bims-noxint 2020-08-16 papers

Issue of 2020‒08‒16
four papers selected by
Laia Caja Puigsubira
Uppsala University

Handb Exp Pharmacol. 2020 Aug 12.

NOX Inhibitors: From Bench to Naxibs to Bedside.

Mahmoud H Elbatreek, Hermann Mucke, Harald H H W Schmidt.

Reactive oxygen species (ROS) are ubiquitous metabolic products and important cellular signaling molecules that contribute to several biological functions. Pathophysiology arises when ROS are generated either in excess or in cell types or subcellular locations that normally do not produce ROS or when non-physiological types of ROS (e.g., superoxide instead of hydrogen peroxide) are formed. In the latter scenario, antioxidants were considered as the apparent remedy but, clinically, have consistently failed and even sometimes induced harm. The obvious reason for that is the non-selective ROS scavenging effects of antioxidants which interfere with both qualities of ROS, physiological and pathological. Therefore, it is essential to overcome this "antidote or neutralizer" strategy. We here review the most promising alternative approach by identifying the disease-relevant enzymatic sources of ROS, target these selectively, but leave physiological ROS signaling through other sources intact. Among all ROS sources, NADPH oxidases (NOX1-5 and DUOX1-2) stand out as their sole function is to produce ROS, whereas most other enzymatic sources only produce ROS as a by-product or upon biochemical uncoupling or damage. This qualifies NOXs as the main potential drug-target candidates in diseases associated with dysfunction in ROS signaling. As a reflection of this, the development of several NOX inhibitors has taken place. Recently, the WHO approved a new stem, "naxib," which refers to NADPH oxidase inhibitors, and thereby recognized NOX inhibitors as a new therapeutic class. This has been announced while clinical trials with the first-in-class compound, setanaxib (initially known as GKT137831) had been initiated. We also review the differences between the seven NOX family members in terms of structure and function in health and disease and then focus on the most advanced NOX inhibitors with an exclusive focus on clinically relevant validations and applications. Therapeutically relevant NADPH oxidase isoforms type 1, 2, 4, and 5 (NOX1, NOX2, NOX4, NOX5). Of note, NOX5 is not present in mice and rats and thus pre-clinically less studied. NOX2, formerly termed gp91phox, has been correlated with many, too many, diseases and is rather relevant as genetic deficiency in chronic granulomatous disease (CGD), treated by gene therapy. Overproduction of ROS through NOX1, NOX4, and NOX5 leads to the indicated diseases states including atherosclerosis (red), a condition where NOX4 is surprisingly protective.

Keywords: Mechanism-based redox therapeutics; NADPH oxidases; NOX inhibitors; Reactive oxygen species; Setanaxib

DOI: https://doi.org/10.1007/164_2020_387

Cells. 2020 Aug 06. pii: E1849. [Epub ahead of print]9(8):

Cross-Talk between NADPH Oxidase and Mitochondria: Role in ROS Signaling and Angiogenesis.

Tohru Fukai, Masuko Ushio-Fukai.

Angiogenesis, a new vessel formation from the pre-existing ones, is essential for embryonic development, wound repair and treatment of ischemic heart and limb diseases. However, dysregulated angiogenesis contributes to various pathologies such as diabetic retinopathy, atherosclerosis and cancer. Reactive oxygen species (ROS) derived from NADPH oxidase (NOX) as well as mitochondria play an important role in promoting the angiogenic switch from quiescent endothelial cells (ECs). However, how highly diffusible ROS produced from different sources and location can communicate with each other to regulate angiogenesis remains unclear. To detect a localized ROS signal in distinct subcellular compartments in real time in situ, compartment-specific genetically encoded redox-sensitive fluorescence biosensors have been developed. Recently, the intercellular communication, "cross-talk", between ROS derived from NOX and mitochondria, termed "ROS-induced ROS release", has been proposed as a mechanism for ROS amplification at distinct subcellular compartments, which are essential for activation of redox signaling. This "ROS-induced ROS release" may represent a feed-forward mechanism of localized ROS production to maintain sustained signaling, which can be targeted under pathological conditions with oxidative stress or enhanced to promote therapeutic angiogenesis. In this review, we summarize the recent knowledge regarding the role of the cross-talk between NOX and mitochondria organizing the sustained ROS signaling involved in VEGF signaling, neovascularization and tissue repair.

Keywords: NADPH oxidase; angiogenesis; endothelial cell; mitochondria; reactive oxygen species; redox signaling; vascular endothelial growth factor

DOI: https://doi.org/10.3390/cells9081849

J Cell Physiol. 2020 Aug 10.

IRE1α/NOX4 signaling pathway mediates ROS-dependent activation of hepatic stellate cells in NaAsO2 -induced liver fibrosis.

Ye Tao, Tianming Qiu, Xiaofeng Yao, Liping Jiang, Ningning Wang, Jintong Jiang, Xue Jia, Sen Wei, Jingyuan Zhang, Yuhan Zhu, Wenyue Tian, Guang Yang, Xiaofang Liu, Shuang Liu, Yang Ding, Xiance Sun.

Liver fibrosis is a severe health problem worldwide, and it is characterized by the activation of hepatic stellate cells (HSCs) and excessive deposition of collagen. Prolonged arsenic exposure can induce HSCs activation and liver fibrosis. In the present study, the results showed that chronic NaAsO2 ingestion could result in liver fibrosis and oxidative stress in Sprague-Dawley rats, along with representative collagen deposition and HSCs activation. In addition, the inositol-requiring enzyme 1α (IRE1α)-endoplasmic reticulum (ER)-stress pathway was activated, and the activity of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was upregulated in rat livers. Simultaneously, the excessive production of reactive oxygen species (ROS) could induce HSCs activation, and NOX4 played an important role in generating ROS in vitro. Moreover, ER stress occurred with HSCs activation at the same time under NaAsO2 exposure, and during ER stress, the IRE1α pathway was responsible for NOX4 activation. Therefore, inhibition of IRE1α activation could attenuate the HSCs activation induced by NaAsO2 . In conclusion, the present study manifested that inorganic arsenic exposure could activate HSCs through IRE1α/NOX4-mediated ROS generation.

Keywords: NOX4; ROS; arsenic; hepatic stellate cells; liver fibrosis

DOI: https://doi.org/10.1002/jcp.29952

J Cell Physiol. 2020 Aug 11.

The role of NOX4 in pulmonary diseases.

Zi-Ming Li, Sheng-Ya Xu, Yi-Zhuo Feng, Yu-Rui Cheng, Jian-Bing Xiong, Yong Zhou, Cha-Xiang Guan.

Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is a subtype of the NOX family, which is mainly expressed in the pulmonary vasculature and pulmonary endothelial cells in the respiratory system. NOX4 has unique characteristics, and is a constitutively active enzyme that primarily produces hydrogen peroxide. The signaling pathways associated with NOX4 are complicated. Negative and positive feedback play significant roles in regulating NOX4 expression. The role of NOX4 is controversial because NOX4 plays a protective or damaging role in different respiratory diseases. This review summarizes the structure, enzymatic properties, regulation, and signaling pathways of NOX4. This review then introduces the roles of NOX4 in different diseases in the respiratory system, such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, and pulmonary fibrosis.

Keywords: NOX4; acute respiratory distress syndrome; chronic obstructive pulmonary disease; pulmonary fibrosis; signaling pathway

DOI: https://doi.org/10.1002/jcp.30005