bims-noxint 2020-05-10 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2020–05–10
seven papers selected by
Laia Caja Puigsubira, Uppsala University

NADPH oxidases: Pathophysiology and therapeutic potential in age-associated pulmonary fibrosis.
The role of NADPH oxidases in neuronal development.
Insulin-like growth factor-I activates NFκB and NLRP3 inflammatory signalling via ROS in cancer cells.
Immunotherapeutic Response in Tumors Is Affected by Microenvironmental ROS.
Calcitonin gene-related peptide inhibits angiotensin II-induced NADPH oxidase-dependent ROS via the Src/STAT3 signalling pathway.
MnTE-2-PyP, a manganese porphyrin, reduces cytotoxicity caused by irradiation in a diabetic environment through the induction of endogenous antioxidant defenses.
Potent Inhibitory Effect of BJ-3105, a 6-Alkoxypyridin-3-ol Derivative, on Murine Colitis Is Mediated by Activating AMPK and Inhibiting NOX.

Redox Biol. 2020 Apr 17. pii: S2213-2317(20)30158-0. [Epub ahead of print] 101541

NADPH oxidases: Pathophysiology and therapeutic potential in age-associated pulmonary fibrosis.

Kosuke Kato, Louise Hecker.

Oxidative stress has been associated with a number of human fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Although oxidative stress is associated with both fibrosis and aging, the precise cellular sources(s) of reactive oxygen species (ROS) that contribute to the disease pathogenesis remain poorly understood. NADPH oxidase (Nox) enzymes are an evolutionarily conserved family, where their only known function is the production of ROS. A growing body of evidence supports a link between excessive Nox-derived ROS and numerous chronic diseases (including fibrotic disease), which is most prevalent among the elderly population. In this review, we examine the evidence for Nox isoforms in the pathogenesis of IPF, and the potential to target this enzyme family for the treatment of IPF and related fibrotic disorders. A better understanding of the Nox-mediated redox imbalance in aging may be critical to the development of more effective therapeutic strategies for age-associated fibrotic disorders. Strategies aimed at specifically blocking the source(s) of ROS through Nox inhibition may prove to be more effective as anti-fibrotic therapies, as compared to antioxidant approaches. This review also discusses the potential of Nox-targeting therapeutics currently in development.

DOI: https://doi.org/10.1016/j.redox.2020.101541
Free Radic Biol Med. 2020 May 01. pii: S0891-5849(20)30584-0. [Epub ahead of print]

The role of NADPH oxidases in neuronal development.

Aslihan Terzi, Daniel M Suter.

  Reactive oxygen species (ROS) are critical for maintaining cellular homeostasis and function when produced in physiological ranges. Important sources of cellular ROS include NADPH oxidases (Nox), which are evolutionary conserved multi-subunit transmembrane proteins. Nox-mediated ROS regulate variety of biological processes including hormone synthesis, calcium signaling, cell migration, and immunity. ROS participate in intracellular signaling by introducing post-translational modifications to proteins and thereby altering their functions. The central nervous system (CNS) expresses different Nox isoforms during both development and adulthood. Here, we review the role of Nox-mediated ROS during CNS development. Specifically, we focus on how individual Nox isoforms contribute to signaling in neural stem cell maintenance and neuronal differentiation, as well as neurite outgrowth and guidance. We also discuss how ROS regulates the organization and dynamics of the actin cytoskeleton in the neuronal growth cone. Finally, we review recent evidence that Nox-derived ROS modulate axonal regeneration upon nervous system injury.

Keywords:  Actin; Cytoskeleton; Growth cone; Hydrogen peroxide; NADPH oxidases; Neural stem cells; Neurite growth; Neurogenesis; Neuronal development; Nox; ROS; Regeneration

DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.04.027
Mol Cell Probes. 2020 Apr 29. pii: S0890-8508(20)30140-7. [Epub ahead of print] 101583

Insulin-like growth factor-I activates NFκB and NLRP3 inflammatory signalling via ROS in cancer cells.

Chao Wang, Yanan An, Yang Wang, Keshu Shen, Xuefei Wang, Wenjing Luan, Fangxue Ma, Lihui Ni, Mingyuan Liu, Lu Yu.

  Previous studies have demonstrated that insulin-like growth factor-I (IGF-1) and reactive oxygen species (ROS) are involved in the development and progression of various cancers. However, their regulatory mechanism remains unknown. In this study, we treated cancer cells (HeLa, HepG2 and SW1116 cells) and normal cells (NCM-460) with IGF-1 at different concentrations and for different times and found that cancer cells produced large amounts of cytoplasmic ROS in cancer cells but not in normal cells. Further mechanistic analysis demonstrated that IGF-1 activated NFκB and NLRP3 inflammatory signalling in HeLa cells; systematic analysis indicated that IGF-1 activates NFκB and NLRP3, and the activation was cytosolic ROS- and NADPH oxidase 2 (NOX2)-dependent. Additionally, through coimmunoprecipitation experiments, we found that the IRS-1/COX2/mPGES-1/MAPKs/RAC2/NOX2 pathway nexus was involved in IGF-1-induced NFκB and NLRP3 production. Finally, we validated the regulatory mechanisms through IRS-1, mPGES-1 or NOX2 inhibition using their respective selective inhibitors or shRNA knockdown. Taken together, this is the first report on the mechanism by which IGF-1 activates NFκB and NLRP3 inflammatory signalling via ROS. These findings pave the way for an in-depth study of the role of IGF-1 and ROS in inflammation associated with the development and progression of cancer.

Keywords:  HeLa; IGF-1; NFκB; NLRP3; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.mcp.2020.101583
Cancer Res. 2020 May 01. 80(9): 1799-1800

Immunotherapeutic Response in Tumors Is Affected by Microenvironmental ROS.

Simon W Hayward.

Carcinoma-associated fibroblasts (CAF) are a potential therapeutic target for both direct and indirect regulation of cancer progression and therapy response. In this issue of Cancer Research, Ford and colleagues investigate the influence of CAF on the immune environment of tumors, specifically focusing on the regulation of CD8+ T cells, required for immune therapy response. Their work suggests a role for stromally expressed NADPH oxidase 4 (NOX4) as a modulator of reactive oxygen species that in turn can reduce the number of CD8+ T cells locally. Inhibition of NOX4 increased CD8+ T cells and restored responsiveness to immune therapy, suggesting an indirect stromally targeted avenue for therapy resensitization.See related article by Ford et al., p. 1846.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-0590
J Cell Mol Med. 2020 May 05.

Calcitonin gene-related peptide inhibits angiotensin II-induced NADPH oxidase-dependent ROS via the Src/STAT3 signalling pathway.

Hong-Min Luo, Xia Wu, Xian Xian, Lu-Yao Wang, Liang-Yu Zhu, Hong-Yu Sun, Lei Yang, Wen-Xuan Liu.

  We had previously demonstrated that the calcitonin gene-related peptide (CGRP) suppresses the oxidative stress and vascular smooth muscle cell (VSMC) proliferation induced by vascular injury. A recent study also indicated that CGRP protects against the onset and development of angiotensin II (Ang II)-induced hypertension, vascular hypertrophy and oxidative stress. However, the mechanism behind the effects of CGRP on Ang II-induced oxidative stress is unclear. CGRP significantly suppressed the level of reactive oxygen species (ROS) generated by NADPH oxidase in Ang II-induced VSMCs. The Ang II-stimulated activation of both Src and the downstream transcription factor, STAT3, was abrogated by CGRP. However, the antioxidative effect of CGRP was lost following the expression of constitutively activated Src or STAT3. Pre-treatment with H-89 or CGRP8-37 also blocked the CGRP inhibitory effects against Ang II-induced oxidative stress. Additionally, both in vitro and in vivo analyses show that CGRP treatment inhibited Ang II-induced VSMC proliferation and hypertrophy, accompanied by a reduction in ROS generation. Collectively, these results demonstrate that CGRP exhibits its antioxidative effect by blocking the Src/STAT3 signalling pathway that is associated with Ang II-induced VSMC hypertrophy and hyperplasia.

Keywords:  Ang II; CGRP; ROS; STAT3; Src; VSMCs

DOI:  https://doi.org/10.1111/jcmm.15288
Redox Biol. 2020 Apr 21. pii: S2213-2317(20)30374-8. [Epub ahead of print]34 101542

MnTE-2-PyP, a manganese porphyrin, reduces cytotoxicity caused by irradiation in a diabetic environment through the induction of endogenous antioxidant defenses.

Arpita Chatterjee, Elizabeth A Kosmacek, Shashank Shrishrimal, J Tyson McDonald, Rebecca E Oberley-Deegan.

  Radiation is a common anticancer therapy for many cancer patients, including prostate cancer. Diabetic prostate cancer patients suffer from increased lymph node metastasis, tumor recurrence and decreased survival as compared to non-diabetic prostate cancer patients. These patients are also at increased risk for enhanced radiation-induced normal tissue damage such as proctitis. Diabetics are oxidatively stressed and radiation causes additional oxidative damage. We and others have reported that, MnTE-2-PyP, a manganese porphyrin, protects normal prostate tissue from radiation damage. We have also reported that, in an in vivo mouse model of prostate cancer, MnTE-2-PyP decreases tumor volume and increases survival of the mice. In addition, MnTE-2-PyP has also been shown to reduce blood glucose and inhibits pro-fibrotic signaling in a diabetic model. Therefore, to investigate the role of MnTE-2-PyP in normal tissue protection in an irradiated diabetic environment, we have treated human prostate fibroblast cells with MnTE-2-PyP in an irradiated hyperglycemic environment. This study revealed that hyperglycemia causes increased cell death after radiation as compared to normo-glycemia. MnTE-2-PyP protects against hyperglycemia-induced cell death after radiation. MnTE-2-PyP decreases expression of NOX4 and α-SMA, one of the major oxidative enzymes and pro-fibrotic molecules respectively. MnTE-2-PyP obstructs NF-κB activity by decreasing DNA binding of the p50-p50 homodimer in the irradiated hyperglycemic environment. MnTE-2-PyP increases NRF2 mediated cytoprotection by increasing NRF2 protein expression and DNA binding. Therefore, we are proposing that, MnTE-2-PyP protects fibroblasts from irradiation and hyperglycemia damage by enhancing the NRF2- mediated pathway in diabetic prostate cancer patients, undergoing radiotherapy.

Keywords:  Diabetes; Hyperglycemia; Manganese porphyrin; NRF2; ROS; Radiation

DOI:  https://doi.org/10.1016/j.redox.2020.101542
Int J Mol Sci. 2020 Apr 29. pii: E3145. [Epub ahead of print]21(9):

Potent Inhibitory Effect of BJ-3105, a 6-Alkoxypyridin-3-ol Derivative, on Murine Colitis Is Mediated by Activating AMPK and Inhibiting NOX.

Pallavi Gurung, Sadan Dahal, Prakash Chaudhary, Diwakar Guragain, Ujjwala Karmacharya, Jung-Ae Kim, Byeong-Seon Jeong.

  Inflammatory bowel disease (IBD) is a chronic relapsing inflammation in the gastrointestinal tract. Biological therapeutics and orally available small molecules like tofacitinib (a JAK inhibitor) have been developed to treat IBD, but half of the patients treated with these drugs fail to achieve sustained remission. In the present study, we compared the therapeutic effects of BJ-3105 (a 6-alkoxypyridin-3-ol derivative) and tofacitinib in IBD. BJ-3105 induced activation of AMP-activated protein kinase (AMPK) in the kinase activity measurement and recovery from cytokine-induced AMPK deactivation in HT-29 human colonic epithelial cells. Similar to tofacitinib and D942 (an AMPK activator), BJ-3105 inhibited IL-6-induced JAK2/STAT3 phosphorylation and TNF-α-stimulated activation of IKK/NF-κB, and consequently, stimulus-induced upregulations of inflammatory cytokines and inflammasome components. In addition, unlike tofacitinib or D942, BJ-3105 inhibited NADPH oxidase (NOX) activation and consequent superoxide production induced by activators (mevalonate and geranylgeranyl pyrophosphate) of the NOX cytosolic component Rac. In mice, oral administration with BJ-3105 ameliorated dextran sulfate sodium (DSS)-induced colitis and azoxymethane/DSS-induced colitis-associated tumor formation (CAT) much more potently than that with tofacitinib. Moreover, BJ-3105 suppressed the more severe form of colitis and CAT formation in mice with AMPK knocked-out in macrophages (AMPKαfl/fl-Lyz2-Cre mice) with much greater efficacy than tofacitinib. Taken together, our findings suggest BJ-3105, which exerted a much better anti-colitis effect than tofacitinib through AMPK activation and NOX inhibition, is a promising candidate for the treatment of IBD.

Keywords:  AMP-activated protein kinase (AMPK); BJ-3105; NADPH oxidase (NOX); colitis; colitis-associated tumor formation; tight junction molecule

DOI:  https://doi.org/10.3390/ijms21093145