Role Of NADPH Oxidase Research Articles

The role of NADPH Oxidase 4 in Iraqi Osteoporosis Patients

Background: Osteoporosis is a common condition that occurs in bone leading to the loss of bone mass. It is caused by increased osteoclast activity which is differentiated by low bone density measured by dual-energy X-ray absorptiometry (DEXA).Objective: This study aimed to estimate the levels of NADPH oxidase (NOX4), Alkaline phosphatase, and vitamin D in Iraqi osteoporosis patients diagnosed by DEXA. Methods: A total of 88 volunteers were split into two groups for this investigation. There were 58 patients in group 1 and 30 controls in group 2 , the samples were taken from both sexes of range age (20-60) years, the levels of Alkaline phosphatase (ALP), Vitamin D, and NOX 4 were evaluated. NADPH oxidase 4 levels were measured by enzyme-linked immunosorbent assay (ELISA), Alkaline phosphates levels were measured using a spectrophotometer, and the concentration of vitamin D was measured by electrochemiluminescence binding assay using Cobas e 411. Whereas the T-score was measured using DEXA.Results: The results of NADPH oxidase 4, AlP, and vitamin D did not show any significant change (P>0.05) when compared osteoporosis group to the control group. Whereas T score showed a significant variance when contrasting between the studied groups (P<0.05). Conclusion: according to the presented results NADPH oxidase 4 is not affected by osteoporosis.

P25-03 Exploration of the novel role of NADPH oxidases in the biotransformation of T2 mycotoxin

P25-03 Exploration of the novel role of NADPH oxidases in the biotransformation of T2 mycotoxin

Role of NADPH Oxidases in Stroke Recovery.

Stroke is one of the most significant causes of death and long-term disability globally. Overproduction of reactive oxygen species by NADPH oxidase (NOX) plays an important role in exacerbating oxidative stress and causing neuronal damage after a stroke. There is growing evidence that NOX inhibition prevents ischemic injury and that the role of NOX in brain damage or recovery depends on specific post-stroke phases. In addition to studies on post-stroke neuroprotection by NOX inhibition, recent reports have also demonstrated the role of NOX in stroke recovery, a critical process for brain adaptation and functional reorganization after a stroke. Therefore, in this review, we investigated the role of NOX in stroke recovery with the aim of integrating preclinical findings into potential therapeutic strategies to improve stroke recovery.

Salt-Sensitive Hypertension and Renal Damage are Amplified by Adoptive Transfer of CD4+ and Not CD8+ T Cells: A Role of NADPH Oxidase 2 (NOX2)

Infiltration of T cells into the kidney of the Dahl Salt Sensitive (SS) rat model of human disease accompanies the development of salt-sensitive hypertension and renal damage. Deletion of T cells on the Dahl SS genetic background (SSCD247−/−) attenuates hypertension and renal damage, and subsequent replacement of T cells by splenocyte transfer restores the disease phenotype. The present studies were performed to assess if the T cell subtype (CD4+ vs CD8+) is important in Dahl SS hypertension and interrogate the mechanism of action. In initial experiments, adoptive transfer of purified CD4+ or CD8+ T cells (~5 million) from splenocytes isolated from the Dahl SS (CD4+ SS→CD247 or CD8+ SS→CD247) or PBS vehicle (PBS→CD247) into the SSCD247−/− rat was performed on postnatal day 5. Animals were recovered and instrumented with radiotelemeters at 7 weeks of age. After a week of recovery, baseline measurements of blood pressure and albumin excretion were obtained while rats were fed a low salt (LS, 0.4% NaCl) diet. Rats were then switched to a high salt (HS, 4.0% NaCl) diet for 21 days, with continuous blood pressure measurements and urine collections every 7 days. On day 21, the rats were euthanized, and their kidneys were perfused and collected for immune cell analysis by flow cytometry. During the LS baseline period there was no significant difference observed in mean arterial pressure (MAP) between the CD4+ SS→CD247, CD8+ SS→CD247, or PBS→CD247 groups (113±1, 115±1, 114±1 mmHg; n=21, 10, 24, respectively). After three weeks of HS, rats receiving CD4+ T cells from the SS (CD4+ SS→CD247) demonstrated an amplified salt-sensitive hypertension (154±3 mmHg) and albuminuria (184±22 mg/day) compared to blood pressure (140±3 and 145±3 mmHg) and albuminuria (82±9 and 85±8 mg/day) in the CD8+ SS→CD247 or PBS→CD247 groups, respectively. Since the deletion of the p67phox subunit of NADPH oxidase 2 (NOX2) in adoptively transferred splenocytes attenuated Dahl SS hypertension and kidney damage, parallel studies examined the influence of deletion of p67phox in CD4+ (n=14) and CD8+ T cells (n=8). The adoptive transfer of either CD4+ or CD8+ T cells lacking functional NOX2 did not alter the LS or HS blood pressure or albuminuria when compared to the PBS control group. Finally, a flow cytometric analysis at the end of the experiment confirmed the absence of CD3+ T cells in the PBS→CD247 and documented the reconstitution of equal numbers of CD4+ cells in the blood and kidney of the rats receiving CD4+ cells with intact or deficient NOX2. Interestingly, no difference was observed in CD8+ T cells in the kidney and blood of rats receiving CD8+ cells with intact or deficient NOX2, but a significant number of CD4+ T cells were also observed in the SSCD247−/− rats receiving the purified CD8+ T cells. In summary, these studies demonstrate that CD4+ T cells amplify salt-sensitive hypertension and renal damage in the Dahl SS via a NOX2-dependent mechanism while CD8+ T cells do not alter disease phenotypes when compared to PBS control. GRANTS: HL161231, HL166458, Georgia Research Alliance. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Role of NADPH Oxidase 4 on Dry Eye Syndrome in Mice.

Objective: This study aims to investigate the effect of NADPH oxidase 4 (NOX4)-mediated inflammation on concanavalin A (ConA)-induced dry eye syndrome (DES) in mice. Methods: Thirty-six mice were randomly divided into Control, Model, no-load Control, and NOX4 interference group. Adenovirus was injected (10 μL) into the lacrimal glands of both eyes of mice in no-load Control group and NOX4 interference group. Four days after adenovirus injection, the Control group was injected with phosphate-buffered saline, and the other groups were injected with ConA (200 μg) in the lacrimal glands of mice to establish DES models. The tear secretion rate was estimated by phenol red thread test. Lissamine green eye staining was used to evaluate conjunctival damage. The corneal surface was observed by hematoxylin-eosin (HE) staining and scanning electron microscopy (SEM). The morphology and quantity of conjunctival epithelial cells and goblet cells were observed by Periodic acid-Schiff staining. The expression of NOX4, NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), interleukin-1β (IL-1β), and mucin 5 subtype AC (MUC5AC) was detected by immunohistochemistry. Results: Compared with the Control group, the Model group showed a significant decrease in tear secretion and an upregulation in microscopic image score. The HE staining and SEM showed corneal and conjunctiva damage in the Model group. The protein expression of NOX4, NLRP3, and IL-1β was upregulated, but MUC5AC was downregulated in the Model group. After interfering with NOX4, all these indicators were reversed. Conclusion: The pathological process of concanavalin A-induced DES appears to be related to NOX4.

PKC Inhibition Improves Human Penile Vascular Function and the NO/cGMP Pathway in Diabetic Erectile Dysfunction: The Role of NADPH Oxidase.

Erectile dysfunction (ED) is a frequent and difficult-to-treat condition in diabetic men. Protein kinase C (PKC) is involved in diabetes-related vascular and cavernosal alterations. We aimed to evaluate the role of PKC in endothelial dysfunction and NO/cGMP impairment associated with diabetic ED in the human corpus cavernosum (CC) and penile resistance arteries (PRAs) and the potential mechanisms involved. Functional responses were determined in the CC and PRAs in patients with non-diabetic ED and diabetic ED undergoing penile prosthesis insertion. PKC activator 12,13-phorbol-dibutyrate (PDBu) impaired endothelial relaxations and cGMP generation in response to acetylcholine in the CC from non-diabetic ED. PDBu also impaired responses to a PDE5 inhibitor, sildenafil, in non-diabetic ED patients. Conversely, a PKC inhibitor, GF109203X, improved endothelial, neurogenic, and PDE5-inhibitor-induced relaxations and cGMP generation only in the CC in diabetic ED patients. Endothelial and PDE5-inhibitor-induced vasodilations of PRAs were potentiated only in diabetes. Improvements in endothelial function in diabetes were also achieved with a specific inhibitor of the PKCβ2 isoform or an NADPH-oxidase inhibitor, apocynin, which prevented PDBu-induced impairment in non-diabetic patients. PKC inhibition counteracted NO/cGMP impairment and endothelial dysfunction in diabetes-related ED, potentially improving response to PDE5 inhibition.

The roles of NADPH oxidase and PKC pathways in the modulation of GLP-1 induced-vasorelaxation in diabetic rat aorta

A hormone of the incretin system known as glucagon-like peptide-1 (GLP-1) is important for a number of glucoregulatory functions. This study aimed to investigate the effect of inhibitors on the vasorelaxant response of GLP-1 in T1D rats. A single subcutaneous injection of 50 mg/kg of streptozotocin (STZ) was used to develop diabetes mellitus. Eighty aortic rings from twenty male albino rats were prepared. An Automatic Organ Bath was used. In our study, apocynin increased vascular response to GLP- 1 in the non-diabetic group with (Emax:72.40±0.350) and (pD2: -9.923±0.444). In induced diabetes, the NADPH oxidase inhibitor decreased GLP-1 vasodilatation property with (Emax; 68.91±2.002) and (pD2: -9.480±0.138). The results show that bisindolylmaleimide IX (RO31-8220) has an increased effect on GLP-1 vasodilation in non-diabetic groups with (Emax:88.45±38.18) and (pD2: -10.81±0.281). While in induced diabetic rat’s vascular relaxation of GLP-1 decreased with (Emax: 77.73±2.801) and (pD2: - 10.28±0.203). The data analysis demonstrated that rotenone with (Emax: 63.69±35.10) (pD2: - 9.612±0.246), and in diabetic rats with (Emax:69.98±22.94) and (pD2: -9.612±0.246). In our study oxypurinol with (Emax: 82.16±16.10) and (pD2: - 9.434±0.443), and in diabetic rats with (Emax: 58.03±8.350) and (pD2: -9.612±0.246). We concluded that inhibitors could increase the vasorelaxant response of GLP-1 in non-diabetic rats, while this vasorelaxant response of GLP-1 diminished in diabetic-induced rats.

NADPH oxidase 4 (NOX4) as a biomarker and therapeutic target in neurodegenerative diseases.

Diseases like Alzheimer's and Parkinson's diseases are defined by inflammation and the damage neurons undergo due to oxidative stress. A primary reactive oxygen species contributor in the central nervous system, NADPH oxidase 4, is viewed as a potential therapeutic touchstone and indicative marker for these ailments. This in-depth review brings to light distinct features of NADPH oxidase 4, responsible for generating superoxide and hydrogen peroxide, emphasizing its pivotal role in activating glial cells, inciting inflammation, and disturbing neuronal functions. Significantly, malfunctioning astrocytes, forming the majority in the central nervous system, play a part in advancing neurodegenerative diseases, due to their reactive oxygen species and inflammatory factor secretion. Our study reveals that aiming at NADPH oxidase 4 within astrocytes could be a viable treatment pathway to reduce oxidative damage and halt neurodegenerative processes. Adjusting NADPH oxidase 4 activity might influence the neuroinflammatory cytokine levels, including myeloperoxidase and osteopontin, offering better prospects for conditions like Alzheimer's disease and Parkinson's disease. This review sheds light on the role of NADPH oxidase 4 in neural degeneration, emphasizing its drug target potential, and paving the path for novel treatment approaches to combat these severe conditions.

Angiotensin II acts through Rac1 to upregulate pendrin: role of NADPH oxidase.

Angiotensin II increases apical plasma membrane pendrin abundance and function. This study explored the role of the small GTPase Rac1 in the regulation of pendrin by angiotensin II. To do this, we generated intercalated cell (IC) Rac1 knockout mice and observed that IC Rac1 gene ablation reduced the relative abundance of pendrin in the apical region of intercalated cells in angiotensin II-treated mice but not vehicle-treated mice. Similarly, the Rac1 inhibitor EHT 1864 reduced apical pendrin abundance in angiotensin II-treated mice, through a mechanism that does not require aldosterone. This IC angiotensin II-Rac1 signaling cascade modulates pendrin subcellular distribution without significantly changing actin organization. However, NADPH oxidase inhibition with APX 115 reduced apical pendrin abundance in vivo in angiotensin II-treated mice. Moreover, superoxide dismutase mimetics reduced Cl- absorption in angiotensin II-treated cortical collecting ducts perfused in vitro. Since Rac1 is an NADPH subunit, Rac1 may modulate pendrin through NADPH oxidase-mediated reactive oxygen species production. Because pendrin gene ablation blunts the pressor response to angiotensin II, we asked if pendrin blunts the angiotensin II-induced increase in kidney superoxide. Although kidney superoxide was similar in vehicle-treated wild-type and pendrin knockout mice, it was lower in angiotensin II-treated pendrin-null kidneys than in wild-type kidneys. We conclude that angiotensin II acts through Rac1, independently of aldosterone, to increase apical pendrin abundance. Rac1 may stimulate pendrin, at least partly, through NADPH oxidase. This increase in pendrin abundance contributes to the increment in blood pressure and kidney superoxide content seen in angiotensin II-treated mice.NEW & NOTEWORTHY This study defines a new signaling mechanism by which angiotensin II modulates oxidative stress and blood pressure.

Ang-(1–7)/Mas axis ameliorates bleomycin-induced pulmonary fibrosis in mice via restoration of Nox4-Nrf2 redox homeostasis

Pulmonary fibrosis (PF) is a chronic, progressive interstitial lung disease characterized by diffuse alveolar inflammation, fibroblast differentiation, and the excessive deposition of extracellular matrix. During the progression of PF, redox imbalance caused by excessive reactive oxygen species (ROS) production can result in further destruction of lung tissue. At present, data on the role of NADPH oxidase-4 (Nox4)-nuclear factor erythroid 2-related factor 2 (Nrf2) redox imbalance in PF are limited. The angiotensin (1–7) [Ang-(1–7)]/Mas axis is a protective axis in the renin-angiotensin system (RAS) that exerts antifibrotic effects. Therefore, this study aimed to investigate the role of the Ang-(1–7)/Mas axis in PF and to explore its mechanism in depth. The results revealed that the Ang-(1–7)/Mas axis inhibited TGF-β1-induced lung fibroblast differentiation, inflammation and fibrosis in bleomycin (BLM)-treated lung tissue. A mechanistic study suggested that the Ang-(1–7)/Mas axis may restore Nox4-Nrf2 redox homeostasis by upregulating the level of p62, reducing oxidative stress and the inflammatory response and thus delaying the progression of lung fibrosis. This study provides a theoretical basis for exploring the mechanisms of PF and therapeutic targets for PF.

Role of NADPH Oxidase 4 in Corneal Endothelial Cells Is Mediated by Endoplasmic Reticulum Stress and Autophagy.

Human corneal-endothelial cells (hCEnCs) are located on the inner layer of the cornea. Injury to CEnCs leads to permanent corneal edema, requiring corneal transplantation. NADPH oxidase 4 (NOX4) has been reported to be implicated in the pathogenesis of CEnCs diseases. Thus, we investigated the role of NOX4 in CEnCs in this study. In an animal study, siRNA for NOX4 (siNOX4) or plasmid for NOX4 (pNOX4) was introduced into the corneal endothelium of rats by electroporation, using a square-wave electroporator (ECM830, Havard apparatus) to decrease or increase the expression of NOX4, respectively, and the rat corneas were cryoinjured through contact with a metal rod of 3 mm diameter frozen in liquid nitrogen for 10 min. The immunofluorescence staining of NOX4 and 8-OHdG showed that the levels of NOX4 and 8-OHdG were decreased in the siNOX4 group compared to the siControl, and increased in the pNOX4 group compared to the pControl at one week after treatment. Without cryoinjury, corneal opacity was more severe, and the density of CEnCs was lower, in pNOX4-treated rats compared to pControl. After cryoinjury, the corneas were more transparent, and the CEnC density was higher, in siNOX4-treated rats. The hCEnCs were cultured and transfected with siNOX4 and pNOX4. The silencing of NOX4 in hCEnCs resulted in a normal cell shape, higher viability, and higher proliferation rate than those transfected with the siControl, while NOX4 overexpression had the opposite effect. NOX4 overexpression increased the number of senescent cells and intracellular oxidative stress levels. NOX4 overexpression increased ATF4 and ATF6 levels, and nuclear translocation of XBP-1, which is the endoplasmic reticulum (ER) stress marker, while the silencing of NOX4 had the opposite effect. Additionally, the mitochondrial membrane potential was hyperpolarized by the silencing of NOX4, and depolarized by NOX4 overexpression. The LC3II levels, a marker of autophagy, were decreased by the silencing of NOX4, and increased by NOX4 overexpression. In conclusion, NOX4 plays a pivotal role in the wound-healing and senescence of hCEnCs, by modulating oxidative stress, ER stress, and autophagy. The regulation of NOX4 may be a potential therapeutic strategy for regulating the homeostasis of CEnCs, and treating corneal-endothelial diseases.

The Expression and Role of NADPH Oxidase 2 in Colon Cancer.

Recent studies have reported that nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are expressed in various cancers and play important roles in tumor progression. However, no studies have examined the expression and role of NOX2 in colon cancer. The aim of this study is to investigate the pathophysiological roles of NOX2 in colon cancer patients and cell lines. One-hundred and sixteen primary colon cancer samples of patients who underwent radical resection for locally advanced colon cancer were used for immunohistochemistry of NOX2 protein. The relationship between NOX2 expression and clinicopathological factors was assessed and the prognostic significance of NOX2 expression was evaluated in colon cancer patients. NOX2 siRNA transfection experiments were performed using two colon cancer cell lines (HCT116 and RKO) to analyze the impact of NOX2 expression on cellular physiological functions. The expression of NOX2 protein in noncancerous tissue was scarcely observed, and 45 samples (38.8%) showed positively stained NOX2 expression in cancer tissue. There were no clinicopathological factors significantly associated with NOX2 expression. The 5-year recurrence-free survival rate of the NOX2 positive group was significantly lower than that of the NOX2 negative group (61.1% vs. 79.3%, p=0.029). NOX2 depletion significantly inhibited cell proliferation with G1 arrest, and motility in the two cell lines. NOX2 expression level has a close association with the prognosis of colon cancer patients and physiological functions of colon cancer cells. NOX2 may be a useful prognostic biomarker for colon cancer patients.

Two ways to die: Species dependent PCD modes in grapevine cells

Programmed cell death (PCD) is considered as a hallmark of strain-specific immunity. In contrast, generic basal immunity is thought to act without PCD. This classical bifurcation has been questioned during recent years. Likewise, the role of jasmonate signalling for these two modes of innate immunity has remained ambiguous. We have addressed both questions using two closely related grapevine cell lines (V. rupestris, V. vinifera cv. ‘Pinot Noir’) that contrast in their cell-death response to the bacterial elicitor harpin and the hormonal trigger methyl jasmonate (MeJA). We follow different cellular (loss of membrane integrity, mortality), molecular (induction of transcripts for phytoalexin synthesis and for metacaspases), as well as metabolic (sphingolipid profiles) responses to the two triggers in the two cell lines. The role of NADPH oxidases and induction of transcripts for the class-II metacaspases MC5 differ qualitatively between the two cell lines. We tested a possible role of sphingolipid metabolism but can rule this out. We propose a model, where V. rupestris, originating from co-evolution with several biotrophic pathogens, readily activates a hypersensitive cell death in response to harpin, while the context of MeJA-induced cell death in ‘Pinot Noir’ might not be related to immunity at all. We propose that the underlying signalling is modular, recruiting metacaspases differently depending on upstream signalling.

Role of NADPH Oxidases in Renal Aging

Introduction: Aging of the kidney is associated with complex molecular, histological, and functional changes. Although the aging process itself does not induce renal damage, underlying disease such as diabetes mellitus can aggravate kidney injury during aging. Although oxidative stress is considered an important mediator in age-related renal fibrosis, it is unclear how oxidative stress increases during normal and diabetic aging. Methods: In this study, we investigated molecular changes in the kidney in normal and diabetic aging mice. C57BL/6 mice were studied at 2, 12, and 24 months of age, and leptin receptor-deficient db/db mice were studied at 8, 12, 16, 20, 24, and 38 weeks of age. We measured renal functional parameters, fibrotic and inflammatory markers, and oxidative stress markers at all the above time points. Results: Both nondiabetic and diabetic mice exhibited progressive microalbuminuria during their lifespan. Interestingly, both diabetic aging and normal aging mice showed progressive increases in oxidative stress markers such as plasma and urinary 8-isoprostane, as well as renal lipid hydroperoxide content. In renal tissues, proinflammatory and profibrotic molecules were significantly upregulated in an age-dependent manner. Expression of three NADPH oxidase (Nox) isoforms, namely, Nox1, Nox2, and Nox4, was significantly increased during aging. Compared with normal aging mice, diabetic db/db mice demonstrated more dramatic changes during aging process. Conclusions: Our findings suggest that NADPH oxidases play an important role in the aging kidney under both normal and diabetic conditions. Targeting of these oxidases might be a new promising therapy to treat issues associated with aging kidneys.

New Insights into How Melatonin Ameliorates Bisphenol A-Induced Colon Damage: Inhibition of NADPH Oxidase.

Bisphenol A (BPA) is an endocrine disruptor, widely employed, and detected in many consumer products and food items. Oral intake poses a great threat to intestinal health. Melatonin (MT) stands out as an endogenous, dietary, and therapeutic molecule with potent antioxidant capacity. To explore the protective effect of MT against BPA-induced colon damage and the role of NADPH oxidase (NOX) in this process, we established mice and colonic epithelial cell (NCM460) models of BPA exposure and treated with MT. In vitro and in vivo results showed that MT ameliorated BPA-induced oxidative stress, DNA damage, and the G2/M cell cycle arrest. MT also downregulated the expression of NOX family-related genes, reversed the inhibition of the base excision repair (BER) pathway, promoted the activation of non-homologous end-joining (NHEJ) pathway, and suppressed the mRNA and protein expression of ATM, Chk1/2, and p53. Diphenyleneiodonium chloride (DPI), a NOX-specific inhibitor, also attenuated the toxic effects of BPA on NCM460 cells. Furthermore, molecular docking revealed that MT could bind to NOX. Conclusively, our finding suggested that MT can ameliorate BPA-induced colonic DNA damage by scavenging NOX-derived ROS, which further attenuates G2/M cell cycle arrest dependent on the ATM-Chk1/2-p53 axis.

Low dose radiation upregulates Ras/p38 and NADPH oxidase in mouse colon two months after exposure.

Exposure to ionizing is known to cause persistent cellular oxidative stress and NADPH oxidase (Nox) is a major source of cellular oxidant production. Chronic oxidative stress is associated with a myriad of human diseases including gastrointestinal cancer. However, the roles of NADPH oxidase in relation of long-term oxidative stress in colonic epithelial cells after radiation exposure are yet to be clearly established. Mice were exposed either to sham or to 0.5Gy γ radiation, and NADPH oxidase, oxidative stress, and related signaling pathways were assessed in colon samples 60days after exposure. Radiation exposure led to increased expression of colon-specific NADPH oxidase isoform, Nox1, as well as upregulation of its modifiers such as Noxa1 and Noxo1 at the mRNA and protein level. Co-immunoprecipitation experiments showed enhanced binding of Rac1, an activator of NADPH oxidase, to Nox1. Increased 4-hydroxynonenal, 8-oxo-dG, and γH2AX along with higher protein carbonylation levels suggest increased oxidative stress after radiation exposure. Immunoblot analysis demonstrates upregulation of Ras/p38 pathway, and Gata6 and Hif1α after irradiation. Increased staining of β-catenin, cyclinD1, and Ki67 after radiation was also observed. In summary, data show that exposure to a low dose of radiation was associated with upregulation of NADPH oxidase and its modifiers along with increased Ras/p38/Gata6 signaling in colon. When considered along with oxidative damage and proliferative markers, our observations suggest that the NADPH oxidase pathway could be playing a critical role in propagating long-term oxidative stress after radiation with implications for colon carcinogenesis.

Recent topics and advanced therapies in chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by the inability of phagocytes to produce reactive oxygen species (ROS) owing to a defect in any of the five components (CYBB/gp91phox, CYBA/p22phox, NCF1/p47phox, NCF2/p67phox, and NCF4/p40phox) and a concomitant regulatory component of Rac1/2 and CYBC1/Eros of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Patients with CGD are at an increased risk of life-threatening infections caused by catalase-positive bacteria and fungi and of inflammatory complications such as CGD colitis. Antimicrobial and azole antifungal prophylaxes have considerably reduced the incidence and severity of bacterial and improved fungal infections and overall survival. CGD studies have revealed the precise epidemiology and role of NADPH oxidase in innate immunity which has led to a new understanding of the importance of phagocyte oxygen metabolism in various host-defense systems and the fields leading to cell death processes. Moreover, ROS plays central roles in the determination of cell fate as secondary messengers and by modifying of various signaling molecules. According to this increasing knowledge about the effects of ROS on the inflammasomal system, immunomodulatory treatments, such as IFN-γ and anti-IL-1 antibodies, have been established. This review covers the current topics in CGD and the relationship between ROS and ROS-mediated pathophysiological phenomena. In addition to the shirt summary of hematopoietic stem cell transplantation and gene therapy, we introduce a novel ROS-producing enzyme replacement therapy using PEG-fDAO to compensate for NADPH oxidase deficiency.

Role of NADPH Oxidases in Blood-Brain Barrier Disruption and Ischemic Stroke.

NADPH oxidases (Nox) are one of the main sources of reactive oxygen species (ROS) in the central nervous system (CNS). While these enzymes have been shown to be involved in physiological regulation of cerebral vascular tone, excessive ROS produced by Nox1-5 play a critical role in blood–brain barrier (BBB) dysfunction in numerous neuropathologies. Nox-derived ROS have been implicated in mediating matrix metalloprotease (MMP) activation, downregulation of junctional complexes between adjacent brain endothelial cells and brain endothelial cell apoptosis, leading to brain microvascular endothelial barrier dysfunction and consequently, increases in BBB permeability. In this review, we will highlight recent findings on the role played by these enzymes in BBB disruption induced by ischemic stroke.

Role of NADPH oxidase 4 (NOX4) in resistance to metabolic iodine-131 radiotherapy in metastatic thyroid tumors carrying the BRAFV600E mutation

Role of NADPH oxidase 4 (NOX4) in resistance to metabolic iodine-131 radiotherapy in metastatic thyroid tumors carrying the BRAFV600E mutation

The role of NADPH oxidase 1 in alcohol-induced oxidative stress injury of intestinal epithelial cells

Alcohol-mediated reactive oxygen species (ROS) play a vital role in intestinal barrier injury. However, the mechanism of ROS accumulation in enterocytes needs to be explored further. In our study, we found that chronic–binge ethanol-fed mice had increased levels of gut oxidative stress and high intestinal permeability. The transcription profiles of the colonic epithelial cells showed that the level of NADPH oxidase 1 (NOX1) was significantly elevated in alcohol-exposed mice compared with isocaloric-exposed mice. In vitro, NOX1 silencing alleviated ROS accumulation and the apoptosis of human colonic epithelial cells (NCM460), while NOX1 overexpression accelerated oxidative stress injury of NCM460 cells. Propionic acid was reduced in the gut of chronic–binge ethanol-fed mice, compared with isocaloric-fed mice, as observed through untargeted metabolomic analysis. Supplementation with propionate relieved ethanol-induced liver and intestinal barrier injuries and reduced the level of ROS accumulation and apoptosis of ethanol-induced colonic epithelial cells. Propionate alleviating NOX1 induced ROS injury of colonic epithelial cells, independent of G protein-coupled receptors. Propionate significantly inhibited histone deacetylase 2 (HDAC2) expressions both in ethanol-exposed colonic epithelial cells and TNF-α-treated NCM460. Chromatin immunoprecipitation (ChIP) assays showed that propionate suppressed the NOX1 expression by regulating histone acetylation in the gene promoter region. In conclusion, NOX1 induces oxidative stress injury of colonic epithelial cells in alcohol-related liver disease. Propionate, which can act as an endogenous HDAC2 inhibitor, can decrease levels of apoptosis of intestinal epithelial cells caused by oxidative stress.Graphical