• Akt/PKB
• early endosome
• hydrogen peroxide
• receptor-mediated endocytosis
• the Leucine zipper motif 1 (APPL1)

• RS-2022-NR068424 National Research Foundation of Korea
• RS-2024-00436263 Korea Basic Science Institute
• RS-2019-NF000007 Korea Basic Science Institute
• 2021R1A6C103A408 Korea Basic Science Institute
• 2021R1A6C102A513 Korea Basic Science Institute

• Anti-TNFα agents
• NOX2
• Pathomechanism
• Pharmacogenomics
• Rheumatoid arthritis

• Humans
• Arthritis, Rheumatoid/drug therapy
• Arthritis, Rheumatoid/immunology
• Arthritis, Rheumatoid/genetics
• Female
• Male
• Middle Aged
• Leukocytes, Mononuclear/immunology
• Leukocytes, Mononuclear/drug effects
• Leukocytes, Mononuclear/metabolism
• NADPH Oxidase 2/genetics
• NADPH Oxidases/genetics
• NADPH Oxidases/metabolism
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Lipopolysaccharide Receptors/genetics
• Lipopolysaccharide Receptors/immunology
• Adult
• Antirheumatic Agents/therapeutic use
• Aged
• Immunophenotyping
• NADPH Oxidase 4
• RNA, Messenger/genetics

• Acute pancreatitis
• Medicine
• Oxidative stress
• Reactive oxygen species
• Treatment

• Humans
• Oxidative Stress
• Reactive Oxygen Species/metabolism
• Antioxidants/therapeutic use
• Antioxidants/metabolism
• Pancreatitis/metabolism
• Pancreatitis/therapy
• Signal Transduction
• Disease Progression
• Acute Disease
• Animals
• Pancreas/pathology
• Pancreas/metabolism

• Aging
• Autophagy
• Cytokines
• Inflammation
• Mitochondria

• Humans
• Aging/immunology
• Aging/metabolism
• Aging/physiology
• Cytokines/metabolism
• Animals
• Longevity/physiology
• Longevity/immunology
• Inflammation/immunology
• Inflammation/metabolism
• Signal Transduction

• E-26/200.628/2022 Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

• Cardiometabolic risk factors
• Hormones
• Melatonin
• PCOS
• Pregnancy

• Humans
• Melatonin/pharmacology
• Melatonin/therapeutic use
• Polycystic Ovary Syndrome/drug therapy
• Polycystic Ovary Syndrome/blood
• Female
• Oxidative Stress/drug effects
• Cardiometabolic Risk Factors
• Randomized Controlled Trials as Topic
• Dietary Supplements
• Pregnancy
• Hormones/blood
• Antioxidants/pharmacology
• Antioxidants/therapeutic use
• Antioxidants/administration & dosage

• Acute kidney injury
• Cisplatin
• Inflammation
• NOX4
• Vaccarin

• atrial fibrillation
• carotid artery diseases
• peripheral vascular diseases

The roles of both neuroinflammation and oxidative stress in the pathophysiology of epilepsy have begun to receive considerable attention in recent years. However, these concepts are predominantly studied as separate entities despite the evidence that neuroinflammatory and redox-based signaling cascades have significant crosstalk. Oxidative post-translational modifications have been demonstrated to directly influence the function of key neuroinflammatory mediators. Neuroinflammation can further be controlled on the transcriptional level as the transcriptional regulators NF-KB and nrf2 are activated by reactive oxygen species. Further, neuroinflammation can induce the increased expression and activity of NADPH oxidase, leading to a highly oxidative environment. These factors additionally influence mitochondria function and the metabolic status of neurons and glia, which are already metabolically stressed in epilepsy. Given the implication of this relationship to disease pathology, this review explores the numerous mechanisms by which neuroinflammation and oxidative stress influence one another in the context of epilepsy. We further examine the efficacy of treatments targeting oxidative stress and redox regulation in animal and human epilepsies in the literature that warrant further investigation. Treatment approaches aimed at rectifying oxidative stress and aberrant redox signaling may enable control of neuroinflammation and improve patient outcomes.

• R01 NS039587 NINDS NIH HHS
• R01 NS045748 NINDS NIH HHS
• R37 NS039587 NINDS NIH HHS
• National Institutes of Health

Objective: Sirtuin deacetylases are major regulators of organismal aging, and while depletion of sirtuin 6 (SIRT6) in mice results in a profound progeroid phenotype, the role of SIRT6 in the regulation of vasomotor function is unknown. Thus, our objective was to test the hypothesis that reductions in SIRT6 elicit endothelial dysfunction in young, genetically altered mice.

Results and Approach: We used young (3 month old), littermate-matched, SIRT6 wild-type (WT), and SIRT6 heterozygous (HET) mice. SIRT6 expression (qRT-PCR) was reduced by 50% in HET mice. Carotid vessel responses to acetylcholine, sodium nitroprusside, U46619, and serotonin were examined in isolated organ chamber baths. Relaxation in response to acetylcholine (ACH) was impaired in HET mice compared to littermate-matched WT controls (67 ± 3% versus 76 ± 3%, respectively; p < 0.05), while responses to sodium nitroprusside were unchanged. Short-term incubation of carotid rings with the NAD(P)H oxidase inhibitor, apocynin, significantly improved in vessels from HET mice but not their WT littermates. Peak tension generated in response to either U46619 or serotonin was significantly blunted in HET mice compared to their WT littermates.

Conclusion: These data suggest that SIRT6 is a key regulator of vasomotor function in conduit vessels. More specifically, we propose that SIRT6 serves as a tonic suppressor of NAD(P)H oxidase expression and activation, as inhibition of NAD(P)H oxidase improved endothelial function in SIRT6 haploinsufficient mice. Collectively, SIRT6 activation and/or histone acetyltransferase inhibition may be useful therapeutic approaches to reduce endothelial dysfunction and combat age-associated cardiovascular disease.

• aging
• endothelial dysfunction
• histone deacetylation
• sirtuin 6
• vascular function

Glutathione is a water‐soluble tripeptide with a potent oxidant scavenging activity. We hypothesized that glutathione administration immediately before and after primary angioplasty (primary percutaneous coronary intervention) could be effective in modulating immune cell activation, thereby preventing infarct expansion.

One hundred consecutive patients with ST‐segment–elevation myocardial infarction, scheduled to undergo primary percutaneous coronary intervention were randomly assigned before the intervention to receive an infusion of glutathione (2500 mg/25 mL over 10 minutes), followed by drug administration at the same doses at 24, 48, and 72 hours elapsing time or placebo. Total leukocytes, NOX2 (nicotinamide adenine dinucleotide phosphate oxidase 2) activation, NO bioavailability, cTpT (serum cardiac troponin T), hsCRP (high‐sensitivity C‐reactive protein), and TNF‐α (tumor necrosis factor α) levels were measured. Left ventricular size and function were assessed within 120 minutes, 5 days, and 6 months from percutaneous coronary intervention. Following reperfusion, a significant reduction of neutrophil to lymphocyte ratio (P<0.0001), hsCRP generation (P<0.0001), NOX2 activation (P<0.0001), TNF‐α levels (P<0.001), and cTpT release (P<0.0001) were found in the glutathione group compared with placebo. In treated patients, blunted inflammatory response was linked to better left ventricular size and function at follow‐up (r=0.78, P<0.005).

Early and prolonged glutathione infusion seems able to protect vital myocardial components and endothelial cell function against harmful pro‐oxidant and inflammatory environments, thus preventing maladaptive cardiac repair and left ventricular adverse remodeling.

URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2014‐004486‐25.

• STEMI
• immune cells
• inflammation
• left ventricular remodeling
• oxidative stress
• reperfusion injury

• Acetic acid-induced colitis
• Canagliflozin
• Inflammatory response
• NOX2
• Oxidative stress
• SGLT-2

• Acetic Acid
• Animals
• Antioxidants/metabolism
• Canagliflozin/therapeutic use
• Colitis/chemically induced
• Colitis/drug therapy
• Colitis/metabolism
• Colon/pathology
• Glucose/metabolism
• Male
• NADPH Oxidase 2/metabolism
• Organ Size
• Oxidative Stress/drug effects
• Rats
• Rats, Wistar
• Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
• Sulfasalazine/therapeutic use

As the application of silica nanomaterials continues to expand, increasing chances of its exposure to the human body and potential harm are anticipated. Although the toxicity of silica nanomaterials is assumed to be affected by their physio-chemical properties, including size and surface functionalization, its molecular mechanisms remain unclear. We hypothesized that analysis of intracellular localization of the particles and subsequent intracellular signaling could reveal a novel determinant of inflammatory response against silica particles with different physico-chemical properties.

We employed a murine intratracheal instillation model of amorphous silica nanoparticles (NPs) exposure to compare their in vivo toxicities in the respiratory system. Pristine silica-NPs of 50 nm diameters (50 nm-plain) induced airway-centered lung injury with marked neutrophilic infiltration. By contrast, instillation of pristine silica particles of a larger diameter (3 μm; 3 μm-plain) significantly reduced the severity of lung injury and neutrophilic infiltration, possibly through attenuated induction of neutrophil chemotactic chemokines including MIP2. Ex vivo analysis of alveolar macrophages as well as in vitro assessment using RAW264.7 cells revealed a remarkably lower cellular uptake of 3 μm-plain particles compared with 50 nm-plain, which is assumed to be the underlying mechanism of attenuated immune response. The severity of lung injury and neutrophilic infiltration was also significantly reduced after intratracheal instillation of silica NPs with an amine surface modification (50 nm-NH₂) when compared with 50 nm-plain. Despite unchanged efficacy in cellular uptake, treatment with 50 nm-NH₂ induced a significantly attenuated immune response in RAW264.7 cells. Assessment of intracellular redox signaling revealed increased reactive oxygen species (ROS) in endosomal compartments of RAW264.7 cells treated with 50 nm-plain when compared with vehicle-treated control. In contrast, augmentation of endosomal ROS signals in cells treated with 50 nm-NH₂ was significantly lower. Moreover, selective inhibition of NADPH oxidase 2 (NOX2) was sufficient to inhibit endosomal ROS bursts and induction of chemokine expressions in cells treated with silica NPs, suggesting the central role of endosomal ROS generated by NOX2 in the regulation of the inflammatory response in macrophages that endocytosed silica NPs.

Our murine model suggested that the pulmonary toxicity of silica NPs depended on their physico-chemical properties through distinct mechanisms. Cellular uptake of larger particles by macrophages decreased, while surface amine modification modulated endosomal ROS signaling via NOX2, both of which are assumed to be involved in mitigating immune response in macrophages and resulting lung injury.

The online version contains supplementary material available at 10.1186/s12989-021-00415-0.

• Endosome
• Lung
• Macrophage
• NADPH oxidase
• ROS
• Silica nanoparticle

• Brain trauma
• damp-mediated microglial activation
• neuronal death
• nutraceuticals
• peroxynitrite

• N-acetylcysteine
• AMPK
• berberine
• butyric acid
• glucagon-like peptide 2
• intestinal barrier
• intestinal permeability
• nutraceuticals
• phycocyanobilin
• tight junction

• Dietary Supplements
• Humans
• Intestinal Mucosa
• Phosphatidylinositol 3-Kinases
• Signal Transduction
• Tight Junctions

• COVID-19
• N-acetylcysteine
• NLRP3
• berberine
• ferulic acid
• glucosamine
• inflammasomes
• lipoic acid
• macular degeneration
• phycocyanobilin
• zinc

• Animals
• Antioxidants/therapeutic use
• COVID-19/diet therapy
• COVID-19/metabolism
• COVID-19/pathology
• Dietary Supplements
• Humans
• Inflammasomes/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• SARS-CoV-2/metabolism

• Cancer
• Inflammation
• NADPH oxidase
• Oxidative stress
• Reactive oxygen species

• CRISPR
• Warburg effect
• cancer
• glucose 6-phosphate dehydrogenase (G6PD)
• glycolysis
• lactate
• metabolism

Neuroinflammation is one of the critical events in neurodegenerative diseases, whereas microglia play an important role in the pathogenesis of neuroinflammation. In this study, we investigated the effects of a natural sesquiterpene lactone, 6-O-angeloylplenolin (6-OAP), isolated from the traditional Chinese medicine Centipeda minima (L.) A.Br., on neuroinflammation and the underlying mechanisms. We showed that treatment with lipopolysaccharide (LPS) caused activation of BV2 and primary microglial cells and development of neuroinflammation in vitro, evidenced by increased production of inflammatory cytokines TNF-α and IL-1β, the phosphorylation and nuclear translocation of NF-κB, and the transcriptional upregulation of COX-2 and iNOS, leading to increased production of proinflammatory factors NO and PGE₂. Moreover, LPS treatment induced oxidative stress through increasing the expression levels of NOX2 and NOX4. Pretreatment with 6-OAP (0.5−4 μM) dose-dependently attenuated LPS-induced NF-κB activation and oxidative stress, thus suppressed neuroinflammation in the cells. In a mouse model of LPS-induced neuroinflammation, 6-OAP (5−20 mg·kg⁻¹·d⁻¹, ip, for 7 days before LPS injection) dose-dependently inhibited the production of inflammatory cytokines, the activation of the NF-κB signaling pathway, and the expression of inflammatory enzymes in brain tissues. 6-OAP pretreatment significantly ameliorated the activation of microglia and astrocytes in the brains. 6-OAP at a high dose caused a much stronger antineuroinflammatory effect than dexamethansone (DEX). Furthermore, we demonstrated that 6-OAP pretreatment could inhibit LPS-induced neurite and synaptic loss in vitro and in vivo. In conclusion, our results demonstrate that 6-OAP exerts antineuroinflammatory effects and can be considered a novel drug candidate for the treatment of neuroinflammatory diseases.

• 6-O-angeloylplenolin
• LPS
• NF-κB
• Traditional Chinese medicine
• dexamethansone
• microglia
• neuroinflammation
• oxidative stress

• BCR signaling
• NADPH oxidases
• Reactive oxygen species
• Second messenger

• atrophy
• exercise
• glucose metabolism
• insulin resistance
• skeletal muscle

• NADPH oxidase 1
• apoptosis signal-regulating kinase 1
• endocytosis
• inflammation
• tumor necrosis factor-α
• vascular smooth muscle cells

Development of the nervous system relies on a balance between axon and dendrite growth and subsequent pruning and degeneration. The developmental degeneration of dorsal root ganglion (DRG) sensory axons has been well studied in part because it can be readily modeled by removing the trophic support by nerve growth factor (NGF) in vitro. We have recently reported that axonal fragmentation induced by NGF withdrawal is dependent on Ca²⁺, and here, we address the mechanism of Ca²⁺ entry required for developmental axon degeneration of mouse embryonic DRG neurons. Our results show that the transient receptor potential vanilloid family member 1 (TRPV1) cation channel plays a critical role mediating Ca²⁺ influx in DRG axons withdrawn from NGF. We further demonstrate that TRPV1 activation is dependent on reactive oxygen species (ROS) generation that is driven through protein kinase C (PKC) and NADPH oxidase (NOX)-dependent pathways that become active upon NGF withdrawal. These findings demonstrate novel mechanistic links between NGF deprivation, PKC activation, ROS generation, and TRPV1-dependent Ca²⁺ influx in sensory axon degeneration.

• NGF
• TRPV1
• TrkA
• calcium
• neurodegeneration
• pruning

• EPR
• Immuno-affinity isolation
• Iodixanol
• Lucigenin
• NOX
• ROS
• Rac1
• Redoxosomes
• TRAF

• Cell Fractionation/methods
• Cell Line
• Centrifugation, Density Gradient
• Chromatography, Affinity
• Endosomes/metabolism
• Enzyme Activation
• Humans
• NADPH Oxidases/metabolism
• Oxidation-Reduction
• Reactive Oxygen Species/metabolism

• P30 DK054759 NIDDK NIH HHS
• R24 DK096518 NIDDK NIH HHS

• Bcl-2
• Myc
• RAS
• ROS
• STAT
• tumorigenesis

• NFkB
• cellular senescence
• cytokines
• heart rate variability
• parasympathetic activity
• reactive oxygen species
• telomere damage
• the neuro-immuno-senescence integrative model

• Cataract
• Cornea
• Glaucoma
• Lens
• Oxidative stress
• Peroxiredoxin 6
• Retina
• Trabecular meshwork

• Antioxidants/chemistry
• Antioxidants/metabolism
• Apoptosis/genetics
• Cataract/genetics
• Cataract/pathology
• Endothelium, Corneal/metabolism
• Endothelium, Corneal/pathology
• Humans
• Oxidation-Reduction
• Oxidative Stress/genetics
• Peroxiredoxin VI/chemistry
• Peroxiredoxin VI/genetics
• Reactive Oxygen Species/chemistry
• Ultraviolet Rays

• Chemotherapy
• Cisplatin
• Lysophosphatidic acid (LPA)
• Ovarian cancer
• Reactive oxygen species (ROS)
• Taxol

• Antioxidants/metabolism
• Apoptosis/drug effects
• Cell Death/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cisplatin/pharmacology
• Female
• Humans
• Lysophospholipids/antagonists & inhibitors
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Paclitaxel/pharmacology
• Reactive Oxygen Species/metabolism

• P30 CA012197 NCI NIH HHS
• R01 CA142838 NCI NIH HHS

• Ischaemia–reperfusion injury
• Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases
• Nitric oxide synthases
• Reactive oxygen species (ROS)
• Xanthine oxidases

• antiphosphatidylethanolamine
• antiphospholipid syndromes
• duramycin
• early endosome
• phosphatidylethanolamine

• Antiphospholipid antibodies
• Antiphospholipid syndrome
• Endosomes
• Hydroxychloroquine
• NADPH-oxidase
• Signal transduction

Normal fibroblasts surrounding tumor cells play a crucial role in cancer progression through formation of the tumor microenvironment. Because factors secreted from normal fibroblasts can modulate the tumor microenvironment, it is necessary to identify key factors associated with regulation of secreted factors and to investigate the molecular mechanisms contributing to the tumor microenvironment formation process. In this study, we found that radiation induced the expression and K63-linkage poly-ubiquitination of TRAF4 in normal lung fibroblasts. The K63-linkage poly-ubiquitinated TRAF4 formed complexes with NOX2 or NOX4 by mediating phosphorylated p47-phox in normal lung fibroblasts. Moreover, we showed that TRAF4 stabilized NOX complexes by decreasing lysosomal degradation of NOX2 and NOX4 after irradiation. NOX complexes increased endosomal ROS levels that were permeable into cytoplasm, leading to NF-κB-mediated ICAM1 up-regulation. Soluble ICAM1 was subsequently secreted into conditioned media of radiation-activated normal lung fibroblasts. The conditioned media from irradiated normal fibroblasts enhanced proliferation and epithelial-mesenchymal transition of non-small cell lung cancer cells both in vitro and in vivo. These results demonstrate that TRAF4 in irradiated fibroblasts is positively associated with aggressiveness of adjacent cancer cells by altering the tumor microenvironment. Thus, we suggest that regulation of TRAF4 might be a promising strategy for cancer therapy.

The intracellular scaffold KRIT1/CCM1 is an established regulator of vascular barrier function. Loss of KRIT1 leads to decreased microvessel barrier function and to the development of the vascular disorder Cerebral Cavernous Malformation (CCM). However, how loss of KRIT1 causes the subsequent deficit in barrier function remains undefined. Previous studies have shown that loss of KRIT1 increases the production of reactive oxygen species (ROS) and exacerbates vascular permeability triggered by several inflammatory stimuli, but not TNF−α. We now show that endothelial ROS production directly contributes to the loss of barrier function in KRIT1 deficient animals and cells, as targeted antioxidant enzymes reversed the increase in permeability in KRIT1 heterozygous mice as shown by intravital microscopy. Rescue of the redox state restored responsiveness to TNF-α in KRIT1 deficient arterioles, but not venules. In vitro, KRIT1 depletion increased endothelial ROS production via NADPH oxidase signaling, up-regulated Nox4 expression, and promoted NF-κB dependent promoter activity. Recombinant yeast avenanthramide I, an antioxidant and inhibitor of NF-κB signaling, rescued barrier function in KRIT1 deficient cells. However, KRIT1 depletion blunted ROS production in response to TNF-α. Together, our data indicate that ROS signaling is critical for the loss of barrier function following genetic deletion of KRIT1.

• AMPK
• GAbp
• TNF-α
• atherogenesis
• liver

• Antiphospholipid Antibodies
• Cytokines
• DMARDs (synthetic)
• Rheumatoid Arthritis
• TNF-alpha

• Adult
• Aged
• Animals
• Antibodies, Antiphospholipid/adverse effects
• Antibodies, Antiphospholipid/pharmacology
• Antirheumatic Agents/pharmacology
• Antirheumatic Agents/therapeutic use
• Cells, Cultured
• Disease Models, Animal
• Endosomes/enzymology
• Enzyme Induction/drug effects
• Female
• Gene Expression/drug effects
• Humans
• Hydroxychloroquine/pharmacology
• Hydroxychloroquine/therapeutic use
• Immunoglobulin G/pharmacology
• Interleukin-1beta/pharmacology
• Intravital Microscopy
• Male
• Membrane Glycoproteins/metabolism
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Monocytes
• NADPH Oxidase 2
• NADPH Oxidases/biosynthesis
• NADPH Oxidases/metabolism
• NF-kappa B/genetics
• Protein Transport/drug effects
• Reactive Oxygen Species/metabolism
• Signal Transduction/drug effects
• Thromboplastin/genetics
• Tumor Necrosis Factor-alpha/pharmacology
• Vena Cava, Inferior
• Venous Thrombosis/chemically induced
• Venous Thrombosis/diagnostic imaging
• Venous Thrombosis/prevention & control
• Young Adult

Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic.

• Alzheimer’s disease
• Amyotrophic lateral sclerosis
• Huntington’s disease
• Multiple sclerosis
• NADPH oxidase
• Neurodegeneration
• Oxidative stress
• Parkinson’s disease
• Stroke
• Traumatic brain injury

Reactive oxygen species (ROS) participate as signaling molecules in response to exercise in skeletal muscle. However, the source of ROS and the molecular mechanisms involved in these phenomena are still not completely understood. The aim of this work was to study the role of skeletal muscle NADPH oxidase isoform 2 (NOX2) in the molecular response to physical exercise in skeletal muscle. BALB/c mice, pre-treated with a NOX2 inhibitor, apocynin, (3 mg/kg) or vehicle for 3 days, were swim-exercised for 60 min. Phospho–p47^phox levels were significantly upregulated by exercise in flexor digitorum brevis (FDB). Moreover, exercise significantly increased NOX2 complex assembly (p47^phox–gp91^phox interaction) demonstrated by both proximity ligation assay and co-immunoprecipitation. Exercise-induced NOX2 activation was completely inhibited by apocynin treatment. As expected, exercise increased the mRNA levels of manganese superoxide dismutase (MnSOD), glutathione peroxidase (GPx), citrate synthase (CS), mitochondrial transcription factor A (tfam) and interleukin-6 (IL-I6) in FDB muscles. Moreover, the apocynin treatment was associated to a reduced activation of p38 MAP kinase, ERK 1/2, and NF-κB signaling pathways after a single bout of exercise. Additionally, the increase in plasma IL-6 elicited by exercise was decreased in apocynin-treated mice compared with the exercised vehicle-group (p < 0.001). These results were corroborated using gp91-dstat in an in vitro exercise model. In conclusion, NOX2 inhibition by both apocynin and gp91dstat, alters the intracellular signaling to exercise and electrical stimuli in skeletal muscle, suggesting that NOX2 plays a critical role in molecular response to an acute exercise.

• IL-6
• NADPH oxidase
• antioxidant defense
• muscle adaptation
• reactive oxygen species
• redox signaling

• Cell adhesion molecules
• Endocytosis
• Endothelial cells
• Intracellular delivery
• Vascular immunotargeting

The circadian clock is a transcriptional network that functions to regulate the expression of genes important in the anticipation of changes in cellular and organ function. Recent studies have revealed that the recognition of pathogens and subsequent initiation of inflammatory responses are strongly regulated by a macrophage-intrinsic circadian clock. We hypothesized that the circadian pattern of gene expression might be influenced by inflammatory stimuli and that loss of circadian function in immune cells can promote pro-inflammatory behavior. To investigate circadian rhythms in inflammatory cells, peritoneal macrophages were isolated from mPer2^luciferase transgenic mice and circadian oscillations were studied in response to stimuli. Using Cosinor analysis, we found that LPS significantly altered the circadian period in peritoneal macrophages from mPer2^luciferase mice while qPCR data suggested that the pattern of expression of the core circadian gene (Bmal1) was disrupted. Inhibition of TLR4 offered protection from the LPS-induced impairment in rhythm, suggesting a role for toll-like receptor signaling. To explore the mechanisms involved, we inhibited LPS-stimulated NO and superoxide. Inhibition of NO synthesis with L-NAME had no effect on circadian rhythms. In contrast, inhibition of superoxide with Tempol or PEG-SOD ameliorated the LPS-induced changes in circadian periodicity. In gain of function experiments, we found that overexpression of NOX5, a source of ROS, could significantly disrupt circadian function in a circadian reporter cell line (U2OS) whereas iNOS overexpression, a source of NO, was ineffective. To assess whether alteration of circadian rhythms influences macrophage function, peritoneal macrophages were isolated from Bmal1-KO and Per-TKO mice. Compared to WT macrophages, macrophages from circadian knockout mice exhibited altered balance between NO and ROS release, increased uptake of oxLDL and increased adhesion and migration. These results suggest that pro-inflammatory stimuli can disrupt circadian rhythms in macrophages and that impaired circadian rhythms may contribute to cardiovascular diseases by altering macrophage behavior.

• Animals
• Cell Adhesion/drug effects
• Cell Movement/drug effects
• Circadian Rhythm/drug effects
• Circadian Rhythm/genetics
• Endotoxins/toxicity
• Gene Expression Regulation/drug effects
• Lipopolysaccharides/pharmacology
• Lipoproteins, LDL/metabolism
• Macrophages, Peritoneal/cytology
• Macrophages, Peritoneal/drug effects
• Macrophages, Peritoneal/metabolism
• Male
• Mice, Knockout
• Nitric Oxide/metabolism
• Reactive Oxygen Species/metabolism
• Real-Time Polymerase Chain Reaction
• Toll-Like Receptor 4/metabolism
• Transcription Factors/metabolism

• P01 HL101902 NHLBI NIH HHS
• R01 HL095556 NHLBI NIH HHS
• R01 HL124773 NHLBI NIH HHS
• National Institutes of Health

• antimicrobial
• cell death
• chloramine
• hydrogen peroxide
• hypochlorous acid
• hypothiocyanous acid
• inflammation
• myeloperoxidase
• redox signaling
• superoxide

• Drug delivery
• Vascular immunotargeting

Inflammation is considered to play a central role in a diverse range of disease outcomes associated with exposure to various types of inhalable particulates. The initial mechanisms through which particles trigger cellular responses leading to activation of inflammatory responses are crucial to clarify in order to understand what physico-chemical characteristics govern the inflammogenic activity of particulate matter and why some particles are more harmful than others. Recent research suggests that molecular triggering mechanisms involved in activation of proinflammatory genes and onset of inflammatory reactions by particles or soluble particle components can be categorized into direct formation of reactive oxygen species (ROS) with subsequent oxidative stress, interaction with the lipid layer of cellular membranes, activation of cell surface receptors, and direct interactions with intracellular molecular targets. The present review focuses on the immediate effects and responses in cells exposed to particles and central down-stream signaling mechanisms involved in regulation of proinflammatory genes, with special emphasis on the role of oxidant and non-oxidant triggering mechanisms. Importantly, ROS act as a central second-messenger in a variety of signaling pathways. Even non-oxidant mediated triggering mechanisms are therefore also likely to activate downstream redox-regulated events.

• ROS
• asbestos
• cytokines
• fibers
• inflammasome
• nanoparticles
• oxidants
• particles
• particulate matter
• quartz
• receptors
• silica
• transcription factors

• Animals
• Humans
• Inflammation/chemically induced
• Inflammation/genetics
• Inflammation/metabolism
• Inflammation/pathology
• Mucous Membrane/drug effects
• Mucous Membrane/metabolism
• Mucous Membrane/pathology
• Oxidants/metabolism
• Particulate Matter/metabolism
• Particulate Matter/toxicity
• Respiratory System/drug effects
• Respiratory System/metabolism
• Respiratory System/pathology

• Aging/physiology
• Animals
• Biomarkers/metabolism
• Endothelium, Vascular/pathology
• Humans
• Membrane Glycoproteins/metabolism
• NADPH Oxidase 2
• NADPH Oxidases/metabolism
• Neurodegenerative Diseases/physiopathology
• Oxidation-Reduction
• Oxidative Stress/physiology
• Reactive Oxygen Species/metabolism
• Signal Transduction/physiology

• cardiovascular diseases
• oxidative stress
• reactive oxygen species
• signal transduction