bims-noxint 2022-07-24 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2022‒07‒24
seven papers selected by
Laia Caja Puigsubira
Uppsala University

Induction of reactive oxygen species by mechanical stretch drives endothelin production in neonatal pig renal epithelial cells.
BMAL1 modulates ROS generation and insulin secretion in pancreatic β-cells: An effect possibly mediated via NOX2.
lncRNA PINK1-AS Aggravates Cerebral Ischemia/Reperfusion Oxidative Stress Injury through Regulating ATF2 by Sponging miR-203.
Coordinated NADPH oxidase/hydrogen peroxide functions regulate cutaneous sensory axon de- and regeneration.
NADPH-Oxidase Derived Hydrogen Peroxide and Irs2b Facilitate Re-oxygenation-Induced Catch-Up Growth in Zebrafish Embryo.
mTORC1 activation induced proximal tubular damage via the pentose phosphate pathway in lupus nephritis.
Bisphenol A Promotes the Progression of Colon Cancer Through Dual-Targeting of NADPH Oxidase and Mitochondrial Electron-Transport Chain to Produce ROS and Activating HIF-1α/VEGF/PI3K/AKT Axis.

Redox Biol. 2022 Jul 04. pii: S2213-2317(22)00166-5. [Epub ahead of print]55 102394

Induction of reactive oxygen species by mechanical stretch drives endothelin production in neonatal pig renal epithelial cells.

Ravi Kumar, Hitesh Soni, Jeremiah M Afolabi, Praghalathan Kanthakumar, Pratheesh D Mankuzhy, Samson A Iwhiwhu, Adebowale Adebiyi.

  Vasoactive endothelin (ET) is generated by ET converting enzyme (ECE)-induced proteolytic processing of pro-molecule big ET to biologically active peptides. H2O2 has been shown to increase the expression of ECE1 via transactivation of its promoter. The present study demonstrates that H2O2 triggered ECE1-dependent ET1-3 production in neonatal pig proximal tubule (PT) epithelial cells. A uniaxial stretch of PT cells decreased catalase, increased NADPH oxidase (NOX)2 and NOX4, and increased H2O2 levels. Stretch also increased cellular ECE1, an effect reversed by EUK-134 (a synthetic superoxide dismutase/catalase mimetic), NOX inhibitor apocynin, and siRNA-mediated knockdown of NOX2 and NOX4. Short-term unilateral ureteral obstruction (UUO), an inducer of renal tubular cell stretch and oxidative stress, increased renal ET1-3 generation and vascular resistance (RVR) in neonatal pigs. Despite removing the obstruction, UUO-induced increase in RVR persisted, resulting in early acute kidney injury (AKI). ET receptor (ETR)-operated Ca2+ entry in renal microvascular smooth muscle (SM) via transient receptor potential channel 3 (TRPC3) channels reduced renal blood flow and increased RVR. Although acute reversible UUO (rUUO) did not change protein expression levels of ETR and TRPC3 in renal microvessels, inhibition of ECE1, ETR, and TRPC3 protected against renal hypoperfusion, RVR increase, and early AKI. These data suggest that mechanical stretch-driven oxyradical generation stimulates ET production in neonatal pig renal epithelial cells. ET activates renal microvascular SM TRPC3, leading to persistent vasoconstriction and reduction in renal blood flow. These mechanisms may underlie rUUO-induced renal insufficiency in infants.

Keywords:  Acute kidney injury; Endothelin; Endothelin converting enzyme; Hydrogen peroxide; Mechanical stretch; Neonatal pigs; Urinary tract obstruction

DOI:  https://doi.org/10.1016/j.redox.2022.102394
Mol Cell Endocrinol. 2022 Jul 19. pii: S0303-7207(22)00173-3. [Epub ahead of print] 111725

BMAL1 modulates ROS generation and insulin secretion in pancreatic β-cells: An effect possibly mediated via NOX2.

Daniel Simoes de Jesus, Paula Bargi-Souza, Vinicius Cruzat, Vijay Yechoor, Angelo Rafael Carpinelli, Rodrigo Antonio Peliciari-Garcia.

  The pancreatic β cells circadian clock plays a relevant role in glucose metabolism. NADPH oxidase (NOX) family is responsible for producing reactive oxygen species (ROS), such as superoxide anion and hydrogen peroxide, using NADPH as an electron donor. In pancreatic β-cells, NOX-derived ROS inhibits basal and glucose-stimulated insulin secretion. Thus, we hypothesized that the absence of BMAL1, a core circadian clock component, could trigger an increase of NOX2-derived ROS in pancreatic β cells, inhibiting insulin secretion under basal and stimulated glucose conditions. To test such hypothesis, Bmal1 was knocked down (KD) in cultured clonal β-cell line (INS-1E) and knocked out in isolated pancreatic islets, using a tissue-specific β-cells Bmal1 knockout (KO) mice. The insulin secretion was assessed in the presence of NOX inhibitors. The Bmal1 KD within INS-1E cells elicited a rise of intracellular ROS content under both glucose stimuli (2.8 mM and 16.7 mM), associated with an increase in Nox2 expression. Additionally, alterations of glutathione levels, CuZnSOD and catalase activities, reduction of ATP/ADP ratio, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and aconitase activities, followed by glucokinase and Slc2a2 (Glut2) expression were also observed in INS-1E β-cells, reflecting in a diminished insulin secretion pattern. The isolated islets from β-cell Bmal1-/- mice have shown a similar cellular response, where an increased NOX2-derived ROS content and a reduced basal- and glucose-stimulated insulin secretion were observed. Therefore, together with NOX inhibition (Apocynin), polyethene-glycol linked to superoxide dismutase (PEG-SOD), phorbol myristate acetate (PMA), and diethyldithiocarbamate (DDC) data, our findings suggest a possible BMAL1-mediated NOX2-derived ROS generation in pancreatic β cells, leading to the modulation of both basal- and glucose-stimulated insulin secretion.

Keywords:  Circadian clock; Insulin; Islets; NADPH oxidase; ROS; Superoxide

DOI:  https://doi.org/10.1016/j.mce.2022.111725
Oxid Med Cell Longev. 2022 ;2022 1296816

lncRNA PINK1-AS Aggravates Cerebral Ischemia/Reperfusion Oxidative Stress Injury through Regulating ATF2 by Sponging miR-203.

Zhong-Bao Yang, Yu Xiang, Mei-Lin Zuo, Li Mao, Guo-Huang Hu, Gui-Lin Song, Md Sayed Ali Sheikh, Li-Ming Tan.

Ischemic stroke is a common disease that led to high mortality and high disability. NADPH oxidase 2- (NOX2-) mediated oxidative stress and long noncoding RNA have important roles in cerebral ischemia/reperfusion (CI/R) injury, whereas whether there is interplay between them remains to be clarified. This study was performed to observe the role of lncRNA PINK1-antisense RNA (PINK1-AS) in NOX2 expression regulation. An in vivo rat model (MCAO) and an in vitro cell model (H/R: hypoxia/reoxygenation) were utilized for CI/R oxidative stress injury investigation. The expression levels of lncRNA PINK1-AS, activating transcription factor 2 (ATF2), NOX2, and caspase-3 and the production level of ROS and cell apoptosis were significantly increased in CI/R injury model rats or in H/R-induced SH-SY5Y cells, but miR-203 was significantly downregulated. There was positive correlation between PINK1-AS expression level and ROS production level. PINK1-AS and ATF2 were found to be putative targets of miR-203. Knockdown of lncRNA PINK1-AS or ATF2 or the overexpression of miR-203 significantly reduced oxidative stress injury via inhibition of NOX2. Overexpression of lncRNA PINK1 significantly led to oxidative stress injury in SH-SY5Y cells through downregulating miR-203 and upregulating ATF2 and NOX2. lncRNA PINK1-AS and ATF2 were the targets of miR-203, and the lncRNA PINK1-AS/miR-203/ATF2/NOX2 axis plays pivotal roles in CI/R injury. Therefore, lncRNA PINK1-AS is a possible target for CR/I injury therapy by sponging miR-203.

DOI: https://doi.org/10.1155/2022/1296816
Proc Natl Acad Sci U S A. 2022 Jul 26. 119(30): e2115009119

Coordinated NADPH oxidase/hydrogen peroxide functions regulate cutaneous sensory axon de- and regeneration.

Antonio Cadiz Diaz, Natalie A Schmidt, Mamiko Yamazaki, Chia-Jung Hsieh, Thomas S Lisse, Sandra Rieger.

  Tissue wounding induces cutaneous sensory axon regeneration via hydrogen peroxide (H2O2) that is produced by the epithelial NADPH oxidase, Duox1. Sciatic nerve injury instead induces axon regeneration through neuronal uptake of the NADPH oxidase, Nox2, from macrophages. We therefore reasoned that the tissue environment in which axons are damaged stimulates distinct regenerative mechanisms. Here, we show that cutaneous axon regeneration induced by tissue wounding depends on both neuronal and keratinocyte-specific mechanisms involving H2O2 signaling. Genetic depletion of H2O2 in sensory neurons abolishes axon regeneration, whereas keratinocyte-specific H2O2 depletion promotes axonal repulsion, a phenotype mirrored in duox1 mutants. Intriguingly, cyba mutants, deficient in the essential Nox subunit, p22Phox, retain limited axon regenerative capacity but display delayed Wallerian degeneration and axonal fusion, observed so far only in invertebrates. We further show that keratinocyte-specific oxidation of the epidermal growth factor receptor (EGFR) at a conserved cysteine thiol (C797) serves as an attractive cue for regenerating axons, leading to EGFR-dependent localized epidermal matrix remodeling via the matrix-metalloproteinase, MMP-13. Therefore, wound-induced cutaneous axon de- and regeneration depend on the coordinated functions of NADPH oxidases mediating distinct processes following injury.

Keywords:  EGFR; Wallerian degeneration; axon fusion; axon regeneration; hydrogen peroxide

DOI:  https://doi.org/10.1073/pnas.2115009119
Front Endocrinol (Lausanne). 2022 ;13 929668

NADPH-Oxidase Derived Hydrogen Peroxide and Irs2b Facilitate Re-oxygenation-Induced Catch-Up Growth in Zebrafish Embryo.

Ayaka Zasu, Futa Hishima, Marion Thauvin, Yosuke Yoneyama, Yoichiro Kitani, Fumihiko Hakuno, Michel Volovitch, Shin-Ichiro Takahashi, Sophie Vriz, Christine Rampon, Hiroyasu Kamei.

  Oxygen deprivation induces multiple changes at the cellular and organismal levels, and its re-supply also brings another special physiological status. We have investigated the effects of hypoxia/re-oxygenation on embryonic growth using the zebrafish model: hypoxia slows embryonic growth, but re-oxygenation induces growth spurt or catch-up growth. The mitogen-activated kinase (MAPK)-pathway downstream insulin-like growth factor (IGF/Igf) has been revealed to positively regulate the re-oxygenation-induced catch-up growth, and the role of reactive oxygen species generated by environmental oxygen fluctuation is potentially involved in the phenomenon. Here, we report the role of NADPH-oxidase (Nox)-dependent hydrogen peroxide (H2O2) production in the MAPK-activation and catch-up growth. The inhibition of Nox significantly blunted catch-up growth and MAPK-activity. Amongst two zebrafish insulin receptor substrate 2 genes (irs2a and irs2b), the loss of irs2b, but not its paralog irs2a, resulted in blunted MAPK-activation and catch-up growth. Furthermore, irs2b forcedly expressed in mammalian cells allowed IGF-MAPK augmentation in the presence of H2O2, and the irs2b deficiency completely abolished the somatotropic action of Nox in re-oxygenation condition. These results indicate that redox signaling alters IGF/Igf signaling to facilitate hypoxia/re-oxygenation-induced embryonic growth compensation.

Keywords:  NADPH-oxidase; catch-up growth; hydrogen peroxide; hypoxia; insulin receptor substrate 2; insulin-like growth factor; re-oxygenation; zebrafish

DOI:  https://doi.org/10.3389/fendo.2022.929668
Free Radic Biol Med. 2022 Jul 18. pii: S0891-5849(22)00492-0. [Epub ahead of print]

mTORC1 activation induced proximal tubular damage via the pentose phosphate pathway in lupus nephritis.

Zhaomin Mao, Ying Tan, Juan Tao, Linlin Li, Feng Yu, Minghui Zhao.

  More recent studies suggested that metabolic disorders could contribute to the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). The present work aimed at identifying metabolic reprogramming in the kidney of lupus nephritis via proteomics and investigating the potential regulatory mechanism. The proteomic studies on the renal biopsies revealed that the pentose phosphate pathway (PPP) was significantly enriched in the kidneys of LN patients compared with normal controls (NCs). Immunohistochemical stanning of glucose-6-phosphate dehydrogenase (G6PD), the key rate-limiting enzyme of PPP, verify the results of proteomics. We found that G6PD was highly expressed in the kidneys of LN patients and correlated with several clinicopathological indices. The univariate Cox regression analysis (HR, 95%CI, 1.877 (1.059-3.328), P = 0.031) and Kaplan-Meier (KM) analysis (P = 0.028) suggested that high G6PD expression in the tubulointerstitial area was a risk factor for worse prognosis. Moreover, the Gene set enrichment analysis (GSEA) demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway ranked first in the kidneys of LN patients with high G6PD expression and G6PD was co-localized with mTORC1 activation in the tubule. Immunoglobulin G (IgG) isolated from LN patients significantly activated the mTORC1 pathway and increased G6PD expression, G6PD activity, NADPH production, NADPH oxidase 2 (NOX2) expression, reactive oxygen species (ROS) production, and cell apoptosis in tubule cells in vitro. The above phenotypes were partially rescued after the addition of rapamycin or knock-down of G6PD. Overall, our study suggested that renal G6PD expression was associated with the overall enhanced disease activity and worse renal prognosis. mTORC1 activation might be involved in IgG-LN-induced tubular damage via PPP.

Keywords:  G6PD; Lupus nephritis; Pentose phosphate pathway; mTORC1

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.07.010
Front Endocrinol (Lausanne). 2022 ;13 933051

Bisphenol A Promotes the Progression of Colon Cancer Through Dual-Targeting of NADPH Oxidase and Mitochondrial Electron-Transport Chain to Produce ROS and Activating HIF-1α/VEGF/PI3K/AKT Axis.

Tianyi Xia, Junnan Guo, Bomiao Zhang, Chengxin Song, Qunye Zhao, Binbin Cui, Yanlong Liu.

  Bisphenol A (BPA) is a high-production-volume industrial chemical. Despite recent research conducted on its carcinogenicity, its role in the development of colon cancer (CC) has been rarely studied. This study aims to evaluate the effects of BPA on the migration and invasion of CC cells. First, we clinically verified that patients with CC exhibit higher serum BPA level than healthy donors. Subsequently, different CC cell lines were exposed to a series of BPA concentrations, and the migration and invasion of cells were detected by the wound healing test and transwell assay. Finally, N-acetyl-L-cysteine (NAC) and siHIF-1α intervention was used to explore the effects of ROS and HIF-1α on cell migration and invasion, respectively. The results demonstrated that the occurrence of BPA-induced migration and invasion were dependent on the dose and time and was most pronounced in DLD1 cells. ROS production was jointly driven by NADPH oxidase (NOX) and mitochondrial electron-transport chain (ETC). Furthermore, the intervention of NAC and siHIF-1α blocked the HIF-1α/VEGF/PI3K/AKT axis and inhibited cell migration and invasion. In conclusion, our results suggest that BPA exposure promotes the excessive production of ROS induced by NOX and ETC, which in turn activates the HIF-1α/VEGF/PI3K/AKT axis to promote the migration and invasion of CC cells. This study provides new insights into the carcinogenic effects of BPA on CC and warns people to pay attention to environmental pollution and the harm caused to human health by low-dose BPA.

Keywords:  HIF-1α/VEGF/PI3K/AKT axis; ROS; bisphenol A; colon cancer; progression

DOI:  https://doi.org/10.3389/fendo.2022.933051