bims-noxint 2021-05-23 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2021‒05‒23
nine papers selected by
Laia Caja Puigsubira
Uppsala University

Butyrate Protects Endothelial Function Through PPARδ/miR-181b Signaling.
NADPH-Oxidase 2 Promotes Autophagy in Spinal Neurons During the Development of Morphine Tolerance.
Coordinated Contribution of NADPH Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Metabolic Syndrome and Its Implication in Renal Dysfunction.
NOX2 inhibitor GSK2795039 metabolite identification towards drug optimization.
Redox signaling in heart failure and therapeutic implications.
TLR4/TRAF6/NOX2 signaling pathway is involved in ventilation-induced lung injury via endoplasmic reticulum stress in murine model.
Targeting integrated stress response regulates microglial M1/M2 polarization and attenuates neuroinflammation following surgical brain injury in rat.
ROS induces NETosis by oxidizing DNA and initiating DNA repair.
Silver nanoparticles induce apoptosis via NOX4-derived mitochondrial reactive oxygen species and endoplasmic reticulum stress in colorectal cancer cells.

Pharmacol Res. 2021 May 18. pii: S1043-6618(21)00265-6. [Epub ahead of print] 105681

Butyrate Protects Endothelial Function Through PPARδ/miR-181b Signaling.

Qinqin Tian, Fung Ping Leung, Francis M Chen, Xiao Yu Tian, Zhenyu Chen, Gary Tse, Shuangtao Ma, Wing Tak Wong.

  Reports of the beneficial roles of butyrate in cardiovascular diseases, such as atherosclerosis and ischemic stroke, are becoming increasingly abundant. However, the mechanisms of its bioactivities remain largely unknown. In this study, we explored the effects of butyrate on endothelial dysfunction and its potential underlying mechanism. In our study, ApoE-/- mice were fed with high-fat diet (HFD) for ten weeks to produce atherosclerosis models and concurrently treated with or without sodium butyrate daily. Thoracic aortas were subsequently isolated from C57BL/6 wild-type (WT), PPARδ-/-, endothelial-specific PPARδ wild-type (EC-specific PPARδ WT) and endothelial-specific PPARδ knockout (EC-specific PPARδ KO) mice were stimulated with interleukin (IL)-1β with or without butyrate ex vivo. Our results demonstrated that butyrate treatment rescued the impaired endothelium-dependent relaxations (EDRs) in thoracic aortas of HFD-fed ApoE-/- mice. Butyrate also rescued impaired EDRs in IL-1β-treated thoracic aorta ring ex vivo. Global and endothelial-specific knockout of PPARδ eliminated the protective effects of butyrate against IL-1β-impairment to EDRs. Butyrate abolished IL-1β-induced reactive oxygen species (ROS) production in endothelial cells while the inhibitory effect was incapacitated by genetic deletion of PPARδ or pharmacological inhibition of PPARδ. IL-1β increased NADPH oxidase 2 (NOX2) mRNA and protein expressions in endothelial cells, which were prevented by butyrate treatment, and the effects of butyrate were blunted following pharmacological inhibition of PPARδ. Importantly, butyrate treatment upregulated the miR-181b expression in atherosclerotic aortas and IL-1β-treated endothelial cells. Moreover, transfection of endothelial cells with miR-181b inhibitor abolished the suppressive effects of butyrate on NOX2 expressions and ROS generation in endothelial cells. To conclude, butyrate prevents endothelial dysfunction in atherosclerosis by reducing endothelial NOX2 expression and ROS production via the PPARδ/miR-181b pathway.

Keywords:  Butyrate; Endothelial function; GSK0660 (CID: 46233311); GW0742 (CID: 9934458); MiR-181b; NOX2; PPARδ; Sodium butyrate (CID: 5222465)

DOI:  https://doi.org/10.1016/j.phrs.2021.105681
Neurochem Res. 2021 May 18.

NADPH-Oxidase 2 Promotes Autophagy in Spinal Neurons During the Development of Morphine Tolerance.

Xuyang Xiao, Huilian Bu, Zhisong Li, Zheng Li, Qian Bai, Zhitao Wang, Lin Yan, Daiqiang Liu, Xiaoling Peng, Xiaoqian Jia, Feng Gao.

  Repeated morphine administration results in analgesic tolerance. However, the underlying mechanism of morphine analgesic tolerance remains unclear. NADPH-oxidase 2 (NOX2) is the first discovered NADPH oxidase, which mainly functions to produce reactive oxygen species. Its specific role in morphine tolerance has not been fully investigated. In this work, we found that chronic morphine administration significantly increased the expression of NOX2 in spinal cord. Pretreatment of NOX2 inhibitor blocked the upregulation of NOX2 and autophagy markers, including LC3B and P62, and consequently the development of morphine tolerance. NOX2 and LC3B were both colocalized with NeuN in spinal dorsal horn in morphine-tolerant rats. Our results suggest that the increased autophagy activity in spinal neurons promoted by NOX2 activation contributes to the development of morphine tolerance. NOX2 may be considered as a new therapeutic target for morphine tolerance.

Keywords:  Autophagy; Morphine tolerance; NADPH oxidase; Reactive oxygen species

DOI:  https://doi.org/10.1007/s11064-021-03347-5
Front Pharmacol. 2021 ;12 670076

Coordinated Contribution of NADPH Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Metabolic Syndrome and Its Implication in Renal Dysfunction.

Hewang Lee, Pedro A Jose.

  Metabolic syndrome (MetS), a complex of interrelated risk factors for cardiovascular disease and diabetes, is comprised of central obesity (increased waist circumference), hyperglycemia, dyslipidemia (high triglyceride blood levels, low high-density lipoprotein blood levels), and increased blood pressure. Oxidative stress, caused by the imbalance between pro-oxidant and endogenous antioxidant systems, is the primary pathological basis of MetS. The major sources of reactive oxygen species (ROS) associated with MetS are nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases and mitochondria. In this review, we summarize the current knowledge regarding the generation of ROS from NADPH oxidases and mitochondria, discuss the NADPH oxidase- and mitochondria-derived ROS signaling and pathophysiological effects, and the interplay between these two major sources of ROS, which leads to chronic inflammation, adipocyte proliferation, insulin resistance, and other metabolic abnormalities. The mechanisms linking MetS and chronic kidney disease are not well known. The role of NADPH oxidases and mitochondria in renal injury in the setting of MetS, particularly the influence of the pyruvate dehydrogenase complex in oxidative stress, inflammation, and subsequent renal injury, is highlighted. Understanding the molecular mechanism(s) underlying MetS may lead to novel therapeutic approaches by targeting the pyruvate dehydrogenase complex in MetS and prevent its sequelae of chronic cardiovascular and renal diseases.

Keywords:  NLRP3; metabolic syndrome; mitochondria; nicotinamide-adenine dinucleotide phosphate oxidase; oxidative stress; pyruvate dehydrogenase complex; reactive oxygen species; renal dysfunction

DOI:  https://doi.org/10.3389/fphar.2021.670076
J Pharm Biomed Anal. 2021 Apr 26. pii: S0731-7085(21)00213-2. [Epub ahead of print]201 114102

NOX2 inhibitor GSK2795039 metabolite identification towards drug optimization.

Elias Carvalho Padilha, Pranav Shah, Ganesha Rai, Xin Xu.

  Overproduction of reactive oxygen species (ROS) can lead to several disease states, such as diabetic nephropathy and amyotrophic lateral sclerosis. One of the most studied mechanisms to inhibit the over production of ROS is the inhibition of NADPH oxidase (NOX) enzymes, which catalyze the conversion of cytoplasmic NADPH to NADP+, resulting in the formation of superoxide anions. GSK2795039 has been shown to selectively inhibit the NOX2 isoform, however, clearance of the compound was high in rats and mice. Therefore, identifying metabolic soft spots would be crucial in guiding the optimization process to improve its pharmacokinetic properties. GSK2795039 (10 μM) was incubated in the presence of mouse, rat and human liver microsomal (1 mg/mL) and cytosolic (2 mg/mL) fractions and appropriate co-factors, followed by MSe fragment analysis to identify metabolic soft spots. GSK2795039 showed marked species differences in its metabolism. The alkyl side chains and indoline moiety were the most common sites of biotransformation. The compound was identified to be an aldehyde oxidase substrate. Additionally, unique human metabolites were observed in vitro. Our study sheds light on structure optimization opportunities for developing improved NOX2 inhibitors, and it will help overcome the challenges involved in preclinical species selection for its safety evaluations.

Keywords:  Aldehyde oxidase metabolism; GSK2795039; Metabolite identification; NOX2 inhibitor; Structure optimization

DOI:  https://doi.org/10.1016/j.jpba.2021.114102
Free Radic Biol Med. 2021 May 18. pii: S0891-5849(21)00294-X. [Epub ahead of print]

Redox signaling in heart failure and therapeutic implications.

David Weissman, Christoph Maack.

  Heart failure is a growing health burden worldwide and characterized by alterations in excitation-contraction coupling, cardiac energetic deficit and oxidative stress. While current treatments are mostly limited to antagonization of neuroendocrine activation, more recent data suggest that also targeting metabolism may provide substantial prognostic benefit. However, although in a broad spectrum of preclinical models, oxidative stress plays a causal role for the development and progression of heart failure, no treatment that targets reactive oxygen species (ROS) directly has entered the clinical arena yet. In the heart, ROS derive from various sources, such as NADPH oxidases, xanthine oxidase, uncoupled nitric oxide synthase and mitochondria. While mitochondria are the primary source of ROS in the heart, communication between different ROS sources may be relevant for physiological signalling events as well as pathologically elevated ROS that deteriorate excitation-contraction coupling, induce hypertrophy and/or trigger cell death. Here, we review the sources of ROS in heart, the modes of pathological activation of ROS formation as well as therapeutic approaches that may target ROS specifically in mitochondria.

Keywords:  Mitochondria; NADPH oxidases; Reactive oxygen species; Redox signaling; heart failure

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.05.013
Int Immunopharmacol. 2021 May 18. pii: S1567-5769(21)00410-0. [Epub ahead of print]96 107774

TLR4/TRAF6/NOX2 signaling pathway is involved in ventilation-induced lung injury via endoplasmic reticulum stress in murine model.

Qi Zeng, Liu Ye, Maoyao Ling, Riliang Ma, Junda Li, Haishao Chen, Linghui Pan.

  In ventilation-induced lung injury (VILI), prolonged nonpathogen-mediated inflammation is triggered as a result of alveolar hyperinflation. In our previous study, we suggested that endoplasmic reticulum (ER) stress-mediated inflammation was involved in VILI, but how ER stress is triggered remains unknown. Toll-like receptor 4 (TLR4) activation plays an important role in mechanical ventilation (MV)-induced lung inflammation, however, it is unknown whether ER stress is activated by TLR4 to participate in VILI. In this study, C57BL/6 mice were exposed to MV with high tidal volumes (HTV 20 ml/kg). Mice were pretreated with TAK-242 the TLR4 inhibitor, C25-140, the TRAF6 inhibitor, or GSK2795039, the NOX2 inhibitor. Lung tissue and bronchoalveolar lavage fluid (BALF) were collected to measure lung injury, inflammatory responses and mRNA/protein expression associated with ER stress and the TLR4/TRAF6/NOX2 signaling pathway. Our results indicate that MV with HTV caused the TLR4/TRAF6/NOX2 signaling pathway activation and production of large amounts of ROS, which led to ER stress and NF-κB mediated inflammation in VILI. Furthermore, TLR4/TRAF6/NOX2 signaling pathway inhibition attenuated ER stress response and alleviate lung injury in mice.

Keywords:  Endoplasmic reticulum stress; NADPH oxidase 2; Reactive oxygen species; TNF receptor associated factor 6; Toll-like receptor 4; Ventilation-induced lung injury

DOI:  https://doi.org/10.1016/j.intimp.2021.107774
Cell Signal. 2021 May 17. pii: S0898-6568(21)00137-6. [Epub ahead of print] 110048

Targeting integrated stress response regulates microglial M1/M2 polarization and attenuates neuroinflammation following surgical brain injury in rat.

Teng-Chao Huang, Lun Luo, Shi-Hai Jiang, Chuan Chen, Hai-Yong He, Chao-Feng Liang, Wen-Sheng Li, Hui Wang, Lei Zhu, Kun Wang, Ying Guo.

  Integrated stress response (ISR) contributes to various neuropathological processes and acting as a therapy target in CNS injuries. However, the fundamental role of ISR in regulating microglial polarization remains largely unknown. Currently no proper pharmacological approaches to reverse microglia-driven neuroinflammation in surgical brain injury (SBI) have been reported. Here we found that inhibition of the crucial ISR effector, activating transcription factor 4 (ATF4), using the RNA interference suppressed the lipopolysaccharide (LPS)-stimulated microglial M1 polarization in vitro. Interestingly, counteracting ISR with a small-molecule ISR inhibitor (ISRIB) resulted in a significant microglial M1 towards M2 phenotype switching after LPS treatment. The potential underlying mechanisms may related to downregulate the intracellular NADPH oxidase 4 (NOX4) expression under the neuroinflammatory microenvironment. Notably, ISRIB ameliorated the infiltration of microglia and improved the neurobehavioral outcomes in the SBI rat model. Overall, our findings suggest that targeting ISR exerts a novel anti-inflammatory effect on microglia via regulating M1/M2 phenotype and may represent a potential therapeutic target to overcome neuroinflammation following SBI.

Keywords:  ISRIB; Integrated stress response; M1/M2; Microglia; Neuroinflammation; Surgical brain injury

DOI:  https://doi.org/10.1016/j.cellsig.2021.110048
Cell Death Discov. 2021 May 18. 7(1): 113

ROS induces NETosis by oxidizing DNA and initiating DNA repair.

Dhia Azzouz, Meraj A Khan, Nades Palaniyar.

Reactive oxygen species (ROS) are essential for neutrophil extracellular trap (NET) formation or NETosis. Nevertheless, how ROS induces NETosis is unknown. Neutrophil activation induces excess ROS production and a meaningless genome-wide transcription to facilitate chromatin decondensation. Here we show that the induction of NADPH oxidase-dependent NETosis leads to extensive DNA damage, and the subsequent translocation of proliferating cell nuclear antigen (PCNA), a key DNA repair protein, stored in the cytoplasm into the nucleus. During the activation of NETosis (e.g., by phorbol myristate acetate, Escherichia coli LPS, Staphylococcus aureus (RN4220), or Pseudomonas aeruginosa), preventing the DNA-repair-complex assembly leading to nick formation that decondenses chromatin causes the suppression of NETosis (e.g., by inhibitors to, or knockdown of, Apurinic endonuclease APE1, poly ADP ribose polymerase PARP, and DNA ligase). The remaining repair steps involving polymerase activity and PCNA interactions with DNA polymerases β/δ do not suppress agonist-induced NETosis. Therefore, excess ROS produced during neutrophil activation induces NETosis by inducing extensive DNA damage (e.g., oxidising guanine to 8-oxoguanine), and the subsequent DNA repair pathway, leading to chromatin decondensation.

DOI: https://doi.org/10.1038/s41420-021-00491-3
Nanomedicine (Lond). 2021 May 19.

Silver nanoparticles induce apoptosis via NOX4-derived mitochondrial reactive oxygen species and endoplasmic reticulum stress in colorectal cancer cells.

Juan-Hua Quan, Fei Fei Gao, Jia-Qi Chu, Guang-Ho Cha, Jae-Min Yuk, Weiyun Wu, Young-Ha Lee.

  Aim: To investigate the anticancer mechanisms of silver nanoparticles (AgNPs) in colorectal cancer. Methods: Anticancer effects of AgNPs were determined in colorectal cancer HCT116 cells and xenograft mice using cellular and molecular methods. Results: AgNPs induced mitochondrial reactive oxygen species production, mitochondrial dysfunction and endoplasmic reticulum (ER) stress responses through NOX4 and led to HCT116 cell apoptosis. Pretreatment with DPI or 4-PBA significantly inhibited mitochondrial reactive oxygen species production, apoptosis, ER stress response, NOX4 expression and mitochondrial dysfunction in AgNP-treated HCT116 cells. AgNPs also significantly suppressed HCT116 cell-based xenograft tumor growth in nude mice by inducing apoptosis and ER stress responses. Conclusion: AgNPs exert anticancer effects against colorectal cancer via ROS- and ER stress-related mitochondrial apoptosis pathways.

Keywords:  ER stress; NOX4; apoptosis; colorectal cancer; reactive oxygen species; silver nanoparticles; xenograft nude mice

DOI:  https://doi.org/10.2217/nnm-2021-0098