Linarin alleviates dextran sulfate sodium-induced colitis in C57BL/6J mice by suppressing the NADPH oxidase 1/ROS/NLRP3 inflammasome signaling axis.

Uncovering the metabolic variations of sulfur dioxide in the brain of Parkinson's disease and air pollution: From imaging to therapeutic evaluations.

Connexin32 inhibits renal tubulointerstitial fibrosis in diabetic kidney disease by regulating NOX4/MRTF-A positive feedback loop.

NOX4 mediates ferroptosis through oxidative stress in diabetic keratopathy.

Lycorine protects against inflammatory hemorrhagic skin injury via suppression of neutrophil-driven NADPH oxidase activation.

Cerebral ischemia/reperfusion (I/R) injury represents a significant challenge to recanalization therapy for ischemic stroke and is critically influenced by microglial polarization. Although inhibition of Rho-associated protein kinase (ROCK) has been shown to mitigate cerebral I/R injury and associated neuroinflammation, its specific effect on the balance between M1 and M2 (anti-inflammatory) microglial polarization remains incompletely understood. This study aimed to elucidate the role and underlying mechanism of ROCK inhibition in regulating M1 and M2 microglial polarization, using the classical antidepressant fluoxetine as a positive control. ROCK inhibitor fasudil and positive control fluoxetine effectively alleviated cerebral I/R injury and facilitated a shift in microglial polarization from the M1 to the M2 phenotype, both invivo and in vitro. In the hippocampal tissues of cerebral I/R mice exposed to lipopolysaccharide, we observed an upregulation of thioredoxin-interacting protein (TXNIP) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2). ROCK2 knockdown promoted the M2 microglial polarization, suppressed the expression of NOX2 and TXNIP, and inhibited the activation of NF-κB P65 in mouse hippocampal tissue. Notably, pharmacological inhibition of NF-κB reduced the expression of NOX2 and TXNIP, as well as the production of reactive oxygen species (ROS), in microglia subjected to oxygen-glucose deprivation/reoxygenation. Correspondingly, inhibition of NOX2 also decreased TXNIP expression.Conclusion and Innovation:ROCK inhibition promotes a shift in microglial polarization from the M1 to the M2 subtype by suppressing the NF-κB/NOX2/ROS/TXNIP signaling pathway. This study provides the first evidence demonstrating the mechanism by which ROCK inhibition drives microglial polarization toward the M2 phenotype. Antioxid. Redox Signal. 45, 149-168.

High-intensity interval exercise (HIIE) induces transient increases in reactive oxygen species (ROS) and inflammatory mediators that drive skeletal muscle adaptations. Sex influences oxidative stress and inflammation, yet the interplay between sex and exercise-induced signaling remains incompletely understood. The purpose of this study was to investigate sex differences in markers of inflammation, oxidative stress, and antioxidant status at rest and following acute HIIE in young, healthy males and females matched for aerobic fitness. Twenty-four participants (12/sex) underwent muscle biopsies and blood sampling at rest and immediately postexercise (10 × 1 min at 90% HRmax). Skeletal muscle was analyzed for oxidative stress [NADPH oxidase 2 (NOX2), 4-hydroxynonenal (4HNE), total protein carbonylation via oxyblot, p38 MAPK], antioxidant enzymes [thioredoxin 1 (TRX1), glutathione reductase (GR), and glutathione peroxidase 1 (GPX1)], and cytokine content (array), and plasma was analyzed for inflammatory markers (IL-6 and TNFα) and antioxidant status. Acute HIIE increased plasma IL-6 and TNFα and decreased total antioxidant status with no differences between sexes. Basally, females had higher phosphorylation of p38 MAPK and elevated growth- and repair-associated cytokines [insulin-like growth factor binding protein 1 and 3 (IGFBP-1/3), tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1/2), transforming growth factor- β2/3 (TGF-β2/3), FGF-7/9, macrophage colony-stimulating factor (M-CSF), and stromal cell derived factor (SDF)-1], whereas males had higher basal proinflammatory cytokines (IL-1α, IL-13, IP-10, and oncostatin M). Following exercise, males showed a greater upregulation of growth and repair mediators, whereas females had broader suppression of inflammatory and chemotactic factors. No sex differences were observed in muscle oxidative stress markers or antioxidant content. These findings indicate that although acute HIIE elicits comparable plasma inflammatory responses in males and females, underlying skeletal muscle cytokine signaling and adaptive potential are sex-specific, emphasizing the need to consider sex in exercise physiology studies. NEW & NOTEWORTHY We investigated whether sex influenced the inflammatory or oxidative stress response to acute exercise. Although no differences were observed in plasma markers, in skeletal muscle, females had elevated growth- and repair-associated cytokines, whereas males had higher proinflammatory cytokines at rest. Following exercise, males had greater upregulation of growth and repair mediators, whereas inflammatory and chemotactic factors were suppressed in females. The sex divergence in skeletal muscle cytokines may have implications postexercise signaling and chronic adaptations.

Heart failure remains a leading cause of mortality worldwide with limited therapeutic options. Xinyang Tablet (XYT), a clinically used traditional Chinese medicine, demonstrates cardioprotective effects, but its mechanisms against cardiac hypertrophy remain unclear. This study aimed to elucidate the therapeutic mechanisms of XYT in heart failure with a focus on oxidative stress and hypertrophy pathways. Pressure-overload heart failure was induced by transverse aortic constriction (TAC) in mice. Cardiac function was assessed via histology (hematoxylin-eosin [H&E], Masson's trichrome), oxidative stress markers (dihydroethidium [DHE] staining, superoxide dismutase [SOD]/malondialdehyde [MDA]/glutathione peroxidase [GSH-Px] assays), and molecular analyses. In vitro, angiotensin II (AngII)-treated HL-1 cardiomyocytes evaluated hypertrophy and oxidative stress responses. Multiomic approaches, including ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS), network pharmacology, RNA sequencing (RNA-seq), and single-cell RNA sequencing (scRNA-seq), identified XYT's bioactive compounds and hub targets, validated by AKT inhibitor (MK-2206) experiments. XYT attenuated TAC-induced cardiac hypertrophy and fibrosis, reducing heart volume, cardiomyocyte cross-sectional area, and fibrotic markers (collagen type I alpha 1 [COL1A1]/collagen type III alpha 1 [COL3A1]). XYT suppressed oxidative stress by decreasing reactive oxygen species (ROS)/NADPH oxidase 2 (NOX2)/NOX4 while increasing superoxide dismutase 2 (SOD2)/GSH-Px in vivo and in vitro. Bioinformatics identified 18 hub genes (e.g., histone deacetylase 2 [HDAC2], SOD2) and enriched phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)/oxidative stress pathways. XYT inhibited HDAC2/AKT/glycogen synthase kinase-3β (GSK-3β) phosphorylation, while AKT inhibition with MK-2206 mimicked XYT's protective effects. XYT ameliorates heart failure by targeting HDAC2 to suppress AKT/GSK-3β signaling, mitigating oxidative stress, cardiac hypertrophy, and fibrosis, providing mechanistic evidence for clinical translation.

NOX2 inhibitor baicalein alleviates rheumatoid arthritis and inactivating mitochondrial oxidative stress-mediated cGAS-STING signaling in fibroblast-like synoviocytes.

The mechanosensitive ion channel Piezo1 promotes colitis by modulating oxidative stress and ferroptosis-related markers.

Light is a key cue for primordium initiation in basidiomycetes, but the downstream molecular coordination remains unclear. Here, we integrated DIA proteomics, untargeted LC-MS/MS metabolomics, enzymatic assays, and multistrain phenotyping to characterize light-associated primordium initiation in Lentinula edodes. Light-exposed primordium-forming tissues showed 1,521 differentially expressed proteins enriched in redox/cofactor metabolism, proteostasis, membrane/lipid remodeling, cell-wall reorganization, and translation. Metabolomics revealed coordinated changes in cofactor biosynthesis, ABC transporters, aminoacyl-tRNA metabolism, and sugar interconversion. Enzymatic assays showed increased NADPH oxidase and pyruvate decarboxylase activities, reduced superoxide dismutase, alcohol dehydrogenase, and Complex V activities, supporting redox remodeling and altered pyruvate-node metabolism while requiring future ROS and flux validation. Across 57 strains, directional illumination confined primordia to illuminated zones, reduced primordium number and total yield, but increased individual fruiting-body weight. These findings support a working "Signal-Supply-Structure" framework for fungal photomorphogenesis and light-regime optimization.

Nicotine-associated cardiovascular dysfunction: From pharmacological insights to emerging therapeutic interventions.

Retraction notice to "Leonurine (SCM-198) attenuates myocardial fibrotic response via inhibition of NADPH oxidase 4" [Free Radical Biol. Med. 54 (2013) 93-104

Neutrophils are key in acute and chronic cardiovascular diseases (CVD) by mediating inflammation during myocardial infarction, stroke, and heart failure. Reactive oxygen species (ROS) generated by neutrophil NADPH oxidase 2 (NOX2) have been linked to CVD pathology by inducing tissue injury via oxidative stress. There is, however, only limited data investigating the impact of neutrophil-derived ROS on clinical outcome in patients with CVD. This study measured neutrophil oxidative burst capacity (NOBC) in patients with CVD and evaluated its association with major adverse cardiac events (MACE) and infection. In a population of 201 (median age 69years (interquartile range (IQR) = 61-80years); 33.4% female) out of 1128 patients from the prospective all-comer Essen Coronary Artery Registry II (ECAD II registry), NOBC was measured using a Seahorse XF analyzer with phorbol-12-myristat-13-acetat (PMA) stimulation. Based on NOBC values, the study collective was divided by median split. The primary endpoint was MACE, comprising of acute myocardial infarction, acute ischemic stroke, or hospitalization for heart failure, with a median follow-up time of 287days (IQR = 225-349days). A secondary endpoint occurrence of infection was assessed with a median follow-up time of 273days (IQR = 214-332days). Patients with low NOBC showed 20% lower values (98.8nmol (IQR = 92.9-104.2nmol; high NOBC) vs. 79.4nmol (IQR = 71.8-84.9nmol; low NOBC); p < 0,001). In this group, we observed a significantly higher portion of females (26.7% (high NOBC) vs. 41.0% (low NOBC); p = 0.03). Despite lower CCL2 and hemoglobin levels in patients with low NOBC, further inflammatory markers were unaltered. Occurrence of MACE (hazard ratio (HR) = 2.78; 95% confidence interval (CI) 1.17-6.63; p = 0.02) and infection (HR = 3.67; 95% CI = 1.16-11.62; p = 0.03) was significantly increased in patients with low NOBC. The latter remained significant, while the association between low NOBC and incidence of MACE lost its significance after adjustment for anemia and further confounders. Incidence of MACE and infection was increased in patients with low NOBC. Whether low NOBC is directly associated with patient outcome or acts in combination with other factors remains unclear.

A novel role for magnetotactic bacterium: Magnetospirillum magneticum AMB-1 prolonged healthy lifespan of Caenorhabditis elegans via regulating ferroptosis.

This study aims to address NOX4 (NADPH oxidase 4)-driven oxidative injury in Alzheimer's disease (AD) and the poor bioavailability of the natural flavonoid Quercetagetin, we developed an α7 nicotinic acetylcholine receptor (α7-nAChR)-targeted, Quercetagetin-loaded PLGA nanocarrier (PLGA@Quercetagetin@α7-nAChR) for receptor-mediated delivery, NOX4 suppression, and neuroprotection. Using the GSE97760 dataset, bioinformatic screening combined with LASSO regression was performed to identify candidate targets. Single-cell RNA sequencing (scRNA-seq) with pseudotime analysis was applied to delineate cell type-resolved and trajectory-associated expression patterns. Nanoparticles were fabricated by a double-emulsion method and characterized for physicochemical properties. In an Aβ-induced HT-22 neuronal injury model, genetic perturbation, western blotting, and flow cytometry were used to validate the pathogenic role of NOX4 and to evaluate the pharmacological efficacy of the nanoplatform. NOX4 emerged as the key gene, showing enriched expression in oligodendrocytes and endothelial cells and an increase along the inferred disease-associated trajectory. In vitro, Aβ stimulation upregulated NOX4, whereas NOX4 knockdown or Quercetagetin treatment alleviated Aβ-induced cytotoxicity and apoptosis. The nanoparticles exhibited an average diameter and sustained drug release over 72h. α7-nAChR targeting enhanced neuronal uptake by ~ fivefold, markedly reduced NOX4 mRNA levels, and decreased the apoptotic rate from 18.3% to 5.0%. Notably, encapsulation also mitigated the hepatorenal toxicity observed with high-dose free Quercetagetin. These in vitro findings suggest NOX4 as a potential target in AD, and the PLGA@Quercetagetin@α7-nAChR nanoplatform shows improved cellular uptake and reduced short-term toxicity compared to free drug. However, claims regarding brain targeting and translational potential are limited by the absence of in vivo validation, non-targeted controls, drug exposure normalization, and key formulation parameters (e.g., encapsulation efficiency). Future in vivo studies are required to substantiate this targeted strategy for AD.

To explore the mechanism of electroacupuncture (EA) at "Zusanli" (ST36) in combination with omeprazole in treating gastrointestinal injury induced by indomethacin in mice. Thirty C57BL/6J mice were randomly divided into normal control, model, omeprazole, EA combined with omeprazole (combination), and combination + nuclear factor E2-related factor 2 (Nrf2) inhibitor (inhibitor) groups, with 6 mice in each group. The gastrointestinal injury mouse model was established by intragastric administration of indomethacin (30 mg/kg). EA was applied to bilateral ST36 for 20 min, a total of 2 times. The omeprazole (10 mg/kg) was given by gavage. Mice in the inhibitor group were intraperitoneally injected with the Nrf2 inhibitor ML385 (30 mg/kg). HE staining was used to observe the morphological changes of the gastrointestinal mucosa. The contents of glutathione (GSH), malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in gastric tissue and the activities of SOD and glutathione peroxidase (GSH-Px) in colon tissue were detected by colorimetric method. The level of reactive oxygen species (ROS) in colon tissue was detected by flow cytometry. The mRNA and protein expressions of Nrf2/heme oxygenase-1 (HO-1) signaling pathway-related factors Kelch-like epichlorohydrin-related protein factor 1 (Keap1), Nrf2, HO-1 and NADPH oxidase 1 (NOX1) in colon tissue were detected by qPCR and Western blot, respectively. After modeling and compared with the normal control group, the mice of model group showed severe gastrointestinal mucosal damage, with decreased GSH content and SOD activity in gastric tissue (P<0.01), increased MDA content (P<0.01), elevated ROS levels, and increased Keap1 and NOX1 mRNA and protein expressions in colon tissue (P<0.01), reduced SOD and GSH-Px activities (P<0.01, P<0.05), decreased Nrf2 and HO-1 mRNA and protein levels in colon tissue (P<0.01). Compared with the model group, the gastric mucosal injury was improved, the content of GSH and the activity of SOD in the gastric tissue were increased (P<0.01, P<0.05), while the content of MDA was decreased (P<0.05, P<0.01) in both omeprazole and combination groups. In comparison with the model and the omeprazole groups, the combination group showed improved colonic mucosal injury, decreased ROS level (P<0.01), increased SOD and GSH-Px activities (P<0.05), up-regulated mRNA and protein expressions of Nrf2 and HO-1 (P<0.01), and down-regulated mRNA and protein expressions of Keap1 and NOX1 (P<0.01, P<0.05) in colon tissue. However, the improvement of gastrointestinal oxidative stress of combination treatment was reversed after the injection of Nrf2 inhibitor in the inhibitor group (P<0.01, P<0.05). The integration of acupuncture and medication can effectively ameliorate indomethacin-induced gastrointestinal oxidative stress injury, which may be related to its function in activating the Nrf2/HO-1 signaling pathway.

Hypertension increases the risk for cardiovascular and cerebrovascular diseases and both its preventive and current therapeutics measures require extensive investigations. Despite that Gastrodin, a neuroprotective compound extracted from a Traditional Chinese medicine (TCM), reportedly has preventive and curative potentials in hypertensive patients, its molecular mechanisms in lowering blood pressure still remain obscure. This study was designed to test the hypothesis that gastrodin lowers blood pressure by targeting the PPAR-γ/NF-κB/NLRP3 signaling axis in the hypothalamic paraventricular (PVN). Gastrodin or vehicle (artificial cerebrospinal fluid, aCSF) was directly infused into the PVN through a mini osmotic pump for 28 days to Spontaneous hypertensive rats (SHRs) and Wistar Kyoto (WKY). Four groups of rats were set: WKY + PVN vehicle; WKY + PVN Gastrodin; SHR + PVN vehicle; and SHR + PVN Gastrodin. Blood pressure was monitored and at the conclusion of experiment, plasma and PVN samples were collected and processed for ELISA, PCR, Western blotting and Immunofluorescence analyses. SHRs had elevated blood pressure (BP), heart rate (HR) and plasmatic norepinephrine (NE) validating their hypertensive status. PVN micro-infusion of gastrodin markedly reversed these hypertensive features in SHRs. At molecular level, gastrodin attenuated the local production of reactive oxygen species (ROS), reduced NADPH Oxidases (NOX)2 and NOX4 messenger RNA (mRNA) level and attenuated the activation of PPAR-γ in the PVN. In addition, gastrodin reduced the inflammasome activation and the expression of interleukin-1β (IL-1β). Furthermore, pretreatment with gastrodin reduced the expression of caspase-1 p10 and inflammation (IL-1β and MCP-1), the ratio of phosphorylated kappa B kinase (p-IKK)/IKK, and that of p-p65/p65 in the PVN of SHRs. In conclusion, gastrodin-lowered blood pressure is associated with balanced PPAR-γ/NF-κB/NLRP3 signaling axis within the PVN local highlighting its promising properties in the management of hypertension.

Neutrophil extracellular traps (NETs) are chromatin-based extracellular structures consisting of DNA, histones and multiple antimicrobial proteins, which exert dual biological effects in host defense and inflammation-triggered tissue injury. This review focuses on NET-associated signaling pathways and their regulatory crosstalk with diverse forms of regulated cell death (RCD) in inflammatory disorders. First, we summarize the structural characteristics and biogenesis pathways of NETs closely linked to inflammatory amplification, including lytic and non-lytic NETosis as well as reactive oxygen species (ROS)-dependent and ROS-independent mechanisms, and elaborate the functions of NADPH oxidase, myeloperoxidase, neutrophil elastase, peptidylarginine deiminase 4 and gasdermin D during these processes. Second, we discuss how NET-derived damage-associated molecular patterns, such as DNA, histones, granular proteases, ROS and mitochondrial DNA, interact with apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy and cuproptosis. Under pathological conditions, excessive NET formation or impaired NET clearance leads to autoantigen exposure, accelerated thrombosis, enhanced inflammasome activation, parenchymal cell damage and modulated tumor progression. Finally, we outline therapeutic interventions targeting NET biogenesis, NET clearance and downstream NETs-driven signaling, with an emphasis on the translational potential and safety concerns of these strategies across distinct diseases. Future investigations are required to decipher context-dependent NETs-RCD regulatory circuits, standardize NETs detection protocols, and develop precision-targeted therapeutics that restrain pathological inflammation while preserving host antimicrobial defense.

Plants restrict microbial entry into their leaves by closing their stomata upon recognition of conserved microbe-associated molecular patterns (MAMPs). The hydathode pore is a stomata-like opening on leaf margins which are thought to lack MAMP recognition and to be an entry point for microbial pathogens. Here, we observe marginal hydathode pore closure in response to abscisic acid, and the MAMPs chitin and flg22 in Arabidopsis thaliana leaves. Hydathode pore closure occurs within 3-9 hours of chitin exposure and pores reopen after 12 hours. Under conditions when hydathode pores are open, external fluids enter approximately 80% of the marginal hydathodes within a leaf. After hydathode pores close in response to ABA, chitin or flg22, external fluids accumulate in under 20% of hydathodes with in a leaf. MAMP-induced hydathode restriction was similar for dye or fluorescent Pseudomonas syringae pv. tomato bacteria and was dependent on pattern recognition receptors including CERK1 for chitin and FLS2 for flg22. Chitin-induced hydathode limitation was also dependent on the NADPH oxidase RBOHF and was partially hampered in rbohD, lyk4 lyk5, bak1-5 bkk1, slac1-3 slah3-1 knockout mutants. Together, this work indicates that MAMP recognition regulates entry into the hydathode and induces transient closure of the hydathode pores.