bims-noxint 2021-10-10 papers

Issue of 2021‒10‒10
three papers selected by
Laia Caja Puigsubira
Uppsala University

Rep Biochem Mol Biol. 2021 Jul;10(2): 327-333

Association Between NOX4 And Nrf2 Genes in Non-Small-Cell Lung Carcinoma: A Case-Control Study.

Nasim Bakhtiyari, Akbar Sharifi, Younes Aftabi, Neda Gilani, Venus Zafari, Atefeh Ansarin, Ensiyeh Seyedrezazadeh.

Background: Epithelial malignancy in lung cancer, which is initiated with myofibroblast differentiation and remodeling, promotes hypoxia and intracellular ROS generation most affected by the prototypical enzyme, NADPH oxidase 4 (NOX4). In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) acts as a critical transcription factor by stimulating antioxidant proteins as redox homeostasis regulators. The aim of this study was to investigate a possible correlation between lung tissue NOX4 and Nrf2 genes (NOX4 and Nrf2) mRNA expression and bronchoalveolar lavage fluid (BALF) protein expression in non-small-cell lung carcinoma (NSCLC) patients.Methods: Samples from 25 patients with various NSCLC types and stages and 20 healthy controls were collected. NOX4 and Nrf2 mRNA were measured by qRT-PCR, and protein by western blot analysis.
Results: NOX4 mRNA and protein expression was significantly up-regulated in NSCLC patients' lung tissues and BALFs (p= 0.03 and 0.01, respectively). In addition, by adjusting for age, sex, and NSCLC types and stages, a significant and positive correlation was observed between NOX4 and Nrf2 mRNA expression (r= 0.927, p= 0.001). This was also true when not adjusted as above (r= 0.944, p< 0.001).
Conclusion: NOX4 mRNA and protein expression is significantly up-regulated in NSCLC patients' lung tissues and BALFs, and NOX4 and Nrf2 mRNA expression is positively correlated in NSCLC tissues.

Keywords: Gene expression; NOX4; Non-small-cell lung cancer; Nrf2

DOI: https://doi.org/10.52547/rbmb.10.2.327

Kidney Dis (Basel). 2021 Sep;7(5): 372-390

Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent Mechanism.

Qin Yang, Li Gao, Xiao-Wei Hu, Jia-Nan Wang, Yao Zhang, Yu-Hang Dong, Hui Yao Lan, Xiao-Ming Meng.

Background: Transforming growth factor-β (TGF-β)/Smad signaling is the central mediator in renal fibrosis, yet its functional role in acute kidney injury (AKI) is not fully understood. Recent evidence showed that TGF-β/Smad3 may be involved in the pathogenesis of AKI, but its functional role and mechanism of action in cisplatin-induced AKI are unclear.Objectives: Demonstrating that Smad3 may play certain roles in cisplatin nephropathy due to its potential effect on programmed cell death and inflammation.
Methods: Here, we established a cisplatin-induced AKI mouse model with Smad3 knockout mice and created stable in vitro models with Smad3 knockdown tubular epithelial cells. In addition, we tested the potential of Smad3-targeted therapy using 2 in vivo protocols - lentivirus-mediated Smad3 silencing in vivo and use of naringenin, a monomer used in traditional Chinese medicine and a natural inhibitor of Smad3.
Results: Disruption of Smad3 attenuated cisplatin-induced kidney injury, inflammation, and NADPH oxidase 4-dependent oxidative stress. We found that Smad3-targeted therapy protected against loss of renal function and alleviated apoptosis, RIPK-mediated necroptosis, renal inflammation, and oxidative stress in cisplatin nephropathy.
Conclusions: These findings show that Smad3 promotes cisplatin-induced AKI and Smad3-targeted therapy protects against this pathological process. These findings have substantial clinical relevance, as they suggest a therapeutic target for AKI.

Keywords: Acute kidney injury; Cisplatin; Inflammation; Nox4; Programmed cell death; Smad3

DOI: https://doi.org/10.1159/000512986

Mol Aspects Med. 2021 Oct 05. pii: S0098-2997(21)00086-8. [Epub ahead of print] 101026

Molecular mechanisms of oxidative stress in asthma.

Charalambos Michaeloudes, Hisham Abubakar-Waziri, Ramzi Lakhdar, Katie Raby, Piers Dixey, Ian M Adcock, Sharon Mumby, Pankaj K Bhavsar, Kian Fan Chung.

The lungs are exposed to reactive oxygen species oxygen (ROS) produced as a result of inhalation of oxygen, as well as smoke and other air pollutants. Cell metabolism and the NADPH oxidases (Nox) generate low levels of intracellular ROS that act as signal transduction mediators by inducing oxidative modifications of histones, enzymes and transcription factors. Redox signalling is also regulated by localised production and sensing of ROS in mitochondria, the endoplasmic reticulum (ER) and inside the nucleus. Intracellular ROS are maintained at low levels through the action of a battery of enzymatic and non-enzymatic antioxidants. Asthma is a heterogeneous airway inflammatory disease with different immune endotypes; these include atopic or non-atopic Th2 type immune response associated with eosinophilia, or a non-Th2 response associated with neutrophilia. Airway remodelling and hyperresponsiveness accompany the inflammatory response in asthma. Over-production of ROS resulting from infiltrating immune cells, particularly eosinophils and neutrophils, and a concomitant impairment of antioxidant responses lead to development of oxidative stress in asthma. Oxidative stress is augmented in severe asthma and during exacerbations, as well as by air pollution and obesity, and causes oxidative damage of tissues promoting airway inflammation and hyperresponsiveness. Furthermore, deregulated Nox activity, mitochondrial dysfunction, ER stress and/or oxidative DNA damage, resulting from exposure to irritants, inflammatory mediators or obesity, may lead to redox-dependent changes in cell signalling. ROS play a central role in airway epithelium-mediated sensing, development of innate and adaptive immune responses, and airway remodelling and hyperresponsiveness. Nonetheless, antioxidant compounds have proven clinically ineffective as therapeutic agents for asthma, partly due to issues with stability and in vivo metabolism of these compounds. The compartmentalised nature of ROS production and sensing, and the role of ROS in homeostatic responses and in the action of corticosteroids and β2-adrenergic receptor agonists, adds another layer of complexity to antioxidant therapy development. Nox inhibitors and mitochondrial-targeted antioxidants are in clinical development for a number of diseases but they have not yet been investigated in asthma. A better understanding of the complex role of ROS in the pathogenesis of asthma will highlight new opportunities for more targeted and effective redox therapies.

Keywords: Air pollution; Asthma; Mitochondria; NADPH oxidase; Oxidative stress; Redox signalling

DOI: https://doi.org/10.1016/j.mam.2021.101026