Using untargeted proteomics, we identified 199 plasma protein markers of four healthy dietary patterns in adults with CKD. Twenty-one diet-related proteins were associated with CKD progression and 30 proteins were associated with all-cause mortality. These proteins may represent biologic mechanisms through which diet modifies disease course in CKD. Healthy dietary patterns reduce the risk of CKD progression and mortality in people with CKD. Identifying protein biomarkers of diet, and their associations with these outcomes, can elucidate biologic mechanisms through which diet improves prognosis. Using data from the Chronic Renal Insufficiency Cohort study of adults with CKD ( n =2217, mean age 59 years), we examined cross-sectional associations between 4954 plasma proteins and four dietary patterns: Healthy Eating Index-2020, Alternative Healthy Eating Index-2010, Dietary Approaches to Stop Hypertension, and alternate Mediterranean diet. Relative values of proteins were determined using an aptamer-based assay. Dietary intake was assessed using a food frequency questionnaire. We used multivariable linear regression to identify proteins associated with diet, and Cox proportional hazards regression to assess longitudinal associations between diet-related proteins, CKD progression, and mortality. Elastic net regression was used to select subsets of proteins that are associated with these outcomes. At a false discovery rate-adjusted P < 0.05, 199 proteins were associated with ≥1 dietary pattern and 18 were associated with all patterns. Over 7 years of median follow-up, 824 CKD progression events occurred. Twenty-one proteins were associated with CKD progression at P < 2.5×10 -4 (=0.05/199), of which eight were selected in elastic net regression: follistatin-related protein 3, glutaredoxin-1, asialoglycoprotein receptor 1, extracellular superoxide dismutase [Cu-Zn], zinc- α -2-glycoprotein, IL-18 receptor 1, ecto-ADP-ribosyltransferase 3, and ephrin type-A receptor 1. All were inversely associated with healthy dietary patterns and associated with higher risk of CKD progression. Thirty proteins were associated with all-cause mortality, of which 14 were selected by elastic net regression. Large-scale proteomics analyses identified potential protein biomarkers of healthy dietary patterns that were associated with CKD progression and mortality in adults with CKD. Their functions, including regulating blood lipids, insulin sensitivity, vascular homeostasis, inflammation, and oxidative stress, may represent mechanisms through which diet improves disease course.

Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling that leads to elevated pulmonary artery pressures, and subsequent right ventricular dysfunction. Despite advances in understanding PH pathogenesis, treatment options remain limited, underscoring the need to define novel mechanisms that contribute to disease progression. Inflammation and oxidative stress are recognized drivers of pulmonary vascular injury, with extracellular superoxide dismutase (EC-SOD or SOD3), a matrix-bound antioxidant enzyme, playing a role in multiple lung and vascular pathologies. A common human single nucleotide polymorphism (rs1799895) in the SOD3 gene leads to an arginine to glycine amino acid substitution (R213G) and alters EC-SOD localization by reducing its affinity for the extracellular matrix, resulting in increased circulating but decreased lung EC-SOD content. Using a murine knock-in model of the R213G variant, we have previously demonstrated exacerbated chronic hypoxia-induced PH. In this study, we examined the impact of EC-SOD redistribution due to the R213G SOD3 variant on the development of PH in the Sugen-hypoxia (SuHx) model, a more severe model of PH. We hypothesized that R213G mice would also have exaggerated hemodynamic changes, vascular remodeling, and inflammatory changes in this model. However, while SuHx increased pulmonary artery pressure and vascular remodeling in wild-type mice, the R213G variant unexpectedly attenuated SuHx-induced PH. Following SuHx, the increase in pulmonary artery pressures was attenuated in R213G mice. Early immune profiling revealed that SuHx triggered significant neutrophil and interstitial macrophage infiltration in the lungs of wild-type mice, which was markedly blunted in R213G mice. These findings suggest that the redistribution of EC-SOD into the extracellular fluid, though it lowed lung EC-SOD levels, attenuated early inflammatory responses and protected against the development of PH in SuHx. This work highlights a novel, compartment-specific role for EC-SOD in modulating immune-driven mechanisms of PH and may inform future therapeutic strategies targeting oxidative stress and inflammation in vascular disease.

The lung is highly susceptible to oxidative stress because of its exposure to high oxygen tension and environmental stressors, making tight regulation of the redox environment essential for homeostasis and disease pathogenesis. Extracellular superoxide dismutase (EC-SOD, sod3) is an important antioxidant enzyme in the lung that catalyzes the dismutation of superoxide into hydrogen peroxide and oxygen, thereby regulating the redox environment of the extracellular matrix, cell surfaces, and lining fluids of the lung. This review summarizes the structural features, post-translational regulation, genetic variations, and cellular sources of EC-SOD, with a particular focus on its role in acute respiratory distress syndrome (ARDS). We highlight evidence demonstrating that loss of EC-SOD exacerbates dysregulated immune responses, whereas enhanced EC-SOD activity confers protection in multiple experimental models of acute lung injury. We also discuss how inflammatory signaling, epigenetic regulation, aging, and genetic polymorphisms in the sod3 gene influence EC-SOD expression and function. Finally, we review emerging therapeutic strategies, including SOD mimetics and mRNA-based approaches, and address the challenges associated with non-specific antioxidant therapies in ARDS. Collectively, the data position EC-SOD as a central regulator of extracellular redox signaling and a promising, mechanism-driven therapeutic target in acute lung injury and ARDS.

Marteilia sydneyi, an ascetosporean parasite, is the causative agent of Queensland Unknown (QX) disease in Saccostrea glomerata. QX disease outbreaks often lead to high mortality rates and considerable population losses. Investigating molecular host/parasite interactions is imperative to better understand how S. glomerata mounts immune defences and to explore whether M. sydneyi evades host responses. This study aims to investigate S. glomerata's response to M. sydneyi infection through differential gene expression analysis to uncover immune mechanisms and potential markers for resistance. RNA sequencing and differential gene expression analysis revealed widespread transcriptional changes between infected and non-infected oysters. Genes involved in pathogen recognition and immune response signalling, such as galectin-4-like and G-protein coupled receptors, were significantly differentially expressed in infected S. glomerata, suggesting involvement in the host's immune responses. The upregulation of cytochrome P450 family genes indicates an enhanced detoxification response to infection-induced stress. However, extracellular superoxide dismutase, a gene previously implicated in the oxidative stress response to pathogens, was significantly downregulated, suggesting potential suppression of oxidative burst defence mechanisms. These results reveal the complex nature ofS. glomerata'sresponse toM. sydneyiinfection, and possible suppression or evasion of host defences by the parasite. The study also identifies multiple genes that likely play crucial roles in the molecular responses and defence mechanisms ofS. glomeratatoM. sydneyiinfection. The identification of these genes provides potential target genes for future studies and possible biomarkers for breeding QX-resistant oyster lines.

Extracellular superoxide dismutase 3 (SOD3) attenuates non-Sjögren and Sjögren syndrome dry eyes in animal models.

The pollutant naphthalene causes changes in superoxide dismutases (SODs) expression, SOD activity and lipid peroxides in the white shrimp Penaeus vannamei.

Associations of Exposure to Typical Environmental Organic Pollutants with Cardiopulmonary Health and the Mediating Role of Oxidative Stress: A Randomized Crossover Study.

Maternal and fetal overexpression of extracellular superoxide dismutase (EC-SOD) protects offspring lung in a model of late gestational hypoxia

Extracellular Superoxide Dismutase R213G Variant Protects Against Lung Fibrosis by Activating AMPK and Limiting Lipid Accumulation

Accumulation of superoxide radicals leads to disrupted redox signaling and oxidative damage. The primary extracellular scavenger of superoxide is extracellular superoxide dismutase (SOD3), a crucial enzyme in maintaining antioxidant status and proper immune function. SOD3 distribution to the extracellular matrix is determined by the presence of a C-terminal heparin-binding domain (HBD). This region can be removed through intracellular proteolytic processing by furin. Cleavage of the HBD has been shown to be modulated by post-translational cysteine redox status, regulating the secretion of SOD3. Interestingly, other members of the SOD family, SOD1 and SOD2, are known to be inhibited by lysine acetylation, a metabolically linked post-translational modification (PTM) that can alter protein structure, function, and localization. Yet, no reports describe the effect of acetylation on SOD3. Here, immunoblotting and mass spectrometry (MS) were used to quantify the global and site-specific acetylation of recombinant human SOD3. Interestingly, a predicted and targeted parallel reaction monitoring (PRM) MS-based approach was necessary to identify lysine acetylation within the C-terminal HBD of SOD3. Acetylation was found to prevent furin cleavage with no impact on SOD3 activity. Our results also reveal that SOD3 is robustly deacetylated by NAD+-dependent sirtuins (SIRT1 and SIRT3), with moderate activity against K220 and high activity against K211 and K212 in the HBD furin cleavage region. These sites of acetylation have not been previously reported, likely due to the peptide’s unique hydrophilic nature. Overall, our findings reveal that sirtuin-directed deacetylation of SOD3 restored furin cleavage, defining an important link between redox homeostasis and acetylation-directed metabolic regulation of extracellular oxidative stress.

Superoxide dismutases (SODs) are key regulators of reactive oxygen species (ROS) and redox balance. Although intracellular SODs have been extensively studied, growing attention has been directed toward understanding the roles of extracellular SODs in both Dictyostelium and mammalian systems. In Dictyostelium discoideum, SodC is a glycosylphosphatidylinositol (GPI)-anchored enzyme that modulates extracellular superoxide to regulate Ras, PI3K signaling, and cytoskeletal remodeling during directional cell migration. Loss of SodC leads to persistent Ras activation, impaired migration, and defective vesicle trafficking, including contractile vacuole (CV) morphogenesis and function. The mammalian EC-SOD (SOD3) localizes not only on the extracellular heparin-binding sites but also within vesicular compartments such as phagosomes, secretory vesicles, and exosomes. EC-SOD limits inflammation, preserves the extracellular matrix, modulates immune and cancer cell migration, and modulates Ras-Erk and PI3K-PKB signaling pathways. Despite evolutionary divergences, both SodC in Dictyostelium and EC-SOD in humans serve to modulate extracellular oxidative cues and maintain cellular function. The conserved and multifaceted roles of extracellular SODs in redox regulation, signaling, vesicle trafficking, and cell migration offer insights relevant to both fundamental biology and disease.

The aim of this study was to screen lactic acid bacteria (LAB) suitable for starch-based fermentation from traditional fermented shredded potatoes (TFSP). Analysis of the microbial diversity by 16S rDNA sequencing in TFSP revealed that LAB were a genus with high relative abundance of the bacteria population. Thirty LAB strains were isolated and purified from TFSP. Ten LAB strains with sequence similarity greater than 98% from TFSP were obtained, and the fermentation, antioxidant, and probiotic properties were tested. The results showed that 10 strains had acid-producing abilities. Lactiplantibacillus plantarum ZYN-03, ZYN-04, ZYN-05, ZYN-09, and ZYN-10 showed strong extracellular enzyme activity and SOD enzyme activity. Lacticaseibacillus rhamnosus ZYN-08 showed a higher survival rate in 8% ethanol (v/v). Salt tolerance and nitrite degradation capacity assays revealed that Lp. plantarum ZYN-05 and ZYN-09 had high survival rates. Lp. plantarum ZYN-05 and ZYN-10 and L. rhamnosus ZYN-08 displayed good antioxidant activity, while Lp. plantarum ZYN-01 and ZYN-04 and L. rhamnosus ZYN-08 had viable counts of LAB above 5.5 log CFU/mL in gastric acid, bile, and in vitro simulated cultures. Therefore, LAB isolated from TFSP have good fermentation capacity, probiotic properties, and antioxidant activities, and have the potential application for the fermentation of plant-based raw materials.

Integration of proteomics and artificial intelligence-driven OCT biomarker analysis in central retinal vein occlusion.

HighlightsWhat are the main findings?Our study provides novel insights by characterising the antioxidant profiles of amniotic fluid (AF), with a specific focus on superoxide dismutase isoforms (SOD1 and SOD3), glutathione (GSH), and 8-OHdG.AF provides a redox-regulated microenvironment during foetal development of the gastrointestinal tract (GIT).Antioxidant environment of AF is dynamic, undergoing substantial modulation of the oxidative–antioxidative balance throughout gestation.What is the implication of the main finding?Gestational age-specific components of AF, including enzymatic antioxidants such as SOD1, SOD3, and GSH, should be considered in the development of targeted nutritional and pharmacological interventions, particularly for vulnerable populations such as preterm infants and those with congenital gastrointestinal anomalies.Introduction: Amniotic fluid (AF) plays a pivotal role in foetal gastrointestinal development by delivering bioactive factors that support intestinal maturation. However, the redox environment of AF and its potential contribution to foetal intestinal homeostasis remain insufficiently characterised. This study aimed to quantify key antioxidant markers—superoxide dismutase isoforms (SOD1, SOD3), glutathione (GSH), and the oxidative DNA damage marker 8-hydroxy-2-deoxyguanosine (8-OHdG)—in AF across gestational ages and compare them with those in human milk (HM). Methods: AF samples (n = 60) were collected from pregnancies between 15 and 40 weeks of gestation, grouped into preterm (<37 weeks) and term (≥37 weeks). SOD1, SOD3, GSH, and 8-OHdG concentrations were quantified using ELISA. HM samples (n = 45) were similarly analysed. Results: SOD1 and SOD3 in AF concentrations decreased significantly with gestational age (GA) (p < 0.001), while 8-OHdG levels increased (p < 0.001). SOD3 showed a negative correlation with 8-OHdG (p = 0.004). HM contained significantly higher levels of both SOD isoforms compared to AF (AF vs. HM: 35.6 (1.9–172.3) vs. 267.9 (54.6–843.8), p < 0.001 for SOD1 and 1.2 ng/mL (0.1–26.5) vs. 5.5 ng/mL (0.1–300.0), p < 0.001 for SOD3), regardless of GA. Conclusions: Our findings highlight the dynamic nature of the redox environment in AF and its potential importance for foetal GIT development. The disruption of redox balance by preterm birth or inadequate AF intake during foetal life may have long-term consequences for intestinal development and function. These insights provide a foundation for future clinical studies aimed at enhancing neonatal feeding regimens, particularly for preterm infants and those with congenital gastrointestinal disorders.

Superoxide dismutases (SODs) are key enzymes involved in oxidative stress regulation. In most eukaryotes, they typically require both copper and zinc for catalysis and structural stability. However, copper-only SODs, previously identified in bacteria and fungi, represent a novel enzyme class with unique catalytic mechanisms. This study investigates copper-only SOD-repeat proteins (CSRPs) in two oyster species, Crassostrea gigas and Crassostrea sikamea, marking the first functional evidence of these proteins as extracellular SODs. Three CSRP genes were identified in each species, with expression localized primarily to the mantle. Structural modeling of a representative protein, Cs-CSRP1, revealed conserved copper-binding sites essential for SOD activity. Functional assays using recombinant Cs-CSRP1 confirmed its SOD activity, supporting its role as a novel extracellular antioxidant enzyme. These findings offer new insights into oyster antioxidant defense mechanisms and the evolution of SOD family proteins.

The extracellular matrices, such as the haemolymph, in insects are at the centre of most physiological processes and are protected from oxidative stress by the extracellular antioxidant enzymes. In this study, we identified two secreted superoxide dismutase genes (PxSOD3 and PxSOD5) and investigated the oxidative stress induced by chlorpyrifos (CPF) in the aquatic insect Protohermes xanthodes (Megaloptera: Corydalidae). PxSOD3 and PxSOD5 contain the signal peptides at the N-terminus. Structure analysis revealed that PxSOD3 and PxSOD5 contain the conserved CuZn-SOD domain, which is mainly composed of β-sheets and has conserved copper and zinc binding sites. Both PxSOD3 and PxSOD5 are predicted to be soluble proteins located in the extracellular space. After exposure to different concentrations of sublethal CPF, MDA content in P. xanthodes larvae were increased in a dose-dependent manner; SOD and CAT activities were also higher in CPF-treated groups than that in the no CPF control, indicating that sublethal CPF induces oxidative stress in P. xanthodes larvae. Furthermore, PxSOD3 and PxSOD5 expression levels and haemolymph SOD activity in the larvae were downregulated by sublethal CPF at different concentrations. Our results suggest that the PxSOD3 and PxSOD5 are putative extracellular antioxidant enzymes that may play a role in maintaining the oxidative balance in the extracellular space. Sublethal CPF may induce oxidative stress in the extracellular space of P. xanthodes by reducing the gene expression and catalytic activity of extracellular SODs.

Acute respiratory distress syndrome is a serious illness accounting for 10% of ICU admissions and has a high mortality of 31-45%, with a paucity of pharmacologic treatment options. Dysregulated inflammation and oxidative stress are hallmark features of acute respiratory distress syndrome. We previously showed that transgenic mice expressing a naturally occurring polymorphism of the antioxidant enzyme EC-SOD (extracellular superoxide dismutase) are protected against Staphylococcus aureus pneumonia, acute lung injury, and pulmonary neutrophilia. In this mouse strain, an R213G amino acid substitution leads to lower tissue-binding affinity and elevated alveolar and plasma EC-SOD amounts, although the redox-regulated mechanisms responsible for protection against S. aureus are not yet elucidated. Neutrophils are recruited to the areas of injury and inflammation, in part by activated platelets, which contain multiple redox-sensitive targets. Thus, we hypothesize that increased circulating EC-SOD due to the EC-SOD R213G variant protects against S. aureus pneumonia by reducing platelet activation and subsequent neutrophil recruitment to the lung. We demonstrate that, compared with wild-type mice with S. aureus pneumonia, platelet activation, formation of platelet-neutrophil aggregates, and influx of neutrophils and platelet-neutrophil aggregates into the lung are decreased in the infected R213G mice. Furthermore, pretreatment with a MnTE-2-PyP SOD mimetic protects against S. aureus-induced platelet activation, pulmonary neutrophilia, and acute lung injury. Our data highlight the redox regulation of platelet activation as a driver of S. aureus-induced acute lung injury.

BackgroundSuperoxide dismutase enzymes (SOD) mainly the extracellular (EC-SOD) are considered prime antioxidants against superoxide anions (O2•−). EC-SOD R213G mutation has a deleterious effect that disrupts its vascular displacement and allows atherogenesis. Data regarding the EC-SOD gene with cardiovascular diseases (CVD) and ischemic heart disease (IHD) are scarce. The study aimed to clarify the role of EC-SOD-R213G polymorphism and allelic disparities on its levels as an indicator of arterial wall antioxidant status and vascular integrity to provide insights on its role in IHD among Egyptian patients. A case–control study included eighty subjects categorized into four groups: Group I: 20 controls. Group II:20 with chronic angina. Group III:20 with myocardial infarction (MI) without hypertension (HTN). Group IV:20 MI patients with HTN. Restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) and ELISA techniques were applied.ResultsA significant association of EC-SOD + 213G genotype and allele frequencies in all patient groups when compared to controls (G allele frequency was 42%, 52%, 57%, and 10%, respectively, P < 0.05) with an odds ratio (OR) of 95% CI = 6.0 (1.6–24.43), 9.0 (2.42–36.47), and 12.18 (3.26–49.7), respectively (P < 0.05). The R and RR genotype frequencies were significantly lower in groups II, III, and IV than in controls (R allele 58%, 48%, 43%, and 90%, respectively, P < 0.05). Plasma EC-SOD levels were significantly increased in IHD patients than in controls, with a nonsignificant change between the two MI patient groups (t = 1.51, P = 0.147). Notably, EC-SOD levels recorded variant values with different R213G allelic variants in all IHD groups (P < 0.01), with a higher increase in GG and RG than RR carriers.ConclusionThe EC-SOD gene Arg (213) Gly substitution was associated with an increased risk of IHDs among Egyptian patients. The EC-SOD + 213 R allele was significantly associated with protection from IHDs compared to the G allele. In addition, the EC-SOD heterozygous RG and the homozygous GG carriers were detected to have higher plasma EC-SOD levels with decreased arterial wall concentrations than in noncarriers, which reduces the anti-oxidative protection and increases atherogenic risk, increasing the susceptibility of IHD among Egyptian patients.

Dysregulated redox signaling contributes to pulmonary hypertension (PH) and vascular depletion of the redox enzyme extracellular superoxide dismutase (EC-SOD) from smooth muscle cells [EC-SOD SMC knockout (KO)] worsens chronic hypoxic PH. Given the important role of macrophages in PH, this study aimed to determine if interstitial macrophages (IMs) and their interactions with hyaluronan (HA), a component of extracellular matrix (ECM), are modulated by vascular EC-SOD. Floxed wild-type, EC-SOD SMC KO, and SOD mimetic- or vehicle-treated mice were exposed to hypobaric hypoxia [~10% fraction of inspired oxygen (FIO2)], for 4, 14, or 21 days. Using flow cytometry, we demonstrated that the transient increase in IMs at day 4 was exacerbated in EC-SOD SMC KO mice and prevented with SOD mimetic pretreatment. Highlighting the importance of targeting vascular oxidative stress in the early response to hypoxia, pretreatment with a single dose of EC-SOD mimetic decreased right ventricular systolic pressure, right ventricular hypertrophy, and small vessel muscularization at day 21. To assess IM phenotypic reprogramming in hypoxia, RNA-seq was performed on flow-sorted IMs revealing baseline proinflammatory activation and enhanced activation of vascular and ECM remodeling pathways in response to hypoxia in EC-SOD SMC KO IMs compared with controls. To further investigate the ECM remodeling response, we quantified IMs expressing the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1), and IM-hyaluronan binding. Lyve1+ IMs and Lyve1+ HA+ IMs were increased in response to hypoxia in EC-SOD SMC KO mice and accumulated in the perivascular space of the lung. In conclusion, vascular EC-SOD limits IM accumulation and proinflammatory profibrotic IM signaling, including perivascular accumulation of Lyve1+ IMs and their binding to hyaluronan.

Abstract Platelets are important members of the innate immune response, that are subject to redox regulation. Particularly, dysregulated platelet-mediated recruitment of neutrophils is an injurious process and important aspect of pathogenesis in acute lung injury. We previously demonstrated that increased circulating and alveolar extracellular superoxide dismutase (EC-SOD) attenuates platelet activation and neutrophil recruitment to the lung in response to Staphylococcus aureus pneumonia. Here, we aim to determine how redox intravascular environment in the lung modulated by increased circulating EC-SOD or Mn-TE-2PyP SOD mimetic attenuates platelet-mediated neutrophil recruitment. We use a mouse strain with knock-in of EC-SOD polymorphism R213G. This naturally-occurring human SNP results in a single amino acid substitution in the matrix-binding domain and the release of EC-SOD into plasma and alveolar lining fluid without affecting enzyme activity. First, we demonstrate that mice expressing the R213G EC-SOD variant have increased circulating EC-SOD and are protected from significant rise in S. aureus-induced superoxide radical as measured by electron paramagnetic resonance spectroscopy. Next, we show that increased circulating EC-SOD protects against S. aureus-induced platelet activation, formation of platelet-neutrophil aggregates (PNAs), accumulation of platelets and neutrophils in the lung, generation of NETs, and acute lung injury and inflammation. We observe the same protective effects in wild-type (WT) mice pre-treated with MnTE-2-PyP SOD mimetic. Importantly, neither SOD mimetic nor increased circulating EC-SOD impair host's ability to fight S. aureus infection. We observe unchanged bacterial CFUs in the lungs of infected WT and R213G strains, and in WT mice treated with SOD mimetic compared to the untreated controls. Our most recent data demonstrate that platelet-neutrophil aggregation via platelet receptor CLEC-2 is attenuated in presence of increased circulating EC-SOD. We show that phosphorylation of CLEC-2 downstream signaling proteins Syk, SHP-2, PLCγ2, and LAT that lead to platelet activation, is subject to redox regulation. Together this work offers an important insight into EC-SOD effects on platelet functionality, and a novel redox-based mechanism of platelet activation in clinically-relevant model of acute lung injury from bacterial pneumonia.