bims-noxint 2021-06-13 papers

Issue of 2021–06–13
five papers selected by
Laia Caja Puigsubira, Uppsala University

Sci Rep. 2021 Jun 07. 11(1): 11970

A small molecule inhibitor of Nox2 and Nox4 improves contractile function after ischemia-reperfusion in the mouse heart.

Ferenc L M Szekeres, Erik Walum, Per Wikström, Anders Arner.

The NADPH oxidase enzymes Nox2 and 4, are important generators of Reactive oxygen species (ROS). These enzymes are abundantly expressed in cardiomyocytes and have been implicated in ischemia-reperfusion injury. Previous attempts with full inhibition of their activity using genetically modified animals have shown variable results, suggesting that a selective and graded inhibition could be a more relevant approach. We have, using chemical library screening, identified a new compound (GLX481304) which inhibits Nox 2 and 4 (with IC50 values of 1.25 µM) without general antioxidant effects or inhibitory effects on Nox 1. The compound inhibits ROS production in isolated mouse cardiomyocytes and improves cardiomyocyte contractility and contraction of whole retrogradely (Langendorff) perfused hearts after a global ischemia period. We conclude that a pharmacological and partial inhibition of ROS production by inhibition of Nox 2 and 4 is beneficial for recovery after ischemia reperfusion and might be a promising venue for treatment of ischemic injury to the heart.

DOI: https://doi.org/10.1038/s41598-021-91575-8

BMC Musculoskelet Disord. 2021 Jun 05. 22(1): 519

In vitro and in vivo tenocyte-protective effectiveness of dehydroepiandrosterone against high glucose-induced oxidative stress.

Shintaro Mukohara, Yutaka Mifune, Atsuyuki Inui, Hanako Nishimoto, Takashi Kurosawa, Kohei Yamaura, Tomoya Yoshikawa, Ryosuke Kuroda.

BACKGROUND: Dehydroepiandrosterone (DHEA), an adrenal steroid, has a protective role against diabetes. This study aimed to investigate the in vitro and in vivo protective effects of DHEA against high glucose-induced oxidative stress in tenocytes and tendons.
METHODS: Tenocytes from normal Sprague-Dawley rats were cultured in low-glucose (LG) or high-glucose (HG) medium with or without DHEA. The experimental groups were: control group (LG without DHEA), LG with DHEA, HG without DHEA, and HG with DHEA. Reactive oxygen species (ROS) production, apoptosis, and messenger RNA (mRNA) expression of NADPH oxidase (NOX) 1 and 4, and interleukin-6 (IL-6) were determined. Further, diabetic rats were divided into a control group and a DHEA-injected group (DHEA group). NOX1 and NOX4 protein expression and mRNA expression of NOX1, NOX4, IL-6, matrix metalloproteinase (MMP)-2, tissue inhibitors of matrix metalloproteinase (TIMP)-2, and type I and III collagens in the Achilles tendon were determined.
RESULTS: In rat tenocytes, DHEA decreased the expression of NOX1 and IL-6, ROS accumulation, and apoptotic cells. In the diabetic rat Achilles tendon, NOX1 protein expression and mRNA expression of NOX1, IL-6, MMP-2, TIMP-2, and type III collagen were significantly lower while type I collagen expression was significantly higher in the DHEA group than in the control group.
CONCLUSIONS: DHEA showed antioxidant and anti-inflammatory effects both in vitro and in vivo. Moreover, DHEA improved tendon matrix synthesis and turnover, which are affected by hyperglycemic conditions. DHEA is a potential preventive drug for diabetic tendinopathy.

Keywords: Dehydroepiandrosterone; Diabetic tendinopathy; High glucose; NADPH oxidase; Oxidative stress

DOI: https://doi.org/10.1186/s12891-021-04398-z

Redox Biol. 2021 Jun 06. pii: S2213-2317(21)00189-0. [Epub ahead of print]45 102031

Peroxidasin promotes diabetic vascular endothelial dysfunction induced by advanced glycation end products via NOX2/HOCl/Akt/eNOS pathway.

Jing Cao, Guogang Zhang, Zhaoya Liu, Qian Xu, Chan Li, Guangjie Cheng, Ruizheng Shi.

Reactive oxygen species (ROS) derived from NADPH oxidases (NOX) plays an essential role in advanced glycation end products (AGEs)-induced diabetic vascular endothelial dysfunction. Peroxidasin (PXDN, VPO1) is one member of peroxidases family that catalyzes hydrogen peroxide (H2O2) to hypochlorous acid (HOCl). This present study aimed to elucidate the role of PXDN in promoting vascular endothelial dysfunction induced by AGEs in diabetes mellitus. We found that, compared to non-diabetic (db/m) mice, PXDN expression was notably increased in db/db mice with impaired endothelium-dependent relaxation. Knockdown of PXDN in vivo through tail vein injection of siRNA restored the impaired endothelium-dependent relaxation function of db/db mice which is accompanied with up-regulation of eNOS Ser1177 phosphorylation and NO production. AGEs significantly elevated expression of PXDN and 3-Cl-Tyr, but decreased phosphorylation of Akt and eNOS and NO release in HUVECs. All these effects induced by AGEs were remarkable alleviated by silencing PXDN with small interfering RNAs. In addition, HOCl treatment alone as well as HOCl added with Akt inhibitor MK2206 inhibited phosphorylation of Akt and eNOS, reducing NO production. More importantly,AGEs-induced up-regulation of PXDN and 3-Cl-Tyr with endothelial dysfunction were transformed by NOX2 silencing and H2O2 scavengers. Thus, these results support the conclusion that PXDN promotes AGEs-induced diabetic vascular endothelial dysfunction by attenuating eNOS phosphorylation at Ser1177 via NOX2/HOCl/Akt pathway.

Keywords: Advanced glycation end products (AGEs); Endothelial dysfunction; Endothelium nitric oxide synthase (eNOS); Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; Peroxidasin (PXDN); Reactive oxygen species (ROS)

DOI: https://doi.org/10.1016/j.redox.2021.102031

Respir Physiol Neurobiol. 2021 Jun 08. pii: S1569-9048(21)00098-7. [Epub ahead of print] 103713

The role of NADPH oxidase in chronic intermittent hypoxia-induced respiratory plasticity in adult male mice.

Sarah E Drummond, David P Burns, Karen M O'Connor, Gerard Clarke, Ken D O'Halloran.

Reactive oxygen species (ROS) are proposed as mediators of chronic intermittent hypoxia (CIH)-induced respiratory plasticity. We sought to determine if NADPH oxidase 2 (NOX2)-derived ROS underpin CIH-induced maladaptive changes in respiratory control. Adult male mice (C57BL/6 J) were assigned to one of three groups: normoxic controls (sham); chronic intermittent hypoxia-exposed (CIH, 12 cycles/hour, 8 h/day for 14 days); and CIH + apocynin (NOX2 inhibitor, 2 mM) given in the drinking water throughout exposure to CIH. In addition, we studied sham and CIH-exposed NOX2-null mice (B6.129S-CybbTM1Din/J). Whole-body plethysmography was used to measure breathing and metabolic parameters. Ventilation (V̇I/V̇CO2) during normoxia was unaffected by CIH, but apnoea index was increased, which was prevented by apocynin, but not by NOX2 deletion. The ventilatory response to hypercapnia following exposure to CIH was potentiated in NOX2-null mice. Our results reveal ROS-dependent influences on the control of breathing and point to antioxidant intervention as a potential adjunctive therapeutic strategy in respiratory control disorders.

Keywords: Apnoea; Apocynin; Breathing; Chronic intermittent hypoxia; NADPH oxidase

DOI: https://doi.org/10.1016/j.resp.2021.103713

Int J Med Sci. 2021 ;18(12): 2480-2492

Inhibition of Lipopolysaccharide-Induced Inflammatory and Oxidative Responses by Trans-cinnamaldehyde in C2C12 Myoblasts.

Cheol Park, Hyesook Lee, Suhyun Hong, Ilandarage Menu Neelaka Molagoda, Jin-Woo Jeong, Cheng-Yun Jin, Gi-Young Kim, Sung Hyun Choi, Sang Hoon Hong, Yung Hyun Choi.

Background:Trans-cinnamaldehyde (tCA), a bioactive component found in Cinnamomum cassia, has been reported to exhibit anti-inflammatory and antioxidant effects, but its efficacy in muscle cells has yet to be found. In this study, we investigated the inhibitory effect of tCA on inflammatory and oxidative stress induced by lipopolysaccharide (LPS) in C2C12 mouse skeletal myoblasts. Methods: To investigate the anti-inflammatory and antioxidant effects of tCA in LPS-treated C2C12 cells, we measured the levels of pro-inflammatory mediator, cytokines, and reactive oxygen species (ROS). To elucidate the mechanism underlying the effect of tCA, the expression of genes involved in the expression of inflammatory and oxidative regulators was also investigated. We further evaluated the anti-inflammatory and antioxidant efficacy of tCA against LPS in the zebrafish model. Results: tCA significantly inhibited the LPS-induced release of pro-inflammatory mediators and cytokines, which was associated with decreased expression of their regulatory genes. tCA also suppressed the expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor, and attenuated the nuclear translocation of nuclear factor-kappa B (NF-κB) and the binding of LPS to TLR4 on the cell surface in LPS-treated C2C12 cells. Furthermore, tCA abolished LPS-induced generation of ROS and expression levels of ROS producing enzymes, NADPH oxidase 1 (NOX1) and NOX2. However, tCA enhanced the activation of nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) in LPS-stimulated C2C12 myoblasts. In addition, tCA showed strong protective effects against NO and ROS production in LPS-injected zebrafish larvae. Conclusions: Our findings suggest that tCA exerts its inhibitory ability against LPS-induced inflammatory and antioxidant stress in C2C12 myoblasts by targeting the TLR4/NF-κB, which might be mediated by the NOXs and Nrf2/HO-1 pathways.

Keywords: Nrf2/HO-1.; TLR4/NF-κB; Trans-cinnamaldehyde; inflammation; oxidative stress

DOI: https://doi.org/10.7150/ijms.59169