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NADPH Oxidase Enzymes (NOX 1, 2, 4, 5)

Updated: Oct 4, 2023

When somebody with ME / CFS or Long Haul finds me, one of the first things i look for is upregulations in genes that create oxidative stress, which brings me to NOX 1, 2, 4, 5.

NOX 1, 2, 5, all generate the super oxide radical, while NOX 4 generates hydrogen peroxide [1]. All of these genes are also directly connected to histamine and mast cells, and of course additional free radicals can initiate the degranulation of mast cells. Additionally, these enzymes consume NAD / NADPH, in what has been well documented as the "tryptophan steal".

Well, that doesn't sound so great - you feel tired (low NAD) and you feel stressed / inflamed from the extra oxidative stress. Hmmm.

So how do we regulate and inhibit the over expression of these genes - well - curcumin and spirulina were my go to herbs for these genes - but - many folks cannot tolerate either (CYP1A2 issues for curcumin) or NMDA receptor and or glutamate excito-toxicity for Spirulina. So what to do ? More research that's what !

So what does the research indicate will inhibit these genes:

  1. NOX 2, 4 are inhibited by Rosemary, Gypsywort [1]

  2. NOX 1, 2 by Celestrol, Tryperysium [1]

  3. NOX 4 - WildLeadWort [1]

  4. Overall NOX enzymes: Honokiol / Magnolia bark, Gingko, Berberine, Querectin, Fisetin, Blueberry extract, Prodigiosin [3]

  5. NOX2: Paeonol (Paeonia suffruticosa); Reinioside C (Polygala fallax Hemsl.); Celastrol (Tripterygium wilfordii Hook F); Apocynin (Apocynum cannabinum); Quercetin (Berries, onions, and red wine); Delphinidin (Pigmented fruits and vegetables) [4]

  6. NOX4: Paeonol (Paeonia suffruticosa); Reinioside C (Polygala fallax Hemsl.); Quercetin (Berries, onions, and red wine); Delphinidin (Pigmented fruits and vegetables); Thymoquinone( Nigella sativa); Berberine (Rhizoma Coptidis) [4]

Rosemarinic Acid Inhibits NOX2, NOX4 {Rosemary Extract is a source)

Within an initial screening of extracts of alpine plants on their ability to inhibit Nox4 activity in HEK cells, the methanolic extract of the subaerial parts of Lycopus europaeus showed a strong inhibition of Nox4 (81% chemiluminescence quenching) and a simultaneously high cell viability (91% vitality). Rosmarinic acid was isolated and identified as the major compound in this bioactive extract. It showed a dose dependent inhibitory activity on Nox4 with an IC50 of 1 µM. Moreover, it also showed a significant inhibitory activity on Nox2 in the low micromolar range, whereas no inhibition of Nox5 was detected. Further investigations confirmed that the observed effects of rosmarinic acid on Nox2 and Nox4 are real inhibitory activities, and not due to ROS scavenging effects. Therefore, L. europaeus, which we demonstrated to be a good source of rosmarinic acid, has great potential for usage in cosmeceutical products with anti-ageing activity. [1] Others point to plumbagin to inhibit NOX4 [2].

NOX2 Inhibitors Include a good long list [2]:

Apocynin picrorhiza kurroa; Berberine Berberis; Blueberry derived polyphenols; EGCG

green tea; Celastrol Tripterygium wilfordii; Resveratrol red wine; HDMPPA

Fruits and nuts kimchi; Ginko biloba; Emodin and rhein Rhubarb

Celestrol [3] inhibits NOX1, and NOX2

The effect of celastrol was compared with diphenyleneiodonium, an established inhibitor of flavoproteins. Low concentrations of celastrol completely inhibited NOX1, NOX2, NOX4 and NOX5 within minutes with concentration-response curves exhibiting higher Hill coefficients and lower IC₅₀ values for NOX1 and NOX2 compared with NOX4 and NOX5, suggesting differences in their mode of action.

NOX4 - Do we want to downregulate this ?

Nox4 as a constitutive endothelial generator of H2O2 that positively affects vascular function. Low tonic production of H2O2 is vasoprotective and this could, at least in part, explain the failure of antioxidant therapy to prevent vascular disease in clinical trials. Although endogenous Nox4 appears to have a minor impact on function in healthy vessels, it controls eNOS and HO-1 expression. Thus, in disease situations such as ischemia-induced angiogenesis and angiotensin II–induced vascular dysfunction, a lack of Nox4 potentiates the disease phenotype. Nox4 therefore is a protective NADPH oxidase and may antagonize the action of Nox1 and Nox2. Nox4 inhibitors, which are currently being developed for clinical use, therefore should be carefully monitored for negative vascular side effects. Conclusion: Endogenous Nox4 protects the vasculature during ischemic or inflammatory stress. Different from Nox1 and Nox2, this particular NADPH oxidase therefore may have a protective vascular function. [5]

NOX Priming [4]

Before NOX activation, multiple external activators, such as PAF5 (Platelet-Activating Factor), fMLF (formyl-methionyl-leucyl-phenylalanine), LPS (Lipopolysaccharide) and TNFα (Tumor Necrosis Factor), or alternative particulate stimuli such as opsonized bacteria, cause the ‘priming’ of the enzyme. In vitro, these physiological inflammatory agents may induce either a priming effect at low concentrations (<10−7 M), or trigger direct neutrophil activation and the production of ROS at higher concentrations. This pre-activation does not elicit the respiratory burst but allows for an additional secondary stimulus to result in superior microbial killing. Priming leads to a typically faster and enhanced response, ensuring efficient clearance of pathogens during phagocytosis. This priming has been correlated to the phosphorylation of Ser 345 of p47phox. This allows for the action of Pin1 prolyl-isomerase on p47phox, thereby inducing conformational changes and facilitating additional phosphorylation by protein kinase C (PKC) in the activation process.

However, this process is likely to result in subsequent oxidative damages to surroundings tissues, ultimately promoting an uncontrolled inflammation when the intensity of the downstream response is not properly adapted.

Activation by Lipids and Arachidonic Acid [4]

PI3-K action initiates the formation of essential PI derivatives PI(3)P, PIP2 and PIP3 that bind the PX domain of p47phox or p40phox with high specificity [166] (Figure 9). Besides this function, PIP2 and PIP3 also participate in the regulation of PKC activity [167]. Ca2+ ions released downstream of IP3 binding to endoplasmic reticulum receptors allows for the activation of cytosolic Phospholipase A2 (PLA2) [168], an enzyme that catalyzes the production of arachidonic acid (AA). AA then participates in inducing several signaling molecules, such as PKC, involved in the subsequent elicitation of NOX [169]. AA is also suspected to induce a transient conformation of cytosolic factors that enables their association with flavocytochrome b, promoting optimal superoxide production [170,171].

Moreover, the direct action of AA can release the p47phox bis-SH3 tandem domain from the AIR, thus promoting p47phox interaction with p22phox [172,173,174]. Exogeneous supply of AA in Rac2 knock-out neutrophils leads to activation of NOX, suggesting the lipid can in part replace the action of Rac on p67phox [175]. Finally, anionic membrane phospholipids have been shown to be essential for NOX2 activation thanks to the use of chimeric cytosolic factors (see above) in the cell-free assay [176].


NOX1 and NOX3 constitute the closest isoforms to phagocytic NADPH oxidase (Figure 10), sharing 60% sequence identity with NOX2.

NOX1 constitutes the predominant isoform in the colon, prostate, uterus and vascular cells [46,76,181].

NOX3 is typically expressed in the inner ear. NOX3 expressed in cochlea produces ROS that has been linked to hearing loss [182], while NOX3 expressed in the vestibule produces ROS involved in gravity perception [181]. Low abundance of NOX3 has also been identified in the brain and lungs, albeit the function in these tissues is still elusive [183,184,185]. Like NOX2, NOX1 and NOX3 are both glycosylated in vivo.

NOX2, expressed in phagocytic cells, was the first NOX isoform identified [84]. The other human isoforms and homologs in other organisms exhibit varying cellular localization, activation mechanisms, etc., but they all share a common catalytic subunit very similar to that of NOX2. The extensive biochemical characterization of the NOX2 enzyme constituted a fundamental prerequisite towards understanding the functional aspects of the whole family. Regardless of its place in biological evolution, because of its place in the order of discovery and its importance to human health, NOX2 serves as the prototype enzyme for the family. Although NOX2 is now understood to participate in various physiological processes such as signal transduction, angiogenesis or cell death [85,86,87,88,89], for many years the only known role for NOX2 was in innate immunity, so this function similarly provides the prototype for the family.


NOX4, which is highly expressed in the kidney, osteoclasts, fibroblasts and endothelial cells, shares a common catalytic core with NOX1 to 3, but shares only 39% identity with NOX2

NOX5 also shares a common core architecture with the other isoforms (27% identity with NOX2), with the addition of a N-ter extension containing 4 EF-hand motifs. NOX5 is endowed with other specificities compared to other NOX isoforms, such as a Ca2+-dependent activation, no requirement for p22phox and cytosolic factors, and the absence of glycosylation.


The observation of NADPH and Ca2+-dependent hydrogen peroxide production in thyroid cells led to the discovery in 1999 of dual oxidases DUOX1 and 2 [47]. In addition to the NOX catalytic core like NOX1-4, and an EF-hand domain like NOX5 but with two instead of four EF motifs, DUOXes also contain an N-terminal extracellular peroxidase-like domain connected to the rest of the protein by an extra TM helix. In mammalian DUOX, absence of histidines implicated in heme chelation correlate with a lack of intrinsic peroxidase activity; C. elegans Duox does bind heme and shows a low level of peroxidase activity [204]. The DUOX glycosylation state correlates with its maturation and its ROS product [205,206,207,208].

DUOXes are sequestered in an inactive state in the endoplasmic reticulum. They require a maturation factor (DUOXA1 or DUOXA2) to adopt a conformation consistent with the acquisition of post-translational modifications responsible for the migration of the complex from the endoplasmic reticulum to the plasma membrane. It has been reported that in the presence of DUOXA2, the DUOX1 enzyme produces O2●- while DUOX2 also produces H2O2 [209].

Despite the evidence in favor of a prokaryotic origin of NOX as early as 2004 in the independent studies of [210] and [211], the existence of prokaryotic NOX has only been recently confirmed.

Pathologies Related to NOX Deregulation

The ROS produced by the NOX family participate in a variety of physiological mechanisms beyond immune defense, most significantly a large number of signaling pathways that regulate crucial biological functions such as angiogenesis, cell proliferation and apoptosis. The loss of ROS homeostasis directly affects these processes, leading to human pathologies.

Chronic Granulomatous Disease

As described in Section 2, CGD pathology is the result of an inactive NADPH oxidase complex leading to a loss of bactericidal activity of neutrophil, an inability to fight again infections and thus to an inherited innate immunity deficiency. The most common and severe form of CGD (CGD-X) arises from mutations in the NOX2-encoding gene CYBB on the X chromosome. Analysis of X-CGD-related mutations revealed the existence of three distinct cases defined by a total absence of NOX2 (X0-CGD), or by a low expression of the mutated protein correlated with a reduced oxidase activity (X minus-CGD), or finally by normal expression of NOX2 but a loss of oxidase activity (X+CGD) [345]. These alternatives provided crucial models that led to definitions of functional domains and residues in NOX2 [346]. X+ CGD-related mutations mainly affect the catalytic activity of the oxidase, while the mutations responsible for X minus CGD appear to affect the proper maturation and correct folding of NOX2.

Central Nervous System Diseases

The brain includes a variety of oxidation-sensitive lipids but also has reduced antioxidative defense mechanisms. This, combined with the large amount of oxygen consumed by the brain, confers to this organ an acute sensitivity to the misregulation of redox homeostasis [354]. As a consequence, alterations in the ROS production pathways can result in a wide range of neurological disorders and significant damage to this organ. NOX1, 2, 3 and 4 are expressed in cells of the central nervous system (CNS) such as neurons [355], microglia [356,357] and intracranial vessels [358]. Many studies have documented the relationship of NOX enzymes with degenerative diseases of the brain.

Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a stepwise destruction of the dopaminergic neurons in the nigrostriatal pathway of the brain; this destruction triggers complex functional modifications within the basal ganglia circuitry, ultimately leading to motor dysfunctions [359].

Research on PD mainly relies on the development of a mouse model in which the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces the PD-like symptoms of human degeneration [360,361]. MPTP signals the translocation of p47phox to the membrane, and subsequently the activation of NOX2 [362]. Increased levels of p47phox-NOX2 complexes were detected in vivo after systemic injections of MPTP [363]. Additionally, it was notably demonstrated that the CNS, particularly dopaminergic (DA) neurons, is prone to oxidative damage, resulting in cell degeneration and PD pathogenesis [364,365].

In agreement with these findings, NOX2−/− mice given MPTP showed attenuated damage to DA neurons compared to WT counterparts, supporting NOX2’s function in the PD-related loss of dopaminergic neurons [359].

A microglial expression of the NOX enzymes involved in the PD disease is evidenced by immunostaining assays.

Alzheimer’s Disease

Alzheimer’s disease (AD) arises from a stepwise neuronal decline that originates in the hippocampus, a cerebral structure essential for memory. As this decline extends in the brain, it leads to a dramatic loss of higher cognitive functions resulting in dementia. Accumulation of amyloid-β peptide (Aβ) in the brain is generally considered one of the main pathological indicators of AD [369].

Several lines of evidence indicate that NOX contributes to this pathology. In a rodent model, exposing microglial cells to high concentrations of Aβ peptides induced the translocation of NOX regulatory subunits, while inhibiting NOX2 activity with gp91ds-tat peptides diminished degenerative symptoms [370]. The oxidation of cholesterol into 24-hydroxycholesterol, promoted by redox imbalance and more specifically by the large amount of H2O2, potentiates both the pro-apoptotic and pro-necrotic effects of Aβ [371].

The brains of AβPP/PS1 double transgenic mice, a mouse model of AD, showed a significantly higher expression of NOX2 and NOX4 [372]. Treating these mice with phenolic antioxidant tert-butylhydroquinone inhibits NOX2 expression and thereby prevents the cerebral cortex and hippocampus from lipid peroxidation [373], revealing the existence of a significant linear relationship between NOX activity, Aβ production rate, and neuronal decay. In the bilateral cerebral artery occlusion (BBCAO) rodent model of early-stage vascular dementia, upregulated expression of NOX1 and NOX3 mRNAs and corresponding high levels of superoxide have been described [374] in the hippocampus CA1 region responsible for neuronal dementia [375]. Taken together, these findings indicate that NOX enzymes play a role in the development of AD


Several NOX, and their regulatory subunits, show markedly increased expression in many types of human tumors or cancer cell lines cultured at different stages of tumorigenesis, suggesting NOX participation in these events [377,378,379]. Similarly, several studies over a large number of patients suffering from gastric cancers (GC) also showed that high levels of NOX2/4, and DUOX1 at the tumor site, compared to adjacent tissues, constitute reliable prognostic markers in GC [380,381].

Athymic mice with exogenous expression of NOX1 in wild-type fibroblasts of the NIH3T3 cell line presented noticeably enhanced cell growth and tumor formation [46]. In these experiments, NOX1-transfected cells (10-fold over-expression of NOX-1 in NIH3T3 fibroblasts) induced increased growth and transformation despite a restricted production of superoxide anions, revealing that high levels of ROS are not responsible for the initiation of tumor processes [319]. However, NOX1 produces a marked increase in intracellular H2O2, formed from the dismutation of O2 and the coexpression of catalase (CAT) promoting the recovery of the initial phenotype. This demonstrated that H2O2 is nonetheless a likely accountable factor for the induction of these mechanisms.

Tumor Development

The effect of ROS in DNA damage has been extensively reviewed; cell exposure to chronic oxidative stress has been reported to elicit genomic instability [386,387], and there is evidence for increased levels of ROS [388,389] in genomically unstable clones. In this context, NOX-derived ROS is a logical contributor to this phenomenon. Although the exact role of NOX in cellular transformation remains unclear, several studies furnish suggestive evidence.

H2O2 produced by NOX4 damages mitochondrial DNA and induces mitochondrial dysfunction [83,390,391]. NOX4 was also presumed to be responsible for the direct oxidation of nuclear proteins and DNA as indicated by NOX4 localization within the nucleus [392].

Along with the generally attributed role of NOXes in chromosomal instability, NOX 1, 2, 4 and DUOXes have been linked to the regulation of p53 transcription factor activity. Attributed since 1989 to tumor suppression, the gene associated with p53 cell cycle inhibitor appeared to be inactivated in 50% of the human cancers. Several kinds of evidence make clear an extensive crosstalk between NOX4 and p53, in which each affects both the expression and activity of the other, ultimately influencing tumor formation and progression [393,394,395]. The homeodomain-interacting protein kinase 2 (HIPK2) corepressor upregulates NOX1, inhibiting Sirtuin1 (SIRT1) and thus indirectly inhibiting the deacetylation and inactivation of p53 [396]. The induction of NOX1 expression is also connected to an increase in mutation rate in the proto-oncogen K-RAS, involved in 30% of human tumors.

Proliferation, Invasion and Metastasis

Cancerous cells spread and proliferate via a sequential metastatic cascade featuring the invasion of the extracellular matrix by tumor cells, followed by a stepwise migration through the endothelium towards vessels (intravasation/extravasation), colonization, and initiation of a secondary tumor [398,399]. Invadopodia, actin-rich structures mainly containing integrins and metalloproteases, mediate extracellular matrix degradation and extravasation steps. Invadopodia formation relies on superoxide produced by NOX [400,401,402]. Proteins Tks4 and Tks5, which have some similarity to p47phox and are exclusive to invadopodia, bind and activate NOX1 and NOX3 independent of the usual NOX cytosolic subunits [403,404]. Proper assembly of the NOX-Tks protein complex exclusively found in the membranes of these structures appears essential for invadopodia formation.

Tumor-Mediated Angiogenesis

The ability of cancer cells to spread to adjacent or distant tissues depends heavily on oxygen and nutrients delivered by the vascular system [412]. Angiogenesis constitutes an essential process in the development of solid tumors by ensuring the direct delivery of nutrients to cancer cell clusters. The HIF-1α (Hypoxia Inducible Factor 1α)/VEGF/MMP signaling cascade activated by hypoxia and by ROS [413,414] regulates the formation of new blood vessels promoting tumor formation. The underlying mechanisms of this process has been deciphered though the study of the degradation of HIF-1α in normal oxygen conditions, awarded the 2019 Nobel Prize in Medicine. NOX1, 2, 4 and 5 (Figure 22), localized in endothelial cells participate in every stage of angiogenesis (Part 6.2.5), and play a crucial role in cancer-induced blood vessel formation.

In ovarian cancers, NOX4-derived H2O2 regulates HIF-1α expression which in turn governs VEGF levels, essential for tumor-induced angiogenesis [415,418]. ROS production by NOX1 and NOX4 also stimulates HIF-1α-mediated vascularization in prostate cancer and malignant melanoma [416,418]. However, it is noteworthy to mention several studies reporting that ROS-mediated angiogenesis likely occurs in an HIF-1α independent mechanism [416,418,419]. NOX1 was reported to have a role in endothelial cell migration [338] through the downregulation of the expression and activity of the antiangiogenic receptor PPARα (peroxisome proliferator-activated receptor α), which is known to inhibit the transcription factor NF-κβ (Figure 23) and VEGF [338,420]. Another mechanism has been reported for serotonin-induced angiogenesis: serotonin (5-HT, 5 -hydroxytryptamine) activates NOX and induces ROS production, which is probably mediated through the activation of the 5-HT1 receptor-linked Src/PI3K pathway.

Cardiovascular Pathologies

The production of ROS in the blood vessels is essential to redirect the blood stream to the most active tissues and thus maintain vascular homeostasis. However, ROS also contributes to the development of cardiovascular diseases such as hypertension, atherosclerosis, diabetes, hypertrophy and cardiac arrest. Multiple ROS-producing enzymes—including NOX, nitric oxide synthases (NOS), respiratory complex proteins and cytochromes P450—that are unevenly distributed and expressed throughout the vascular system produce ROS. While all of these enzymes participate in various pathological conditions, NOX appears to exert a key role in modulating the stimulation or dysfunction of downstream enzymes [422,423].

The NOX expression profile in vascular cells and tissue varies depending on the specific pathology and also the stages of any disease’s progression [422]. In physiological conditions, vascular NOX present a low basal activity [424]. However, misregulation or chronic production of large amounts of NOX-derived ROS, stimulated by signals such as cytokines [425], growth factors [426] or high glucose levels [427], interferes with vascular homeostasis and promotes the development of cardiovascular pathologies.


Among the first pathologies undoubtedly attributed to NOX activity (Figure 23) [429], hypertension constitutes a multifactorial pathology involving enhanced vascular resistance, increased cardiac output, decline of renal sodium excretion and dysfunction in blood pressure regulation.

Angiotensin-2 (Ang-2), which exerts a crucial role in the development of hypertension, represents a major positive regulator of the NOX-mediated production of ROS in the vascular system. Acting through angiotensin type 1 (AT1) receptors [430], Ang-2 stimulates the expression of NOX1, NOX2 and NOX4 homologues and the cytosolic factor p22phox, all implicated in hypertension and associated vascular dysfunction [429].

The aortas of aged spontaneously hypertensive rats (SHRs) displayed an Ang2-induced overexpression of NOX1, enhanced NOX activity, a significant increase in systolic blood pressure, and hypertrophy. The deletion of NOX1 protected SHRs from vascular dysfunction and complications [431]. Similarly, overexpression of NOX2 genes in SHRs models led to a hypertensive phenotype [422], while p47phox knockout mice with low NOX2 activity exhibited diminished hypertension and preserved endothelial functions after chronic exposure to Ang2 [432,433].

While the molecular studies of NOX1 and NOX2 showed their role in promoting hypertension, NOX4 activity has been linked to a protective function [434]. For example, the overexpression of NOX4 and enhanced H2O2 production stimulated vasodilation and resulted in a reduced basal blood pressure, suggesting a protective role for NOX4 [435]. Under Ang2-induced stress conditions, Nox4−/− mice exhibited impaired expression of the heme oxygenase-1 (HO-1) and endothelial NOS (eNOS). This resulted in a lower production of nitric oxide, consequently promoting apoptotic and inflammatory responses [434]. In contrast to NOX1 and NOX2, NOX4 promotes the protection of the vascular system during ischemic or hypertensive stress.


Atherosclerosis is a condition characterized by the accumulation of arterial plaques, mainly composed of lipids, on the walls of arteries, ultimately resulting in damage to the arterial wall and obstruction of vessels.

Animal models show that vascular cells adjacent to atheromatous plaques presented higher levels of NOX2, NOX4 and NOX5 expression than healthy cells [436,437], suggesting NOX participation.

Molecular-level explanations ensued. In the presence of low-density lipids (LDL), the increased binding and uptake by cell surface LDL receptors may be responsible for the direct activation of NOX. NOX-generated superoxide stimulates lipid endocytosis, thus promoting plaque formation.


Diabetes is associated with a wide range of metabolic degenerations such as insulin resistance and hyperglycemia, but the majority of deaths in diabetic conditions result from cardiovascular complications.

Both animal models [439] and human diabetic patients [440] showed an increased ROS production during hyperglycemia that promotes endothelial dysfunction, further stimulating the detrimental progression of diabetes-related vascular pathologies.

NOX2 and NOX4 have been detected in the aorta of ApoE−/− atherosclerotic mice models exposed to the streptozotocin diabetes inducer [441]. Likewise, NOX1 and NOX4 were found to be over-expressed in db/db diabetic mice, indicating that the NOX1 and NOX4 isoforms may exert a potential role in diabetes-related macrovascular disease [442]. Deletion of NOX1 in diabetic mice, or exposure of these animals to GKT137831 to inhibit NOX1, induced a systematic attenuation of atherosclerotic plaque formation [443]. (The reader is cautioned that this inhibitor probably does not directly inhibit NOX1 [444].) However, the absence of NOX4 did not induce significant changes in vascular conditions in diabetic mice, suggesting that this isoform does not support a direct role in diabetic vasculopathies. It may, instead, exert indirect effects through the regulation of adipogenesis [445] via the ERK1/2 MAPK signaling pathway. NOX4 gene suppression in pre-adipocytes notably blocks the differentiation of stem cells into adipocytes while high levels of NOX4 have been reported in pre-adipocytes. By switching the balance toward differentiation of preadipocytes, NOX4 promotes obesity and inherent heart disease [446].

Hyperglycemia also induces elicitation of vascular NOX. Indeed, contrary to wild-type cells, incubation of endothelial cells with red blood cells from patients suffering from type 1 diabetes led to activation of endothelial NOX [447]. This activation leads to enhanced amounts of ROS, as indicated by the increased production of superoxide detected in the arteries and veins of diabetic patients.


[1] Identification of the NADPH Oxidase 4 Inhibiting Principle of Lycopus europaeus by Silvia Revoltella, Giorgia Baraldo et al. Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria Molecules 2018, 23(3), 653; Received: 31 January 2018 / Revised: 5 March 2018 / Accepted: 9 March 2018 / Published: 14 March 2018

[2] Natural Compounds as Modulators of NADPH Oxidases, Tullia Maraldi* Oxid Med Cell Longev. 2013; 2013: 271602. Published online 2013 Nov 27. doi: 0.1155/2013/271602. PMCID: PMC3863456. PMID: 24381714

[3] NADPH oxidase (NOX) isoforms are inhibited by celastrol with a dual mode of action. April 2011 British Journal of Pharmacology 164(2b):507-20; DOI:10.1111/j.1476-5381.2011.01439.x. PubMed Authors: Vincent Jaquet

[4] NADPH Oxidases (NOX): An Overview from Discovery, Molecular Mechanisms to Physiology and Pathology by Annelise Vermot, Isabelle Petit-Härtlein Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, 38000 Grenoble, France. Antioxidants 2021, 10(6), 890; Received: 30 March 2021 / Revised: 21 May 2021 / Accepted: 26 May 2021 / Published: 1 June 2021.

[5] Natural Bioactive Compounds Targeting NADPH Oxidase Pathway in Cardiovascular Diseases. by Siti Sarah M. Sofiullah, Dharmani Devi Murugan, et. al. Molecules 2023, 28(3), 1047; Received: 25 October 2022 / Revised: 4 December 2022 / Accepted: 10 December 2022 / Published: 20 January 2023

[6] Nox4 Is a Protective Reactive Oxygen Species Generating Vascular NADPH Oxidase , Katrin Schro¨der,* Min Zhang. Downloaded from by on July 11, 2022. Circulation Research is available at DOI: 10.1161/CIRCRESAHA.112.267054

[7] From form to function: the role of Nox4 in the cardio vascular system. FengChen, Stephen Haigh, et al. VascularBiologyCenter,GeorgiaHealthSciencesUniversity,Augusta,GA,USA. Frontiers In Physiology, published:01November2012. e-mail: November2012|Volume3|Article412. doi:10.3389/fphys.2012.00412

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