NADPH Oxidase Activity Research Articles

The Erythrocyte–ROS Axis in Thrombosis and Hemostasis

Abstract Thrombosis and hemostasis are critical processes that maintain vascular integrity, yet imbalances can lead to life-threatening cardiovascular events. Traditionally, erythrocytes were considered passive bystanders in coagulation, but emerging evidence highlights their active role in thrombogenesis, particularly through redox biology. Erythrocytes generate reactive oxygen and nitrogen species (RONS) via Hb autoxidation, NADPH oxidase activation, and external uptake from other blood components. This oxidative environment induces structural and functional modifications, including increased rigidity, phosphatidylserine exposure, microvesicle release, and enhanced adhesion to endothelial cells and platelets, all contributing to a prothrombotic phenotype. Hemorheological alterations such as increased aggregation and decreased deformability further exacerbate blood stasis and thrombus formation. Oxidative stress also accelerates hemolysis, releasing free Hb and heme, which trigger inflammatory responses and endothelial dysfunction, further amplifying thrombogenic potential. Additionally, erythrocyte-derived microvesicles act as carriers of procoagulant factors, enhancing thrombin generation and fibrin network formation. These mechanisms underscore the erythrocyte–ROS axis as a crucial determinant of thrombosis. Despite these insights, the full scope of erythrocyte-mediated redox signaling in thrombotic processes remains incompletely understood. This review discusses the multifaceted impact of erythrocyte oxidative stress on thrombosis and hemostasis, exploring its implications in cardiovascular diseases, metabolic disorders, and hematological conditions. Understanding these pathways may lead to novel therapeutic approaches targeting erythrocyte redox homeostasis to mitigate thrombotic risk and improve patient outcomes.

Prenatal modulation of NADPH-oxidase reverses the deranged GABA switch and rescues behavioral deficits in valproate ASD rat model.

Impaired depolarizing-to-hyperpolarizing (D/H) switch of gamma-aminobutyric acid (GABA) is reported during brain development in rodent valproate-model of autism spectrum disorder (VPA-ASD). We hypothesize that this impairment triggers NADPH oxidases (NOXs)-induced reactive oxygen species (ROS) overproduction. Here, we followed the impact of prenatal exposure to VPA on the synaptic protein expression of potassium chloride cotransporter 2 (KCC2), sodium potassium chloride cotransporter 1 (NKCC1) and, in brains of male and female Wistar rats during infantile (P15), juvenile (P30) and adult (P60) stages. We also assessed alterations in synaptic NOX isoforms 2 and 4 (NOX2 and NOX4) activities and expressions in developing rat brains. Our findings revealed a significant reduction in KCC2 expression and a concomitant increase in NOX activity and NOX4 expression in synaptosomes of VPA-exposed rats, particularly at P15 and P30. Prenatal exposure to shikonin, (10 mg/kg/day, intraperitoneal (i.p.) into pregnant dam, daily from G12.5 until birth), ameliorated these effects by reducing synaptic protein expression of NOX4, generally quenched synaptic NOX activity and enhanced synaptic protein expression of KCC2. Indeed, shikonin reversed VPA-induced sociability deficits in ASD rats. These results suggest that targeting the NOX-ROS pathway may be a potential therapeutic strategy for ASD.

Short-Term Inhibition of NOX2 Prevents the Development of Aβ-Induced Pathology in Mice

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by the formation of neurotoxic beta-amyloid (Aβ) oligomers in the central nervous system. One of the earliest pathological effects of Aβ is the induction of oxidative stress in brain tissue, mediated by NADPH oxidase 2 (NOX2). This study aimed to determine whether short-term inhibition of NOX2 could disrupt the pathological cascade and prevent the development of Aβ-induced pathology. We demonstrated that suppressing NOX2 activity by GSK2795039 during the first three days after intracerebral Aβ administration prevented the development of the pathological process in mice. Two weeks after the induction of Aβ pathology, animals treated with GSK2795039 showed no neuropsychiatric-like behavioral changes, which correlated with the absence of chronic oxidative damage in brain tissue. Moreover, GSK2795039 prevented microglial activation and reduced microglia-associated neuroinflammation. These findings indicate that short-term NOX2 inhibition effectively suppresses the development of Aβ-induced pathology, suggesting that NOX2 is a potential target for treatment and prevention of AD pathology.

NADPH oxidase-2 inhibitor apocynin attenuates high-fat diet-induced kidney and bladder injury

Objective: This study aimed to evaluate the effects of NADPH oxidase-2 (NOX-2) inhibitor apocynin (APC) on high-fat diet (HFD)- induced renal and bladder injury. Materials and Methods: Wistar albino rats were divided into 4 groups: Control, HFD, HFD+dimetyl sulfoxide (DMSO), and HFD+APC. Rats in HFD, HFD+DMSO, and HFD+APC groups were fed with HFD for sixteen weeks. In the last 4 weeks of the experiment, either DMSO or APC (25 mg/kg, dissolved in DMSO) was applied to the HFD+DMSO or HFD+APC groups. Lipid profiles and leptin values were measured in blood serum. Renal and bladder oxidant/antioxidant parameters, histological changes in the tissues, NOX-2-, nuclear factor kappa B (NF-ĸB)-immunopositive and apoptotic cells were evaluated. Results: At the end of the experiment, leptin, cholesterol, and triglyceride levels were higher and high-density lipoprotein levels were lower in the HFD and HFD+DMSO groups compared to controls. In these experimental groups, an increase in malondialdehyde, 8-hydroxy-deoxyguanosine and myeloperoxidase levels and a decrease in glutathione levels, as well as an increase in collagen, NOX-2 – and NFĸ-B-immunopositive and apoptotic cells were found. Also, a deterioration in kidney and bladder morphology was observed. All these biochemical and histopathological findings improved in the HFD+APC group. Conclusion: High-fed diet causes renal and bladder injury by increasing NOX-2 activity and inflammation via oxidative stress. APC might alleviate tissue injury by inhibiting oxidative stress.

Effect of the probiotic Escherichia coli Nissle 1917 on serum levels of NADPH oxidase-2 and lipopolysaccharide in patients with Alzheimer's disease.

BackgroundIntestinal bacteria-derived molecules, such as lipopolysaccharide (LPS) produced by Gram-negative bacteria, can translocate into the bloodstream through the gut wall, contributing to inflammation and neurodegeneration via oxidative stress mechanisms. NADPH oxidase-2 activation and superoxide anion production play a key role in this process, particularly in conditions like Alzheimer's disease (AD), where gut permeability is often altered. This study hypothesized that modulating gut microbiota with the probiotic Escherichia coli Nissle 1917 (ECN) could mitigate LPS translocation and its associated inflammatory effects.ObjectiveTo evaluate the effect of daily ECN administration on serum LPS levels in elderly AD patients.MethodsA randomized, double-blind, placebo-controlled trial was conducted with 40 mild AD patients, with 39 completing the study (20 ECN, 19 placebo). Participants received ECN (2.5-25 × 10^9 CFU/capsule) or placebo for six weeks. The serum activity of soluble NOX2-dp (sNOX2-dp), hydrogen peroxide (H2O2) production, tumor necrosis factor (TNF)-α levels and LPS was evaluated, while serum zonulin levels were measured to assess gut permeability.ResultsThe ECN group showed significant reductions in sNOX2-dp (-21%), H2O2 (-27%), TNF-α (-18%), LPS (-15%), and zonulin (-35%), along with improved Mini-Mental State Examination (MMSE) scores. No significant changes were seen in the placebo group. Mixed ANOVA showed significant time-by-treatment interactions for zonulin (p = 0.04) and MMSE (p < 0.001). Changes in LPS correlated with changes in zonulin (Rs = 0.408, p = 0.011).ConclusionsECN may strengthen gut barrier function, reduce endotoxemia, and attenuate inflammation in AD, though larger studies are needed to confirm these findings.

Synthetic and Natural Red Food Dyes Affect Oxidative Metabolism and the Redox State in the Nauplii of Brine Shrimp Artemia franciscana

The food industry widely uses dyes from animal and plant sources, but their discharge into water bodies can harm aquatic animals. Red food dyes increase reactive oxygen species (ROS) production, disrupting redox homeostasis in Artemia franciscana nauplii, although the underlying mechanisms are unclear. In this study, we exposed Artemia franciscana cysts for 48 h to three different red dyes: E124 (synthetic), E120 (animal-based) or Vegan red (plant-based) and evaluated the oxidative metabolism and redox status in the hatched nauplii. Only E120 and VEG increased oxygen consumption. E124 and VEG increased mitochondrial Complex I activity, while all dyes enhanced the activity of Complex III. The levels of reactive oxygen species (ROS) and NADPH oxidase activity were increased by all red dyes. E120 and E124 increased antioxidant enzyme activity to a greater extent than VEG. Additionally, only E120 and E124 increased total antioxidant capacity. Nevertheless, E124 exposure induced redox imbalance (increased lipid and protein oxidative damage). Our data, as a whole, allow us to conclude that red dyes can influence the oxidative capacity and redox state of Artemia franciscana nauplii with more harmful effects in the presence of E124, thus drawing attention to their potentially severe influence on aquatic life.

Level of reactive oxygen species production in peripheral blood monocytes in patients with Graves' disease after radioiodine therapy

Autoimmune diseases such as Graves' disease are complex pathologies that often require intensive and long-term treatment. However, the mechanisms contributing to the development and maintenance of this pathology are still not fully understood. Understanding the role of the innate immune response, especially in the context of monocytes, in the development of Graves' disease remains a poorly understood aspect. To study the level of ROS production in monocytes in patients with Graves' disease after RAI to identify the level of activation of the macrophage-monocyte system. The hormonal status and monocyte activity were analyzed before and 1, 3 and 6 months after RAI. The level of ROS was determined using spontaneous and luminol- and luceginin-derived chemiluminescence. The study included 48 patients with Graves' disease, aged from 18 to 65 years. In patients with Graves' disease, a decrease in the intensity of free radical processes in monocytes was detected compared to the control group. These changes were observed both before and after RAI. It has been shown that changes in ROS production are independent of thyroid function and antibody levels. The changes indicate the potential immunosuppressive effects of radionuclide treatment and its effect on monocyte NADPH oxidase activity. A decrease in the production of secondary ROS in monocytes was also noted, which may indicate a decrease in the activation of monocytes during antigenic stimulation and inhibition of autoimmune processes. Reduced metabolic activity of monocytes and low levels of ROS synthesis correlate with inhibition of the autoimmune process and decreased activation of the macrophage-monocyte system. The study confirms the importance of the role of monocytes in the ROS production system and their influence on the autoimmune process in Graves' disease. These results may have clinical significance and contribute to the development of new immunotropic strategies for the treatment of this disease.

An essential role for the Hv1 voltage-gated proton channel in Pseudomonas aeruginosa corneal infection.

Assembly of NADPH oxidase 2 (NOX2) proteins in neutrophils plays an essential role in controlling microbial infections by producing high levels of reactive oxygen species (ROS). We reported that neutrophils and NOX2 are required to control P. aeruginosa in a clinically relevant murine model of blinding corneal infection. Given the published role for the voltage-gated proton channel Hv1 in sustaining NOX2 production, we examined the role of Hv1 in P. aeruginosa keratitis. Hvcn1 -/- mice exhibited an impaired ability to kill bacteria that was associated with reduced neutrophil recruitment to infected corneas. Unlike earlier reports, we found that Hvcn1 -/- neutrophils produce more rather than less ROS compared with control neutrophils infected with P. aeruginosa or stimulated with PMA or zymosan. Collectively, we demonstrate that Hv1 has an important role in control of bacterial growth by neutrophils in bacterial infection beyond the regulation of ROS production.

Integrative multi-transcriptomic analysis uncovers core genes and potential defense mechanisms in rice-Magnoporthe oryzae interaction.

Multiple transcriptomic comprehensive analyses highlight key genes and cast new light on multifaceted pathways that may be important arenas in rice innate immunity against Magnoporthe oryzae blast disease. Magnaporthe oryzae (MOR) poses a significant threat to rice production worldwide. However, defense mechanisms in rice against MOR remain inadequately defined. In this study, a multi-transcriptomic integrative analysis on 441 samples from diverse microarrays and RNA-seq sets was conducted to reveal critical factors inrice defense against MOR infection. A robust pattern of 3534 upregulated genes and 2920 repressed genes was commonly identified across all MOR-infected arrays and RNA-seq profiles. Interestingly, enrichment analysis revealed a consistent triggering of endoplasmic reticulum (ER)-related mechanisms and citric acid cycle (TCA) influx in rice response to MOR infection across all the transcriptome profiles, suggesting their critical role in modulating rice immunity against the pathogen. By contrast, chloroplast and photosynthesis pathways were frequently repressed across all the profiles. Among ER-related mechanisms, the phagosome pathway involved in the activation of NADPH oxidase was highly triggered in early response to MOR infection. Moreover, WGCNA analysis highlighted four key co-expressed gene modules and 80 significant hub genes associated with MOR infection. Among the core genes, Sec61 gene involved in the ER-translocation process was identified along with OsMFP (peroxisomal oxidation gene) and OSAHH gene (involved in cyclic-trans-methylation). Furthermore, MPK6, WRKY24, NUP35, and NPR1 genes were observed as core co-expressed genes, suggesting their significance in regulating rice immunity against MOR. Our findings elucidate key genes and multifaceted mechanisms in rice-MOR interaction, proposing new informative clues that can be exploited to improve rice resistance against blast disease.

Alleviation of Accelerated Diabetic Atherogenesis in STZ-treated apoE/NOX1 DKO Mice, Endothelial-specific DHFR Transgenic Mice, and by Folic Acid

We and others have previously shown that uncoupling of endothelial nitric oxide synthase (eNOS) induces oxidative stress in diabetes, contributing to endothelial dysfunction. Activation of NADPH oxidase (NOX) isoform NOX1 by angiotensin II (Ang II) triggers eNOS uncoupling via deficiency in dihydrofolate reductase (DHFR) in streptozotocin (STZ)-induced type 1 diabetic mice. Presently, we investigated whether accelerated atherosclerosis is attenuated in apoE/NOX1 double knockout, and whether mice overexpressing DHFR in the endothelium (tg-EC-DHFR, generated in house) recouples eNOS to alleviate diabetic atherogenesis. At baseline, endothelial-specific DHFR overexpression recoupled eNOS and improved vasorelaxation in the aortas and mesenteric arteries of STZ-induced diabetic mice. Accelerated atherogenesis in STZ/high-fat diet (HFD) treated apoE -/- mice was markedly abrogated in tg-EC-DHFR background, establishing an important role of endothelial DHFR in maintaining vascular function and protecting from diabetic atherogenesis. Moreover, by crossing apoE -/- with NOX1 null mice (NOX1 -/y ), we found that NOX1 deletion markedly diminished atherosclerotic lesion formation in HFD+STZ-treated apoE -/- /NOX1 -/y mice, indicating that NOX1 lies upstream of eNOS uncoupling in facilitating diabetic atherogenesis. Oral administration with folic acid (FA), shown to upregulate DHFR, robustly attnuated atherosclerotic lesion formation in HFD+STZ-treated apoE -/- mice similarly to NOX1 deletion. Taken together, our data for the first time demonstrate that endothelial DHFR plays an important role in the preservation of endothelial function and inhibition of atherosclerosis in diabetes, deficiency of which consequent to NOX1 activation mediates eNOS uncoupling driven lesion formation. Strategies targeting recoupled eNOS prove to be robust treatment options for diabetic endothelial dysfunction and atherogenesis. NHLBI This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Alleviation of accelerated diabetic atherogenesis in STZ-treated apoE/NOX1 DKO mice, apoE-/-/tg-EC-DHFR mice, and by folic acid.

Alleviation of accelerated diabetic atherogenesis in STZ-treated apoE/NOX1 DKO mice, apoE-/-/tg-EC-DHFR mice, and by folic acid.

The brine shrimp Artemia franciscana as a model for astrobiological studies: Physiological adaptations to Mars-like atmospheric pressure conditions.

The brine shrimp Artemia franciscana as a model for astrobiological studies: Physiological adaptations to Mars-like atmospheric pressure conditions.

Human endogenous retrovirus W family envelope protein (ERVWE1) regulates macroautophagy activation and micromitophagy inhibition via NOXA1 in schizophrenia.

Human endogenous retrovirus W family envelope protein (ERVWE1) regulates macroautophagy activation and micromitophagy inhibition via NOXA1 in schizophrenia.

Non-Infectious Complications of Chronic Granulomatous Disease: Knowledge Gaps & Novel Treatment Considerations.

Non-Infectious Complications of Chronic Granulomatous Disease: Knowledge Gaps & Novel Treatment Considerations.

Anoxia tolerance in isolated neurons from the Western painted turtle: insights from mitochondrial energetics

The Western painted turtle ( Chrysemys picta bellii ) is the only known tetrapod to survive anoxia for more than 170 days at 3°C. Among the most important mechanisms of survival in the turtle brain are spike and channel arrest, which greatly decreases ATP consumption and neuronal activity via mitochondrial suppression of ROS generation and calcium release. In mammalian brain, however, oxygen deprivation leads to excitotoxicity and cell death within minutes. Comparatively, reptiles have lower mitochondrial density and proton leak resulting in tighter oxygen coupling. Additionally, previous research in cortical sheets has shown mild mitochondrial membrane potential (ΔΨm) depolarization preserving the proton electrochemical gradient and avoiding membrane collapse along with inhibition of mitochondrial ROS signaling GABA release suppressing electrical activity. Turtles have also been shown to have a well-developed antioxidant system. Lastly, we are unaware of studies measuring changes in NAD(P)H during anoxia, although it is expected that the NADH/NAD+ ratio will be maintained to prevent ROS formation. Using isolated turtle cortical neurons, we tested the hypothesis that anoxia would (1) slightly depolarize ΔΨm, (2) NAD(P)H pool would increase, and (3) ROS production will be limited. Neurons were dissociated from the cerebrocortex using enzymatic digestion and mechanical trituration and cultured for up to 7 days on glass coverslips. Rhodamine-123 was used to measure ΔΨm, NAD(P)H autofluorescence was used to measure redox state changes and glutathione peroxidase (GPX) antioxidant responses, NAD(P)H autofluorescence, and CM-H2DCFDA was used to measure ROS production. During anoxia, Ψm hyperpolarized, indicating dysregulation of ion exchangers and reversal of ETC, while NAD(P)H decreased and was reversed by NADPH-oxidase (NOX) inhibition with apocynin. NADPH acts as a substrate for NOX to produce ROS in addition to being a substrate for antioxidant systems. Surprisingly, ROS production only showed a small increase during reoxygenation, but not during normoxia-anoxia transition indicating that, similarly to previous cortical slices measurements, isolated painted turtle neurons avoid excessive ROS production. Control experiments with pyrogallol showed a large increase in ROS. Upon inhibition of glutathione reductase (GR) enzyme, NAD(P)H levels increased both during normoxia and anoxia, indicating that GPX is a constitutive process in painted turtle neurons and that other antioxidant systems can compensate for the loss of GR. All together these findings indicate: 1) constitutive activities of GR, in conjunction with other antioxidant systems, are adequate to prevent anoxia-induced increases in ROS, 2) ΔΨm and cellular redox state have no bearing on ROS production in turtle neurons, and 3) there is some level of NADPH-oxidase activity during anoxia, but it is unclear whether that activity is induced, or if it is constitutive. National Sciences Foundation[1253939 to D.W.]; and the Saint Louis University President’s Research Fund [to D.W.] This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Red light induced seed germination and seedling growth by modulating antioxidant defense system, Rubisco, and NADPH oxidase activities in Capsicum frutescens

In this study, the impact of light-emitting diodes (LEDs) in different spectrums was investigated on the seed germination and post-germinative performance of Capsicum frutescens seedlings. The seeds were exposed to different LED lights (full spectrum, white, red, blue, and red-blue) for 0, 1, 2, and 4 h (h). The seeds were placed for a week in darkness to investigate germination, and then the growth mechanisms were studied in four-week-old seedlings. Results indicated that germination percentage was promoted markedly under 2 h red and full lights and also in 1 h blue, which was accompanied by the regulation of H2O2 level and NADPH oxidase (NOX) activity. Sprout growth and height were more heightened under 2 h red light, but their contents decreased considerably under blue light with a rising incubation time. Red light induced more biomass yield, chlorophyll (Chl) pigments, Chl a/b ratio and florescence in four-week-old seedlings. Blue light also increased Chl pigments, but decreased biomass yield by enhancing malondialdehyde (MDA) level. Increased growth in seedlings treated to red light was associated with upregulating Rubisco gene expressions (rbcL and rbcS) and its activity. Red and red-blue lights promoted the activity of superoxide dismutase, glutathione reductase, and ascorbate peroxidase enzymes to increase ascorbic acid (ASA) production in the ascorbate–glutathione cycle. Total phenolic (0.22 mg DAG g− 1 DW), ASA (89.58 mg 100 g− 1 FW) and capsaicinoids (2.73 mg g− 1 DW) contents were heightened under red light, while carotenoid (11.78 µg g− 1 FW) content was more accumulated under blue light. The findings of this study suggest red light modulates NOX activity and H2O2 level for inducing seed germination and seedling quality in C. frutescens, which can create important implications for the production of antioxidant metabolites and increase the cultivation area of this plant.

Norepinephrine promotes oxidative stress in vascular adventitial fibroblasts via PKC/NFκB-mediated NOX2 upregulation

ABSTRACT Background: Sympathetic overactivity is closely associated with vascular remodeling. Sympathetic fibers dominantly innervate the adventitia of arteries rather than tunica media. Vascular adventitial fibroblasts (VAFs) play crucial roles in vascular remodeling. However, the link between sympathetic overactivity and VAF proliferation and migration is unknown. Methods: Primary VAFs were isolated from the thoracic aorta of spontaneously hypertensive rats and Wistar–Kyoto rats. Norepinephrine (NE) bitartrate monohydrate was applied to VAFs to simulate the sympathetic overactivity. Results: NE increased NADPH oxidase (NOX) 2 expression and superoxide level, which were almost abolished by NOX2 inhibitor GSK2795039 or α-adrenoceptor antagonist prazosin, but not significantly affected by NOX1 inhibitor ML171, NOX4 inhibitor GLX351322 or β-adrenoceptor antagonist propranolol. Superoxide scavenger tempol or NOX2 inhibitor GSK2795039 attenuated NE-induced VAF proliferation and migration. NE promoted protein kinase C (PKC) phosphorylation and NFκB-p65 nuclear translocation. Either PKC inhibitor Go6983 or NFκB inhibitor BAY11-7082 attenuated NE-induced NOX activation, NOX2 upregulation, superoxide production, proliferation and migration. Conclusion: NE promotes oxidative stress by α-receptor/PKC/NFκB-mediated NOX2 upregulation, which contributes to proliferation and migration of VAFs.

High-mobility group protein B1 derived mutant peptide mB Box-97 inhibits the formation of neutrophil extracellular traps.

Neutrophil Extracellular Traps (NETs) are vital for innate immunity, playing a key role in controlling pathogen and biofilm proliferation. However, excessive NETosis is implicated in autoimmunity, inflammatory and neoplastic diseases, as well as thrombosis, stroke, and post-COVID-19 complications. Managing NETosis, therefore is a significant area of ongoing research. Herein, we have identified a peptide derived from HMGB1 that we have modified via a point mutation that is referred to as mB Box-97. In our recent study in a murine lung infection model, mB Box-97 was shown to be safe and effective at disrupting biofilms without eliciting an inflammatory response typically associated with HMGB1. Here we show that the lack of an inflammatory response of mB Box-97 is in part due to the inhibition of NETosis of which we investigated the mechanism of action. mB Box-97's anti-NETosis activity was assessed using human neutrophils with known NET inducers PMA, LPS, or Ionomycin. Additionally, mB Box-97's binding to Protein Kinase C (PKC), in addition to downstream effects on NADPH oxidase (NOX) activation, Reactive Oxygen Species (ROS) generation and thereby NETosis were assessed. mB Box-97 significantly inhibited NETosis regardless of the type of induction pathway. Mechanistically, mB Box-97 inhibits PKC activity likely through direct binding and thereby reduced downstream activities including NOX activation, ROS production and NETosis. mB Box-97 is a promising dual acting therapeutic candidate for managing NET-mediated pathologies and resolving biofilm infections. Our results reveal that PKC is a viable target for NETosis inhibition independent of NET inducer and worthy of further study. These findings pave the way for a novel class of therapeutics aimed at controlling excessive NETosis, potentially offering new treatments for a range of inflammatory and immune-related diseases.

Impairment of endothelial MerTK accelerates atherosclerosis development.

Atherosclerosis is a chronic inflammatory disease primarily affecting large arteries and is the leading cause of cardiovascular disease. MER proto-oncogene tyrosine kinase (MerTK) plays a key role in regulating efferocytosis, a process for the clearance of apoptotic cells. This study investigates the specific contribution of endothelial MerTK to atherosclerosis development. Big data analytics, human microarray analyses, proteomics, and a unique mouse model with MerTK deficiency in endothelial cells (MerTK flox/flox Tie2 Cre ) were utilized to elucidate the role of endothelial MerTK in atherosclerosis development. Our big data analytics, encompassing approximately 98881 cross analyses including 234 analyses for atherosclerosis in the aortic arch, along with human microarray data, reveal that inflammatory responses play a predominant role in atherosclerosis. In vivo, MerTK flox/flox Tie2 Cre mice and the littermate control MerTK flox/flox mice were used to establish an early stage of atherosclerosis model through a high-fat diet combined with AAV8-PCSK9 treatment. Consistent with big data analytics and human microarray analyses, our proteomics data showed that MerTK flox/flox Tie2 Cre mice demonstrated significantly enhanced proinflammatory signaling, mitochondrial dysfunction, and activated mitogen-activated protein kinase (MAPK) pathway compared to that of MerTK flox/flox mice. Endothelial MerTK deficiency induces endothelial dysfunction (enhanced endothelial inflammation, mitochondrial dysfunction, and activation of NADPH oxidases and MAPK signaling pathways) and subsequently causes smooth muscle cell (SMC) phenotypic alterations, ultimately promoting atherosclerosis development. Our findings provide strong evidence that endothelial MerTK impairment serves as a novel mechanism in promoting atherosclerosis development.

Hyperphosphataemia and NADPH Oxidase Regulation in Pathophysiological Processes: Implications for Oxidative Stress and Disease Progression.

Hyperphosphataemia is a key contributor to oxidative stress (OS) and cellular dysfunction across various pathological conditions. While numerous studies have associated phosphate overload with redox imbalances, the role of NADPH oxidase (NOX) in this process has received limited attention. NOX enzymes are major enzymatic sources of reactive oxygen species (ROS), and their activation has been implicated in the progression of chronic kidney disease, vascular calcification, metabolic disorders, and cancer development. Under hyperphosphataemic conditions, excessive ROS production exacerbates endothelial dysfunction, promotes vascular smooth muscle cell transdifferentiation, induces chronic inflammation, and facilitates tumour progression. Despite increasing evidence linking phosphate metabolism to NOX activation, the underlying molecular mechanisms remain poorly characterised. This review critically examines the relationship between hyperphosphataemia and NADPH oxidase-mediated OS and explores its impact on disease pathophysiology. By providing an integrated analysis of the current findings, this work aims to highlight the pathological consequences of phosphate-induced OS and identify potential therapeutic strategies to mitigate its effects.