasets were analyzed for expression of TLR4, dual oxidase 2 (DUOX2), and NADPH oxidase 1 (NOX1). Epithelial production of hydrogen peroxide (H2O2) was analyzed in murine colonic epithelial cells and colonoid cultures. Colorectal cancer models were carried out in villin-TLR4 mice, carrying a constitutively active form of TLR4, their littermates, and villin-TLR4 mice backcrossed to DUOXA-KO mice. The role of the TLR4-shaped microbiota in tumor development was tested in wild-type germ-free mice.
    RESULTS: Activation of epithelial TLR4 was associated with upregulation of DUOX2 and NOX1 in IBD and colorectal cancer. DUOX2 was exquisitely dependent on TLR4 signaling and mediated the production of epithelial H2O2. Epithelial H2O2 was significantly increased in villin-TLR4 mice; TLR4-dependent tumorigenesis required the presence of DUOX2 and a microbiota. Mucosa-associated microbiota transferred from villin-TLR4 mice to wild-type germ-free mice caused increased H2O2 production and tumorigenesis.
    CONCLUSIONS: Increased TLR4 signaling in colitis drives expression of DUOX2 and epithelial production of H2O2. The local milieu imprints the mucosal microbiota and imbues it with pathogenic properties demonstrated by enhanced epithelial ROS and increased development of colitis-associated tumors. The inter-relationship between epithelial ROS and tumor-promoting microbiota requires a two-pronged strategy to reduce the risk of dysplasia in colitis patients.
    Keywords:  NADPH oxidases; Ulcerative colitis; colitis-associated cancer; microbiome
    DOI:  https://doi.org/10.1053/j.gastro.2020.10.031
  5. Folia Neuropathol. 2020 ;pii: 42120. [Epub ahead of print]58(3): 265-274
    Inhibition of NOX2 contributes to the therapeutic effect of aloin on traumatic brain injury.
    Haihai Dong, Haitao Wang, Xuezhi Zhang.
      Traumatic brain injury (TBI) is a subset of brain injury induced by external mechanical forces to the head or neck. TBI has been reported to be one of the leading causes of disability, and it causes a huge financial burden around the world. Aloin is the major anthraquinone glycoside extracted from Aloe species, and has presented anti-tumour, anti-oxidative and anti-inflammatory activities. However, few studies have focused the effect of aloin in treatment of TBI. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is the only subset of enzymes which produces solely the reactive oxygen species (ROS). A recent study showed that activation of NOX might aggravate the primary TBI, and among these members, NOX2 is the key member in regulation of uncontrolled ROS expression, and thus plays a critical role in development of inflammatory diseases. Here, we noticed that inhibition of NOX2 combined with aloin treatment promoted the recovery of brain function in a mice model as well as the viability rate in a cell model. A further study found that the inflammation response process was also inhibited after treatment. Then, we found that these effects might be mediated by the PI3K/AKT/mTOR signalling pathway and NOX2 might be a therapeutic target for TBI.
    Keywords:   NOX2; PI3K/AKT/mTOR; aloin; apoptosis.; TBI
    DOI:  https://doi.org/10.5114/fn.2020.100069
  6. Front Physiol. 2020 ;11 575260
    HIF-1α-Mediated, NADPH Oxidase-Derived ROS Contributes to Laryngeal Airway Hyperreactivity Induced by Intermittent Hypoxia in Rats.
    You Shuei Lin, Yan-Jhih Shen, Ping-Hsun Ou, Ching Jung Lai.
      Obstructive sleep apnea, similar to intermittent hypoxia (IH) during sleep, is associated with laryngeal airway hyperreactivity (LAH). IH-induced laryngeal oxidative stress may contribute to LAH, but the underlying mechanism remains unknown. Conscious rats were subjected to repetitive 75 s cycles of IH for 7 or 14 consecutive days. Reflex apneic responses to laryngeal provocations with chemical stimulants were measured to reflect laryngeal reflex reactivity. Compared with control rats, rats exposed to IH for 14 days, but not for 7 days, displayed enhanced apneic response to laryngeal chemical stimulants. The apneic response to chemical stimulants, but not to mechanical stimulation, was totally abolished by perineural capsaicin treatment of superior laryngeal nerves (SLNs) or by the sectioning of the SLNs, suggesting that the reflex was mediated through capsaicin-sensitive SLNs. Daily intraperitoneal administration of N-acetyl-L-cysteine [NAC, a reactive oxygen species (ROS) scavenger], apocynin (an inhibitor of NADPH oxidase) or YC-1 (an inhibitor of HIF-1α), but not their vehicles, largely attenuated this augmented apneic response in 14 days IH rats. Laryngeal lipid peroxidation (an index of oxidative stress) was elevated in 7 days IH rats and 14 days IH rats, and was abolished by any of these three pharmacologic interventions. The protein expression of HIF-1α (an index of HIF-1 activation) and p47phox subunit in the membrane fraction (an index of NADPH oxidase activation) in the laryngeal tissues increased in 14 days IH rats; the former was reduced by NAC, whereas the latter was inhibited by YC-1. These results suggest that 14 days of IH exposure may sensitize capsaicin-sensitive SLNs and result in exaggerated apneic reflex response to laryngeal chemical stimulants. This phenomenon depends on the action of HIF-1α-mediated, NADPH oxidase-derived ROS.
    Keywords:  capsaicin-sensitive superior laryngeal nerves; hypoxia-inducible factor-1α; intermittent hypoxia; laryngeal airway hyperreactivity; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphys.2020.575260
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