bims-noxint 2020-04-19 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2020‒04‒19
nine papers selected by
Laia Caja Puigsubira
Uppsala University

NADPH Oxidases in Bone and Cartilage Homeostasis and Disease: A Promising Therapeutic Target.
Modulation of radiation-induced damage of human glomerular endothelial cells by SMPDL3B.
Glycolytic reprograming in Salmonella counters NOX2-mediated dissipation of ΔpH.
Apocynin and catalase prevent hypertension and kidney injury in Cyclosporine A-induced nephrotoxicity in rats.
Constitutive hydrogen inhalation prevents vascular remodeling via reduction of oxidative stress.
Neutrophil extracellular traps mediate the crosstalk between glioma progression and the tumor microenvironment via the HMGB1/RAGE/IL-8 axis.
Aggravated endothelial endocrine dysfunction and intimal thickening of renal artery in high-fat diet-induced obese pigs following renal denervation.
NADPH oxidase contributes to oxidative damage and mitochondrial impairment induced by acute ethanol treatment in rat hippocampal neurons.
Mechanism investigation on Bisphenol S-induced oxidative stress and inflammation in murine RAW264.7 cells: The role of NLRP3 inflammasome, TLR4, Nrf2 and MAPK.

J Orthop Res. 2020 Apr 14.

NADPH Oxidases in Bone and Cartilage Homeostasis and Disease: A Promising Therapeutic Target.

Adam M Wegner, Dominik R Haudenschild.

  Reactive oxygen species (ROS) generated by the NADPH Oxidase (Nox) enzymes are important short-range signaling molecules. They have been extensively studied in the physiology and pathophysiology of the cardiovascular system, where they have important roles in vascular inflammation, angiogenesis, hypertension, cardiac injury, stroke, and aging. Increasing evidence demonstrates that ROS and Nox enzymes also affect bone homeostasis and osteoporosis, and more recent studies implicate ROS and Nox enzymes in both inflammatory arthritis and osteoarthritis. Mechanistically, this connection may be through the effects of ROS on signal transduction. ROS affect both TGFß/Smad signaling, IL-1ß/NFkB signaling, and the resulting changes in MMP expression. The purpose of this review is to describe the role of Nox enzymes in the physiology and pathobiology of bone and joints, and to highlight the potential of therapeutically targeting the Nox enzymes. This article is protected by copyright. All rights reserved.

Keywords:  Arthritis; Bone; Cartilage; NADPH Oxidase; Nox4; Osteoporosis

DOI:  https://doi.org/10.1002/jor.24693
FASEB J. 2020 Apr 15.

Modulation of radiation-induced damage of human glomerular endothelial cells by SMPDL3B.

Alaa Abou Daher, Marina Francis, Patrick Azzam, Anis Ahmad, Assaad A Eid, Alessia Fornoni, Brian Marples, Youssef H Zeidan.

  The intracellular molecular pathways involved in radiation-induced nephropathy are still poorly understood. Glomerular endothelial cells are key components of the structure and function of the glomerular filtration barrier but little is known about the mechanisms implicated in their injury and repair. The current study establishes the response of immortalized human glomerular endothelial cells (GEnC) to ionizing radiation (IR). We investigated the role of sphingolipids and the lipid-modifying enzyme sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) in radiation-induced GEnC damage. After delivering a single dose of radiation, long and very-long-chain ceramide species, and the expression levels of SMPDL3b were elevated. In contrast, levels of ceramide-1-phosphate (C1P) dropped in a time-dependent manner although mRNA and protein levels of ceramide kinase (CERK) remained stable. Treatment with C1P or knocking down SMPDL3b partially restored cell survival and conferred radioprotection. We also report a novel role for the NADPH oxidase enzymes (NOXs), namely NOX1, and NOX-derived reactive oxygen species (ROS) in radiation-induced GEnC damage. Subjecting cultured endothelial cells to radiation was associated with increased NOX activity and superoxide anion generation. Silencing NOX1 using NOX1-specific siRNA mitigated radiation-induced oxidative stress and cellular injury. In addition, we report a novel connection between NOX and SMPDL3b. Treatment with the NOX inhibitor, GKT, decreased radiation-induced cellular injury and restored SMPDL3b basal levels of expression. Our findings indicate the importance of SMPDL3b as a potential therapeutic target in radiation-induced kidney damage.

Keywords:  SMPDL3b; cancer; ceramide; glomerular endothelial cells; nephropathy; radioprotection; reactive oxygen species; sphingolipids

DOI:  https://doi.org/10.1096/fj.201902179R
Nat Commun. 2020 Apr 14. 11(1): 1783

Glycolytic reprograming in Salmonella counters NOX2-mediated dissipation of ΔpH.

Sangeeta Chakraborty, Lin Liu, Liam Fitzsimmons, Steffen Porwollik, Ju-Sim Kim, Prerak Desai, Michael McClelland, Andres Vazquez-Torres.

The microbial adaptations to the respiratory burst remain poorly understood, and establishing how the NADPH oxidase (NOX2) kills microbes has proven elusive. Here we demonstrate that NOX2 collapses the ΔpH of intracellular Salmonella Typhimurium. The depolarization experienced by Salmonella undergoing oxidative stress impairs folding of periplasmic proteins. Depolarization in respiring Salmonella mediates intense bactericidal activity of reactive oxygen species (ROS). Salmonella adapts to the challenges oxidative stress imposes on membrane bioenergetics by shifting redox balance to glycolysis and fermentation, thereby diminishing electron flow through the membrane, meeting energetic requirements and anaplerotically generating tricarboxylic acid intermediates. By diverting electrons away from the respiratory chain, glycolysis also enables thiol/disulfide exchange-mediated folding of bacterial cell envelope proteins during periods of oxidative stress. Thus, primordial metabolic pathways, already present in bacteria before aerobic respiration evolved, offer a solution to the stress ROS exert on molecular targets at the bacterial cell envelope.

DOI: https://doi.org/10.1038/s41467-020-15604-2
PLoS One. 2020 ;15(4): e0231472

Apocynin and catalase prevent hypertension and kidney injury in Cyclosporine A-induced nephrotoxicity in rats.

Yong Chia Tan, Munavvar Abdul Sattar, Ahmad F Ahmeda, Nurzalina Abdul Karim Khan, Vikneswaran Murugaiyah, Ashfaq Ahmad, Zurina Hassan, Gurjeet Kaur, Mohammed Hadi Abdulla, Edward James Johns.

Oxidative stress is involved in the pathogenesis of a number of diseases including hypertension and renal failure. There is enhanced expression of nicotinamide adenine dinucleotide (NADPH oxidase) and therefore production of hydrogen peroxide (H2O2) during renal disease progression. This study investigated the effect of apocynin, an NADPH oxidase inhibitor and catalase, an H2O2 scavenger on Cyclosporine A (CsA) nephrotoxicity in Wistar-Kyoto rats. Rats received CsA (25mg/kg/day via gavage) and were assigned to vehicle, apocynin (2.5mmol/L p.o.), catalase (10,000U/kg/day i.p.) or apocynin plus catalase for 14 days. Renal functional and hemodynamic parameters were measured every week, and kidneys were harvested at the end of the study for histological and NADPH oxidase 4 (NOX4) assessment. Oxidative stress markers and blood urea nitrogen (BUN) were measured. CsA rats had higher plasma malondialdehyde (by 340%) and BUN (by 125%), but lower superoxide dismutase and total antioxidant capacity (by 40%, all P<0.05) compared to control. CsA increased blood pressure (by 46mmHg) and decreased creatinine clearance (by 49%, all P<0.05). Treatment of CsA rats with apocynin, catalase, and their combination decreased blood pressure to near control values (all P<0.05). NOX4 mRNA activity was higher in the renal tissue of CsA rats by approximately 63% (P<0.05) compared to controls but was reduced in apocynin (by 64%), catalase (by 33%) and combined treatment with apocynin and catalase (by 84%) compared to untreated CsA rats. Treatment of CsA rats with apocynin, catalase, and their combination prevented hypertension and restored renal functional parameters and tissue Nox4 expression in this model. NADPH inhibition and H2O2 scavenging is an important therapeutic strategy during CsA nephrotoxicity and hypertension.

DOI: https://doi.org/10.1371/journal.pone.0231472
PLoS One. 2020 ;15(4): e0227582

Constitutive hydrogen inhalation prevents vascular remodeling via reduction of oxidative stress.

Takeshi Kiyoi, Shuang Liu, Erika Takemasa, Hirotomo Nakaoka, Naohito Hato, Masaki Mogi.

Molecular hydrogen is thought to have an inhibitory effect on oxidative stress, thereby attenuating the onset and progression of various diseases including cardiovascular disease; however, few reports have assessed the preventive effect of constitutive inhalation of hydrogen gas on of vascular remodeling. Here, we investigated the effect of constitutive inhalation of hydrogen gas on vascular neointima formation using a cuff-induced vascular injury mouse model. After constitutive inhalation of compressed hydrogen gas (O2 21%, N2 77.7%, hydrogen 1.3%) or compressed air only (O2 21%, N2 79%) by C57BL/6 mice for 2 weeks from 8 weeks of age in a closed chamber, inflammatory cuff injury was induced by polyethylene cuff placement around the femoral artery under anesthesia, and hydrogen gas administration was continued until sampling of the femoral artery. Neointima formation, accompanied by an increase in cell proliferation, was significantly attenuated in the hydrogen group compared with the control group. NADPH oxidase NOX1 downregulation in response to cuff injury was shown in the hydrogen group, but the expression levels of NADPH oxidase subunits, p40phox and p47phox, did not differ significantly between the hydrogen and control groups. Although the increase in superoxide anion production did not significantly differ between the hydrogen and control groups, DNA damage was decreased as a result of reduction of reactive oxygen species such as hydroxyl radical (⋅OH) and peroxynitrite (ONOO-) in the hydrogen group. These results demonstrate that constitutive inhalation of hydrogen gas attenuates vascular remodeling partly via reduction of oxidative stress, suggesting that constitutive inhalation of hydrogen gas at a safe concentration in the living environment could be an effective strategy for prevention of vascular diseases such as atherosclerosis.

DOI: https://doi.org/10.1371/journal.pone.0227582
Cancer Biol Med. 2020 Feb 15. 17(1): 154-168

Neutrophil extracellular traps mediate the crosstalk between glioma progression and the tumor microenvironment via the HMGB1/RAGE/IL-8 axis.

Caijun Zha, Xiangqi Meng, Lulu Li, Shan Mi, Da Qian, Ziwei Li, Pengfei Wu, Shaoshan Hu, Shihong Zhao, Jinquan Cai, Yanhong Liu.

  Objective: Neutrophil extracellular traps (NETs) produced by tumor-infiltrating neutrophils (TINs) are associated with poor prognosis in patients with several types of cancer. However, the mechanisms underlying the involvement of NETs in glioma progression remain largely unknown. This study aimed to elucidate the roles of NETs in biological processes that drive the crosstalk between glioma progression and the tumor microenvironment. Methods: Neutrophil infiltration and NETs formation were investigated in glioma tissue through immunohistochemistry, and their relationships with clinicopathological features and outcomes were statistically evaluated. The effects of NETs on glioma cell progression were studied in a co-culture system. In vivo and in vitro experiments validated the reactive oxygen species activity and cytokine production of TINs, as well as the ERK signaling pathway activation and the metastasis of gliomas. Results: Neutrophil infiltration and NETs formation were induced in high-grade glioma compared with low-grade glioma. NETs induced by TINs were determined to be an oncogenic marker of high-grade gliomas and to be involved in cell proliferation and invasion. NETs overproduction promoted glioma cell proliferation, migration, and invasion. Furthermore, HMGB1 was found to bind to RAGE and activate the NF-κB signaling pathway in vitro. In addition, NETs stimulated the NF-κB signaling pathway, thus promoting IL-8 secretion in glioblastoma. Subsequently, IL-8 recruited neutrophils which in turn mediated NETs formation via the PI3K/AKT/ROS axis in TINs. Conclusions: Our results suggest that NETs produced by TINs mediate the crosstalk between glioma progression and the tumor microenvironment by regulating the HMGB1/RAGE/IL-8 axis. Targeting NETs formation or IL-8 secretion may be an effective approach to inhibit glioma progression.

Keywords:  HMGB1; IL-8; NF-κB; Neutrophil extracellular traps; glioma microenvironment

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2019.0353
BMC Cardiovasc Disord. 2020 Apr 16. 20(1): 176

Aggravated endothelial endocrine dysfunction and intimal thickening of renal artery in high-fat diet-induced obese pigs following renal denervation.

Enyong Su, Linwei Zhao, Xiaohang Yang, Binbin Zhu, Yahui Liu, Wen Zhao, Xianpei Wang, Datun Qi, Lijie Zhu, Chuanyu Gao.

  BACKGROUND: Renal denervation (RDN) targeting the sympathetic nerves in the renal arterial adventitia as a treatment of resistant hypertension can cause endothelial injury and vascular wall injury. This study aims to evaluate the risk of atherosclerosis induced by RDN in renal arteries.METHODS: A total of 15 minipigs were randomly assigned to 3 groups: (1) control group, (2) sham group, and (3) RDN group (n = 5 per group). All pigs were fed a high-fat diet (HFD) for 6 months after appropriate treatment. The degree of intimal thickening of renal artery and the conversion of endothelin 1 (ET-1) receptors were evaluated by histological staining. Western blot was used to assess the expression of nitric oxide (NO) synthesis signaling pathway, ET-1 and its receptors, NADPH oxidase 2 (NOX2) and 4-hydroxynonenal (4-HNE) proteins, and the activation of NF-kappa B (NF-κB).
RESULTS: The histological staining results suggested that compared to the sham treatment, RDN led to significant intimal thickening and significantly promoted the production of endothelin B receptor (ETBR) in vascular smooth muscle cells (VSMCs). Western blotting analysis indicated that RDN significantly suppressed the expression of AMPK/Akt/eNOS signaling pathway proteins, and decreased the production of NO, and increased the expression of endothelin system proteins including endothelin-1 (ET-1), endothelin converting enzyme 1 (ECE1), endothelin A receptor (ETAR) and ETBR; and upregulated the expression of NOX2 and 4-HNE proteins and enhanced the activation of NF-kappa B (NF-κB) when compared with the sham treatment (all p < 0.05). There were no significant differences between the control and sham groups (all p > 0.05).
CONCLUSIONS: RDN aggravated endothelial endocrine dysfunction and intimal thickening, and increased the risk of atherosclerosis in renal arteries of HFD-fed pigs.

Keywords:  Atherosclerosis; Endothelial dysfunction; High-fat diet; Hypertension; Intimal thickening; Renal denervation

DOI:  https://doi.org/10.1186/s12872-020-01472-7
Neuropharmacology. 2020 Apr 11. pii: S0028-3908(20)30168-4. [Epub ahead of print] 108100

NADPH oxidase contributes to oxidative damage and mitochondrial impairment induced by acute ethanol treatment in rat hippocampal neurons.

María José Pérez, Rocío Loyola, Francisco Canelo, Alejandra Aranguiz, Carola Tapia-Monsalves, Cesar Osorio-Fuentealba, Rodrigo A Quintanilla.

  Acute ethanol treatment induces neurodegeneration in cultured neurons and can lead to brain damage in animal models. Neuronal cells exposed to ethanol showed an increase in reactive oxygen species (ROS), oxidative damage and mitochondrial impairment contributing to synaptic failure. However, the underlying mechanisms of these events are not well understood. Here, we studied the contribution of NADPH oxidase, as a relevant source of ROS production in the brain, to mitochondrial impairment and oxidative stress induced by ethanol. We used primary hippocampal neurons subjected to an acute treatment of ethanol at increasing concentrations (25, 50, and 75 mM, 24 h), and we evaluated ROS production, mitochondrial function, and synaptic vesicle activity. Our studies showed that after ethanol administration, hippocampal neurons presented an increase in ROS levels, mitochondrial dysfunction, calcium handling defects, and synaptic impairment. Interestingly, treatment with the NADPH inhibitor, apocynin, significantly prevented oxidative stress, mitochondrial dysfunction, and the impairment of synaptic vesicle activity induced by ethanol treatment. These results indicate that NADPH oxidase could be a key participant in the molecular mechanism by which alcohol affects the brain.

Keywords:  Alcohol; Mitochondria; NADPH oxidase; Oxidative stress

DOI:  https://doi.org/10.1016/j.neuropharm.2020.108100
J Hazard Mater. 2020 Apr 09. pii: S0304-3894(20)30538-0. [Epub ahead of print]394 122549

Mechanism investigation on Bisphenol S-induced oxidative stress and inflammation in murine RAW264.7 cells: The role of NLRP3 inflammasome, TLR4, Nrf2 and MAPK.

Chunfeng Xie, Miaomiao Ge, Jianliang Jin, Haie Xu, Li Mao, Shanshan Geng, Jieshu Wu, Jianyun Zhu, Xiaoting Li, Caiyun Zhong.

  Bisphenol S is considered as a safer alternative to bisphenol A. In the present study, we used murine macrophages to investigate the effects of BPS exposure on oxidative stress and inflammatory response as well as the underlying mechanism. Cells were exposed to BPS at various concentrations for short period of times. Results showed that 10-8 M BPS triggered oxidative stress by increasing ROS/RNS production, increased the levels of oxidant enzyme NOX1/2, and decreased the levels of antioxidant enzymes SOD1/2, CAT and GSH-Px. 10-8 M BPS exposure significantly induced the production of proinflammatory mediators. Activation of the NLRP3 inflammasome, TLR4, and MAPK pathways was involved in this process. Furthermore, we illustrated that NAC pretreatment diminished these effects triggered by BPS exposure. Collectively, our data suggested that BPS at a dose relevant to human serum concentration induced oxidative stress and inflammatory response in macrophages. These novel findings shed light on the concerns regarding the potential adverse effects of BPS exposure that requires further careful attention.

Keywords:  Bisphenol S; Inflammation; NOD-like receptor protein 3 inflammasome; Oxidative stress; Toll like receptor 4

DOI:  https://doi.org/10.1016/j.jhazmat.2020.122549