bims-noxint 2022-06-05 papers

Issue of 2022–06–05
four papers selected by
Laia Caja Puigsubira, Uppsala University

Front Cell Dev Biol. 2022 ;10 884412

NADPH Oxidase 4: A Potential Therapeutic Target of Malignancy.

Shulei Gong, Shiyang Wang, Mingrui Shao.

Reactive oxygen species (ROS) play a crucial role in the regulation of tumor occurrence and development. As a main source of ROS, NADPH oxidases are key enzymes that mediate electron transport within intracellular membranes. Of the NOX members that have been reported to be dysregulated in a wide variety of tumors, NOX4 is the member to be most frequently expressed. Numerous studies have elucidated that NOX4 gets involved in the regulation of tumor proliferation, metastasis, therapy resistance, tumor-stromal interaction and dysregulated tumor metabolism. In this review, we primarily discussed the biological function of NOX4 in tumorigenesis and progression of multiple cancer models, including its role in activating oncogenic signaling pathways, rewiring the metabolic phenotype and mediating immune response. Besides, the development of NOX4 inhibitors has also been unraveled. Herein, we discussed the interplay between NOX4 and tumorigenesis, proposing NOX4 as a promising therapeutic target waiting for further exploration.

Keywords: NOX4; cancer; metabolism; reactive oxygen species; tumor microenevironment

DOI: https://doi.org/10.3389/fcell.2022.884412

Oxid Med Cell Longev. 2022 ;2022 5595781

Reversal of NADPH Oxidase-Dependent Early Oxidative and Inflammatory Responses in Chronic Obstructive Pulmonary Disease by Puerarin.

Pan Zhang, Yixuan Zhang, Lu Wang, Xinjing Wang, Shiqing Xu, Zhenguo Zhai, Chen Wang, Hua Cai.

In the present study, we investigated effects of Puerarin on the early oxidative and inflammatory responses in the lung triggered by acute cigarette smoking (ACS). C57BL/6 mice were exposed to ACS for 1 hr in the presence or absence of Puerarin and harvested at 2, 6, and 24 hours. ACS induced significant increases in superoxide production in mouse lungs at 2 and 6 hours; and superoxide production was also elevated in a time and concentration dependent manner in cigarette smoke extract (CSE) stimulated human small airway epithelial cells (HSAECs), which was dose-dependently abrogated by Puerarin. ACS exposure upregulated NOX1, NOX2, and NOX4 protein expression in mouse lungs. Likewise, NOX1 and NOX4 were upregulated in CSE-stimulated HSAECs. These responses were significantly or completely attenuated by Puerarin. ACS induced significant infiltrations of neutrophils and macrophages in mouse lung parenchyma and BAL fluid, which were completely or significantly abrogated by Puerarin, so was the activation of the NF-кB pathway and the upregulation in inflammatory mediators including TNF-α, KC (murine homolog of IL-8), COX-2, IL-6 and MCP-1. Nuclear translocation of p65, IL-8 secretion, and upregulation of COX-2 in CSE stimulated HSAECs were also markedly attenuated by Puerarin. Moreover, ACS or CSE stimulated upregulation in reactive oxygen species (ROS) production and expression of inflammatory mediators were alleviated by ROS scavenger TEMPO in vivo and vitro, with no synergy combining with Puerarin, indicating that the effects of Puerarin are redox-sensitive following activation of NOX. In summary, our data for the first time demonstrate that Puerarin robustly attenuates NOX isoform-dependent ROS production and inflammatory activation in ACS exposed mice and CSE treated HSAECs, indicating that Puerarin might be used as a robust therapeutic agent for early or early stage COPD.

DOI: https://doi.org/10.1155/2022/5595781

Eur J Pharmacol. 2022 May 26. pii: S0014-2999(22)00309-0. [Epub ahead of print] 175048

Suppression of angiotensin II-activated NOX4/NADPH oxidase and mitochondrial dysfunction by preserving glucagon-like peptide-1 attenuates myocardial fibrosis and hypertension.

Trenton E Banks, Maheshinie Rajapaksha, Li-Hui Zhang, Feng Bai, Ning-Ping Wang, Zhi-Qing Zhao.

This study aims to investigate whether stabilization of glucagon-like peptide-1 (GLP-1) level reduces angiotensin II (Ang II)-induced cardiac fibrosis and -elevated blood pressure accompanying with inhibition of NADPH oxidase (NOX) expression and preservation of mitochondrial integrity. The study was performed in Sprague-Dawley rat model of Ang II infusion (500 ng/kg/min) using osmotic minipumps for 4 weeks. GLP-1 receptor agonist liraglutide (0.3 mg/kg, injected subcutaneously twice daily) and dipeptidyl peptidease-4 inhibitor, linagliptin (8 mg/kg, administered via oral gavage) were selected to preserve GLP-1 level. Blood pressure was measured noninvasively. Heart and aorta were saved for histological analysis. Relative to the animals with Ang II infusion, in the heart, liraglutide and linagliptin comparatively reduced the protein levels of NOX4 and TGFβ1 and expression of monocyte chemoattractant protein 1, and attenuated the proliferation of myofibroblasts (15 ± 4 and 13 ± 3 vs. 42 ± 22/HPF in Ang II group). The number of distorted mitochondria in both groups was significantly reduced (8 ± 4 and 10 ± 6 vs. 27 ± 13/HPF in Ang II group), in company with a significant reduction in cardiac fibrosis. In the aorta, treatment with liraglutide and linagliptin significantly downregulated the expression of NOX4 and intercellular adhesion molecule 1, and enhanced endothelial NOS expression. Aortic wall thickness was reduced comparatively (267 ± 22 and 286 ± 25 vs. 339 ± 40 μm in Ang II group). The area of fibrotic aorta was also reduced (13 ± 6 and 14 ± 5 vs. 38 ± 24 mm2 in Ang II group), respectively, in coincidence with a significant reduction in mean blood pressure. Taken together, these results suggest that the conservation of GLP-1 level with exogenous supply of liraglutide or the prevention of endogenous degradation of GLP-1 with linagliptin protects against Ang II-induced injury in the heart and aorta, potentially associated with inhibition of NOX4 expression and preservation of mitochondrial integrity.

Keywords: Angiotensin II; Glucagon-like peptide-1; Hypertention; Mitochondria; Myocardial fibrosis; NADPH oxidase

DOI: https://doi.org/10.1016/j.ejphar.2022.175048

J Cell Mol Med. 2022 Jun 01.

Participation of lipopolysaccharide in hyperplasic adipose expansion: Involvement of NADPH oxidase/ROS/p42/p44 MAPK-dependent Cyclooxygenase-2.

Chao-Chien Chang, Kee-Chin Sia, Jia-Feng Chang, Chia-Mo Lin, Chuen-Mao Yang, I-Ta Lee, Thi Thuy Tien Vo, Kuo-Yang Huang, Wei-Ning Lin.

Obesity is a world-wide problem, especially the child obesity, with the complication of various metabolic diseases. Child obesity can be developed as early as the age between 2 and 6. The expansion of fat mass in child age includes both hyperplasia and hypertrophy of adipose tissue, suggesting the importance of proliferation and adipogenesis of preadipocytes. The changed composition of gut microbiota is associated with obesity, revealing the roles of lipopolysaccharide (LPS) on manipulating adipose tissue development. Studies suggest that LPS enters the circulation and acts as a pro-inflammatory regulator to facilitate pathologies. Nevertheless, the underlying mechanisms behind LPS-modulated obesity are yet clearly elucidated. This study showed that LPS enhanced the expression of cyclooxygenase-2 (COX-2), an inflammatory regulator of obesity, in preadipocytes. Pretreating preadipocytes with the scavenger of reactive oxygen species (ROS) or the inhibitors of NADPH oxidase or p42/p44 MAPK markedly decreased LPS-stimulated gene expression of COX-2 together with the phosphorylation of p47phox and p42/p44 MAPK, separately. LPS activated p42/p44 MAPK via NADPH oxidase-dependent ROS accumulation in preadipocytes. Reduction of intracellular ROS or attenuation of p42/p44 MAPK activation both reduced LPS-mediated COX-2 expression and preadipocyte proliferation. Moreover, LPS-induced preadipocyte proliferation and adipogenesis were abolished by the inhibition of COX-2 or PEG2 receptors. Taken together, our results suggested that LPS enhanced the proliferation and adipogenesis of preadipocytes via NADPH oxidase/ROS/p42/p44 MAPK-dependent COX-2 expression.

Keywords: COX-2; ROS; adipose tissue; lipopolysaccharide

DOI: https://doi.org/10.1111/jcmm.17419