bims-noxint 2022-05-22 papers

Issue of 2022–05–22
five papers selected by
Laia Caja Puigsubira, Uppsala University

Cell Mol Immunol. 2022 May 18.

NADPH oxidase family proteins: signaling dynamics to disease management.

Rizwana Begum, Shilpa Thota, Abubakar Abdulkadir, Gagandeep Kaur, Prathyusha Bagam, Sanjay Batra.

Reactive oxygen species (ROS) are pervasive signaling molecules in biological systems. In humans, a lack of ROS causes chronic and extreme bacterial infections, while uncontrolled release of these factors causes pathologies due to excessive inflammation. Professional phagocytes such as neutrophils (PMNs), eosinophils, monocytes, and macrophages use superoxide-generating NADPH oxidase (NOX) as part of their arsenal of antimicrobial mechanisms to produce high levels of ROS. NOX is a multisubunit enzyme complex composed of five essential subunits, two of which are localized in the membrane, while three are localized in the cytosol. In resting phagocytes, the oxidase complex is unassembled and inactive; however, it becomes activated after cytosolic components translocate to the membrane and are assembled into a functional oxidase. The NOX isoforms play a variety of roles in cellular differentiation, development, proliferation, apoptosis, cytoskeletal control, migration, and contraction. Recent studies have identified NOX as a major contributor to disease pathologies, resulting in a shift in focus on inhibiting the formation of potentially harmful free radicals. Therefore, a better understanding of the molecular mechanisms and the transduction pathways involved in NOX-mediated signaling is essential for the development of new therapeutic agents that minimize the hyperproduction of ROS. The current review provides a thorough overview of the various NOX enzymes and their roles in disease pathophysiology, highlights pharmacological strategies, and discusses the importance of computational modeling for future NOX-related studies.

Keywords: In silico; Inflammation; Inhibitors; NADPH oxidase; Reactive oxygen species

DOI: https://doi.org/10.1038/s41423-022-00858-1

Neurobiol Dis. 2022 May 13. pii: S0969-9961(22)00146-2. [Epub ahead of print] 105754

NADPH oxidase 2 activity in Parkinson's disease.

Matthew T Keeney, Eric K Hoffman, Kyle Farmer, Christopher R Bodle, Marco Fazzari, Alevtina Zharikov, Sandra L Castro, Xiaoping Hu, Amanda Mortimer, Julia K Kofler, Eugenia Cifuentes-Pagano, Patrick J Pagano, Edward A Burton, Teresa G Hastings, J Timothy Greenamyre, Roberto Di Maio.

Mitochondrial dysfunction and oxidative stress are strongly implicated in Parkinson's disease (PD) pathogenesis and there is evidence that mitochondrially-generated superoxide can activate NADPH oxidase 2 (NOX2). Although NOX2 has been examined in the context of PD, most attention has focused on glial NOX2, and the role of neuronal NOX2 in PD remains to be defined. Additionally, pharmacological NOX2 inhibitors have typically lacked specificity. Here we devised and validated a proximity ligation assay for NOX2 activity and demonstrated that in human PD and two animal models thereof, both neuronal and microglial NOX2 are highly active in substantia nigra under chronic conditions. However, in acute and sub-acute PD models, we observed neuronal, but not microglial NOX2 activation, suggesting that neuronal NOX2 may play a primary role in the early stages of the disease. Aberrant NOX2 activity is responsible for the formation of oxidative stress-related post-translational modifications of α-synuclein, and impaired mitochondrial protein import in vitro in primary ventral midbrain neuronal cultures and in vivo in nigrostriatal neurons in rats. In a rat model, administration of a brain-penetrant, highly specific NOX2 inhibitor prevented NOX2 activation in nigrostriatal neurons and its downstream effects in vivo, such as activation of leucine-rich repeat kinase 2 (LRRK2). We conclude that NOX2 is an important enzyme that contributes to progressive oxidative damage which in turn can lead to α-synuclein accumulation, mitochondrial protein import impairment, and LRRK2 activation. In this context, NOX2 inhibitors hold potential as a disease-modifying therapy in PD.

Keywords: NADPH oxidase 2 activity; Oxidative stress; Parkinson's disease pathogenesis

DOI: https://doi.org/10.1016/j.nbd.2022.105754

Kardiol Pol. 2022 May 17.

Low-grade endotoxemia and NOX-2 in patients with coronary microvascular angina.

Lorenzo Loffredo, Victoria Ivanov, Nicolae Ciobanu, Micaela Ivanov, Paolo Ciacci, Cristina Nocella, Vittoria Cammisotto, Federica Orlando, Aurora Paraninfi, Enrico Maggio, Alessandra D'Amico, Paolo Rosa, Mihail Popovici, Simona Bartimoccia, Francesco Barillà, Elena Deseatnicova, Evgenii Gutu, Francesco Violi, Roberto Carnevale.

BACKGROUND: Endothelial dysfunction and oxidative stress were hypothesized to be involved in the pathogenesis of coronary microvascular angina (MVA). NADPH oxidase-2 (NOX2) activation could provoke increased oxidative stress and endothelial dysfunction but data in MVA have not been provided yet.
AIMS: The aim of this study was to evaluate the interaction among NOX2 activation, serum lipopolysaccharide (LPS) levels as well as oxidative stress production as potential causes of endothelial dysfunction in MVA patients.
METHODS: In this study we wanted to compare serum levels of soluble NOX2-dp (sNOX-2-dp), H2O2 production, hydrogen peroxide breakdown activity (HBA), nitric oxide (NO) bioavailability, endothelin-1 (ET-1), serum zonulin (as intestinal permeability assay) and LPS in 80 consecutive subjects, including 40 MVA patients and 40 controls (CT) matched for age and gender.
RESULTS: Compared with CT, MVA patients had significant higher values of sNOX-2-dp, H2O2, ET-1, LPS and zonulin; conversely HBA and NO bioavailability was significantly lower in MVA patients. Simple linear regression analysis showed that sNOX2 was associated with serum LPS, serum zonulin, H2O2 and ET-1; furthermore, an inverse correlation between sNOX2 and HBA and nitric oxide bioavailability was observed. Multiple linear regression analysis showed that LPS and zonulin emerged as the only independent predictive variables associated with sNOX2.
CONCLUSIONS: this study provides the first report attesting that patients with MVA have high LPS levels, NOX-2 activation and an imbalance between pro-oxidant and antioxidant systems, in favor of the oxidizing molecules that could be potentially implicated in the endothelial dysfunction and vasoconstriction of this disease.

Keywords: LPS; NADPH oxidase; NOX2; coronary microvascular angina; oxidative stress

DOI: https://doi.org/10.33963/KP.a2022.0130

Neuropharmacology. 2022 May 15. pii: S0028-3908(22)00195-2. [Epub ahead of print] 109136

NADPH oxidase-induced activation of transforming growth factor-beta-1 causes neuropathy by suppressing antioxidant signaling pathways in alcohol use disorder.

Saurav Bhowmick, Saleena Alikunju, P M Abdul-Muneer.

Oxidative signaling and inflammatory cascades are the central mechanism in alcohol-induced brain injury, which result in glial activation, neuronal and myelin loss, neuronal apoptosis, and ultimately long-term neurological deficits. While transforming growth factor-beta1 (TGF-β1) has a significant role in inflammation and apoptosis in myriads of other pathophysiological conditions, the precise function of increased TGF-β1 in alcohol use disorder (AUD)-induced brain damage is unknown. In this study, our objective is to study ethanol-induced activation of TGF-β1 and associated mechanisms of neuroinflammation and apoptosis. Using a mouse model feeding with ethanol diet and an in vitro model in mouse cortical neuronal cultures, we explored the significance of TGF-β1 activation in the pathophysiology of AUD. Our study demonstrated that the activation of TGF-β1 in ethanol ingestion correlated with the induction of free radical generating enzyme NADPH oxidase (NOX). Further, using TGF-β type I receptor (TGF-βRI) inhibitor SB431542 and TGF-β antagonist Smad7, we established that the alcohol-induced activation of TGF-β1 impairs antioxidant signaling pathways and leads to neuroinflammation and apoptosis. Blocking of TGF-βRI or inhibition of TGF-β1 diminished TGF-β1-induced inflammation and apoptosis. Further, TGF-β1 activation increased the phosphorylation of R-Smads including Smad2 and Smad3 proteins. Using various biochemical analyses and genetic approaches, we demonstrated the up-regulation of pro-inflammatory cytokines IL-1β and TNF-α and apoptotic cell death in neurons. In conclusion, this study significantly extends our understanding of the pathophysiology of AUD and provides a unique insight for developing various therapeutic interventions by activating antioxidant signaling pathways for the treatment of AUD-induced neurological complications.

Keywords: Alcohol; Apoptosis; NADPH Oxidase; Neuroinflammation; Oxidative stress; Smad proteins; Transforming growth factor-beta1

DOI: https://doi.org/10.1016/j.neuropharm.2022.109136

Compr Physiol. 2022 Mar 29. 12(2): 3167-3192

Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases.

Raja Gopal Reddy Mooli, Dhanunjay Mukhi, Sadeesh K Ramakrishnan.

The increased production of derivatives of molecular oxygen and nitrogen in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to molecular damage called oxidative stress. Under normal physiological conditions, the ROS generation is tightly regulated in different cells and cellular compartments. Any disturbance in the balance between the cellular generation of ROS and antioxidant balance leads to oxidative stress. In this article, we discuss the sources of ROS (endogenous and exogenous) and antioxidant mechanisms. We also focus on the pathophysiological significance of oxidative stress in various cell types of the liver. Oxidative stress is implicated in the development and progression of various liver diseases. We narrate the master regulators of ROS-mediated signaling and their contribution to liver diseases. Nonalcoholic fatty liver diseases (NAFLD) are influenced by a "multiple parallel-hit model" in which oxidative stress plays a central role. We highlight the recent findings on the role of oxidative stress in the spectrum of NAFLD, including fibrosis and liver cancer. Finally, we provide a brief overview of oxidative stress biomarkers and their therapeutic applications in various liver-related disorders. Overall, the article sheds light on the significance of oxidative stress in the pathophysiology of the liver. © 2022 American Physiological Society. Compr Physiol 12:3167-3192, 2022.

DOI: https://doi.org/10.1002/cphy.c200021